PHARMACOLOGY REVIEW

A Comprehensive Reference Guide for Medical, Nursing, and Paramedic

Students

M. Mastenbjörk M.D.
S. Meloni M.D.
 Copyright © 2021 Martin Mastenbjörk MD and Sabrina Meloni MD

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 Contents

PHARMACOLOGY REVIEW
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INTRODUCTION
UNIT I: THE BASICS
CHAPTER 1: ROUTES OF DRUG ADMINISTRATION
CHAPTER 2: PHARMACOKINETICS AND PHARMACODYNAMICS
UNIT II: CENTRAL NERVOUS SYSTEM
CHAPTER 1: GENERAL ANESTHETICS
CHAPTER 2: SEDATIVE-HYPNOTIC DRUGS
CHAPTER 3: OPIOID ANALGESICS
CHAPTER 4: ANTIDEPRESSANTS AND ANTI-MANIC DRUGS
CHAPTER 5 – ANTIPSYCHOTICS
CHAPTER 6 – DRUGS USED IN NEURODEGENERATIVE DISEASES
CHAPTER 7: ANTI-EPILEPTIC DRUGS
UNIT III: THE AUTONOMIC NERVOUS SYSTEM
CHAPTER 1: CHOLINERGIC AND ANTICHOLINERGIC DRUGS
CHAPTER 2 – ADRENERGIC AGONISTS AND ANTAGONISTS
UNIT IV: PERIPHERAL NERVOUS SYSTEM
CHAPTER 1: LOCAL ANESTHETICS
CHAPTER 2: SKELETAL MUSCLE RELAXANTS
UNIT V: DRUGS ACTING ON THE PARACRINE AND ENDOCRINE SYSTEM
CHAPTER 1: HISTAMINE AND ANTIHISTAMINES
CHAPTER 2: PROSTAGLANDINS AND PROSTAGLANDIN INHIBITORS
CHAPTER 3: DRUGS ACTING ON THE HYPOTHALAMUS AND PITUITARY GLAND
CHAPTER 4: THYROID HORMONE AND INHIBITORS
CHAPTER 5: DRUGS INVOLVED IN CALCIUM AND BONE METABOLISM
CHAPTER 6: INSULIN AND ORAL HYPOGLYCEMIC DRUGS
CHAPTER 7: CORTICOSTEROIDS
CHAPTER 8: ANDROGENS, ESTROGENS AND PROGESTINS
UNIT VI – THE CARDIOVASCULAR SYSTEM
CHAPTER 2: DRUGS USED FOR MYOCARDIAL ISCHEMIA
CHAPTER 3: DRUGS USED IN ARRHYTHMIAS
CHAPTER 4: DRUGS USED IN HEART FAILURE
UNIT VII: HEMATOPOIETIC SYSTEM
UNIT VIII – RESPIRATORY SYSTEM
UNIT IX – GASTROINTESTINAL SYSTEM
UNIT X: GENITOURINARY SYSTEM
UNIT XI – ANTIMICROBIALS
CHAPTER 2: ANTIVIRALS
 CHAPTER 3: ANTIFUNGAL DRUGS
CHAPTER 4: ANTIPROTOZOAL AND ANTHELMINTIC DRUGS
UNIT XII - IMPORTANT MISCELLANEOUS DRUGS
APPENDIX
APPENDIX I: IMPORTANT DRUG INTERACTIONS
APPENDIX IIA: PREGNANCY CLASSIFICATION OF DRUGS
APPENDIX IIB: EXAMPLES OF COMMONLY USED DRUGS CLASSIFIED
ACCORDING TO PREGNANCY CATEGORIES
REFERENCES
ANSWERS TO EXERCISES
 INTRODUCTION
Drug therapy remains the mainstay of treatment in medicine. While physicians prescribe
drugs on a daily basis, other healthcare workers also need to familiarize themselves with
pharmacology to ensure that the correct dosage regimen is being received by patients, to
communicate efficiently with other healthcare workers, and to recognize and deal with adverse
effects of pharmacological therapy.

For easy understanding of this complex subject, the book has been divided into multiple units
based on each body system. The key therapeutic drug classes for each major system have been
outlined in separate chapters. Bullet points and tables make the content easy to understand.

Pharmacology is a constantly evolving field, and new drugs are being developed every day.
The main aim of this book is to familiarize the reader with the different categories of drugs. The
most commonly prescribed drugs are described here, but the book is by no means exhaustive and
does not cover all the drugs available today. For detailed descriptions of the latest drugs on the
market, and less commonly prescribed drugs, the reader is referred to one of the more exhaustive
textbooks of pharmacology that have been referenced in the text.
UNIT I: THE BASICS
 CHAPTER 1: ROUTES OF DRUG
ADMINISTRATION
For a drug to begin its pharmacological activity, it must first be introduced into the body.
This can be done through a variety of routes. Depending on their properties, some drugs can have
more than one route of administration.

The ideal route of administration depends on two factors:

· Properties of the drug: Whether it is predominantly lipid based or water based,

degree of ionization, size of the drug particle, etc.

· Desired effects of the drug: Whether the desired effect must be local or systemic,
whether immediate or delayed onset of action is desired, etc.

Broadly, there are two main routes of drug administration:

· Local/Topical: The drug is intended to act on the site of the body at which it is
administered.

· Systemic: The drug acts on a site that is away from the area of administration. In the
systemic route, the drug needs to be absorbed into the bloodstream, and then be transported
to the area where it is intended to act.
 Figure 1 Various routes of drug administration; the ideal route of administration for a particular drug depends on the
properties of the drug and the desired effects of the drug.

LOCAL ROUTES OF ADMINISTRATION

· Inhalation: Inhalation may be oral or nasal. Either way, the drug is delivered directly
to the respiratory epithelium. The nasal route is preferred when the action is specifically
desired for the nasal epithelium. This route eliminates the risk of systemic side effects. This
is useful for patients with respiratory disorders.

· Intrathecal injection: The drug is delivered directly into CNS through the
cerebrospinal fluid. This is useful for drugs that cannot penetrate the blood-brain barrier.
This allows rapid onset of action to take place.

· Topical: The drug is directly applied to the surface of the skin. This is used
specifically for diseases of the skin and surface mucosa.

SYSTEMIC ROUTES OF ADMINISTRATION

Enteral route:

Enteral refers to administration of the drug through the mouth and gastrointestinal system.
This may be oral, sublingual, or rectal.

· Oral route: In the oral route, the drug is swallowed, and needs to be absorbed
through the gastrointestinal tract. This is the most common route of drug administration.

· Sublingual and buccal route: In this route, the drug is placed under the tongue, or
in the fold of the cheek. Since these areas have rich vascular supply, the drug is quickly
absorbed by the capillaries and sent into systemic circulation.

· Rectal route: In this route, the drug is administered through the anal aperture. From
here, the drug is absorbed into the external and internal hemorrhoidal veins. The portion of
the drug that is absorbed from the external hemorrhoidal veins bypasses the first-pass
metabolism.

Parenteral route

In parenteral administration, drugs are directly introduced into systemic circulation. This
route is generally suitable for drugs that cannot survive digestive enzymes or first-pass
metabolism. The parenteral route requires sterile equipment, in the form of syringes or cannulas,
for drug administration.

· Subcutaneous: The drug is injected into the loose subcutaneous tissue. This region
is not as vascular as other tissues such as the muscle, so absorption into circulation may not
be quick. First-pass metabolism is avoided through this route.

· Intravenous: The drug is delivered directly into the blood through a vein. Usually,
veins of the forearm are cannulated and the drug is delivered. The drug may be given
undiluted, which is referred to as a bolus. This delivers the complete drug into the systemic
circulation immediately. Alternatively, the drug may be diluted in a carrier such as normal
saline, and delivered as an infusion. This allows the drug to be delivered at precise plasma
concentrations. The duration of drug action also increases.

· Intramuscular: The drug is injected into the muscle. Usually, muscles of the upper
arm and shoulder (such as the deltoid) or the pelvic region (such as the gluteus maximus)
are selected for intramuscular drug delivery. It is possible to change the rate of absorption of
the drug by modifying its carrier solution. Drugs in aqueous solutions are absorbed rapidly,
while those in non-aqueous suspensions (called depot preparations) are absorbed slowly.
Anticoagulants, such as heparin, cannot be given intramuscularly because they can cause
hematomas in the muscle. First-pass metabolism is avoided through this route.

Other systemic routes

Transdermal: The drug is applied to the skin surface. However, from here it gets absorbed
through the local vasculature into systemic circulation. Drugs are delivered through the use of
skin patches. These patches are stuck onto the skin surface and they remain for a few days to
exert their action.

The advantages and disadvantages of the various routes of drug administration are outlined in
Table 1.

Table 1. Routes of drug administration

ROUTE OF
DRUG ADVANTAGES DISADVANTAGES
ADMINISTRATION
Rapid absorption and onset Potential for addiction as drug is in
of action close proximity to the brain
Inhalation
Lower chances of systemic Requires learning curve to use the
side effects inhaler
Invasive method which requires
Fast and effective route
clinical expertise
No absorption into systemic
Intrathecal Chances of inducing or aggravating
circulation, so fewer systemic
brain infection if sterility of equipment
side effects
is compromised
Non-invasive, painless
Convenient Restricted to diseases of the skin
Topical
Has fewer systemic side and surface mucosa
effects
Requires patient cooperation. Oral
administration is difficult if the patient
is unconscious, or is vomiting.
Convenient and cost-
Some drugs may be subjected to
effective. Does not require
degradation by digestive enzymes. This
medical assistance and sterile
may be avoided by the use of enteric-
equipment such as syringes.
coated preparations.
Oral Painless
Absorption of the drug from the
Toxicity can easily be
GIT is often unpredictable. To a certain
reversed through gastric lavage.
extent, this can be controlled through
This is useful if the drug does
the use of extended-release
not have a specific antidote.
preparations.
Slow onset of action. Hence, not
suitable for emergencies.

Most of the advantages of

oral route
The drug does not enter the Effective only for specific drugs
GIT, so it cannot be affected by that have particular properties, such as
Sublingual/ digestive enzymes. Avoidance high lipid solubility. Otherwise,
Buccal first-pass metabolism by the absorption may be unpredictable.
liver. One must be careful not to swallow
Absorption is rapid and the the drug
onset of action is fast.
 50% of the drug bypasses
first-pass metabolism. The entire
drug, however, escapes the Requires cooperation in the
action of digestive enzymes. conscious patient. Administering the
Absorption is rapid, resulting drug through this route may be
Rectal
in faster onset of action associated with some discomfort.
It can be used in unconscious Drug absorption is erratic and
patients, as well as patients with unpredictable.
vomiting.

Bypasses GIT and metabolic

pathways
Invasive method
Can be self-administered
Subcutaneous Only small volumes of drug can be
with practice
administered.
Effects are slow, sustained
and predictable
Immediate onset of action is Invasive and painful route, requires
achieved, suitable for trained medical personnel
emergencies Potential for infection by
Bypasses GIT and metabolic contamination at the injection site
Intravenous pathways Irritant drugs may cause
The quantity of drug thrombophlebitis
delivered can be precisely Difficult to treat toxicities unless a
controlled specific antidote exists
Invasive method, cannot be self-
administered
Bypasses GIT and metabolic Can cause muscle spasm or pain,
pathways especially with non-aqueous
Intramuscular Can control rate of preparations
absorption Not advisable in patients who are
taking anticoagulants, as it can cause
internal hemorrhage.
Bypasses GIT and metabolic Patches can cause skin irritation
Transdermal pathways Only suitable for lipophilic drugs,
Painless and convenient in small doses.

EXERCISES
1. Which of the following routes must be avoided in patients on anticoagulants?

a. Subcutaneous

b. Oral
c. Intramuscular

d. Transdermal

2. Which of the following routes does not completely bypass the first-pass metabolism
of the liver?

a. Sublingual

b. Transdermal

c. Rectal

d. Subcutaneous

3. Which of the following routes is most effective in delivering the drug directly into
systemic circulation?

a. Intravenous

b. Intramuscular

c. Subcutaneous

d. Sublingual

4. Which of the following routes is ideal for treating CNS infections with a drug that
cannot penetrate the blood brain barrier?

a. Intravenous

b. Intrathecal

c. Sublingual

d. Inhalational

5. Which of the following routes is meant to work by transferring drugs into systemic
circulation?

a. Inhalational

b. Intrathecal

c. Topical

d. Transdermal

6. Which of the following routes is ideal for patients with respiratory infections?
a. Intramuscular

b. Inhalational

c. Intrathecal

d. Intravenous

7. In the intramuscular route, which muscle is preferred for injection?

a. Gluteus minimus

b. Gluteus intermedius

c. Gluteus maximus

d. Piriformis

8. Which of the following routes of administration does not require the use of sterile
equipment?

a. Subcutaneous

b. Sublingual

c. Intravenous

d. Intramuscular

9. Which of the following routes of administration is safest for drugs where no known
antidote exists?

a. Oral

b. Sublingual

c. Rectal

d. Intramuscular

10. In which of the following routes is the drug absorbed through hemorrhoidal veins?

a. Sublingual

b. Rectal

c. Intravenous

d. Intramuscular
 CHAPTER 2: PHARMACOKINETICS AND
PHARMACODYNAMICS
The science of pharmacology basically deals with the interaction of the drug with the body.
This has two main divisions: Pharmacokinetics, which describes what the body does to the drug;
and Pharmacodynamics, which describes what the drug does to the body.

PHARMACOKINETICS

To put it simply, pharmacokinetics describes the journey of the drug through the body. Once
the drug enters the body, it goes through the following phases until it is eliminated:

· Absorption: The drug enters the bloodstream from the tissue in which it was
administered. This phase is only applicable for drugs that are administered through the
systemic route.

· Distribution: The drug leaves the bloodstream and enters the body tissues. It is in
this phase that most drugs exert their clinical effects. This includes both intended biological
effects and adverse effects.

· Metabolism: The body acts on the drug to metabolize it. Metabolism may either
degrade the drug, making it inactive, or may convert an inactive drug form into its active
form. In the latter case, clinical effects take place after metabolism.

· Elimination: This is the phase where the drug, either in its original form, or
metabolized form, leaves the body.

Absorption

Once the drug enters into the body, it must move from the tissue in which it was
administered, into the bloodstream. This process is referred to as absorption. The amount of drug
that is absorbed, and the rate of absorption generally depend on several factors:

· The environment (for instance, pH) from which absorption must take place

· Route of administration

· Properties of the drug

The extent to which a drug is absorbed is referred to as ‘bioavailability’. Only the

bioavailable drug is available for clinical effect; the rest is excreted without absorption. Drugs
administered through intravenous routes have 100% bioavailability. Other parenteral routes may
have slightly less bioavailability because of some amount of local binding. However, the oral
route often has decreased bioavailability. The following section, therefore, focuses on absorption
of drugs from the GIT.
 Methods of drug absorption from the GIT:

When ingested orally, the drugs must pass from within the GIT, through the walls of the
epithelium, into systemic circulation. This is achieved by one of the following methods:

· Passive diffusion: The drug moves naturally from an area of high concentration to
the area of low concentration. Lipid soluble drugs pass easily through the phospholipid
bilayer of the cell membrane, while water soluble drugs use aqueous channels to penetrate
through the cell membrane.

· Facilitated diffusion: Some drugs bind to specialized proteins called transmembrane

carrier proteins. These proteins change their configuration and allow drugs to pass through
them from areas of higher to lower concentration.

· Active transport: The drug moves against a concentration gradient, from areas of
low to high concentration. This requires energy, which is obtained by hydrolysis of
adenosine triphosphate (ATP). Drugs that are structurally similar to naturally occurring
metabolites in the body may require active transport.

· Endocytosis: The drug is engulfed into a portion of the cell membrane, which
pinches off from the rest of the membrane to form a vesicle. This vesicle is transported
inside the cell, and the drug is released. This process occurs when the drug has a large
molecular size.

Figure 2 Drugs that are ingested orally end up in systemic circulation by passive diffusion, facilitated diffusion, active
transport, or endocytosis.
 Factors that affect absorption of the drug from the GIT:

· pH of the external environment and the pKa of the drug: Together, these two
factors determine the ratio of the unionized to the ionized form of the drug. A drug that has
a low pKa (or is acidic) tends to have a higher amount of unionized form when the
surrounding pH is low. A drug that has a high pKa (or is basic) tends to have a higher
proportion of unionized form when the surrounding pH is high. Only the unionized form is
capable of diffusing through the intestinal membranes.

· Blood flow at the site of absorption: More vascularized regions of the GIT tend to
absorb drugs faster. The intestines are more vascular than the stomach, so drugs are
absorbed faster here.

· Surface area available for absorption: Absorption is more efficient over a larger
surface area. The epithelium lining the small intestine has microvilli, which greatly
increases the surface area available. This makes the absorption here more efficient than in
the stomach.

Factors affecting bioavailability from the oral route of administration:

· First-pass metabolism: After absorption from the GIT, before the drug can enter
systemic circulation, it first passes through portal circulation. During this passage, the drug
might become metabolized by the liver. This is referred to as first-pass metabolism, and this
limits the bioavailability of several drugs.

· Resistance to digestive enzymes: Some drugs may not survive degradation by

digestive enzymes, which limits their availability.

· Solubility of the drug: A drug that is highly lipid soluble may find it difficult to gain
access to the cell surface. At the same time, a highly hydrophilic drug cannot permeate the
phospholipid bilayer. Ideally, the drug should be lipophilic, with some amount of
hydrophilic nature.

Distribution

During distribution, the drug leaves the bloodstream and enters the extracellular fluid and
tissues. This is a reversible process, and the drug can re-enter the bloodstream, only to be re-
distributed to other tissues. Drugs administered through the intravenous route skip the absorption
phase and are directly distributed to tissues.

Factors affecting distribution:

· Vascularity of tissues: Organs with high blood supply (such as the brain, liver, and
kidney) receive the drug first. Tissues such as the skeletal muscle come next, while the
adipose tissue, skin, and other organs have lower blood flow and therefore receive the drug
more slowly.

· Capillary permeability: Capillary permeability refers to the ability of the blood

 vessel wall to allow molecules to pass through them. If the endothelial cells in the vessel
wall have numerous slit junctions between them, permeability is high, and the drug can
easily pass out of circulation into the tissues. The liver and spleen, for instance, have high
capillary permeability. If there are no slit junctions, capillary permeability is low. The brain
has tight endothelial cell-to-cell contact, referred to as the blood-brain barrier. Therefore,
some drugs cannot penetrate easily into the brain tissue.

· Binding of the drug to plasma protein: The main plasma protein involved in drug-
binding is albumin. If the drug is in the bound form, the entire drug may not get distributed
into the tissue. Some drugs remain bound to albumin, and serve as a reservoir. This is
released when the free drug is redistributed or eliminated.

· Binding of the drug to tissue protein: The drug may bind to various proteins in the
tissue and serve as a reservoir here. This tends to avoid redistribution, and may prolong the
action of the drug.

· Lipid solubility: Only lipophilic drugs can penetrate the phospholipid bilayer of the
cell membrane. Hydrophilic drugs, on the other hand, cannot penetrate cell membranes, and
must cross the membrane through slit junctions.

Metabolism

Metabolism serves two purposes. Firstly, the active drug may be converted into a form that is
easier to eliminate from the body. This may or may not result in inactivation of the drug.
Secondly, the drug may be inactive to begin with, but metabolism may convert the drug into an
active form. Further metabolism may be needed to prepare the drug for elimination. Most drugs
undergo metabolism in the liver, but some metabolism can occur in the plasma, GIT, or other
organs. Metabolism involves two specific phases:

Phase I reactions

This involves conversion of lipophilic drugs into hydrophilic, or polar molecules, which can
easily be excreted by the kidney. This is achieved by three kinds of reactions – reduction,
oxidation, and hydrolysis. This is achieved through two methods:

· Reactions involving the cytochrome P450 system: The P450 is a superfamily of

isozymes that contain heme. This system is present in most cells, but is especially abundant
in the liver and GIT. While there are several distinct isozymes, four play an important role
in drug metabolism. These include CYP3A4/5, CYP2D6, CYP2C8/9 and CYP1A2.

· Reactions not involving the P450 system: These include amine oxidation, alcohol
dehydrogenation, esterases, and hydrolysis reactions.

Phase II reactions

If sufficient polarity is not achieved through Phase I metabolism, the drugs enter into Phase II
reactions. These are conjugation reactions, where the drug is combined with a naturally occurring
substrate, such as acetic acid or glucuronic acid.
 Elimination

After metabolism, the drug is eliminated from the body. Elimination usually occurs through
the kidneys in the form of urine. Other routes of elimination include the bile and feces, exhaled
air, and breast milk.

Renal elimination of drugs

Sufficiently polarized drugs are usually eliminated through the kidney. Like other metabolic
products, the drug has to pass through the following phases prior to excretion:

· Glomerular filtration: This takes place at the glomerular capillary plexus. Unbound
drug molecules can pass from the bloodstream through capillary slit junctions into the
glomerular filtrate. The only factor which affects this process is the degree of plasma
protein binding of the drug. Bound molecules cannot enter the filtrate.

· Proximal tubular secretion: Drugs which were not filtered at the glomerular level
enter the plexus surrounding the proximal tubule. Here, some drugs can be secreted into the
filtrate by an energy-based active transport system.

· Distal tubular reabsorption: Some quantity of the drug may be reabsorbed into the
bloodstream at this level. Reabsorption is passive and occurs along a concentration gradient.

Other routes of drug elimination

· Feces: Drugs that are secreted into the bile after metabolism, and drugs that are not
absorbed via the oral route of administration are eliminated through the feces.

· Exhaled air: Drugs delivered through inhalation are also usually eliminated through
this route.

· Body fluids: Small quantities of drugs may be eliminated through sweat, saliva, and
tears. Elimination through breast milk is significant because it may cause unnecessary
exposure of the feeding infant to the drug, which may result in undesirable adverse effects.

Measures of drug clearance from the body

To calculate the optimum dosing regimen, and to avoid toxicity, it is important to measure
drug clearance from the body. There are two important measures of drug clearance:

Total body clearance: This is the sum of all clearances from the organs that metabolize
drugs, and the organs that eliminate drugs. So this is usually hepatic clearance plus renal
clearance, but may include clearance from lungs and other organs where applicable.

Drug half-life: Drug half-life, or t1/2, is the unit of time in which the plasma drug
concentration decreases by 50%. Factors that affect t1/2 include diminished renal or hepatic
blood flow, diminished renal function, and hepatic insufficiency. These can increase the t1/2, and
prolong drug action. It takes five cycles of t1/2 for the drug to be completely eliminated from the
body.

PHARMACODYNAMICS

Pharmacodynamics refers to the clinical effect that the drug has on the body, or, to put it
simply, how the drug works. There are basically three methods by which drugs can exert their
effects on the body:

· Through physical properties: Some drugs provide a bulking function (e.g.,

Laxatives like Psyllium husk), or lubricating or coating function (e.g., Dimethicone). These
physical properties produce clinical effects.

· Through chemical properties: Certain drugs work by chemical reactions. For

instance, some drugs work by neutralization of pH (e.g., Antacids), or by their chelating
properties (e.g., EDTA).

· Through receptor binding: This is the most common method through which drugs
exert their effects. In this method, drugs interact with specific receptor proteins present on
the surface of the cell. Once the drug binds with the receptor, it is capable of bringing about
biochemical changes, or molecular activity that causes the clinical effects of the drug.

Types of receptors

All receptors are proteins that extend through the thickness of the cell membrane. There are
essentially four classes of receptors with which drugs interact. These are as follows:

· Transmembrane ligand-gated ion channels: ‘Ligand-gated’ means that the

functioning of the ion channel (opening or closing) depends on the binding of specific
molecules, called ligands. The ligand binding site is located on the outside. When the ligand
(or drug) binds to the channel, the gate opens, allowing influx or efflux of ions. Ionic flow
across the membrane can mediate multiple functions, including nerve impulse transmission
and muscle contraction.

· Transmembrane G-protein-coupled receptors: Like ion channels, the ligand

binding site is located on the external side. When the ligand binds to the receptor, the inner
part of the receptor interacts with G-proteins, causing them to dissociate. The G-protein
subunits in turn activate other intracellular enzymes or proteins, to produce molecular
changes.

· Enzyme-linked receptors: When the drug binds to this class of receptors, the
receptors undergo conformational changes, which increases the activity of intracellular
enzymes. This in turn activates other intracellular signals, and a cascade of activity will
result.

· Intracellular receptors: This is different from other receptors because the drug
binding site is located within the cell. So, for the drug to bind to the receptor, it must diffuse
across the cell membrane (which requires sufficient lipid solubility). The drug-receptor
complex usually translocates to the nucleus, where it binds to transcription factors. This
 may modify transcription of RNA or DNA and protein translation.

Figure 3 Drugs may exert their effects by binding to receptors, proteins that extend through the cell membrane. The four
types of drug receptors are transmembrane ligand-gated ion channels, transmembrane G-protein-coupled receptors, enzyme-
linked receptors, and intracellular receptors.

Effect of drug on the receptors

Not all drugs interact with the receptors in the same way. The actions of the drug may mimic
that of substances within the body (endogenous ligands), or may oppose these actions.
Depending on the effects that they produce as compared to endogenous ligands, the drugs may
be categorized as follows:
 · Full agonists: If the drug produces the same response as the endogenous ligand, and
achieves maximum biological response, it is termed a full agonist.

· Partial agonists: The drug may produce the same response as an endogenous ligand,
but cannot achieve maximum biological response.

· Inverse agonists: Some receptors may get activated spontaneously in the absence of
ligand binding. Inverse agonists act on such receptors to deactivate them and bring them to
their resting state.

· Antagonists: The drug has a high affinity for the receptor site and binds to it.
However, it fails to have any effect on the receptor. In the absence of an agonist (either
endogenous, or drug), the antagonist has no effect. However, if the agonist is also present,
the antagonist can reduce its clinical activity in one of the following ways:

· Competition: The agonist and antagonist compete for the same binding site on the
receptor.

· Irreversible binding: The antagonist binds irreversibly with the binding site of the
receptor, which reduces the receptors available to the agonist for binding.

· Allosteric binding: The antagonist binds to a different site than the agonist, but prevents
receptor activation.

· Functional antagonism: The antagonist binds to a completely different receptor, but

initiates actions that are opposite to the effects of the agonist.
EXERCISES
1. In which of the following forms of absorption does the drug move against a
concentration gradient?

a. Facilitated diffusion

b. Active transport

c. Passive diffusion

d. Endocytosis

2. Which of the following is a hindrance to distribution of the drug within the tissues?

a. Increased tissue protein binding capacity

b. Increased lipid solubility

c. Increased plasma protein binding capacity

d. Increased vascularity of the tissues

 3. Which of the following is a Phase II reaction of drug metabolism?

a. Oxidation

b. Alcohol dehydrogenation

c. Conjugation

d. Hydrolysis

4. How many half-lives of the drug must complete for the drug to be completely
eliminated from the body?

a. Two

b. Three

c. Four

d. Five

5. Which of the following types of drugs has no effect on the receptor when used
alone?

a. Full agonist

b. Partial agonist

c. Inverse agonist

d. Antagonist

6. Which of the following drugs will be absorbed faster from the stomach (low PH)?

a. Low pKa

b. High pKa

c. Neutral pKa

d. pKa does not matter

7. Which of the following drugs deactivates the receptor upon binding?

a. Full agonist

b. Partial agonist

c. Inverse agonist
d. Antagonist

8. How does EDTA produce clinical effects?

a. Through physical properties

b. Through chemical properties

c. Through receptors

d. A combination of the above

9. Which class of receptors induces changes in DNA?

a. Ligand-gated

b. G-protein-coupled

c. Enzyme-linked

d. Intracellular

10. What protein does the cytochrome P450 system have?

a. Albumin

b. Heme

c. Ferritin

d. Ceruloplasmin
UNIT II: CENTRAL NERVOUS SYSTEM
 CHAPTER 1: GENERAL ANESTHETICS
The term anesthesia refers to loss of sensation. ‘General’ anesthesia is the term used when
loss of sensation is accompanied by loss of consciousness. General anesthesia is applied during
interventional medical and surgical procedures. It not only avoids an uncomfortable experience
for the patient, it also makes the process easier for the surgeon. With general anesthesia, the
following effects are obtained:

· Suppressed or complete loss of consciousness

· Amnesia and reduction in anxiety levels

· Suppression of pain (analgesia) and other sensations

· Suppression of reflexes

· Skeletal muscle relaxation

No single drug is capable of producing all the above effects. Therefore, a group of drugs is
combined before and during the anesthetic procedure, in order to achieve all the desired effects.

PREANESTHETIC MEDICATION

To smoothen the process of anesthesia and decrease its side effects, certain drugs are given
prior to the procedure. A brief description of the drugs used in pre-anesthetic medication follows.
A detailed description of each drug will be described in the relevant chapters.

· Anticholinergic drugs: Glycopyrrolate is the most commonly used drug. Its uses are
mainly to prevent bradycardia and hypotension that can occur due to vagal stimulation. It
also helps prevent laryngospasm that can occur due to respiratory secretions.

· H2 blockers and proton pump inhibitors: H2 blockers such as ranitidine, or proton

pump inhibitors such as omeprazole may be given the night before, or on the morning of the
procedure. They raise the pH of gastric secretions, and prevent regurgitation. They can also
prevent stress ulcers.

· Antiemetics: These help decrease the incidence of postoperative nausea and

vomiting, which is a side effect of several anesthetic agents. Commonly used antiemetic
agents include ondansetron, metoclopramide, and domperidone.

· Sedative/hypnotic drugs, and opioids: These drugs allay anxiety, and help
smoothen induction of anesthesia. Opioids also provide analgesia.

STAGES OF GENERAL ANESTHESIA

· Induction: This is the time taken from the administration of the anesthetic agent, to
the time the anesthetic agent takes effect. Induction is generally done using intravenous
drugs. These drugs act within 30 to 40 seconds, to produce loss of consciousness.

· Maintenance: Once anesthesia has been achieved, it must be maintained at the

desired depth. This is done using inhalational drugs. The depth of anesthesia is
characterized by four different stages:

o Stage 1- Analgesia: The patient loses pain sensation, and may feel drowsy. Respiration
and reflexes are intact.

o Stage 2- Excitement and delirium: Blood pressure and respiratory rate increase due to
excitement. This stage may be suppressed with rapid acting induction agents.

o Stage 3- Surgical anesthesia: Respiration becomes regular, there is gradual loss of

muscle tone and skeletal muscle relaxation occurs. As this stage progresses, first the
corneal and laryngeal reflexes, and then the light reflexes are lost. The stage ends with
loss of spontaneous breathing. This is the stage where surgery is carried out, and the
anesthetist must monitor the patient continuously to prevent progression to stage 4.

o Stage 4- Medullary paralysis: The respiratory and vasomotor centers of the medulla are
depressed. The patient will require ventilator and circulatory support to survive.

· Recovery: This is essentially the reverse of induction. Inhalational gases are

withdrawn and the patient is allowed to return to consciousness. Reversal agents may be
required for removing neuromuscular blockage caused by skeletal muscle relaxants.
 Figure 4 Anesthesia must be maintained at the desired depth once achieved. The depth of anesthesia is characterized by four
stages: analgesia, excitement and delirium, surgical anesthesia, and medullary paralysis.

DRUGS USED TO OBTAIN GENERAL ANESTHESIA

In general, there are two classes of drugs that are used for general anesthesia. Intravenous
drugs are primarily used for the induction process, while inhalational drugs are used for
maintenance of anesthesia.

Inhalational agents

General features of most inhaled anesthetics:

· State: Inhalational agents are always gaseous. They are usually non-flammable and
non-explosive.

· Minimum alveolar concentration (MAC): This is defined as the concentration of

anesthetic needed to eliminate responsive movement to incision in at least 50% of the
patients. MAC is inversely related to potency, and therefore, highly potent anesthetics have
low MAC values, and vice versa.

· Pharmacokinetics: Most inhaled anesthetics go through the following stages:

o Alveolar wash-in: This is the stage where the normal gases in the lung are pushed out
and replaced with the anesthetic. The time required for this is directly proportional to
 the functional residual capacity of the lung, and is inversely proportional to the
ventilator rate.

o Uptake of anesthetic by tissues: The anesthetic is carried by the blood from the lungs to
peripheral tissues, where it is taken up. The following factors affect anesthetic uptake:

§ Solubility: Drugs with low solubility move in and out of tissues rapidly. So induction and
recovery is faster.

§ Cardiac output: High cardiac output prevents faster saturation of blood with anesthetic,
and slows induction.

§ Vascularity: Highly vascular tissues such as the brain, heart, liver, and kidney take up the
drug first, followed by skeletal muscles. Poorly perfused tissues such as fat and bone do
not receive the anesthetic.

o Washout: This is the reverse of wash-in. When the anesthetic is discontinued, the gas is
gradually replaced by normal lung gases and the patient recovers.

· Mechanism of action: The mechanism of action of most anesthetics is still unclear.

These gases appear to act at a variety of receptors. Most anesthetics work at the GABA (γ-
amino butyric acid) receptor, and increase the receptor’s sensitivity to GABA, which is an
inhibitory neurotransmitter. Other anesthetics (for example, nitrous oxide and ketamine),
inhibit the NMDA (N-methyl D-aspartate) receptor’s sensitivity to glutamate, which is an
excitatory neurotransmitter.

Halothane:

· This is the prototype anesthetic. It provides rapid induction and quick recovery.

· Effect on body systems:

o Potent bronchodilator. It is non-pungent, and has a pleasant odor.

o Relaxation of skeletal and uterine muscles; therefore, useful in obstetrics

· Adverse effects:

o Halothane hepatitis: The metabolites of halothane are toxic hydrocarbons that, in selected
adult patients, can cause hepatitis and hepatic necrosis.

o Cardiac effects: It can cause bradycardia and cardiac arrhythmias. It may cause
concentration-dependent hypotension.

o Malignant hyperthermia: This can occur in a small percentage of patients. There is an

uncontrolled increase in skeletal muscle metabolism, resulting in dangerously high
body temperatures, and inability to supply oxygen and remove carbon dioxide. The
antidote, dantrolene sodium, must be used immediately to reverse this, and the drug
 must be withdrawn immediately.

Isoflurane:

· Has higher blood solubility, so produces slower onset of action and recovery.

· Does not metabolize, so risk of hepatitis is low.

· Like halothane, it produces concentration-dependent hypotension.

· Stimulates respiratory reflexes like cough and laryngospasm, due to its pungent odor.

Desflurane:

· Has the lowest blood solubility of all anesthetics, so has very rapid induction and
recovery. It is very suited for outpatient procedures.

· Minimal tissue toxicity.

· Also stimulates respiratory reflexes, and has low volatility, so it needs to be

administered through a special heated vaporizer.

Sevoflurane:

· Solubility is higher than desflurane and nitrous oxide, but still allows quick induction
and recovery.

· Non-pungent, does not stimulate respiratory reflexes.

· Undergoes metabolism like halothane, but its metabolites may be nephrotoxic.

Nitrous oxide:

· This has a high MAC and weak potency.

· It is poorly soluble in blood, and can therefore move in and out of tissues rapidly.

· Effects on body systems:

o Does not depress respiration.

o Does not cause muscle relaxation.

o Does not affect the cardiovascular system.

o Does not increase cerebral blood flow.

o Least hepatotoxic of all inhaled anesthetics.

 These properties make it the safest of all anesthetics, although it is the least potent.

· Adverse effects: Because of its rapid movement, it can retard uptake of oxygen
during recovery, leading to diffusion hypoxia. This can be avoided by using large volumes
of oxygen.

Intravenous agents

General features of intravenous anesthetics

· Pharmacokinetics: Because they are injected intravenously, these drugs have 100%
bioavailability. The drug passes from the injected vein, though the heart, into systemic
circulation, and is then delivered to the brain. Diffusibility into the brain depends on degree
of plasma protein binding, degree of ionization, and lipid solubility. Unbound, unionized,
and lipid soluble drugs penetrate the brain faster. After initially flooding the brain, the drug
gets rapidly redistributed to other tissues like skeletal muscles, resulting in rapid recovery
from anesthesia.

· Mechanism of action: Like inhalational anesthetics, the exact mechanism of action

is unknown, but it is probably similar to that of the inhalational agents.

Based on the time of onset of action, there are two classes of intravenous agents – fast-acting
agents and slower-acting agents.

Fast-acting intravenous anesthetics

The fast-acting drugs are generally used for induction of general anesthesia. These drugs can
also be used as the sole anesthetic agent for short procedures.

Propofol:

· Induction occurs within 30-40 seconds after administration. Redistribution half–life

is within 2 to 4 minutes. These are unaltered in hepatic and renal failure.

· Effects on body systems:

o Causes systemic vasodilation, which decreases blood pressure and intracranial pressure.

o Occasionally can cause excitation, such as muscle twitching, hiccups, and spontaneous
movement.

o Can cause sedation alone in lower doses.

o Has an antiemetic effect, so associated with lower incidence of postoperative nausea and
vomiting.

o Does not provide analgesia.

Thiopental:

· This is an ultra-short-acting barbiturate. It produces induction in 15-20 seconds.

Redistribution half-life is 3 minutes.

· Effects on body systems:

o Decrease in blood pressure and intracranial pressure. Can cause severe hypotension in
patients with shock.

o Can cause laryngospasm and bronchospasm if the airway is irritated.

o It is a poor analgesic.

Slower-acting intravenous anesthetics

Benzodiazepines:

· These are primarily sedative-hypnotic drugs. The properties of these drugs are
described in detail in Chapter 2.

· When these drugs are used in larger doses (as compared to their sedative-hypnotic
dose), they may be used as anesthetic agents. The more commonly used benzodiazepines
for this purpose are as follows:

o Diazepam: Diazepam produces unconsciousness in 15 to 30 minutes. Redistribution half-

life is 15 minutes. The sedative effect, however, lasts for at least six hours.

o Midazolam: This is preferred to diazepam as an anesthetic as it is faster, and short-acting.

It is three times more potent than diazepam.

o Lorazepam: It is as potent as midazolam, however, is slower-acting and causes slower

onset and recovery.

Opioids:

· Certain opioids, including fentanyl, sufentanil, and remifentanil are often used as
anesthetic agents. All opioids can lead to hypotension, respiratory depression, muscle
rigidity, and postoperative nausea and vomiting. Naloxone can be used as an antagonist of
opioid effects. The properties of opioids are described in greater detail in Chapter 3.

· Since they are analgesics, they are preferred for painful procedures, such as
angiography and endoscopic procedures. The combination of morphine and nitrous oxide
provides good anesthesia for cardiac surgery. However, they do not produce amnesia, and
are therefore combined with benzodiazepines for better patient comfort.

· Fentanyl can cause bradycardia and respiratory depression. It increases muscle tone,
and must therefore be combined with muscle relaxants to facilitate mechanical ventilation.
Ketamine:

· Ketamine produces a unique state of anesthesia referred to as dissociative anesthesia.

In this state, the patient appears to be awake (eyes open, muscles are stiff, and may
swallow); but the patient is unconscious, and there is immobility, amnesia, and profound
analgesia.

· The drug is highly lipophilic and rapidly enters the cerebral cortex and subcortical
areas. It quickly redistributes and is metabolized in the liver. Elimination half-life is two to
four hours.

· There is cardiac stimulation, with increased blood pressure and cardiac output. It is
contraindicated in hypertensive patients. On the other hand, it produces bronchodilation,
and is beneficial for use in asthmatics. However, increased cerebral blood flow and
postoperative hallucinations have restricted its use.

Etomidate:

· This is a short-acting hypnotic agent that provides rapid induction. It has poor
analgesic activity.

· It does not have any effect on the cardiovascular system, and is therefore suitable in
patients with cardiovascular disease.

· Etomidate suppresses plasma cortisol and aldosterone levels, and therefore should
not be infused for extended periods of time.

Dexmedetomidine:

· This drug functions by activating the central α2 adrenergic receptors. It produces

both sedation and analgesia.

· This drug does not cause respiratory depression, and blunts cardiovascular response
to stress.

· It has relatively minor side effects, including dry mouth, hypotension, and
bradycardia.

EXERCISES
1. Which of the following pre-anesthetic medications helps to prevent laryngospasm?

a. Ranitidine

b. Glycopyrrolate

c. Pantoprazole
d. Metoclopramide

2. In which of the following stages of general anesthesia must surgical procedures be

carried out?

a. Stage 1

b. Stage 2

c. Stage 3

d. Stage 4

3. Which of the following inhalational anesthetics is associated with malignant

hyperthermia?

a. Halothane

b. Isoflurane

c. Desflurane

d. Sevoflurane

4. Which of the following intravenous anesthetic agents produces the phenomenon

called dissociative anesthesia?

a. Fentanyl

b. Thiopental

c. Midazolam

d. Ketamine

5. Which of the following anesthetic agents is suitable for patients with cardiovascular
disease?

a. Midazolam

b. Etomidate

c. Fentanyl

d. Propofol

6. Which of the following anesthetic gases is non-pungent and has a pleasant odor?

a. Halothane
b. Sevoflurane

c. Desflurane

d. Isoflurane

7. Which of the following anesthetics can cause diffusion hypoxia?

a. Halothane

b. Nitrous oxide

c. Midazolam

d. Sevoflurane

8. Which of the following agents has maximum analgesic effect?

a. Fentanyl

b. Diazepam

c. Thiopental

d. Propofol

9. Which of the following anesthetics has an anti-emetic effect?

a. Fentanyl

b. Diazepam

c. Thiopental

d. Propofol

10. Which of the following is the least hepatotoxic?

a. Halothane

b. Sevoflurane

c. Nitrous oxide

d. Isoflurane
 CHAPTER 2: SEDATIVE-HYPNOTIC DRUGS
Sedatives (also known as anti-anxiety or anxiolytic drugs) are agents that depress excitement
and calm the patient. Although sedatives can cause some drowsiness, they do not induce sleep or
loss of consciousness. Hypnotics are drugs that induce normal, arousable sleep, as opposed to
loss of consciousness induced by general anesthetics. Some drugs can function as sedatives at
lower doses, and as hypnotics at higher doses.

There are three main classes of sedative and hypnotic agents:

· Benzodiazepines

· Barbiturates

· Other drugs (sometimes referred to as non-benzodiazepine hypnotics)

BENZODIAZEPINES

Benzodiazepines are the most commonly used sedative-hypnotic drugs today.

Mechanism of action:

Benzodiazepines act at the GABA receptor. GABA (γ- amino butyric acid) is an inhibitory
neurotransmitter. When GABA binds to its receptor, chloride channels open, allowing influx of
chloride into the cell, which causes hyperpolarization of the neuron. This prevents development
of an action potential. Benzodiazepines increase the affinity of GABA for its receptor,
potentiating this action.

Clinical effects:

· Reduction of anxiety and sedation at lower doses, hypnosis at higher doses.

· Anterograde amnesia: Benzodiazepines impair the ability to form new memories.

· Anticonvulsant activity

· Muscle relaxation

Pharmacokinetics:

· Route of administration is generally oral.

· All benzodiazepines are lipophilic to some degree, but there is some variation
between the different drugs. This affects the rate of absorption, and duration of action of the
drug. Based on the duration of action, benzodiazepines may be classified as short-acting,
intermediate-acting, or long-acting drugs. (Table 1)
 · The t 1/2 does not correlate with the clinical duration of action. This is because even
the unmetabolized drug may dissociate from the receptor and redistribute to other tissues of
the body.

· Most benzodiazepines are metabolized in the liver by the hepatic microsomal system
(CYP3A4 and CYP2C19 enzymes) to glucuronides oxidized metabolites.

· Excretion occurs through the urine.

· Benzodiazepines can cross the placental barrier and depress the fetal CNS. It can also
be secreted in breast milk. Therefore, it is not recommended for pregnant and nursing
women.

Table 1. Classification of benzodiazepines based on duration of action.

DRUG T½ CLINICAL
DRUG CATEGORY
EXAMPLES (HOURS) DOSE
Long-acting (less Flurazepam 50-100 15mg to 30 mg
lipophilic) Diazepam 30-60 5mg to 10 mg
0.25 mg to 0.5
Alprazolam 12
Intermediate-acting mg
Temazepam 8-12
10mg to 20 mg
Short-acting (more 0.125mg to
Triazolam 2-3
lipophilic) 0.25mg

Adverse effects:

· Dependence: If high doses are given for long periods of time, physical and
psychological dependence may develop. Abrupt discontinuation can result in withdrawal
symptoms such as anxiety, insomnia, and, in some cases, seizures. The risk is higher with
short-acting drugs such as triazolam.

· Other side effects include drowsiness and confusion, the two most common side
effects of the benzodiazepines, ataxia at high doses, and cognitive impairment.

Indications:

· Treatment of anxiety disorders including panic disorders, social anxiety disorders,

post-traumatic stress disorders, and phobias. Benzodiazepines should not be routinely
prescribed to alleviate the normal stress of day-to-day living. Because of their addictive
nature, they should only be used for short periods of time to mitigate continued severe
anxiety.

· Treatment of anxiety related to other mental health conditions, including depression

and schizophrenia.
 · Treatment of sleep disorders, including insomnia.

· Conscious sedation and amnesia during minor interventions such as endoscopy, or

dental procedures.

· Treatment of seizures: Diazepam is the drug of choice for termination of status

epilepticus.

· Treatment of muscle spasms in muscular disorders such as cerebral palsy and

multiple sclerosis. They may also be used for muscle relaxation following muscle strains.

· Treatment of epilepsy.

Contraindications:

· Patients who are alcoholics, or are taking other CNS depressants: action can be
potentiated.

· Patients with liver disease

· Pregnant women and breastfeeding mothers

. Patients with acute narrow-angle glaucoma

BENZODIAZEPINE ANTAGONIST

· Flumazenil is a specific antagonist for benzodiazepines. It competes with the drug for
the GABA receptor and inhibits GABA action.

· The drug can only be administered intravenously, and it has a rapid onset of action.

· Flumazenil has a short half-life of one hour. Therefore, it is used to reverse toxicity
of long- acting benzodiazepines. Multiple doses may be needed to maintain reversal.

· Flumazenil can precipitate withdrawal symptoms in dependent patients, or cause

seizures, particularly if the benzodiazepine was used to control seizure activity.

BARBITURATES

Barbiturates have largely been replaced today by benzodiazepines because of their potential
to cause tolerance, physical dependence, and severe withdrawal symptoms. However, they were
once the most commonly used sedative-hypnotic drugs.

Mechanism of action:

Like benzodiazepines, barbiturates target GABA receptors to potentiate the inhibitory effect
of GABA. The binding site on the receptor is distinct from the binding site of benzodiazepines.
Barbiturates also bind to glutamate receptors, and inhibit glutamate, which is an excitatory
neurotransmitter. In addition to this, certain barbiturates (like pentobarbital) block sodium
channels which enhances the inhibitory effect.

Clinical effects:

· CNS depression: Barbiturates cause CNS depression in a dose-dependent manner.

At low doses, they have a sedative effect. At slightly higher doses, they act as hypnotics. At
still higher doses, they can cause anesthesia, and, at toxic doses, can result in coma and
death.

· Respiratory depression: Barbiturates block chemoreceptor and hypoxic-mediated

response to carbon dioxide, leading to respiratory depression.

Pharmacokinetics:

· Oral route of administration; Absorbed from the gut and sent to the CNS.

· From the CNS, it redistributes rapidly to the skeletal muscles and adipose tissue.

· Metabolism in the liver, excreted in urine.

· Barbiturates can cross the placental barrier and cause CNS and respiratory depression
in the fetus.

Adverse effects:

· Drowsiness, sluggishness, and impaired ability to concentrate.

· Withdrawal symptoms can be severe and include anxiety, restlessness, tremors,

seizures, and delirium.

· Barbiturates diminish the action of drugs which are metabolized through the
cytochrome P450 system.

. Drug hangover leading to impaired functioning for several hours after the patient
wakes up.

. Barbiturate poisoning due to overdosage.

Indications:

· Anesthesia: Thiopental, an ultrashort-acting barbiturate, has been used as an

induction agent in general anesthesia.

· Anti-epileptic: Phenobarbital has been used for treatment of status epilepticus, as

well as for long-term seizure management.

· Treatment of anxiety and insomnia: They have largely been replaced by

benzodiazepines, because of their adverse effects.
 Contraindications:

· Patients with acute intermittent porphyria

· Pregnant women

OTHER (NON-BENZODIAZEPINE) ANXIOLYTICS

Zolpidem

· Although it is structurally unrelated to benzodiazepines, its mechanism of action is

similar. It binds to the benzodiazepine binding site on the receptor and potentiates GABA.

· It only produces a hypnotic effect. It does not have anti-epileptic or muscle relaxing
properties.

· It is usually absorbed from the oral route, but sublingual preparations are also
available. It has a fast onset of action of 30 minutes. T1/2 is 2 to 3 hours, but the clinical
effect lasts for five hours.

· It is metabolized by hepatic oxidation (CYP450 system).

· Zolpidem can cause anterograde amnesia, daytime drowsiness, agitation, dizziness,

and headaches.

Zaleplon

· It is similar to zolpidem with regard to mechanism of action.

· It has a similar onset of action, but shorter half-life (one hour). Clinical effects last
for three hours. This drug has fewer side effects than zolpidem.

· Metabolism occurs in the liver through the CYP3A4 enzyme

Zopiclone:

● This was the first non-Benzodiazepine anxiolytic to be introduced, and is not much in use
today.
● It has a similar mechanism of action and parmacokinetics as the above drugs. Its t1/2 is
5-6 hours
● Adverse effects include bitter taste, dry mouth and psychological disturbances.
● Indications: Usually used when weaning off from benzodiazepines.
EXERCISES
1. Which of the following drugs does not bind to the benzodiazepine binding site of the
GABA receptor?

a. Diazepam
b. Zolpidem

c. Triazolam

d. Thiopental

2. Which of the following is not a therapeutic use of diazepam?

a. Treatment of anxiety disorders

b. Treatment of status epilepticus

c. Treatment of schizophrenia

d. Treatment of muscle spasm in cerebral palsy

3. Which of the following is a long-acting benzodiazepine?

a. Diazepam

b. Triazolam

c. Alprazolam

d. Temazepam

4. Which of the following is a specific antagonist for benzodiazepines?

a. Flurazepam

b. Flumazenil

c. Fluconazole

d. Fluoxetine

5. Which of the following drugs is contraindicated in patients with acute intermittent

porphyria?

a. Diazepam

b. Zolpidem

c. Phenobarbital

d. Alprazolam

6. What is the half-life of alprazolam?

a. 6 hours
b. 8 hours

c. 12 hours

d. 16 hours

7. What is the correct dosage of triazolam?

a. 0.125 to 0.25 mg

b. 0.25 to 0.5 mg

c. 1 to 2 mg

d. 10 mg

8. How do barbiturates affect drugs metabolized through the P450 system?

a. Enhance activity

b. Diminish activity

c. Enhance some and diminish some drugs

d. No effect

9. What kind of amnesia is produced by benzodiazepines?

a. Retrograde amnesia

b. Anterograde amnesia

c. Complete amnesia

d. No amnesia

10. Which of the following clinical effects is produced by zolpidem?

a. Muscle relaxation

b. Analgesia

c. Hypnotic

d. Anti-epileptic
 CHAPTER 3: OPIOID ANALGESICS
The most common reason that patients seek medical treatment is pain. Acute pain is largely
managed by the use of non-steroidal anti-inflammatory drugs (NSAIDS), which will be dealt
with in a subsequent chapter. However, NSAIDS are not suitable for the management of chronic
pain, because of the undesirable effects associated with long-term use. Moreover, NSAIDS are
ineffective in severe pain syndromes, such as pain in malignancy. In these situations, opioid
analgesics are the preferred agents for pain management.

The body produces endogenous opioids, such as endorphins and enkephalins. These opioids
function as inhibitory neurotransmitters, and prevent the pain impulse from being transmitted
from the spinal cord to the brain. Therapeutic opioids are similar to these compounds.

MECHANISM OF ACTION

Opioids bind to three receptor sites on the neuronal surface – the µ, κ, and δ receptors. These
are G-protein-coupled receptors, and, when the drug binds to the receptor, there is inhibition of
adenylyl cyclase. Drug binding also causes an influx of calcium ions in the presynaptic region,
which impedes neuronal firing, and efflux of potassium ions in the postsynaptic region, which
causes hyper-polarization of the neuron. All these factors help in attenuation of the pain impulse
at a central level, bringing about relief from pain.

Based on their interaction with the opioid receptor, there are three classes of drugs – full
opioid agonists, partial opioid agonists, and opioid antagonists.

OPIOID AGONISTS

Types of opioid analgesics:

Based on their origin, opioids may be classified as natural, semi-synthetic, or synthetic drugs.
These drugs can also be classified based on their chemical structure (Table 1).

Table 1. Classification of opioids based on their chemical structure

PHENANTHRENE BENZMORPHAN PHENYLPIPERIDINES DIPHENYLHEPTANES

Morphine
Fentanyl
Codeine Pentazocine Methadone
Meperidine
Oxycodone

Clinical effects:

· Effects on the central nervous system: Opioids have three effects on the CNS.

o Analgesia: Opioid analgesics attenuate nerve impulses at the spinal cord level. Some
 opioids, like morphine, also alter the brain’s perception of pain, bringing further pain
relief. Codeine is a relatively weak analgesic. Oxycodone is twice as potent as
morphine when given orally, while oxymorphone is three times as potent orally. Oral
hydromorphone is 8 to 10 times more potent than morphine.

o Euphoria: Opioids, morphine in particular, induce a calming effect and can produce a
sense of extreme well-being and contentment.

o Sedation: In larger doses, some opioids have a sedative effect. Sedation is dose-dependent
and progressively higher doses can cause unconsciousness and coma.

· Respiratory effects: Some opioids such as morphine depress the sensitivity of the
respiratory center to carbon dioxide. This respiratory depression is the leading cause of
death due to opioid overdose. However, tolerance develops with repeated doses. Morphine
and codeine also suppress the cough center. Morphine causes histamine release from mast
cells, which can cause bronchoconstriction.

· Ophthalmic effects: Morphine causes pupillary miosis.

· GI effects: Morphine stimulates the chemoreceptor trigger zone for emesis and may
cause vomiting. It increases muscle tone in the intestinal smooth muscles and anal
sphincter, and decreases GI motility. This leads to constipation.

· Cardiovascular effects: At larger doses, opioids can cause hypotension and

bradycardia.

Contraindications:

. Severe brain injury

. Asthmatics

. Liver failure

Pharmacokinetics:

· Morphine is usually administered parenterally because it undergoes high first-pass

metabolism. The other opioids are given as oral preparations.

· Morphine enters most body tissues, and can cross the placenta. It is not lipophilic and
therefore does not cross the blood-brain barrier.

· Opioids usually undergo metabolism in the liver. Most opioids are metabolized by
the cytochrome P450 system. Morphine, however, undergoes conjugation reaction. Some of
the metabolites are also clinically effective. For instance, morphine is conjugated to
morphine 6-glucuronide, which is a potent analgesic.

· Excretion primarily occurs through urine.

 Adverse effects:

· Respiratory depression: This is most common with morphine, and patients with
emphysema or cor pulmonale are at high risk.

· Dependence: Chronic use can produce physical and psychological dependence.

PARTIAL AGONISTS AND MIXED AGONISTS-ANTAGONISTS

When partial agonists bind to the opioid receptor, they do not activate the receptors
completely. Mixed agonist-antagonists can stimulate one receptor, but block others. When these
drugs are used in opioid-naïve individuals (those who have not received opioids before), they act
similar to opioids, and can produce analgesia. In patients who are opioid-tolerant, they may show
blocking or antagonist effects. Some important drugs in this category are as follows:

Buprenorphine:

· Used through parenteral, sublingual, or transdermal route. It is metabolized in the

liver and excreted through bile and urine.

· This has an analgesic effect that lasts for 6-8 hours, but does not cause respiratory
depression, hypotension, or sedation

· This is used in opioid detoxification.

Pentazocine:

· It is administered orally or parenterally.

· Produces moderate analgesia, but less euphoria.

· It can cause respiratory depression and constipation at higher doses. It increases

blood pressure, including systemic and pulmonary arterial pressure. It should therefore be
avoided in patients with coronary artery disease.

OPIOID ANTAGONISTS

These drugs bind to the opioid receptors but do not activate them. They do not have any
effect in opioid-naïve individuals. However, they reverse the effects of opioids in patients who
have consumed them. They are therefore useful in managing drug overdose. The two important
opioid antagonists are:

Naloxone:

· This is mainly used in morphine overdose. Injected intravenously, it acts within 30

seconds to reverse respiratory depression and coma

· Its half-life is 30 to 81 minutes. Therefore, doses may need to be repeated until

opioids have been eliminated from the system.
Naltrexone:

This has a longer duration of action, which lasts for up to 24 hours. It may be given orally.
EXERCISES
1. Which of the following is not a clinical effect of morphine?

a. Constipation

b. Suppression of cough center

c. Mydriasis

d. Bradycardia

2. Which of the following opioids has the most potent analgesic effect?

a. Morphine

b. Oxycodone

c. Hydromorphone

d. Oxymorphone

3. Which of the following drugs is preferred for opioid detoxification?

a. Codeine

b. Naltrexone

c. Buprenorphine

d. Pentazocine

4. Apart from morphine, which of the following opioids exhibits antitussive activity?

a. Oxycodone

b. Buprenorphine

c. Codeine

d. Pentazocine

5. Which of the following drugs is used as an emergency treatment for morphine

overdose?

a. Methadone
b. Buprenorphine

c. Fentanyl

d. Naloxone

6. Which of the following is not an opioid receptor?

a. µ

b. γ

c. δ

d. κ

7. Why does morphine cause bronchoconstriction?

a. Serotonin release

b. Histamine release

c. Prostaglandin release

d. Adrenaline release

8. Which of the following opioids is a partial agonist?

a. Methadone

b. Buprenorphine

c. Codeine

d. Oxymorphone

9. In which category of patients should pentazocine be avoided?

a. Asthmatics

b. Patients with emphysema

c. Patients with cardiovascular disease

d. Patients with malignancy

10. What is the cause of death in morphine overdose?

a. Myocardial infarction
b. Respiratory depression

c. Cardiac arrest

d. Pulmonary embolism
 CHAPTER 4: ANTIDEPRESSANTS AND ANTI-
MANIC DRUGS
Depression is simply defined as a state of sadness. In more complex terms, depression is a
psychoneurotic disorder characterized by feelings of sadness or grief, difficulty in thinking and
concentration, and a decline in mental and sometimes physical activity. Antidepressants, or
mood elevators, are drugs that are used to treat depressive disorders.

Depressive disorders may either be unipolar or bipolar. Unipolar disorders are associated
chiefly with depression. However, in bipolar disorders, bouts of depression alternate with bouts
of mania (or excitation).

MECHANISM OF ACTION OF ANTIDEPRESSANTS:

The mechanism of action of antidepressants is based on the ‘amine theory’ of depression.

The theory states that depression is caused by a functional deficiency of neurotransmitters,
especially norepinephrine. Neurotransmitters serve as communicators between different neurons
in the brain. They are released from the axons of one neuron, and are taken up by another neuron
(re-uptake) once the transmission function is complete. Most antidepressants work by inhibiting
reuptake of the neurotransmitter. This increases the concentration of the neurotransmitter in the
extracellular fluid around the neurons.

Five key categories of drugs are used in the management of depressive disorders:

· Selective serotonin re-uptake inhibitors (SSRIs)

· Serotonin/ norepinephrine re-uptake inhibitors (SNRIS)

· Monoamine oxidase inhibitors (MAOIs)

· Tricyclic antidepressants (TCAs)

· Atypical antidepressants
 Figure 5 Amine theory states that depression is caused by a deficiency of neurotransmitters. Neurotransmitters are released
from the axons of one neuron and are taken up (reuptake) by another neuron. Most antidepressants work by inhibiting reuptake,
thereby increasing the concentration of neurotransmitter in the extracellular fluid around the neurons.

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS

SSRIs are the first-line drugs used in treatment of depression. These drugs have minimal side
effects as compared to the other classes of drugs. These drugs block the re-uptake of serotonin,
increasing its concentration at the neuronal synapse.

Pharmacokinetics:

. Route of administration is oral. Some SSRIs, like sertraline, have increased absorption if
taken along with food.

· Most SSRIs have a plasma half-life between 16 to 36 hours. Fluoxetine alone has a
longer half-life of 50 hours.

· Metabolism usually occurs in the liver, through the cytochrome P450 system and
through conjugation by glucuronides and sulfates. However, some SSRIs like fluoxetine
and paroxetine inhibit the CYP2D6 component of the P450 system.

Adverse effects:

· Minor adverse effects: SSRIs have minor adverse effects, including nausea, anxiety,
sleep disturbances (both drowsiness and insomnia), and sexual dysfunction.

· Overdose: One SSRI, citalopram, can cause cardiac arrhythmias if overdose is taken.
Other SSRIs are relatively safe even in overdose. If taken with an MAOI, all SSRIs can
 cause a serotonin syndrome manifested as hyperthermia, muscle rigidity, myoclonus, and
alterations in vital signs and mental status.

· Discontinuation syndrome: If stopped abruptly, SSRIs can cause headache, flu-like

symptoms, irritability, and sleep disturbances.

SEROTONIN/NOREPINEPHRINE RE-UPTAKE INHIBITORS

These drugs act by preventing the re-uptake of both serotonin as well as noradrenaline. The
drug venlafaxine primarily inhibits serotonin, and, at larger doses, inhibits noradrenaline. On the
other hand, duloxetine inhibits both serotonin and noradrenaline at all doses. They are therefore
more effective than SSRIs. SNRIs have two main therapeutic applications:

· Treating depression in cases where SSRIs have proven ineffective

· Treating depression-associated chronic pain, such as backaches and muscle pain

Pharmacokinetics:

· All SNRIs are taken orally.

· They are metabolized by the cytochrome P450 system. Duloxetine may inhibit
CYP2D6 isozymes. Duloxetine has maximum liver metabolism, and should be avoided in
patients with liver disease.

Adverse effects:

· Minor effects: Nausea, headache, constipation, sexual dysfunction, dizziness, and

sleep disturbances.

· Discontinuation syndrome may be seen similar to SSRIs.

TRICYCLIC ANTIDEPRESSANTS

Tricyclic antidepressants were the earlier first-line drugs used in depression. They have
largely been replaced by SSRIs now because of their multiple side effects.

Mechanism of action:

· Most TCAs block re-uptake of both serotonin and noradrenaline into the presynaptic
terminal. Some TCAs like maprotiline and desipramine selectively prevent only
noradrenaline re-uptake.

· TCAs also block other receptors, including histaminic, muscarinic, α-adrenergic, and
serotonergic receptors. This activity is largely responsible for the adverse effects of the
TCAs.
 Pharmacokinetics:

· Route of administration is oral. Bioavailability is unpredictable due to high first-pass

metabolism.

· TCAs are lipophilic, and can easily penetrate the CNS.

· Metabolism occurs in the liver through the cytochrome P450 system as well as
conjugation.

· Excreted in urine as inactive metabolites.

Therapeutic effects:

· Treatment of moderate-to-severe depression: TCAs improve mood and mental

alertness, and even increase physical activity.

· Treatment of bed-wetting: Imipramine has been used to control bed-wetting in

children older than six years of age.

· Chronic pain syndromes: Amitriptyline has been used for migraines and other
chronic pain syndromes.

· Insomnia: Doxepin, in low doses, has been used for insomnia.

Adverse effects:

· Muscarinic receptors blockade: Xerostomia, blurred vision, constipation, urinary

retention. They can cause sinus tachycardia, and, in overdoses, can cause arrhythmias.

· α-adrenergic receptors blockade: Orthostatic hypotension, reflex tachycardia.

· Histamine receptors blockade: Sedation, weight gain.

MONOAMINE OXIDASE INHIBITORS

Monoamine oxidase is a mitochondrial enzyme that serves to deactivate excess

neurotransmitters (including noradrenaline, serotonin, and dopamine). MAOIs inhibit this
enzyme, causing the neurotransmitters to accumulate in the synaptic space. Most MAOIs cause
irreversible inactivation, by forming stable complexes with the enzyme.

Therapeutic uses: MAOIs are used in depression that is unresponsive to SSRIs and TCAs.
Atypical depression may be responsive only to MAOIs.

Pharmacokinetics:

They are well absorbed after oral administration. Although MAO is fully inhibited within a
few days, the antidepressant action takes several weeks. The drug is metabolized in the liver and
excreted through urine. Upon discontinuation, regeneration of MAO enzyme takes several
weeks.

Adverse effects: MAOIs inhibit monoamine oxidase activity not only in the brain, but also in
the gut and liver. This prevents oxidative deamination of drugs and toxins, which can lead to
dangerous side effects. For instance, MAO catalyzes the degradation of dietary tyramine. With
MAOIs, the accumulated tyramine can cause release of large amounts of catecholamines, which
may lead to hypertensive crisis. This presents with hypertension, cardiac arrhythmias, seizures,
occipital headache, and even stroke. Selegiline may avoid first-pass metabolism if administered
as a transdermal patch, and may be used as a safer alternative.

ATYPICAL ANTIDEPRESSANTS

These are a mixed group of drugs which have different mechanisms of action. Some of the
more important drugs in this category are as follows:

Bupropion:

· This drug inhibits re-uptake of dopamine and norepinephrine.

· Adverse effects: It does not cause sexual dysfunction. May cause dry mouth,
sweating, nervousness, and tremors. Seizures may occur, and this is dose-dependent.

· This drug is used for managing withdrawal symptoms related to nicotine in patients
who are quitting smoking.

Mirtazapine:

· This drug acts at the presynaptic α-2 adrenergic receptors and serotonergic receptors.
It enhances the activity of both noradrenaline and serotonin.

· It can cause sedation, increased appetite, and weight gain

Trazodone and Nefazodone:

· These drugs weakly inhibit serotonin re-uptake.

· They are weakly sedating, and are also used to manage insomnia.

ANTI-MANIA DRUGS

Anti-mania drugs, or mood stabilizers, are primarily used in the treatment of bipolar
depressive disorder. These drugs help prevent mood swings and may be employed for treatment
of both depression and mania.

Lithium salts

The exact mechanism of action of lithium is unknown. Some authors believe that it replaces
intracellular and extracellular sodium, while others believe that it selectively inhibits dopamine
and noradrenaline, with no effect on serotonin.
 Clinical effects:

· It does not have any effect in normal patients. However, in patients with bipolar
disorder, it stabilizes the mood within 2 to 3 weeks.

· It inhibits the action of anti-diuretic hormone in the kidney, and may cause diabetes
insipidus.

· It inhibits the release of thyroid hormones, and has an insulin-like effect on glucose
metabolism.

· It may decrease leukocyte count.

Pharmacokinetics:

· It is well absorbed orally.

· It does not bind to plasma or tissue proteins. It enters the extracellular fluid first
before being taken up by cells.

· It does not undergo any metabolism, and is excreted by the kidney in a manner
similar to sodium ions.

Adverse effects:

Minor adverse effects: Headache, dry mouth, polyuria, polyphagia, polydipsia, sedation,
and dermatological reactions.

Other anti-mania drugs

Other classes of CNS drugs are used for treatment of mania. They are described in detail in
the appropriate sections. These drugs include:

· Antiepileptic drugs: Carbamazepine, sodium valproate, lamotrigine.

· Neuroleptics and newer antipsychotic drugs: Chlorpromazine, haloperidol,

risperidone etc.
EXERCISES
1. Which of the following drugs does not inhibit noradrenaline reuptake?

a. Amitriptyline

b. Desipramine

c. Duloxetine

d. Sertraline
 2. Which of the following SSRIs has the longest duration of action?

a. Paroxetine

b. Fluoxetine

c. Sertraline

d. Citalopram

3. Which of the following classes of antidepressants are the safest to use as first-line
treatment in depression?

a. Selective serotonin reuptake inhibitors

b. Serotonin norepinephrine reuptake inhibitors

c. Tricyclic antidepressants

d. Monoamine oxidase inhibitors

4. Which of the following drugs are used for treatment of typical depression?

a. Selective serotonin reuptake inhibitors

b. Serotonin norepinephrine reuptake inhibitors

c. Tricyclic antidepressants

d. Monoamine oxidase inhibitors

5. Which of the following is not used in the management of mania?

a. Lithium

b. Carbamazepine

c. Sertraline

d. Chlorpromazine

6. Which of the following classes of antidepressants has the maximum adverse effects?

a. SSRIs

b. SNRIs

c. TCAs

d. MAOIs
 7. Mechanism of action of antidepressants is based on which theory?

a. Oxidation theory

b. Amine theory

c. Glucuronide theory

d. Catecholamine theory

8. How is lithium metabolized in the body?

a. Oxidation

b. Hydrolysis

c. Conjugation

d. Does not get metabolized

9. What is the half-life of most SSRIs?

a. 10-15 hours

b. 16-36 hours

c. 26-46 hours

d. 40-50 hours

10. Which of the following is not an atypical antidepressant?

a. Bupropion

b. Mirtazapine

c. Buprenorphine

d. Trazodone
 CHAPTER 5 – ANTIPSYCHOTICS
Antipsychotics are a specific class of drugs that are primarily used in the treatment of
schizophrenia. However, these drugs may also be applied to the treatment of mania, and other
psychotic disorders.

Antipsychotic drugs work on the ‘dopamine hypothesis’ of psychotic disorders. According to

this hypothesis, psychotic disorders such as schizophrenia occur due to dysregulation of
dopamine in the neurological pathways of the brain. Specifically, there is hyperactivity of
dopamine in the mesolimbic area, while other areas, such as mesocortical area,
tuberoinfundibular area, and nigrostriatal area show hypoactivity.

MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGS:

Based on their mechanism of action, these drugs have been classified into first generation
and second generation antipsychotics (Table 1).

First generation drugs act by competitively blocking dopamine D2 receptors of all the
neuronal pathways apart from the mesolimbic area. Therefore, functioning of other areas where
dopamine hypoactivity may be present (like the mesocortical area) may be worsened. The high
potency drugs in this category block only D2 receptors, however, low potency drugs may also
block the α-adrenergic, cholinergic, and histamine receptors.

The second generation antipsychotics (also called atypical antipsychotics) block dopamine
D2 receptors, as well as serotonin 5HT-2A receptors. The D2 receptor blockade is temporary,
unlike first generation drugs. Since serotonin inhibits dopamine, and these drugs inhibit
serotonin, they basically cause an increase in dopamine levels at certain areas of the brain. So,
areas like the mesocortical area may benefit from using these drugs over first generation drugs.

Table 1. Classification of antipsychotic drugs

FIRST GENERATION
SECOND GENERATION
HIGH POTENCY LOW POTENCY
Aripiprazole
Haloperidol
Chlorpromazine Risperidone
Loxapine
Thioridazine Clozapine
Pimozide
Prochlorperazine Olanzapine
Fluphenazine
Quetiapine

CLINICAL EFFECTS:
 · CNS: In normal individuals, these drugs can produce ‘neurolept anesthesia’. The
individual becomes indifferent to surroundings, and may go off to sleep, but is arousable. In
individuals suffering from schizophrenia, these drugs can reduce hallucinations and
delusions (mediated by hyperactivity of the mesolimbic pathway). However, the drugs also
act on already hypoactive pathways, such as the mesocortical pathway, which mediates
apathy and cognitive impairment. These symptoms do not resolve, and can even worsen.

· Extrapyramidal effects: These occur due to blockade of D2 receptors in the

nigrostriatal pathway. This leads to dystonia, tremors, involuntary movements, and motor
restlessness. This is less common with second generation drugs.

· Endocrine effects: Neuroleptic drugs can stimulate excess release of prolactin. This
leads to gynecomastia and galactorrhea.

· Antiemetic effects: The drugs block D2 receptors in the chemoreceptor trigger zone
(CTZ) in the medulla. This suppresses nausea.

· Anticholinergic effects: Some antipsychotics suppress the cholinergic receptors.

This leads to dry mouth, blurred vision, constipation, and urinary retention.

· Anti-adrenergic effects: Blockade of α-adrenergic receptors can cause orthostatic

hypotension.

PHARMACOKINETICS:

· Route of administration is mostly oral. The absorption of selected drugs, including

ziprasidone and paliperidone is increased on intake with food.

· It has a large volume of distribution due to high degree of binding with both plasma
and tissue proteins.

· Metabolism occurs in the liver through the CY-P450 system. The metabolites are
often active, and many metabolites themselves have been developed for clinical use.

· Excretion occurs through the urine. The t1/2 of the drugs is highly variable. Half-life
of the most common drugs is listed in Table 2.

Table 2. Half-life and dosage of common antipsychotics

CATEGORY DRUG HALF-LIFE DOSE

Chlorpromazine 18-30 hours 100-800 mg/day
FIRST GENERATION Haloperidol 24 hours 2-20 mg/day
Pimozide 48-60 hours 2-6 mg/day
Clozapine 12 hours 100-300 mg/day
Olanzapine 24-30 hours 2.5-20 mg/day
SECOND GENERATION Quetiapine 6 hours 50-400 mg/day
Ziprasidone 8 hours 40-160mg/day
 Aripiprazole 72 hours 5-30 mg/day

ADVERSE EFFECTS:

· Extrapyramidal effects: These are mostly seen in first generation drugs.

· Metabolic effects: Some antipsychotics (olanzapine, clozapine) can increase glucose

and triglyceride levels. They can precipitate or worsen diabetes.

· Other effects due to blockade of cholinergic and adrenergic receptors, and due to
stimulation of prolactin – are mild but undesirable.

· Neuroleptic malignant syndrome: This sometimes develops with first generation

high- potency drugs. The patient develops muscle rigidity, fever, myoglobinemia, and
altered mental status. Treatment is supportive, and the antipsychotic must be discontinued.

INDICATIONS:

· Psychotic disorders, primarily schizophrenia

· Prevention of nausea and vomiting:

o Vertigo related: Meclizine

o Motion sickness: Promethazine

o Related to cancer chemotherapy: Haloperidol, Prochlorperazine

· Intractable hiccups: Chlorpromazine is usually used.

CONTRAINDICATIONS:

Patients with seizure disorders – may precipitate seizures.

EXERCISES:
1. Which neurotransmitter is dysregulated in psychotic disorders?

a. Serotonin

b. Dopamine

c. Noradrenaline

d. Acetylcholine

2. Which of the following drugs is not a high-potency drug?

a. Pimozide
b. Chlorpromazine

c. Haloperidol

d. Fluphenazine

3. Intake of which of the following drugs with food increases its absorption?

a. Ziprasidone

b. Fluphenazine

c. Risperidone

d. Olanzapine

4. Which of the following conditions may be precipitated with antipsychotics?

a. Myocardial infarction

b. Asthma

c. Epilepsy

d. Angina

5. Which of the following hormones undergoes increased production when

antipsychotic drugs are given?

a. Estrogen

b. Prolactin

c. Progesterone

d. Testosterone

6. Which of the following areas of the brain becomes hyperactive in psychotic

disorders?

a. Nigrostriatal

b. Tuberoinfundibular

c. Mesocortical

d. Mesolimbic

7. What is the half-life of aripiprazole?

a. 12 hours

b. 24 hours

c. 48 hours

d. 72 hours

8. Which drug is used to treat intractable hiccups?

a. Prochlorperazine

b. Chlorpromazine

c. Haloperidol

d. Fluphenazine

9. Which of the following drugs can precipitate hyperglycemia?

a. Olanzapine

b. Quetiapine

c. Ziprasidone

d. Aripiprazole

10. The extrapyramidal adverse effects are reduced in second generation drugs. This is
due to blockade of which receptors?

a. Serotonin

b. Adrenergic

c. Muscarinic

d. Cholinergic
 CHAPTER 6 – DRUGS USED IN
NEURODEGENERATIVE DISEASES
Neurodegenerative diseases are conditions that are caused due to destruction and
degeneration of neurons in the central nervous system. The most common neurodegenerative
diseases include Parkinsonism and Alzheimer’s.

PARKINSON’S DISEASE

Parkinsonism is a neurodegenerative disease that affects areas of the brain that control
muscle movements. The two main areas of the brain that control muscle activity are the
substantia nigra and the neostriatum. The substantia nigra sends signals to the neostriatum
through release of dopamine from dopaminergic neurons. In Parkinson’s, there is degeneration of
these neurons, which results in a deficiency of dopamine. Within the neostriatum, dopamine
tends to inhibit GABA and acetylcholine. In its absence, there is overproduction of acetylcholine,
which causes abnormal signaling. This is ultimately responsible for the uncontrolled movements
seen in Parkinsonism.

Strategy for therapy in Parkinsonism:

Drug therapy in Parkinsonism usually involves the use of multiple drugs. The different
classes are as follows:

Drugs used to replenish dopamine levels:

The ideal drug to use would be dopamine itself. However, this is not practical as dopamine
does not cross the blood-brain barrier. Therefore, a more feasible alternative is the use of
levodopa (L-dopa), which is its precursor. L-dopa easily crosses the barrier, and once within the
brain, may be metabolized to dopamine.

Clinical effects:

· CNS: Once converted to dopamine, L-dopa exerts its clinical effects by providing
symptomatic improvements. There is a decrease in muscle rigidity and tremors. With
continued therapy, even gait, speech, and facial expressions are improved.

· CVS: Peripherally converted dopamine acts on β-adrenergic receptors, leading to

tachycardia and postural hypotension.

· Others: Stimulation of receptors at the CTZ can trigger nausea and vomiting.
Stimulation of the pituitary causes prolactin release.

Pharmacokinetics: Oral route of administration. It is absorbed from the small intestine. Prior
to entering the brain, this drug may be degraded by two key enzymes – DDC (Dopa
decarboxylase) and COMT (Catechol-O Methyltransferase). This reduces the bioavailability of
the active drug. Once within the brain, it gets converted by DDC to dopamine, through which it
exerts its actions.

Within the brain, L-dopa may be degraded by COMT as well as MAO (Monoamine oxidase).
The inactive metabolites undergo conjugation and are excreted in urine. The plasma half-life of
the drug is usually 1-2 hours.

Adverse effects:

· Nausea and vomiting, altered taste sensation.

· Postural hypotension, tachycardia.

· Visual and auditory hallucinations, mood changes, anxiety, depression, psychosis.

Indications:

· Early stages of Parkinson’s disease

Contraindications:

· Patients on MAO inhibitors: can precipitate hypertensive crisis.

· Patients with psychosis: symptoms may be exacerbated.

· Patients with heart disease: can precipitate arrhythmias and angina.

Drugs used to maximize the effects of L-dopa:

L-dopa undergoes metabolism outside the CNS before it can cross into the brain. Within the
brain also, it can undergo fast degradation. Therefore, certain drugs are given along with L-dopa
to prevent its metabolism and increase the clinical effect. Some of these drugs are listed below:

Carbidopa: Carbidopa inhibits DDC. This prevents the metabolism of L-dopa in the periphery.
Carbidopa can reduce the dose of L-dopa by four to five times, which in turn reduces the severity
of adverse effects. It cannot penetrate the blood-brain barrier, and therefore, has no effect on L-
dopa in the brain.

Selegiline and Rasagiline: These drugs inhibit MAO type B, which is responsible for the
degradation of dopamine in the brain. As a result, these drugs increase dopamine levels in the
brain, and enhance the action of L-dopa. These drugs may cause hypertension in high doses.
Selegiline is metabolized to amphetamines, and may cause insomnia if taken in the evening.

Entacapone and Tolcapone: These drugs inhibit COMT. They are taken orally, are readily
absorbed, and bind to plasma albumin, which decreases their distribution. These drugs are
metabolized in the liver, and excreted in both urine and feces. Tolcapone has a longer duration of
action, but also has the potential to cause fulminant hepatic necrosis, so is not preferred. These
drugs reduce the ‘wearing off’ effect that is seen with L-dopa.
 Using dopaminergic drugs:

L-dopa is only effective in the early stages of the disease. In later stages, there is
degeneration of dopaminergic neurons, so that dopamine can no longer be synthesized from L-
dopa within the neuron. Therefore, instead of L-dopa, dopaminergic drugs may be used. These
drugs are agonists of dopamine. They bind to the dopamine receptors and exert actions similar to
dopamine. A few drugs in this category are as follows:

Bromocriptine:

· This is a potent D2 agonist.

· Side effects include hallucinations, confusion, delirium, vomiting, and orthostatic

hypotension. It can also cause pulmonary and retroperitoneal fibrosis.

Pramipexole and ropinirole:

· These are agonists for D2 and D3 receptors.

· They may be taken orally. Pramipexole does not metabolize much, while ropinirole
undergoes extensive hepatic metabolism. They are excreted in the urine.

· The drug half-life is 8 hours and 6 hours respectively.

· They may cause daytime sleepiness, hallucinations, and postural hypotension.

· Apomorphine and rotigotine are similar drugs, which are used in injectable and
transdermal forms respectively.

Amantadine:

· This drug has multiple effects. It increases dopamine secretion, and also inhibits
cholinergic and NMDA type of glutamate receptors.

· This is used for early stages of the disease, and, for advanced cases, may be used in
combination with L-dopa.

· Side effects: it can cause restlessness, confusion, and hallucinations. It can also cause
orthostatic hypotension, constipation, urinary retention, and dry mouth.

Use of anticholinergic drugs:

Another strategy of treatment is to inhibit the over-activity of acetylcholine. This is done by

the use of anticholinergic drugs. Anticholinergic drugs are described in detail in Unit 3.

ALZHEIMER DISEASE

Alzheimer disease is another neurodegenerative disease, which is characterized by abnormal

protein deposition in the brain. The protein may deposit as plaques (amyloid) or tangle (tau).
This deposition affects neurotransmission, and levels of critical neurotransmitters, such as
acetylcholine, are reduced. Over time, there is degeneration of cholinergic neurons. There also
appears to be overstimulation of NMDA glutamate receptors, which is believed to accelerate the
degenerative process. Treatment in Alzheimer’s therefore has the following strategies:

Improving cholinergic transmission:

This is done by the use of drugs that inhibit the enzyme acetylcholinesterase (ACE
inhibitors). Inhibition of ACE prevents degradation of acetylcholine, which increases its levels
and improves cholinergic transmission. ACE inhibitors that are used for Alzheimer disease
include galantamine, rivastigmine, and donepezil.

Inhibiting NMDA glutamate stimulation:

Memantine is an NMDA receptor antagonist. It binds to the receptor and prevents inflow of
excessive amounts of calcium ions, which are responsible for cell apoptosis.

Both the above drug classes may produce short term benefits in improving symptoms.
However, the treatment is largely palliative as the underlying degenerative process cannot be
halted.
EXERCISES
1. What kind of neuron is associated with degeneration in Parkinson’s disease?

a. Cholinergic

b. NMDA associated

c. Dopaminergic

d. Adrenergic

2. Which of the following enzymes is inhibited by carbidopa?

a. Dopa decarboxylase

b. Catechol O methyltransferase

c. Monoamine oxidase A

d. Monoamine oxidase B

3. Which of the following enzymes is inhibited by selegiline?

a. Dopa decarboxylase

b. Catechol O methyltransferase

c. Monoamine oxidase A
d. Monoamine oxidase B

4. Which of the following enzymes is inhibited by Entocapone?

a. Dopa decarboxylase

b. Catechol O methyltransferase

c. Monoamine oxidase A

d. Monoamine oxidase B

5. What is the half-life of Pramipexole?

a. 6 hours

b. 8 hours

c. 10 hours

d. 12 hours

6. Which dopaminergic drug can be combined with L-dopa in later stages of

Parkinsonism?

a. Bromocriptine

b. Ropinirole

c. Apomorphine

d. Amantadine

7. Which of the following drugs reduces the peripheral adverse effects of L-dopa,
including nausea, vomiting and postural hypotension?

a. Selegiline

b. Amantadine

c. Carbidopa

d. Entocapone

8. Which of the following drugs can cause fulminant hepatic necrosis?

a. Selegiline

b. Rasagiline
c. Entocapone

d. Tolcapone

9. Which of the following neurotransmitters is reduced in Alzheimer disease?

a. Glutamate

b. Acetylcholine

c. Noradrenaline

d. Dopamine

10. Which of the following drugs used for Alzheimer’s works by blocking NMDA
receptors?

a. Galantamine

b. Rivastigmine

c. Donepezil

d. Memantine
 CHAPTER 7: ANTI-EPILEPTIC DRUGS
Epilepsy, or seizure disorders, are a group of conditions that occur due to sudden, excessive,
and synchronous discharge of cerebral neurons. The excessive electrical activity may manifest in
several different ways, and based on this, there are two main types of seizures – focal seizures,
which are restricted to a specific portion of the brain, and generalized seizures, which may affect
both the hemispheres of the brain. A broader classification is given below:

· FOCAL SEIZURES:

o Simple partial: Abnormal activity of a single group of muscles, or limb.

o Complex partial: Associated with altered consciousness or hallucinations. Abnormal

motor movements include diarrhea, urination, and chewing.

· GENERALIZED SEIZURES:

o Tonic-clonic seizures: Most common. Loss of consciousness followed by tonicity

(continuous contraction) and clonicity (rapid contraction and relaxation) occuring in
alternating phases.

o Absence seizures: Characterized by self-limiting loss of consciousness.

o Clonic and myoclonic seizures: Consist of episodes of muscle contractions.

o Tonic seizures: Consist of increased muscle tone.

o Atonic seizures: Reverse of tonic seizures; there is a sudden loss of muscle tone.

o Status epilepticus: A life-threatening condition characterized by a series of seizures

without recovery of consciousness in between.

DRUGS USED FOR THE MANAGEMENT OF EPILEPSY:

The following classes of drugs are used in the treatment of epilepsy:

· Hydantoin drugs: Phenytoin, Fosphenytoin

· Iminostilbenes: Carbamazepine, Oxcarbazepine

· Succinimide: Ethosuximide

· Aliphatic carboxylic acid: Sodium valproate

· Phenyltriazines: Lamotrigine
 · Cyclic GABA analogues: Gabapentin, Pregabalin

· Benzodiazepines: Diazepam, Clonazepam, Lorazepam

· Barbiturates and deoxybarbiturates: Phenobarbitone, Primidone

· Miscellaneous drugs: Topiramate, Vigabatrin

A few of the most commonly used anti-epileptic drugs are described in detail below.

Hydantoin drugs

Mechanism of action: Binding, and blockade of voltage-gated sodium channels.

Pharmacokinetics: Oral absorption is slow and bioavailability is poor because of high

degree of plasma protein binding. It is metabolized in the liver by hydroxylation and glucuronide
conjugation. Metabolites are excreted through urine. The liver enzymes have limited capacity to
metabolize phenytoin. As a result, the half-life increases with an increase in dose. While the
initial t1/2 may be 12-24 hours, it can increase to as much as 60 hours.

Adverse effects:

· Gingival hypertrophy: This occurs due to increase in collagen bundles of the gingiva.

· Hirsutism, acne, and coarsening of facial features.

· Osteomalacia: Phenytoin interferes with vitamin D activation.

· Megaloblastic anemia

· Fetal hydantoin syndrome: If used by pregnant women, phenytoin can cause cleft lip
and palate, microcephaly, and other hypoplastic changes.

Indications:

Focal seizures, generalized tonic-clonic seizures, status epilepticus.

Contraindications:

Pregnant women.

Carbamazepine:

Mechanism of action: It prolongs the inactive state of voltage-gated sodium channels.

Pharmacokinetics: Oral absorption is poor, and it binds to plasma proteins. Metabolism

occurs through oxidation, hydroxylation, and conjugation reactions. Unlike phenytoin, its t1/2
decreases over time due to auto-induction of metabolism. While the initial t1/2 is 20-40 hours, it
can decrease to 10-20 hours over long-term use.
 Adverse effects:

· Urinary retention and hyponatremia: Enhances the action of antidiuretic hormone.

· Dizziness, sedation, vertigo, ataxia.

· May cause hypersensitivity reactions including rashes, photosensitivity, and

hepatitis.

Indications:

· Focal seizures, generalized tonic-clonic seizures.

· First choice drug for trigeminal neuralgia.

· Bipolar disorder.

Contraindications:

Absence seizures – may enhance these seizures.

Ethosuximide:

Mechanism of action: Inhibition of T-type calcium channels.

Pharmacokinetics: It is completely absorbed orally, does not bind to plasma proteins, and
distributes well. Metabolism occurs in the liver through hydroxylation and glucuronide
conjugation, and the drug is excreted through the urine. The plasma half-life ranges from 32 to
48 hours.

Adverse effects:

· Mood changes and agitation.

· Lack of concentration, headache, and drowsiness.

Indications:

Absence seizures

Sodium Valproate:

Mechanism of action: This works by multiple mechanisms, which include inhibition of

GABA transaminase (an enzyme that degrades the inhibitory neurotransmitter GABA), blockade
of sodium channels, as well as T-type calcium channels.

Pharmacokinetics: Good oral absorption, but binds to plasma proteins. Valproate is

metabolized in the liver by oxidation and glucuronide conjugation, and is then excreted in the
urine. It has a plasma half-life of 10-15 hours.
 Adverse effects:

· Anorexia, vomiting, diarrhea

· Alopecia, weight gain

· Thrombocytopenia and bleeding tendencies.

Indications:

Both focal and generalized seizures, including absence seizures.

Contraindications:

Pregnancy – has been associated with neural tube defects.

Lamotrigine:

Mechanism of action: Blocks voltage-gated sodium channels and prolongs sodium channel
inactivation. It also blocks high voltage calcium channels.

Pharmacokinetics: Well absorbed by oral route, metabolized in liver through glucuronide

conjugation. Its plasma half-life is 24 hours. Concomitant valproate dosing may prolong its half-
life as metabolism is inhibited.

Adverse effects:

· Dizziness, sleepiness, ataxia

· Vomiting

Indications:

Focal seizures, all generalized seizures

Gabapentin:

Mechanism of action: Exact mechanism of action is unknown. However, it may interfere

with voltage-dependent calcium channels.

Pharmacokinetics: Absorbed well through oral route, it does not undergo metabolism. It is
excreted unchanged in urine. Plasma half-life is 6 hours.

Adverse effects: Dizziness, tiredness, sedation, and nystagmus.

Indications:

· Add-on drug for focal and generalized seizures

 · Neuropathic pain

. Postherpetic pain

Topiramate:

Mechanism of action: It blocks voltage-gated sodium channels, and L-type calcium

currents. It inhibits NMDA glutamate, and is a carbonic anhydrase inhibitor.

Pharmacokinetics: Similar to gabapentin, it is absorbed orally, does not metabolize, and is

excreted unchanged in the urine. Its half-life is 24 hours.

Adverse effects:

· Impaired concentration, ataxia, poor memory, sedation

· Glaucoma, decreased sweating, hyperthermia

· Weight loss, renal stones

Indications:

· Focal seizures, generalized tonic-clonic and myoclonic seizures

· Prevention of migraine
EXERCISES:
1. What is the first-line drug to be used in trigeminal neuralgia?

a. Carbamazepine

b. Topiramate

c. Gabapentin

d. Valproate

2. Which of the following drugs is not preferred for absence seizures?

a. Carbamazepine

b. Lamotrigine

c. Ethosuximide

d. Valproate

3. What is the half-life of gabapentin?

a. 6 hours

b. 10 hours

c. 12 hours

d. 16 hours

4. Which of the following channels are blocked when ethosuximide is used?

a. Sodium channels

b. T-type calcium channels

c. L-type calcium channels

d. Potassium channels

5. Which of the following drugs, if used during pregnancy, can cause the fetus to
develop cleft lip?

a. Topiramate

b. Carbamazepine

c. Valproate

d. Phenytoin

6. Which of the following anticonvulsants can increase the half-life of lamotrigine?

a. Topiramate

b. Gabapentin

c. Valproate

d. Carbamazepine

7. Which of the following drugs does not undergo any metabolism?

a. Gabapentin

b. Carbamazepine

c. Lamotrigine

d. Phenytoin

8. Which drug is used for prevention of migraine?

a. Topiramate

b. Carbamazepine

c. Lamotrigine

d. Phenytoin

9. Which of the following drugs can enhance the action of antidiuretic hormone?

a. Carbamazepine

b. Lamotrigine

c. Phenytoin

d. Valproate

10. Which of the following drugs is preferred for non-specific neuropathic pain?

a. Topiramate

b. Gabapentin

c. Lamotrigine

d. Valproate
UNIT III: THE AUTONOMIC NERVOUS
SYSTEM
 CHAPTER 1: CHOLINERGIC AND
ANTICHOLINERGIC DRUGS
INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM

The nerves in our body form two main organized systems – the central nervous system,
which consists of the brain and spinal cord, and the peripheral nervous system, which comprises
all the nerves of the body.

The peripheral nervous system, again, is organized into two systems. The somatic nervous
system deals with voluntary movements, while the autonomic system deals with vital functions
and involuntary movements.

The autonomic nervous system, again, consists of two main components – the sympathetic
nervous system and the parasympathetic nervous system.

Table 1. Highlights of sympathetic and parasympathetic nervous system

PROPERTY SYMPATHETIC PARASYMPATHETIC

Cranial nerves 2,7,9,10
Anatomical Thoracic and lumbar Sacral region of spinal
location region of spinal cord cord

Presynaptic Short Long

Length of axons Postsynaptic Long Short
Presynaptic Acetylcholine Acetylcholine
Neurotransmitter Postsynaptic Noradrenaline Acetylcholine
Overall Fight or flight Rest and digest
response response response
Eyes Pupillary dilation Pupillary constriction
Inhibition of salivary Stimulation of salivary
Secretions
secretion secretion
Respiratory Relaxation of airway
Bronchoconstriction
system muscles - bronchodilation
Cardiovascular
Tachycardia Bradycardia
system
Effect on body Inhibits digestion and
Stimulates digestive
systems gallbladder function
Digestive activity and intestinal
Stimulated release of
system movement
glucose from liver
 Relaxation of Stimulated glucose
intestinal movements uptake by liver

Stimulates adrenal
Endocrine medulla to secrete
No effect
system epinephrine and
norepinephrine
Urinary
Relaxation of bladder Bladder contraction
system
 Figure 6 The autonomic nervous system, responsible for vital functions and involuntary movements in the body, comprises
the sympathetic and parasympathetic nervous systems.

RECEPTORS IN THE AUTONOMIC NERVOUS SYSTEM:

Nerve cells, or neurons interact with each other at a junction called synapse. The first neuron
releases its neurotransmitter into the synaptic region. The neurotransmitter then attaches itself to
the second neuron at a specific point on the cell membrane, referred to as the receptor. There are
different kinds of receptors in the autonomic nervous system.

Receptors between the presynaptic and postsynaptic neurons in the brain/spinal cord:

Nicotinic receptors: These are common to both the sympathetic and parasympathetic
nervous system. These are also called ionotropic receptors. When acetylcholine binds to these
receptors, the ion channels open, facilitating influx of sodium and other ions. Nicotinic receptors
are of two important subtypes – NM and NN. NM receptors are found at the neuromuscular
junction, while NN receptors are found in the adrenal medulla and at autonomic ganglia.

Receptors between the postsynaptic neurons and the effector organs:

These are also called metabotropic receptors. When the neurotransmitter binds to these
receptors, they activate second messengers, which then cause a cascade of events. This involves
the presence of G-protein. These receptors are of two types:

Adrenergic receptors: These are located in the sympathetic nervous system, and are
activated by adrenaline and noradrenaline. Adrenergic receptors are classified as α receptors and
β receptors, and each of these have specific subtypes. Each subtype of adrenergic receptor is
involved with specific sympathetic functions. These are detailed further in Chapter 2 of this unit.

Muscarinic receptors: These are located in the parasympathetic nervous system, and are
activated by acetylcholine. This has five subtypes, named M1 to M5. Only M1 to M3 have been
functionally characterized. M1 is located in the gastric glands, M2 in the heart, and M3 in the
eyes, exocrine glands, lungs, and digestive tract.

CHOLINERGIC DRUGS

These are drugs that act at the cholinergic receptors. Based on the mechanism of action, they
are classified into four subtypes, which are summarized in Table 2.

Table 2. Classification of cholinergic drugs

INDIRECTLY INDIRECTLY DRUGS CAUSING

DIRECTLY ACTING ACTING REACTIVATION OF
ACTING REVERSIBLE IRREVERSIBLE ACETYLCHOLINE
DRUGS DRUGS ESTERASE
Physostigmine
Acetylcholine Neostigmine
Carbachol Pyridostigmine
 Bethanechol Edrophonium Echothiophate Pralidoxime
Cevimeline Rivastigmine
Nicotine Donepezil
Pilocarpine Galantamine

Kinetics of acetylcholine:

Acetylcholine acts as a neurotransmitter in two kinds of cholinergic neurons – nicotinic and

muscarinic. The following steps outline its synthesis and action:

· Free choline from plasma is taken into the cell. It combines with Coenzyme A to
form acetylcholine. The enzyme that catalyzes this reaction is choline acetyltransferase.

· Within the cell, acetylcholine is stored in vesicles.

· When the action potential arrives at the neuron, there is an influx of calcium ions into
the cell. This causes fusion of the vesicle to the cell membrane, and the contents get
expelled into the synaptic space.

· Acetylcholine from the synaptic space can undergo three courses of action:

· Bind with receptors on the postsynaptic cell membrane, which is responsible for
effector response.

· Bind to receptors on the presynaptic membrane, which serves as negative feedback

and prevents further release of acetylcholine.

· Excess gets degraded by acetylcholinesterase into choline and acetate. The choline is
recycled into the cell.

Pharmacological actions of acetylcholine:

Actions through muscarinic receptors:

· Heart: Effects are exerted through M2 receptors. Bradycardia occurs due to effect on
SA node. Slowing of conduction may cause partial or complete heart block. There is a
decrease in force of atrial contraction and to some extent, ventricular contraction, which
may decrease cardiac output.

· Blood vessels: Effect on M3 receptors causes vasodilation. This can cause facial
flushing and hypotension.

· Smooth muscle contraction: This is also exhibited through M3 receptors. There is an

increase in tone and peristalsis of GIT, and evacuation of bowel. Increase in ureteric
peristalsis and bladder contraction causes voiding of urine. Contraction of bronchial smooth
muscles can cause spasm and dyspnea.
 · Secretory activity: Parasympathetically innervated glands are stimulated (M3
receptors) leading to increased salivation, sweat, and tears.

· Eye: Pupillary constriction occurs. Ciliary muscle contraction can increase outflow
and reduce intraocular tension. This is beneficial in glaucoma.

Actions through nicotinic receptors:

· There is stimulation of both sympathetic and parasympathetic autonomic ganglia.

· Skeletal muscle contraction

Directly acting cholinergic drugs:

These drugs bind to cholinergic receptors and mimic the actions of acetylcholine. Based on
the receptors with which they interact, they produce specific pharmacological effects. The drugs
and their effects are summarized in Table 3.

Table 3. Summary of directly acting cholinergic drugs

RECEPTOR THERAPEUTIC
DRUG CLINICAL EFFECTS
STIMULATED APPLICATIONS
Stimulates intestinal tone Non-obstructive
and peristalsis urinary retention
Bethanechol M3
Increases bladder tone and Neurological atony
ureter peristalsis Megacolon
Releases adrenaline from
adrenal medulla
M2, M3, Nn Topically only – in the
Carbachol Both stimulation and
eye to treat glaucoma
depression of cardiac, GI
systems.
Xerostomia
Miosis, stimulation of sweat,
Pilocarpine M3 Emergency reduction
tears and saliva.
of intraocular pressure
Cevimeline M3 Salivary stimulation Xerostomia

Indirectly acting reversible choline agonists:

These drugs are also known as anticholinesterase agents. They inhibit the enzyme
acetylcholine esterase, and prevent the breakdown of acetylcholine. This increases the levels of
acetylcholine in the synaptic region, and enhances its action. Some important drugs in this class
are discussed below:

Edrophonium:

· This is a short-acting agent.

 · It is absorbed and eliminated in urine rapidly. The duration of action lasts between 10
to 20 minutes.

· It is primarily used for diagnosis of myasthenia gravis. In MG, antibodies destroy the
nicotinic receptors. Edrophonium boosts acetylcholine availability to the remaining
receptors, and increases muscle strength.

Physostigmine:

. This is an intermediate-acting agent, and duration of action lasts from 30 minutes to 2

hours.

. It is used for treatment of atonic conditions of the bladder and intestine.

. It is also used to reverse atropine toxicity.

. It may adversely cause bradycardia and decreased cardiac output.

Neostigmine:

. Like physostigmine, this has an intermediate duration of action.

. It has a greater effect on the skeletal muscles. It is therefore used for management of
myasthenia gravis, and to stimulate the bladder and GIT.

. It is also used to reverse neuromuscular blockade that is given as a part of general

anesthesia.

. It does not enter the brain and cannot be used to counteract central effects of atropine
toxicity.

Rivastigmine, Donepezil, Galantamine:

· These are specifically used for the management of Alzheimer disease.

· These drugs boost the availability of acetylcholine to cholinergic neurons, which are
deficient in this condition. However, they cannot halt disease progression.

Indirectly acting irreversible choline agonists:

These drugs bind covalently and irreversibly to acetylcholinesterase. This results in

consistently high levels of acetylcholine. These drugs are highly toxic, and many were developed
as ‘nerve gases’ for use in wartime. Pesticides, including malathion and parathion, belong to this
category (this is clinically relevant in cases of poisoning). The only clinically useful drug in this
category is echothiophate.

Echothiophate:

· It produces intense miosis, and increases outflow of aqueous humor.

 · It is used topically for treatment of open-angle glaucoma. It has a long duration of
action, lasting up to 100 hours.

· Side effects of the topical solution include development of cataract. It is not

commonly used now.

Antidote: Pralidoxime:

· Toxicity of these drugs can be reversed using pralidoxime. This drug reactivates
acetylcholinesterase, by breaking the bond between the drug and the enzyme.

· If the drug ‘ages’ (loses an alkyl group), pralidoxime is no longer effective. Different
drugs age at different rates.

· It cannot penetrate the central nervous system, and therefore does not reverse CNS
symptoms.

· Pralidoxime is not effective for reversible ACE inhibitors.

ANTICHOLINERGIC DRUGS

These drugs antagonize the actions of acetylcholine at its receptors. Based on the kind of
receptors at which these drugs act, they can be divided into three categories:

· Antimuscarinic agents: They are also called parasympatholytics. They only

antagonize muscarinic receptors, thus allowing unopposed sympathetic action (through
adrenergic receptors).

· Antinicotinic agents: They are also called ganglionic blockers, and block the actions
of both sympathetic and parasympathetic ganglia.

· Neuromuscular blockers: They are also called skeletal muscle relaxants. They
block the action of acetylcholine at the neuromuscular junction of skeletal muscles, which
also has nicotinic receptors.

Antimuscarinic agents:

These drugs usually allow unopposed sympathetic activity. The only exception is the neurons
innervating the salivary and sweat glands (which are cholinergic). Some important drugs in this
category are detailed below:

ATROPINE:

This drug has a high affinity for muscarinic receptors.

Clinical effects:

· Eye: Mydriasis, cycloplegia, increased intraocular pressure

 · GIT: Has an antispasmodic effect, decreases GI motility.

· Cardiovascular: Tachycardia is seen at high doses.

· Others: Decrease in sweat can cause increased body temperature. There is decreased
salivary secretion, causing xerostomia.

Pharmacokinetics: It is readily absorbed and undergoes partial metabolism in the liver.

Excretion is through urine and the drug half-life is about four hours.

Indications:

· Topically to induce mydriasis, for diagnosis of refractive errors

· Antispasmodic and antisecretory agent

· For treatment of bradycardia

· Antidote for organophosphate poisoning

Adverse effects:

· Dry mouth, blurred vision

· Urinary retention, constipation

· Restlessness, confusion, hallucinations, delirium

SCOPOLAMINE:

· This has greater effects on the CNS as compared to atropine, and a longer duration of
action. It blocks short-term memory. In small doses, it can cause sedation, but higher doses
cause excitement and euphoria.

· Clinical uses: For prevention of motion sickness, and prevention of postoperative

nausea and vomiting.

Other antimuscarinic agents:

Other antimuscarinic agents have been developed for specific therapeutic uses. These are
summarized in Table 4.

Table 4. Uses of common antimuscarinic agents

DRUG THERAPEUTIC BENEFIT

Ipratropium
Inhalational agents used to treat asthma and COPD
Tiotropium
Oxybutynin
(transdermal patch) Treatment of overactive urinary bladder
Fesoterodine
Darifenacin
To induce mydriasis and cycloplegia prior to checking for refractive
Tropicamide
errors in the eye. Tropicamide produces mydriasis for 6 hours,
Cyclopentolate
cyclopentolate for 24 hours.
Benztropine
Parkinson’s disease, to manage extrapyramidal symptoms.
Trihexyphenidyl

Antinicotinic drugs (Ganglionic blockers)

These drugs basically block the entire output of the autonomic nervous system, as they act at
the ganglionic level. These drugs are not used therapeutically.

NICOTINE:

· This drug is of clinical interest because it is a component of cigarette smoke, and is

therefore widely used. This drug first causes stimulation, and then depression of all
autonomic ganglia.

· It induces enhanced release of several neurotransmitters.

· Increased release of dopamine and noradrenaline can cause pleasure and appetite
suppression.

· There is tachycardia and increase in blood pressure.

· Increase in secretions and peristalsis.

· At high doses, there is fall in secretions, peristalsis, and drop in blood pressure.

Neuromuscular blockers:

These drugs block the transmission of acetylcholine at the motor endplate of the
neuromuscular junction. These drugs are categorized as nondepolarizing blockers and
depolarizing blockers.

NONDEPOLARIZING BLOCKERS:

These are also called competitive blockers. These drugs compete with acetylcholine for the
nicotinic receptors. However, they do not stimulate the receptors upon binding. At low doses,
this binding prevents depolarization of the cell membrane and inhibits muscle contraction. At
high doses these drugs inhibit the ion channels as well, which further weakens neuromuscular
transmission.

Clinical effects: These drugs cause muscle paralysis. Paralysis begins with small muscles of
the face and eye, and progresses to muscles of the fingers and limbs, and then, the neck and
trunk. The intercostal muscles and diaphragm are the last to be affected.

Pharmacokinetics:

This is summarized in Table 5.

Table 5. Kinetics of nondepolarizing blockers

ONSET/DURATION
DRUG ABSORPTION METABOLISM EXCRETION
OF ACTION
Atracurium 2 min / 40 min Degraded
spontaneously in
--
Cisatracurium 3 min / 90 min plasma by ester
Intravenous or hydrolysis
Pancuronium intramuscular 3 min / 86 min No metabolism Urine
Rocuronium 1 min / 43 min Bile
Liver
Vecuronium 2 min / 44 min

Adverse effects:

· Pancuronium – vagolytic, may cause tachycardia

· Atracurium – releases histamine and can provoke seizures

Depolarizing blockers:

These agents act similar to acetylcholine, and work by depolarizing the muscle membrane.
However, they are resistant to degradation by acetylcholinesterase, and therefore remain attached
to the receptor for a long time, thus producing constant stimulation. This eventually results in a
longer refractory period, during which the muscle remains paralyzed. The only clinically useful
drug in this category is succinylcholine.

SUCCINYLCHOLINE:

Clinical effects: Causes brief muscle fasciculations, followed by flaccid paralysis. Paralysis
occurs in one minute and lasts for 8 minutes.

Pharmacokinetics: After intravenous injection, it undergoes rapid redistribution. It is

degraded in plasma by the enzyme pseudocholinesterase.

Adverse effects:

· Postoperative muscle pain

· Increased intraocular and intragastric pressure

 · Potential for malignant hyperthermia

· Patients with an atypical form of pseudocholinesterase may develop prolonged

apnoea.
EXERCISES:
1. Which of the following is not an effect of the sympathetic nervous system?

a. Miosis

b. Mydriasis

c. Increased bladder tone

d. Bronchodilation

2. What kind of neurotransmitter is seen at the neuro-effector junction of the

sympathetic nervous system?

a. Noradrenaline

b. Dopamine

c. Acetylcholine

d. Serotonin

3. What neurotransmitter is seen at the nicotinic receptors?

a. Noradrenaline

b. Dopamine

c. Acetylcholine

d. Serotonin

4. Which muscarinic receptor is involved with regulation of cardiac activity?

a. M1

b. M2

c. M3

d. M4

5. Which of the following drugs is used to reverse neuromuscular block following

general anesthesia?
a. Physostigmine

b. Neostigmine

c. Rivastigmine

d. Pyridostigmine

6. How does Rivastigmine provide symptom relief in Alzheimer’s disease?

a. Decreases neurological tangles

b. Dissolves amyloid plaques

c. Increases acetylcholine levels available for the existing receptors

d. Prevents degradation of cholinergic neurons

7. Which drug is used as a diagnostic agent for myasthenia gravis?

a. Edrophonium

b. Echothiophate

c. Physostigmine

d. Neostigmine

8. Which of the following drugs used for glaucoma has the longest duration of action?

a. Edrophonium

b. Echothiophate

c. Pilocarpine

d. Neostigmine

9. Which drug is preferred to induce mydriasis and cycloplegia, as it has the least
duration of action?

a. Atropine

b. Pilocarpine

c. Tropicamide

d. Cyclopentolate

10. Which of the following neuromuscular blocker does not get degraded in plasma?
a. Vecuronium

b. Succinylcholine

c. Atracurium

d. Cisatracurium
 CHAPTER 2 – ADRENERGIC AGONISTS AND
ANTAGONISTS
The adrenergic receptors are located at the neuro-effector junction of the sympathetic
nervous system. They are also located on the surface of the adrenal medulla.

ADRENERGIC AGONISTS

These are also known as adrenergic drugs, or sympathomimetic drugs. These drugs activate
the adrenergic receptors either directly, or indirectly by increasing levels of norepinephrine
available for binding to the receptors. They are classified as:

· Directly acting agonists: Like norepinephrine, they directly act at the receptor to
produce similar actions. Examples include epinephrine, albuterol, salmeterol, isoproterenol,
terbutaline, and phenylephrine.

· Indirectly acting agonists: They stimulate the release of norepinephrine, which

enhances the clinical effect. Examples include cocaine and amphetamines.

· Mixed action agonists: They act both by interacting with the receptor, as well as by
boosting the production of norepinephrine. Examples include ephedrine and
pseudoephedrine.

Functions mediated by adrenergic receptors:

As stated in the previous chapter, each adrenergic receptor mediates specific sympathetic
functions. These are summarized in Table 1.

Table 1. Functions of adrenergic receptors

α β
RECEPTOR
α1 α2 β1 β2
Increases
METABOLIC Decreases Activation of adenylyl cyclase,
intracellular calcium
EFFECT cAMP production increased cAMP production
ions
Tachycardia Vasodilation
Vasoconstriction Decreased
Increased
Increased peripheral peripheral vascular
force of
vascular resistance Inhibits the resistance
myocardial
Increased blood release of: Bronchodilation
CLINICAL pressure contraction
Norepinephrine Lipolysis Glycogenolysis
EFFECT Mydriasis Acetylcholine Increases Increased
Increased tone Insulin renin production secretion of
of internal sphincter glucagon
– causes
 of bladder vasoconstriction. Uterine smooth
muscle relaxation

Directly acting adrenergic agonists:

Kinetics of endogenous norepinephrine:

· Norepinephrine is synthesized from dopamine. Dopamine is synthesized from the

amino acid tyrosine. Tyrosine is transported from plasma into the adrenergic neuron, where
the enzyme tyrosine hydroxylase converts it into DOPA (dihydroxyphenylalanine). The
enzyme DOPA decarboxylase then converts this into dopamine.

· Dopamine is stored in synaptic vesicles, and norepinephrine is synthesized within the

vesicles. The enzyme dopamine β-hydroxylase converts dopamine into norepinephrine.

· The mechanism of release is similar to acetylcholine. An action potential triggers

calcium influx into the cell, which in turn causes the synaptic vesicle to fuse with the cell
membrane and release its contents into the synaptic cleft.

· Norepinephrine interacts with postsynaptic receptors, and initiates a cascade of

events through second messengers. Interaction with the presynaptic receptors regulates
further release of norepinephrine.

· Final fate of norepinephrine:

o It may be absorbed into systemic circulation.

o It may be taken back into the neuron. Here it can either be stored in the synaptic vesicle
again, or undergo degradation through the enzyme monoamine oxidase.

o It may be degraded in the synaptic space itself by the enzyme catechol o-

methyltransferase.

EPINEPHRINE:

This is a naturally occurring hormone that is formed by methylation of norepinephrine in the

adrenal medulla. Epinephrine acts at both α and β receptors. At low doses, β effects predominate,
while at higher doses, α effects predominate.

Clinical effects:

· CVS: Increases myocardial contractility. It stimulates renin production. There is

vasoconstriction of the skin, mucous membranes, and visceral blood vessels, as well as of
the kidney, but vasodilation of vessels leading to liver and skeletal muscles. Overall, there is
an increase in systolic blood pressure but mild drop in the diastolic pressure.

· Respiratory: Causes powerful bronchodilation.

 · Prevents release of histamine from mast cells.

· Hyperglycemia occurs due to glycogenolysis, increased secretion of glucagon, and

decreased secretion of insulin.

· Increase in plasma levels of free fatty acids and glycerol due to lipolysis.

Pharmacokinetics:

This is usually given parenterally, intramuscularly, or, in acute emergencies, intravenously. It

may also be given through the subcutaneous route or by inhalation. Onset of action is rapid,
followed by a brief duration of action. It is rapidly metabolized by MAO and COMT, and
metabolites are excreted in urine.

Adverse effects:

· CNS effects: Headache, tension, fear, anxiety, tremors

· Cardiac arrhythmias

· Pulmonary edema

Indications:

Because of its powerful effects, epinephrine is the drug of choice for several medical
emergencies, which include:

· Life-threatening bronchospasm that occurs in asthma and anaphylaxis

· Cardiac arrest: To restore normal rhythm

· Local anesthetic supplementation: It is combined with local anesthetic drugs used for
injection. This gives the following benefits:

o Increases duration of action of local anesthetics by preventing plasma clearance of the

drug.

o Decreases systemic toxicity of local anesthetics.

o Provides bloodless field for surgery.

NOREPINEPHRINE:

When administered as an external agent, norepinephrine influences only α receptors.

Clinical effects:

· CVS: Intense vasoconstriction and increase in peripheral vascular resistance cause

rise in both systolic and diastolic blood pressure. The high blood pressure can stimulate
 baroreceptors, which may then stimulate the vagus nerve to lower the blood pressure.

Pharmacokinetics:

It is usually given intravenously. Like adrenaline, it is rapidly metabolized by MAO and

COMT and the metabolites are excreted in urine.

Adverse effects:

Apart from the side effects produced by adrenaline, it may also cause sloughing or necrosis
of the tissue into which it is injected.

Indications:

Treatment of shock – helps increase peripheral vascular resistance.

DOPAMINE:

Like epinephrine, dopamine stimulates β receptors at low doses and α receptors at high
doses. In addition, it also stimulates peripheral dopaminergic receptors.

Clinical effects:

· CVS: It has positive inotropic and chronotropic effects.

· By acting through dopaminergic receptors, it increases renal, splanchnic, and visceral

blood flow.

Indications:

Cardiogenic and septic shock: It increases systemic circulation without compromising

visceral and renal blood flow.

Adverse effects:

· Nausea

· Hypertension and arrhythmias

DOBUTAMINE:

· This is a synthetic drug that acts exclusively on β1 receptors.

· It increases myocardial rate and contractility. It has no effect on vasculature.

· It is useful in acute heart failure, and to improve cardiac output after surgery.

· It can increase conduction rate, and must therefore not be used in atrial fibrillation.
OXYMETAZOLINE:

· This stimulates α1 and α2 receptors.

· This drug is largely used topically. It provides vasoconstriction of tissues, and can
relieve congestion. However, long-term use can cause rebound congestion and dependence.

· In the form of nasal sprays, it is used as a decongestant. In the form of ophthalmic

drops, it is used to decrease redness in the eyes.

· The drug may be absorbed into systemic circulation, and it can cause nervousness,
headaches, and insomnia.

PHENYLEPHRINE:

· This drug selectively stimulates α1 receptors and raises both systolic and diastolic
blood pressures. It may induce reflex bradycardia.

· It is used for treatment of hypotension, especially when it presents with tachycardia.

· Taken orally or topically in the form of a spray, it is used as a nasal decongestant.

ISOPROTERENOL:

· This drug non selectively stimulates β1 and β2 receptors. It does not have much
effect on α receptors.

· Its actions on the heart and vasculature are similar to epinephrine. It raises systolic
blood pressure and causes a slight drop in diastolic blood pressure. It is also a potent
bronchodilator.

· Its therapeutic use is restricted to treatment of atrioventricular block.

CLONIDINE:

· Clonidine is a specific α2 agonist. It therefore is mainly involved in inhibition of

neurotransmitters such as norepinephrine, acetylcholine, and the hormone insulin.

· This drug is used in the management of hypertension. However, abrupt cessation of

the drug can cause rebound hypertension.

· This drug has also been used to manage withdrawal from habit-forming substances,
including tobacco, opiates, and benzodiazepines.

· Adverse effects include lethargy, constipation, sedation, and xerostomia.

ALBUTEROL and TERBUTALINE:

· These are β2 agonists, and their main effect is bronchodilation.

 · They have a short duration of action and are primarily used via the inhalational route
for managing acute asthma attacks.

· Terbutaline has also been used as a uterine relaxant. However, systemic

administration may stimulate β1 receptors, and may cause arrhythmias and tachycardia.

· Side effects include tremors, restlessness, apprehension, and anxiety.

SALMETEROL and FORMOTEROL:

· These are also β2 agonists, but they have a longer duration of action.

· They are used as maintenance therapy in asthma, in combination with

corticosteroids.

Indirectly acting adrenergic agonists:

These drugs potentiate the action of epinephrine and norepinephrine at their receptors. The
main drugs in this category are the amphetamines.

Mechanism of action: These drugs stimulate the release of norepinephrine from the nerve
membrane into the synapse. They also inhibit MAO, which in turn prevents degradation of
norepinephrine.

Clinical effects:

· CNS: Stimulation of all areas of the brain leads to decreased sleepiness and fatigue,
alertness, and decreased appetite.

· Sympathetic actions: These are similar to epinephrine and norepinephrine and

include raised blood pressure and cardiac output.

Pharmacokinetics: The drug is fully absorbed through the oral route. It easily enters the
CNS. Metabolism occurs in the liver and metabolites are excreted in urine.

Adverse effects:

· Dizziness, tremors, confusion, and panic

· Anorexia, nausea, vomiting, abdominal cramps, and diarrhea

· Hypertension, cardiac arrhythmias, circulatory collapse

Indications:

· Attention deficit hyperactivity disorder

· Narcolepsy
 Mixed action adrenergic agonists:

EPHEDRINE and PSEUDOEPHEDRINE:

These drugs stimulate both α and β receptors. Moreover, they stimulate the release of
norepinephrine from the nerve endings into the synapse.

Clinical effects:

· Increase in systolic and diastolic blood pressure.

· Bronchodilation

· CNS stimulation: Increases alertness, decreases sleep and fatigue.

Pharmacokinetics: These drugs are absorbed well orally. They can penetrate the blood-brain
barrier and enter the brain. While ephedrine is not metabolized, pseudoephedrine undergoes
partial metabolism in the liver. The drugs are eliminated in the urine.

Indications:

· Hypotension

· Pseudoephedrine is used as a decongestant.

ADRENERGIC ANTAGONISTS

These drugs bind either reversibly or irreversibly to the adrenergic receptors. They may be
categorized as α blockers and β blockers.

α blockers:

These drugs cause a decrease in peripheral vascular resistance and hypotension. This in turn
results in reflex tachycardia. Some common α blockers are described below:

PHENOXYBENZAMINE:

· This drug irreversibly blocks both α1 and α2 receptors. The actions of this drug can
be reversed only after the body synthesizes new adrenoreceptors. This takes about 24 hours.

· It is primarily used for the medical management of pheochromocytoma (a tumor

which secretes catecholamines). It is used both in inoperable cases, and prior to tumor
removal to avoid hypertensive crises.

· It is also used to improve blood circulation in Raynaud’s disease and frostbite.

· Adverse effects include nausea, vomiting, nasal stuffiness, and postural hypotension.

PHENTOLAMINE:
 When injected, this drug reversibly blocks both α1 and α2 receptors. The effect lasts for
about four hours.

· It is contraindicated in patients with coronary artery disease, as it can induce

arrhythmias and angina.

· Used in the treatment of hypertensive crisis, especially that induced by clonidine

withdrawal and tyramine poisoning.

· It may also be used for the management of pheochromocytoma.

Selective α1 blockers:

· A group of drugs, including prazosin, terazosin, tamsulosin, and alfuzosin,

selectively blocks only the α1 receptor.

· They decrease blood pressure and lower peripheral vascular resistance largely by
acting on the smooth muscles of blood vessel walls. They do not affect cardiac output and
renal blood flow.

· They also relax muscles of the prostate and bladder, and improve flow of urine.

· They are used as add-on drugs for the management of hypertension.

· They can cause nasal congestion, headache, drowsiness, and orthostatic hypotension.

Yohimbine:

· This is a selective α2 blocker.

· It is believed to be effective in the treatment of erectile dysfunction.

· It has the potential to worsen cardiovascular disease, renal dysfunction, and

psychiatric disorders.

β blockers:

β blockers may be either non-selective blockers (which block both β1 and β2), or they may
be cardioselective blockers (block only β1).

NON-SELECTIVE β BLOCKERS:

Some drugs in this category include propranolol, nadolol, timolol, and carteolol.

Clinical effects:

· CVS: They have negative inotropic and chronotropic effects. The cardiac workload
and oxygen consumption decreases, and there is bradycardia and lowering of blood
pressure.
 · Respiratory: They can cause bronchoconstriction and can exacerbate dyspnea in
patients with lung disease.

· Endocrine: These drugs decrease glycogenolysis and secretion of glucagon, thereby

lowering blood glucose levels. Caution must be used when prescribing these drugs to
diabetic patients on insulin.

Pharmacokinetics: These drugs are usually taken orally. Propranolol usually undergoes
extensive first-pass metabolism, with only 25% of the drug available to exert clinical effects.
Metabolism occurs in the liver and metabolites are excreted in urine.

Adverse effects:

· Can cause significant bronchoconstriction.

· Abrupt cessation can lead to cardiac arrhythmias.

· May induce hypoglycemia.

· CNS effects: Depression, lethargy, dizziness, and visual disturbances.

Indications:

· Prevention of angina and myocardial infarction.

· Primary management of patients with hypertension.

· Supraventricular cardiac arrhythmias.

· Migraine: Propranolol can penetrate the CNS and is most useful for this purpose.

· Hyperthyroidism: They reduce sympathetic stimulation, and are protective against

arrhythmias.

· Glaucoma: Nadolol and timolol are more potent, and therefore, are quite effective
topically in diminishing intraocular pressure. These drugs also reduce the secretion of
aqueous humor in the eye.

SELECTIVE β1 ANTAGONIST:

These drugs are also called cardioselective drugs, because they affect primarily the heart.
Some drugs in this category include atenolol, acebutolol, esmolol, bisoprolol, and metoprolol.

Clinical effects:

· They have negative inotropic and chronotropic effects, and they lower blood
pressure.

· They do not have any effect on pulmonary function, glucose metabolism, or

 peripheral vascular resistance.

Indications:

· Hypertensive patients who have impaired pulmonary function.

· Primary treatment for stable angina.

· Chronic heart failure

Combined α and β antagonists:

· Labetalol and carvedilol are drugs that block both α and β adrenergic receptors.

· They have the clinical effect of lowering blood pressure, while at the same time
producing peripheral vasodilation.

· Labetalol is useful in pregnancy hypertension.

· Carvedilol is more useful in chronic heart failure, as it prevents vessel wall

thickening in addition to reducing sympathetic stimulation of the heart.

· Adverse effects include dizziness and orthostatic hypotension

EXERCISES:
1.Which of the following drugs cannot be used in an acute asthma attack?

a.Albuterol

b.Formoterol

c.Adrenaline

d.Terbutaline

2.Which of the following drugs effectively restores rhythm after cardiac arrest?

a.Isoproterenol

b.Adrenaline

c.Dopamine

d.Noradrenaline

3.Which of the following drugs increases cardiac output without compromising renal
blood flow?

a.Isoproterenol
 b.Adrenaline

c.Dopamine

d.Noradrenaline

4.Which of the following drugs is effective as a nasal spray decongestant?

a.Phenylephrine

b.Oxymetazoline

c.Pseudoephedrine

d.Adrenaline

5.Which of the following drugs acts at the adrenergic receptors, and also stimulates the
release of neurotransmitters?

a.Phenylephrine

b.Isoproterenol

c.Oxymetazoline

d.Ephedrine

6.What is the bioavailability of oral propranolol?

a.10%

b.25%

c.50%

d.75%

7.Which of the following drugs inhibits both α and β adrenergic receptors?

a.Propranolol

b.Atenolol

c.Labetalol

d.Esmolol

8.Which of the following drugs is useful for managing hypertension in pregnancy?

a.Esmolol
 b.Labetalol

c.Atenolol

d.Isoproterenol

9.Which of the following drugs used for management of hypertension is actually an

adrenergic agonist?

a.Propranolol

b.Clonidine

c.Atenolol

d.Labetalol

10.Which of the following drugs are used in the management of attention deficit
hyperactivity disorder?

a.Amphetamine

b.Clonidine

c.Dopamine

d.Atropine
UNIT IV: PERIPHERAL NERVOUS SYSTEM
 CHAPTER 1: LOCAL ANESTHETICS
Local anesthetics are a group of drugs which, when they are applied to a specific part of the
body, cause reversible loss of sensation in that body part. They are classically used to ‘numb’
body parts when minor interventions are required. They may be injected, or applied topically as a
spray or gel. Based on their chemical structure, local anesthetics are categorized into ester-linked
drugs and amide-linked drugs (Table 1).

Table 1. Classification of local anesthetics

ESTER-LINKED LOCAL AMIDE-LINKED LOCAL
ANESTHETICS ANESTHETICS
Lidocaine
Procaine
Prilocaine
Chloroprocaine
Mepivacaine
Tetracaine
Bupivacaine
Benzocaine
Articaine

MECHANISM OF ACTION:

Local anesthetics interfere with depolarization of the nerve. These drugs bind to receptors
located on the inner side of transmembrane sodium channels. This blocks sodium ions from
entering into the neuronal cell, which is essential for depolarization to take place. This in turn
results in failure of the nerve to generate an action potential and conduct a nerve impulse.

PROPERTIES OF LOCAL ANESTHETICS THAT AFFECT THEIR ACTION:

● pKa: The local anesthetic molecule exists in two forms – the base form and ionized
form. While the base form alone can penetrate to the interior of the cell, the ionized
form binds to the receptor on the sodium channel. An equilibrium usually exists
between the two forms. In general, drugs with lower pKa have a faster onset of action.
● Lipid solubility: If the base form is more lipid soluble, it can easily penetrate the nerve
membrane. This increases drug potency.
● Protein binding: The greater the protein binding, the longer the time that the ionized
form remains attached to the receptor site. This increases the duration of action of the
anesthetic drug.
● Non-nervous tissue distribution, and vasodilation: Both these factors divert the local
anesthetic away from the site of action, decreasing the duration of action.
● Based on their potency and duration of action, local anesthetics may be classified as
follows:
○ Low potency and short duration of action: Procaine, Chloroprocaine
○ Intermediate potency and duration: Lignocaine, Prilocaine
○ High potency and long duration: Tetracaine, Bupivacaine, Ropivacaine

CLINICAL EFFECTS:
 Local effects:

● Local anesthetics block nerve impulse transmission in sensory, somatic, and autonomic
nerves.
● They also reduce the release of acetylcholine at the neuromuscular junction, which can
cause temporary muscle paralysis.
● Sensations are blocked in the following order: pain, temperature, touch, deep pressure.

Systemic effects:

● CNS: Local anesthetics initially stimulate the CNS, and then depress it. Stimulation
occurs due to inhibition of inhibitory neurons. Stimulation is most powerful with
cocaine, and can manifest as excitement, euphoria, restlessness, mental confusion,
tremors, twitching, and convulsions. With other drugs like lignocaine, there is
circumoral numbness, abnormal tongue sensation, blurred vision, and tinnitus. CNS
depression manifests as lethargy, dysphoria, drowsiness, and loss of consciousness.
● CVS: Local anesthetics do not have cardiac effects at normal doses. At high doses, they
decrease myocardial conduction and contractility. Some drugs like lignocaine shorten
the refractory period, and have an antiarrhythmic effect. On the other hand,
bupivacaine can cause ventricular tachycardia and fibrillation.
● Blood vessels: Local anesthetics cause vasodilation. At low doses, this is due to the
effect of blocking sympathetic conduction. At higher doses, the drug directly causes
relaxation of the smooth muscles of the vessel wall.

PHARMACOKINETICS:

Local anesthetics are either applied or injected topically at the site of action. Some drugs are
absorbed systemically through the vascularity of that region, and are widely distributed.

Amide-linked local anesthetics bind to α1 glycoproteins in plasma. They are metabolized in

the liver by dealkylation and hydrolysis. Ester-linked local anesthetics are degraded in the
plasma itself by the enzyme pseudocholinesterase.

ADVERSE EFFECTS:

Usually adverse effects are only noted when a large volume of the drug is absorbed
systemically. This may occur with inadvertent injections of the anesthetic into a blood vessel.
These include:

● Dizziness, confusion, visual and auditory disturbances, twitching, tremors and

convulsions. At toxic doses, respiratory arrest can occur.
● Bradycardia, hypotension, arrhythmias
● Ester-linked anesthetics may cause hypersensitivity reactions.

INDICATIONS:

It is used to provide ‘numbness’ during interventional procedures. There are several different
techniques of producing local anesthesia. These are summarized in Table 2.
 Table 2. Techniques of local anesthesia administration
TECHNIQUE METHOD USES
The local anesthetic, in the form of creams,
Surface Mucosal ulcers and
gels, or sprays, is directly applied to the surface. It
anesthesia abrasions, pain relief.
also includes eye/ear drops.
The anesthetic solution is deposited Small incisions,
subcutaneously directly into the area of suturing lacerations,
Infiltration
intervention. This blocks free nerve dental procedures.
endings.
This is a subcutaneous injection, which blocks Larger incisions and
Field block
all the nerves entering a particular field. suturing procedures
The anesthetic solution is injected near the main Dental and
Nerve block
trunk of a nerve or one of its specific branches. ophthalmic procedures
The anesthetic is injected directly into the Surgical procedures
Spinal
subarachnoid space. It causes anesthesia and on the lower abdomen,
anesthesia
paralysis of the lower abdomen and limbs. pelvis and lower limbs.
The anesthetic is injected into the epidural
Epidural space. It acts similar to spinal anesthesia, but Obstetric purposes
anesthesia requires greater volumes of drug, and is more Postoperative pain relief
technically demanding.

CONTRAINDICATIONS:

● Mepivacaine can cause toxicity to the newborn child. It must be avoided for obstetrics
procedures.
● Liver dysfunction: Amide local anesthetics must be avoided.

EXERCISES:

1. Which of the following drugs is not an amide local anesthetic?

1. Lignocaine
2. Articaine
3. Procaine
4. Mepivacaine
2. Which of the following ion channels is blocked by local anesthetics?
1. Sodium
2. Calcium
3. Magnesium
4. Chloride
3. Which of the following is true of the local anesthetic tetracaine?
1. Low potency
2. Intermediate potency
3. High potency
 4. Intermediate duration of action
4. Which of the following properties increases the potency of the local anesthetic drug?
1. Lipid solubility
2. Water solubility
3. Low pKa
4. High pKa
5. Which of the following is dependent on the pKa of the local anesthetic?
1. Onset of action
2. Duration of action
3. Potency
4. Adverse effect profile
6. Which of the following local anesthetics has an antiarrhythmic effect?
1. Articaine
2. Lignocaine
3. Mepivacaine
4. Bupivacaine
7. Where does metabolism of ester linked local anesthetics take place?
1. Liver
2. Skeletal muscle
3. Kidney
4. Plasma
8. Which of the following anesthetic techniques targets free nerve endings?
1. Infiltration
2. Nerve block
3. Spinal block
4. Epidural block
9. Which of the following anesthetic techniques is suitable for obstetric procedures?
1. Infiltration
2. Nerve block
3. Spinal block
4. Epidural block
10. Which of the following local anesthetics is contraindicated in pregnant women?
1. Articaine
2. Lignocaine
3. Mepivacaine
4. Bupivacaine
 CHAPTER 2: SKELETAL MUSCLE RELAXANTS
These are drugs that inhibit activity at the neuromuscular junction. They can reduce muscular
tone, and can cause reversible paralysis. Depending on their site of action, they may be classified
as peripherally acting muscle relaxants, or centrally acting muscle relaxants.

PERIPHERALLY ACTING MUSCLE RELAXANTS

Peripherally acting muscle relaxants are of two types – neuromuscular blocking agents and
directly acting agents.
 Figure 7 Skeletal muscle relaxants act on receptors of the neuromuscular junction, the synapse between a motor neuron and
muscle fiber. Under typical circumstances, the motor neuron transmits a signal to the muscle fiber, causing muscle contraction.
Skeletal muscle relaxants inhibit activity at the neuromuscular junction, ultimately reducing muscular tone and causing
reversible paralysis.

NEUROMUSCULAR BLOCKING AGENTS

These drugs act at the nicotinic receptors of the neuromuscular junction. Based on their
mechanism of action, they are further classified as non-depolarizing, or depolarizing blockers.

NON-DEPOLARIZING BLOCKERS
 These drugs are competitive antagonists for acetylcholine. At low doses, they bind to
nicotinic receptors instead of acetylcholine, but do not stimulate the receptor. Therefore, muscle
contraction does not occur. At high doses, they also block the ion channels. While low doses can
be reversed by cholinesterases, high doses make reversal difficult.

Clinical actions:

● The main clinical action is paralysis of muscles.

● Muscle paralysis occurs in a centrifugal manner, starting with the muscles of the eye and
face, followed by fingers and toes. After that, muscles of the limbs are affected, and
finally, paralysis of the neck and trunk muscles occurs.

Pharmacokinetics:

These drugs are not effective when taken orally. They are usually administered
intravenously, and sometimes, intramuscularly. They are selectively distributed to the muscles
and do not penetrate membranes, including the blood brain barrier. They are usually not
metabolized, and are excreted unchanged in the urine. Based on their duration of action, these
drugs are classified as:

● Long acting: Pancuronium, pipercuronium, doxacurium

● Intermediate acting: Vecuronium, rocuronium, atracurium
● Short acting: Mivacurium

Adverse effects:

● Postoperative muscle pain

● Hypokalemia
● Increased intraocular and intragastric pressure

Indications:

Non-depolarizing blockers are commonly used during general anesthesia to maintain a state
of muscle relaxation that is conducive to intubation and surgery.

DEPOLARIZING BLOCKERS:

These agents are agonists for acetylcholine. They work similar to acetylcholine, and cause
depolarization of the motor end plate. However, while acetylcholine degrades rapidly, these
agents are resistant to degradation. The continuous depolarization prevents the transmission of
further nerve impulses, by closing off the sodium channel. The main depolarizing blocker in use
today is succinylcholine.

Clinical actions: These are similar to depolarizing agents. There might be mild fasciculations
or twitching of the muscles before paralysis sets in.

Pharmacokinetics:
 Succinylcholine is usually administered intravenously. After it acts at the neuromuscular
junction, it rapidly redistributes, and is hydrolyzed in plasma by the enzyme
pseudocholinesterase. The duration of action lasts only up to five minutes.

Adverse effects:

● Succinylcholine has the potential to induce malignant hyperthermia

● Apnea: Certain susceptible patients may not be able to metabolize succinylcholine. This
occurs in patients who have a genetically altered form of the enzyme
pseudocholinesterase. Patients who have electrolyte disturbances, or those receiving
digoxin may also be susceptible to apnea.
● Hyperkalemia.

Indications:

Used along with rapid endotracheal intubation, during induction of general anesthesia.

DIRECTLY ACTING MUSCLE RELAXANTS

Rather than acting at the neuromuscular junction, these drugs act on the muscles themselves.
The important drug in this category is dantrolene sodium.

Dantrolene:

● This drug blocks the calcium channels present on the sarcoplasmic reticulum of skeletal
muscles. This decreases intracellular calcium available for excitation-contraction
coupling, and inhibits muscle contraction.
● It may be given either orally or intravenously. It is well absorbed from the GIT, and can
penetrate the brain. It is metabolized in the liver and excreted by the kidney. The half
life is 8 to 12 hours.
● Adverse effects include sedation, weakness, muscle weakness and diarrhea.
● Indications:
○ Oral dantrolene: Hemiplegia, paraplegia, cerebral palsy and multiple sclerosis to reduce
spasticity.
○ Intravenous dantrolene: drug of choice for malignant hyperthermia.

CENTRALLY ACTING MUSCLE RELAXANTS

These drugs act on the spinal and supraspinal polysynaptic pathways that are responsible for
maintenance of muscle tone. They decrease muscle tone and cause some sedation, but do not
affect the neuromuscular transmission and hence do not cause complete paralysis. Some
commonly used skeletal muscle relaxants include:

Chlorzoxazone:

● It is used to relieve painful muscle spasms, and increase joint mobility.

● It undergoes glucuronide conjugation by the liver, and is excreted in urine.
● Side effects include: nausea, vomiting, light-headedness, headache, drowsiness.
Chlormezanone:

● Primarily used for muscle spasm, it has anti-anxiety and hypnotic actions as well.
● Side effects: Nausea, abdominal pain, fatigue, dizziness. At toxic doses, it can cause
cerebral edema, liver and kidney damage.

Thiocolchicoside:

● Apart from being a muscle relaxant, it has anti-inflammatory and analgesic effects.
● It is administered orally, and bioavailability is 25%. It is metabolized in plasma, and
excreted through urine and feces.
● Can induce seizures and is contraindicated in patients with epilepsy.

Tizanidine:

● It has a short duration of action, and is used to relieve muscle spasticity before specific
activities.
● It is absorbed orally, with a bioavailability of 40%. It undergoes significant first pass
metabolism, and is 30% bound to plasma proteins. It is metabolized in the liver and
excreted in urine.
● Can increase the heart rate and blood pressure.
● Benzodiazepines and other drugs acting on the CNS: These include diazepam and
baclofen, which have been described in Unit II.

EXERCISES:

1. Which of the following drugs is not a non-depolarizing blocker?

a. Pancuronium

b. Vecuronium

c. Succinylcholine

d. Atracrium

2. What action do non-depolarizing blockers have on the nicotinic receptors?

a. Agonist

b. Antagonist

c. Neither

d. Both agonist and antagonist

3. Which of the following is a short acting non-depolarizing blocker?

a. Atracurium
 b. Mivacurium

c. Doxacurium

d. Pancuronium

4. What is the preferred route of administration for peripheral muscle relaxants?

a. Oral

b. Intramuscular

c. Intravenous

d. Subcutaneous

5. What is the duration of action of succinylcholine?

a. 2 minutes

b. 5 minutes

c. 8 minutes

d. 10 minutes

6. What is the drug of choice to treat malignant hyperthermia?

a. Quinine

b. Dantolene

c. Tizanidine

d. Chlorzoxazone

7. What is the half-life of dantrolene sodium?

a. 2 to 4 hours

b. 4 to 8 hours

c. 8 to 12 hours

d. 12 to 16 hours

8. Which of the following drugs has analgesic properties?

a. Chlorzoxazone
 b. Tizanidine

c. Thiocolchicoside

d. Chlormezanone

9. Which of the following drugs can cause anxiolysis and sedation?

a. Chlorzoxazone

b. Tizanidine

c. Thiocolchicoside

d. Chlormezanone

10. Which of the following drugs is contraindicated in seizure patients?

a. Chlorzoxazone

b. Tizanidine

c. Thiocolchicoside

d. Chlormezanone
UNIT V: DRUGS ACTING ON THE PARACRINE
AND ENDOCRINE SYSTEM
 CHAPTER 1: HISTAMINE AND
ANTIHISTAMINES
The current unit deals with paracrine (autacoid) drugs and endocrine drugs. Paracrine, or
autacoid compounds are those which act locally at the site where they are released. In contrast,
endocrine compounds, or hormones, act at sites distant from where they are produced.

HISTAMINE

Histamine is a paracrine chemical messenger. It is found in mast cells and basophils, which
are distributed in tissues all over the body. Tissues that contain high amounts of histamine
include the skin, gastric mucosa, lungs, liver, and placenta. Histamine is also present outside of
the mast cells, in regions such as the brain. While histamine is not used clinically, it is essential
to understand the properties of this compound to understand the applications of antihistamine
drugs.

Synthesis and storage:

Synthesis occurs within mast cells, from the amino acid histidine. The reaction is catalyzed
by the enzyme histidine decarboxylase. After synthesis, histamine is stored in granules within the
mast cells.

Mechanism of action:

Histamine is released from mast cells upon stimulation by toxins, micro-organisms, or

trauma. Upon release, histamine exerts its effects through four classes of histamine receptors –
H1, H2, H3, and H4. The clinical actions have been detailed only for three receptors, and only
H1 and H2 have effective antagonists.

Table 1. Clinical effects mediated through different histamine receptors

H1 H2 H3
Smooth muscle
contraction
Blood vessels:
Vasoconstriction of
larger vessels, due to its Present at
action on smooth muscles Gastric acid secretion presynaptic region,
Vasodilation due to Vasodilation inhibits further
CLINICAL release of nitric oxide Positive chronotropic histamine release and
EFFECTS Stimulation of and inotropic effect on causes sedation
MODULATED afferent nerve endings the heart Inhibits
Stimulation of Uterine relaxation acetylcholine release in
ganglionic cells Neurotransmitter intestines
Release of in the brain
 catecholamines from
adrenal medulla
Neurotransmitter
in the brain

ANTIHISTAMINES

Depending on the receptor at which drugs exert their clinical effects, antihistamines are
broadly categorized as H1 antihistamines and H2 antihistamines.

H1 antihistamines

Mechanism of action: H1 antihistamines block the receptor-mediated response of histamine.

These drugs are divided into two main categories:

● First-generation drugs: These drugs can penetrate the blood-brain barrier. They also
tend to stimulate receptors other than the histamine receptors. Therefore, they may have
more adverse effects. However, they are still used due to their low cost.
● Second-generation drugs: These drugs do not penetrate the blood-brain barrier easily.
They specifically act only on the peripheral H1 receptors, and therefore have lesser
adverse effects.

Clinical actions and indications:

● Effect on inflammation and allergies: H1 antihistamines prevent the interaction of

antigens with IgE antibodies. Therefore, they are useful in preventing allergic
conditions. These include urticaria, allergic rhinitis, and allergic conjunctivitis. In
allergic conditions that involve massive release of histamine, such as
anaphylaxis, epinephrine is preferred over H1 antihistamines.
● CNS depression: This is largely seen with the first-generation antihistamines. Some
second-generation antihistamines, including cetirizine and levocetirizine, may be
partially sedating. First-generation drugs such as diphenhydramine and doxylamine are
often prescribed in the treatment of insomnia.
● Motion sickness and nausea: First-generation drugs that act on both the
histamine and muscarinic M1 receptors are useful in treating motion sickness. The
drugs of choice include promethazine, cyclizine, meclizine, diphenhydramine, and
dimenhydrinate. Promethazine is also used to control nausea that occurs in pregnancy.
Some antihistamines, such as cyproheptadine, may have an appetite stimulating effect.

● Anticholinergic effects: Some first-generation drugs, including diphenhydramine,

dimenhydrinate, pheniramine, and promethazine act at muscarinic receptors and
inhibit the effects of acetylcholine. This can cause dry mouth, blurred vision, and
urinary retention.
 Pharmacokinetics:

These drugs are well absorbed from the oral route. They are widely distributed, and reach all
tissues (except the brain in the case of second-generation agents). These drugs are mostly
metabolized in the liver through the cytochrome P450 system. Cetirizine, levocetirizine, and
fexofenadine do not undergo any metabolism. The former two are excreted unchanged in the
urine, while the latter passes out unchanged through the feces. The drugs usually reach peak
levels in plasma within one to two hours, and the half-life is usually 4 to 6 hours for first-
generation drugs, and 12 to 24 hours for the second-generation drugs.

Adverse effects:

● CNS effects: First-generation drugs can cause sedation, fatigue, dizziness, tremors, and
lack of coordination. These drugs must not be taken when people work jobs that require
them to be alert. Second-generation drugs can cause headaches.
● Antimuscarinic effects: These drugs can cause dry mouth, blurred vision, urinary
retention, and tachycardia.
● Hypersensitivity reactions: Contact dermatitis can occur on topical application.

H2 antihistamines

These drugs block the actions of histamine at the H2 receptor. Usually, they produce
competitive antagonism. However, famotidine alone works through competitive-noncompetitive
blockade of H2 receptors.

Clinical actions:

The main effect of the H2 blockers is on the GIT. Histamine, along with acetylcholine and
gastrin, stimulates gastric acid production. H2 blockers basically suppress gastric acid secretion.
They decrease all phases of gastric acid secretion, including basal, gastric, neurogenic, and
psychic phases.

Pharmacokinetics:

Absorption occurs through the oral route. These drugs undergo first-pass metabolism, and so
only have a bioavailability of 60% to 80%. They do not cross the blood-brain barrier, but they
can cross the placenta, and are also secreted in breast milk. Some oxidative metabolism occurs,
but the drug is largely excreted unchanged in bile and urine. The half-life is two to three hours.

Indications:

● Peptic ulcers: Gastric and duodenal ulcers can be treated with H2 blockers.
However, ulcers induced by drugs like NSAIDS are resistant.
● Stress ulcers: H2 blockers are used to manage stress ulcers in hospitalized
patients. Tolerance may develop on prolonged use.

Gastroesophageal reflux disease: These are not the preferred choice, and have been
replaced with antacids and proton pump inhibitors.
 Adverse effects:

● CNS: Hallucinations and confusion observed basically in elderly patients or if the drug is
given intravenously.
● Headache, dizziness, muscular pain, diarrhea
● Endocrine effects: Observed with cimetidine. These include gynecomastia, galactorrhea,
and decreased sperm count.
● All H2 blockers except famotidine, interfere with the absorption of ketoconazole.
EXERCISES:

1. Which one of the following receptors is responsible for inhibition of further histamine
release?

1. H1
2. H2
3. H3
4. H4

2. Which of the following receptors mediates uterine relaxation?

1. H1
2. H2
3. H3
4. H4
3. Which of the following antihistamine drugs does not cause sedation at all?

1. Diphenhydramine
2. Cetirizine
3. Fexofenadine
4. Chlorpheniramine
4. Which of the following is the most common adverse effect of second-generation H1
antihistamines?

1. Nausea
2. Weight gain
3. Dizziness
4. Headache
5. In addition to histamine receptors, which of the following receptors are stimulated by
first-generation antihistamines?

1. Adrenergic
2. Muscarinic
3. Dopaminergic
4. Serotonin
6. Which of the following drugs is indicated to control nausea in pregnancy?
1. Promethazine
 2. Dimenhydrinate
3. Cyproheptadine
4. Levocetirizine
7. Which of the following drugs does not undergo metabolism in the body, and is
excreted through feces?

1. Cetirizine
2. Fexofenadine
3. Meclizine
4. Promethazine
8. Whichof the following drugs is used as an appetite stimulant?

1. Cyproheptadine
2. Promethazine
3. Pheniramine
4. Meclizine
9. Which of the following is the primary indication for use of H2 antihistamines?

1. Allergic rhinitis
2. Sinusitis
3. Pepticulcer
4. Asthma
10. What is the bioavailability of H2 antihistamines?

1. 10 – 20%
2. 20 – 40%
3. 40 – 60%
4. 60- 80%
 CHAPTER 2: PROSTAGLANDINS AND
PROSTAGLANDIN INHIBITORS
Prostaglandins are autacoids that are produced by almost all the tissues in the body. Once
they exert their actions at the site of synthesis, they are degraded rapidly.

SYNTHESIS OF PROSTAGLANDINS:

Prostaglandins are synthesized from arachidonic acid. This is a long-chain free fatty acid that
is generally present as a component of cell membranes, and is cleaved from this region by the
enzyme phospholipase A2. Arachidonic acid then enters one of two metabolic pathways:

● Cyclooxygenase pathway: The enzyme cyclooxygenase (COX) exists in two isoforms.

COX-1 is responsible for prostaglandin production in normal health. COX-2 is
responsible for prostaglandin production during inflammation, and its expression is
influenced by the presence of inflammatory mediators, including tumor necrosis factor-
α (TNF-α) and interleukin-1 (IL-1). The COX pathway produces three
prostaglandins – PGD2, PGE2, PGF2, prostacyclin (PGI2), and thromboxane A2.

● Lipoxygenase pathway: The enzyme lipoxygenase acts on arachidonic acid to produce

leukotrienes.
Figure 8 Two metabolic pathways (COX and Lipoxygenase) produce prostaglandins that act on various systems in the body.

CLINICAL ACTIONS:

● Cardiovascular system: Most prostaglandins (PGE2, PGD2, and PGI2) cause

vasodilation. Vasodilation results in a fall in blood pressure, which in turn causes an
increase in cardiac output. PGF2α may cause vasoconstriction of larger vessels.
Thromboxane A2 uniformly causes vasoconstriction. In the fetus, PGE2 production
keeps the ductus arteriosus patent.
● Injury and inflammation: Thromboxanes can cause platelet aggregation, while
prostacyclin tends to inhibit it. Both prostaglandins and leukotrienes are analgesic
 agents and they sensitize peripheral nerves to pain stimulus. They also
modulate pain during inflammatory processes. Leukotrienes increase capillary
permeability and cause neutrophil migration.
● Smooth muscle contraction: Prostaglandins cause uterine contraction, in gravid and
non-gravid women. PGD2, PGF2α, and thromboxanes cause bronchoconstriction.
However, PGE2 causes bronchodilation. Leukotrienes also cause bronchoconstriction.

● GIT: Prostaglandins increase propulsive activity of the GIT. They also stimulate the
production of mucus and bicarbonate, and are protective against ulcers.
● Renal system: Prostaglandins have a diuretic effect. They increase the excretion of
water, as well as sodium and potassium ions.
● Nervous system: Prostaglandins are pyrogenic and play a role in the development of
fever. PGE2 is the main compound involved, and stimulates the hypothalamic
thermoregulatory center to cause fever. Prostaglandins also modulate sympathetic
transmission.

PROSTAGLANDIN ANALOGUES:

Synthetic forms of prostaglandins are used therapeutically for several purposes. A list of
analogues, with their indications is summarized in Table 1.

Table 1. Prostaglandin analogues and their uses

ANALOGUE
DRUG INDICATIONS
OF
To maintain patent ductus arteriosus in infants with
Alprostadil PGE1 congenital heart conditions
Treatment of erectile dysfunction
PGE1 Treatment of constipation: increases intestinal fluid
Lubiprostone
derivative secretion by stimulating chloride channels
Gastroprotective drug, given with NSAIDS in ulcer
Misoprostol PGE1 patients

To induce labour in pregnant women

Bimatoprost
Latanoprost PGF2α Treatment of open angle glaucoma
Travoprost analogues Eyelash hypotrichosis
Tafluprost
Epoprostenol
Prostacyclin Treatment of pulmonary arterial hypertension
Treprostinil

PROSTAGLANDIN INHIBITORS – NON-STEROIDAL ANTI-INFLAMMATORY

DRUGS (NSAIDs)

NSAIDs are a group of drugs that exert clinical effects by inhibiting the metabolic pathways
that synthesize prostaglandins. NSAIDs are classified according to their chemical structure and
mechanism of action. This is summarized in Table 2.

Table 2. Classification of NSAIDS

DRUG CATEGORY SUB-CATEGORY DRUG NAMES

Salicylates
Propionic acid
derivatives Aspirin
Fenemates Ibuprofen, Flurbiprofen,
NaproxenMefenamic acid
Non-selective COX inhibitors Enolic acid Piroxicam, Tenoxicam
derivatives Indomethacin, Ketorolac
Acetic acid Phenylbutazone,
derivatives Oxyphenbutazone
Pyrazolone
derivatives
Nimesulide, diclofenac,
Preferential COX-2 inhibitors
aceclofenac, etodolac
Selective COX-2 inhibitors Celecoxib, etoricoxib

Para-aminophenol
derivative Paracetamol
Analgesic-antipyretics with poor Pyrazolone
anti-inflammatory action Dipyrone,
derivatives propyphenazone
Benzoxazocine Nefopam
derivatives

MECHANISM OF ACTION:

Most NSAIDs reversibly inhibit cyclooxygenase. Aspirin, however, alters the structure of the
enzyme, and this action is irreversible.

CLINICAL EFFECTS:

● Anti-inflammatory agent: NSAIDs reduce inflammation that is caused by

prostaglandins. They are often used in inflammatory conditions like arthritis. While
they do not slow the progression of the disease, they can improve symptoms.

● Analgesic effect: NSAIDs are the most common drugs used in pain management.
Most analgesics are effective in the management of musculoskeletal pain. Some
drugs, like ketorolac, are useful for severe acute pain.
 ● Antipyretic effect: NSAIDs reduce body temperature in patients with fever. They
induce sweating and peripheral vasodilation, which rapidly dissipates heat.
● CVS effects: Low doses of aspirin inhibits thromboxane, which causes aggregation of
platelets. It is therefore prescribed for patients who are at risk of developing ischemic
events such as myocardial infarction or stroke. Aspirin is also used in acute myocardial
infarction. It has been shown to reduce the size of the infarct and decrease
mortality rates. Other non-selective NSAIDs can also inhibit platelet aggregation, but
are not therapeutically useful. COX-2 inhibitors have no effect on platelets.

● Respiratory effects:

At clinical doses: Raised alveolar ventilation.

At high doses: Respiratory alkalosis compensated by the kidneys.

At toxic doses: Central respiratory paralysis.

● GIT effects: They inhibit the protective effect of prostaglandins. They increase gastric
acid secretion and decrease mucus production, thereby increasing the risk of
developing ulcers.
● Renal effects: They decrease renal blood flow and can cause retention of sodium and
water. This leads to urinary retention.

PHARMACOKINETICS:

Aspirin is degraded in various tissues of the body, including plasma, to form salicylate,
which forms the active component. Salicylates are rapidly distributed throughout the body, and
they cross the blood-brain barrier as well as the placenta. They are metabolized in the liver by
conjugation reactions. They are excreted in the urine at the expense of uric acid, and can lead to
accumulation of uric acid in the body.

Most of the other NSAIDs bind to plasma proteins and are metabolized in the liver. Excretion
occurs through urine.

Table 3. Half-life and indications of various NSAIDs

HALF-LIFE INDICATIONS
DRUG
Low dose – in ischemic diseases, acute
rheumatic fever, and as an analgesic and antipyretic
Mild to moderate postoperative pain
Pain relief in patients with cardiovascular
3 to 5 hours disease
2 hours Dysmenorrhoea. Pain in muscles, joints,
Aspirin (as 12 to 16 hours soft tissues
salicylate) 2 to 4 Acute pain and musculoskeletal pain, long-
Ibuprofen hours term drug in inflammatory conditions
Naproxen 57 hours Acute postoperative pain, dental,
Mefenemic 5 to 7 musculoskeletal pain
acid hours Reserve drug in inflammatory conditions
Piroxicam
Ketorolac 2 to 5 hours Fever refractory to other drugs
Indomethacin Closure of patent ductus arteriosus
2 to 5
Nimesulide hours Pain of short duration – injuries, sinusitis
Diclofenac 2 hours, up to
Etodolac 6 hours in joints Inflammatory pain – arthritis, bursitis,
Celecoxib 7 hours toothache, spondylitis
Etoricoxib 10 hours Arthritis and musculoskeletal pain
Paracetamol 24 hours Acute pain, rheumatoid arthritis,
2 to 3 osteoarthritis
hours Analgesic in patients with high risk of GI
bleed
Antipyretic drug of choice. Analgesic in
patients with gastric ulcers.

ADVERSE EFFECTS:

● Liver damage: Paracetamol produces toxic metabolites, which can cause liver damage in
high doses. Fulminant hepatic failure has also been reported with nimesulide.
● Cardiovascular events: The risk of events like myocardial infarction increases with
COX-2 inhibitors.
● Trigger for asthma: Since NSAIDs suppress only prostaglandins, leukotrienes exert
severe bronchoconstriction. This can trigger asthmatic attacks in susceptible patients.

● Peptic ulcer: The risk is higher with non-selective COX inhibitors.

● Renal failure: Patients with compromised renal function can develop renal failure.

● Minor effects: Headache and dizziness may occur with some drugs. Frontal
headache is common with ketorolac. Some non-selective NSAIDs can cause
hypersensitivity reactions like rashes.

CONTRAINDICATIONS:

●Third trimester of pregnancy – can cause premature closure of ductus arteriosus

●Patients with gout, or those taking probenecid
●Patients at high risk of renal failure
●Patients with cardiovascular disease (COX-2 inhibitors are contraindicated)
EXERCISES:
1. Which of the following fatty acids is a substrate for synthesis of prostaglandins?

1. Linoleic acid
2. Linolenic acid
3. Arachidonic acid
4. Eicosa-tetraenoic acid

2. Which of the following prostaglandins keeps the ductus arteriosus patent in

the fetus?
1. PGD2
2. PGE2
3. PGF2α
4. PGI2
3. Which of the following drugs is a synthetic analog of PGF2α?
1. Alprostadil
2. Misoprostol
3. Bimatoprost
4. Epoprostenol
4. In which trimester of pregnancy is the use of NSAIDs contraindicated?
1. First
2. Second
3. Third
4. Throughout pregnancy
5. Which of the following NSAIDs is preferred for patients with cardiovascular disease?
1. Ibuprofen
2. Naproxen
3. Diclofenac
4. Etodolac
6. Which of the following NSAIDs has been associated with a high risk of cardiovascular
events?
1. Aspirin
2. Indomethacin
3. Celecoxib
4. Ketorolac
7. Which of the following NSAIDs is used as a prophylaxis for ischemic events?
1. Aspirin
2. Indomethacin
3. Sulindac
4. Propyphenazone
8. Which of the following drugs causes frontal headache?
1. Diclofenac
2. Ketorolac
3. Piroxicam
4. Etoricoxib
 9. What is the half-life of celecoxib?
1. 5 hours
2. 7 hours
3. 10 hours
4. 12 hours
10. Which NSAID is indicated for patients with pain due to dysmenorrhea?
1. Piroxicam
2. Indomethacin
3. Mefenamic acid
4. Aspirin
 CHAPTER 3: DRUGS ACTING ON THE
HYPOTHALAMUS AND PITUITARY GLAND
This chapter deals with the hormones secreted by the hypothalamus and the pituitary gland.
These areas secrete hormones which influence the production of hormones by the other
endocrine glands. The hypothalamus secretes regulatory hormones, which are transmitted to the
anterior pituitary via the hypothalamo-hypophyseal portal system. These hormones regulate
secretion of hormones from the pituitary.

ANTERIOR PITUITARY HORMONES:

Adrenocorticotropic hormone (ACTH)

The hypothalamus secretes corticotropin releasing hormone (CRH), which acts on the
anterior pituitary to secrete ACTH, also known as corticotropin.

Physiological function:

ACTH acts on receptors present on the surface of the adrenal cortex. By activating G-protein-
coupled receptors, it stimulates the release of corticosteroids (Cortisol) and adrenergic hormones.

Cortisol has a negative feedback relationship with CRH and ACTH. If cortisol levels are
high, they suppress CRH and ACTH release, which in turn suppresses cortisol secretion.

Therapeutic indications:

● Synthetic ACTH (cosyntropin) is used to diagnose adrenal insufficiency.

● It is also used in treating West Syndrome, a disease of infants that causes spasms.

Growth hormone (GH)

Somatotropin, also known as growth hormone, is produced by the anterior pituitary when it is
stimulated by somatotropin-releasing-hormone produced by the hypothalamus. Another
hypothalamic hormone, calles somatostatin, inhibits the secretion of this hormone.

Physiological effects:

Somatotropin has the following metabolic effects on tissue cells.

● It causes hyperplasia of tissues, and increases protoplasm production in cells.

● There is increased uptake of amino acids and protein synthesis.
● There is increased fat utilization and a tendency to spare carbohydrates.
 ● Increased gluconeogenesis and glycogenolysis.
● The above effects result in overall growth of bones as well as soft tissues.

Therapeutic indications:

Synthetic growth hormone is indicated in:

● GH deficiency and failure to grow

● AIDS wasting syndrome
● To improve athletic performance and enhance lean muscle mass.

Somatostatin

● This is an inhibitor of growth hormone. It is available in the synthetic form as octreotide

and lanreotide.
● It is used for the management of acromegaly and bleeding esophageal varices.
● Adverse effects include nausea, diarrhea, steatorrhea, flatulence, and abdominal pain.

Thyroid stimulating hormone (TSH)

Thyrotropin or TSH is released by the anterior pituitary, upon stimulation from the
thyrotropin-releasing-hormone produced by the hypothalamus. It stimulates the thyroid gland to
produce its hormones, triiodothyronine and thyroxine by the following mechanisms:

● Induces hypertrophy and hyperplasia of the thyroid cells.

● Improves blood supply to the thyroid gland.
● Increases trapping of iodine into the thyroid cells, and incorporation of iodine into the
thyroid hormones.
● As such, it has no therapeutic application. It may sometimes be used for diagnosis, to
differentiate primary hypothyroidism from hypothyroidism due to thyroid dysfunction.

Gonadotropins

The gonadotropin-releasing-hormone stimulates the release of gonadotropins from the

anterior pituitary. The gonadotropins include follicle stimulating hormone (FSH) and luteinizing
hormone (LH).

Physiological functions:

● In the ovaries, FSH induces follicular growth and development of the ovum. It also
stimulates secretion of estrogen.
● In males, FSH supports spermatogenesis and development of the seminiferous tubules.

● LH supports ovulation and luteinization of the follicle. It maintains the integrity of the
corpus luteum. It is also responsible for the secretion of progesterone.
 ● In males, the equivalent of LH is the interstitial cell stimulating hormone (ICSH). It is
responsible for the secretion of testosterone.

Therapeutic indications:

● GnRH is available as synthetic analogs – leuprolide, goserelin, and histelin. They are
used for suppression of gonadal hormones in conditions like prostate cancer,
endometriosis, and precocious puberty.
● Gonadotropins are used for treatment of amenorrhea and infertility.
● Hypogonadism and undescended testes: Gonadotropins may induce androgens which
can stimulate sexual maturation.

Adverse effects:

GnRH analogs may cause decreased libido, hot flushes, sweating, gynecomastia, and ovarian
cysts.

Prolactin

Prolactin has a negative feedback with GnRH. When high levels of prolactin are present,
GnRH secretion is suppressed, and vice-versa.

Physiological function:

● During pregnancy, it stimulates the production of ductal and acinar cells in the breast.
Within these cells, it stimulates the production of lactose and milk proteins.
● After delivery, it stimulates milk production. Prolactin is responsible for amenorrhoea
during the lactation period. It can inhibit ovulation and fertility during this period.

Inhibitors of prolactin

● Bromocriptine and cabergoline are basically dopamine (D2) agonists. They bind to
dopamine receptors on the pituitary and inhibit the release of prolactin.
● Bromocriptine is short acting and has a half-life of three to five hours. However,
cabergoline has a half-life of almost 60 hours.
● These drugs are indicated in hyperprolactinemia due to prolactin secreting
tumors. They are also used in acromegaly, and to some extent, in management of
Parkinsonism.
● Adverse effects include nausea, vomiting, hypotension. and constipation.

POSTERIOR PITUITARY HORMONES

Oxytocin
 ● This hormone stimulates uterine contraction and is used in obstetrics to induce labor.

● Adverse effects include water retention, hypertension, and uterine rupture.

Vasopressin

● Also known as antidiuretic hormone, it plays a key role in urinary retention.

● It increases reabsorption of water in the collecting tubules of the kidney.

● It is mainly used to treat diabetes insipidus. It is used to manage bleeding from

esophageal varices.
● Adverse effects include hyponatremia and water intoxication, abdominal pain and
tremors. It causes vasoconstriction and may increase blood pressure. An analog of
vasopressin, called desmopressin, does not cause vasoconstriction and is preferred for
diabetes insipidus.

EXERCISES:

1. Which of the following hormones is released by the hypothalamus?

1. Adrenocorticotropic hormone
2. Corticotropin releasing hormone
3. Cosyntropin
4. Cortisol
2. Which of the following drugs is used in the management of acromegaly?
1. Octreotide
2. Cabergoline
3. Leuprolide
4. Desmopressin
3. Which of the following hormones maintains the integrity of the corpus luteum?

1. Follicle stimulating hormone

2. Luteinizing hormone
3. Interstitial cell stimulating hormone
4. Prolactin
4. Which of the following hormones is absent in men?
1. Follicle stimulating hormone
2. Luteinizing hormone
3. Interstitial cell stimulating hormone
4. Prolactin
5. Which of the following receptors, on activation, inhibits prolactin secretion?

1. Adrenergic
2. Dopaminergic
3. Serotonin
4. Muscarinic
6. Which of the following drugs is used to induce labour?
 1. Goserelin
2. Bromocriptine
3. Prolactin
4. Oxytocin
7. Which of the following hormones is preferred for the treatment of diabetes
insipidus?
1. Prolactin
2. Oxytocin
3. Vasopressin
4. Desmopressin
8. Which of the following drugs are used in the treatment of bleeding esophageal
varices?
1. Octreotide
2. Vasopressin
3. Lanreotide
4. All of the above
9. What is the half-life of cabergoline?
1. 20 hours
2. 40 hours
3. 60 hours
4. 80 hours
10. Which of the following is not an adverse effect of vasopressin?
1. Hyponatremia
2. Dehydration
3. Tremors
4. Abdominal pain
 CHAPTER 4: THYROID HORMONE AND
INHIBITORS
The thyroid hormones, secreted by the thyroid gland, regulate basic metabolic processes
throughout the body. The two major thyroid hormones are tri-iodothyronine (T3) and thyroxine
(T4).

SYNTHESIS AND KINETICS:

The synthesis of these hormones involves the following steps:

● Dietary iodine is taken up into the thyroid cell through the Na+ I symporter.Within the
cell, it undergoes oxidation.
● Thyroglobulin is another protein that is synthesized within the cell.
● Iodine combines with the tyrosine residue of thyroglobulin to form monoiodothyronine
and di-iodothyronine.
● The iodinated tyrosine residues then couple together to form T3 and T4. These hormones
are stored in the thyroid follicles until they are released into circulation.
● In circulation, the hormones bind to thyroxine binding protein, and dissociate from it
prior to entering the cell. Once within the cell, T4 is converted into T3. T3 exerts its
action on the nucleus, and results in protein synthesis.
● T3 and T4 exert a negative feedback on TSH and TRH.
● Synthetic hormones are well absorbed after oral administration. They are
metabolized by deiodination, and by conjugation with glucuronides and sulfates.
Excretion occurs through the bile.

PHYSIOLOGICAL FUNCTIONS OF T3 AND T4:

● Normal growth and development: T3 and T4 are essential for normal growth of
the body.
● Metabolism: These hormones enhance lipolysis and increase plasma free fatty acid
levels. They also stimulate glycogenolysis and gluconeogenesis, leading to
hyperglycemia. While they enhance synthesis of certain proteins, they also degrade
proteins to be used as a source of energy. Overall, they stimulate metabolism and
increase the basal metabolic rate.
● CVS: They increase the heart rate, contractility, and cardiac output. Hyperthyroid
patients may develop tachycardia, along with atrial fibrillation and congestive heart
failure. Hypothyroid patients develop bradycardia. Hypothyroid patients may also
develop anemia.
● CNS: Thyroid hormones boost mental function. Hypothyroid patients are sluggish and
have impaired mental faculties. Hyperthyroid patients tend to be tense, anxious, and
may develop tremors.
● Skeletal muscle: These hormones increase muscle tone. In hypothyroidism,
 skeletal muscles become weak and flabby.
● GIT: Thyroid hormones increase the motility of the GI tract.

THERAPEUTIC INDICATIONS:

Levothyroxine and liothyronine are the synthetic analogs of T4 and T3 respectively.

● Cretinism: This is hypothyroidism that occurs in infancy due to iodine deficiency or

hypoplasia of the gland. Treatment must be instituted as soon as possible to avoid
mental retardation.
● Myxedema: This is hypothyroidism that occurs in adults. It can occur due to
autoimmune destruction of the gland, or surgical removal of the gland.

THYROID HORMONE INHIBITORS

Hyperthyroidism can occur due to an autoimmune disease called Grave's disease, or due to
tumors of the thyroid gland. While surgical removal of all or part of the thyroid gland is the best
option for the management of tumors, autoimmune conditions may be managed by thyroid
hormone inhibitors. A few of the commonly used inhibitors are described below.

Drugs that inhibit synthesis of thyroid hormones

● This group includes propylthiouracil, methimazole, and carbimazole. They inhibit

oxidation of iodine as well as coupling reactions. Propylthiouracil also inhibits the
conversion of T4 to T3.
● These drugs can be taken orally, are metabolized in the liver and excreted in the urine.
They cross the placenta and are secreted in breast milk. Prophylthiouracil has a
short half-life of 1-2 hours, whereas carbimazole has a long half-life of 6-10 hours.

● These drugs are indicated in Grave's disease and toxic nodular goiter. They are also used
preoperatively to bring the patient to the euthyroid state prior to removal of the gland.

● Adverse effects include loss of taste, GI intolerance, and liver damage. Fever, skin
rashes, and joint pain have also been reported. Prolonged use of these drugs
may lead to hypothyroidism.

Drugs that inhibit iodine trapping by thyroid cells

These drugs include thiocyanates, perchlorates, and nitrates. They act by blocking the
sodium/iodide symporter (NIS) system. Although they have similar indications, these drugs are
no longer used because of their high adverse effect profile. Thiocyanates can cause toxicity of
the liver, brain, bone marrow, and kidney. Perchlorates have been linked to aplastic anemia and
agranulocytosis.

Drugs that inhibit release of thyroid hormones

 ● Iodine and iodides tend to block the release of thyroid hormones. These drugs are
effective for short-term use. After around ten days, the effect is lost, and excess
hormones are released, leading to a toxic state.
● They are generally indicated for pre-operative control, and in emergencies like thyroid
storm, to rapidly bring down thyroid levels.

Drugs that destroy thyroid cells

● Radioactive iodine is used to destroy thyroid cells from within. I131 emits radiation in the
form of x-rays and beta particles. When this is ingested, it is preferentially taken up by
the thyroid gland. The radiation causes necrosis of the thyroid cells.
● It is employed for diagnostic purposes, to detect 'hot spots' within the gland on scanning.
It is also employed as a therapeutic measure in Grave's disease, toxic nodular goiter,
and as palliative therapy in metastatic cancer of the thyroid gland.

MANAGEMENT OF THYROID STORM

Thyroid storm is an acute, toxic state of hyperthyroidism, where all the symptoms of this
condition are exaggerated. The treatment regimen for this emergency must include the following:

● Non-selective beta blockers: These reduce peripheral conversion of T4 to T3. Control

tachycardia.
● Propylthiouracil: Reduces the synthesis of thyroid hormone.
● Iodine containing contrast media like iopanoic acid: Inhibits release of hormones, as
well as conversion of T4 to T3.
● Corticosteroids: May control concomitant adrenal crisis, provides symptomatic relief.

EXERCISES:

1. When dietary iodine is taken up inside the cell, which ion is involved in its symporter?
1. Potassium
2. Sodium
3. Calcium
4. Chloride
2. How are synthetic thyroid hormones excreted?
1. Urine
2. Feces
3. Bile
4. Sweat
3. Which of the following metabolic processes is not mediated by thyroid hormones?

1. Gluconeogenesis
2. Glycogenesis
 3. Lipolysis
4. Glycogenolysis
4. Which of the following is not a feature of hyperthyroid patients?

1. Tachycardia
2. Tremors
3. Anemia
4. Increased GI motility
5. What is the half-life of carbimazole?
1. 1 to 2 hours
2. 4 to 6 hours
3. 6 to 10 hours
4. 10 to 14 hours
6. Which of the following drugs has the potential to cause agranulocytosis?

1. Thiocyanates
2. Percolate
3. Nitrate
4. Iodide
7. Which of the following is not suitable for long-term control of hyperthyroidism?

1. Propylthiouracil
2. Methimazole
3. Carbimazole
4. Iodide
8. Which of the following is the commonly employed radioactive form of iodine?

1. I-127
2. I-129
3. I-130
4. I-131
9. Which drug is preferred for management of thyroid storm?

1. Propylthiouracil
2. Methimazole
3. Carbimazole
4. Thiocyanate
10. Which amino acid is involved in synthesis of thyroid hormone?
1. Aspartate
2. Glutamate
3. Tyrosine
4. Histidine
 CHAPTER 5: DRUGS INVOLVED IN CALCIUM
AND BONE METABOLISM
Calcium plays a vital role in body functioning. It is an important intracellular component and
also forms a major component of mineralized bone. Calcium metabolism is regulated by two
important hormones in the body – the parathyroid hormone and calcitonin. This chapter
discusses calcium, these hormones, and other drugs involved in bone metabolism.

CALCIUM

Physiological functions:

● Essential component of mineralized part of bone.

● Calcium excitation-coupling plays a role in muscle contraction, secretion from glands,
and release of neurotransmitters.
● Serves as an intracellular messenger.
● Controls generation of electrical activity in the heart.
● Activation of clotting factors during the coagulation cascade.

Kinetics:

Calcium metabolism is regulated by a balanced interaction between three hormones –

parathormone, calcitonin, and vitamin D (Calcitriol). Dietary calcium is absorbed from the small
intestine. Usually, only about one-third of ingested calcium is absorbed. Around 40% of calcium
binds to plasma proteins. It is excreted through the urine, but large amounts are reabsorbed.
Unabsorbed calcium is also excreted through feces.

Therapeutic indications:

● Osteoporosis
● Increased requirements – children, pregnant and lactating women
● For acute treatment in tetany

PARATHYROID HORMONE:

Parathormone (PTH) is secreted by the parathyroid glands. The secretion is usually regulated
by plasma calcium levels in an inverse fashion.

Physiological functions:

The overall effect of PTH is to increase plasma levels of calcium. This is achieved by:

● Bone: It increases osteoclastic activity, which promotes release of calcium from bone
into the bloodstream. This encourages bone remodeling.
● Kidney: It increases calcium reabsorption from the distal convoluted tubule. It also
 activates the enzyme 1α hydroxylase, which converts dietary vitamin D into calcitriol.
This indirectly increases plasma calcium levels.

CALCITONIN:

Calcitonin is produced by the parafollicular cells (C cells) of the thyroid gland. Its secretion
is directly regulated by plasma calcium levels.

Physiological functions:

● Calcitonin functions as an antagonist to PTH, and decreases calcium levels in plasma.

● Bone: It inhibits osteoclastic activity and promotes bone deposition.
● Kidney: It inhibits reabsorption of calcium and phosphate from the proximal convoluted
tubule.

Therapeutic indications:

Intranasal calcitonin is used to treat osteoporosis in post-menopausal women.

VITAMIN D:

Inactive vitamin D (Cholecalciferol) is usually synthesized in the skin, on exposure to

sunlight. Under ideal conditions, dietary supplementation is not required, and this is therefore
considered a hormone. Cholecalciferol is activated in the kidney to calcitriol, under the influence
of the enzyme 1α hydroxylase.

Physiological functions:

● It promotes the absorption of calcium and phosphorus from the intestine.

● It promotes recruitment and differentiation of osteoclasts, which in turn promotes release
of calcium and phosphorus from bone. It indirectly helps to maintain bone
mineralization. If vitamin D levels fall, more PTH is secreted, which increases
demineralization of bone. Therefore, bones become soft, and leads to rickets in children
and osteomalacia in adults.
● It enhances reabsorption of calcium and phosphate from the kidney.

Pharmacokinetics:

Vitamin D3 is well absorbed from the intestines. It binds to plasma α-globulin in circulation,
and is stored in the adipose tissue. When needed, it is activated to calcitriol. Calcitriol is
metabolized in the liver, and metabolites are excreted in bile.

Therapeutic uses:

● Vitamin D deficiency (rickets, osteomalacia), or supplementation when there is an

increased requirement (pregnant women).
● Hypoparathyroidism: It is preferred to administer PTH, in order to maintain calcium
balance.
 ● Osteoporosis: It is more useful in preventing osteoporosis due to secondary
hypoparathyroidism.

BISPHOSPHONATES

Bisphosphonates are a group of drugs that are used in the treatment of bone disorders.

Mechanism of action:

Bisphosphonates decrease osteoclastic activity and increase apoptosis of osteoclasts. This

leads to an inhibition of bone resorption, which gradually increases bone mass.

Pharmacokinetics:

Bisphosphonates are not absorbed efficiently via the oral food, and absorption can be
retarded by food or medication intake. Intravenous route is more effective. They are rapidly
distributed to bone, where they persist for a long period of time. Elimination eventually occurs
through the urine.

Adverse effects:

● Esophagitis, diarrhea, abdominal pain

● Musculoskeletal pain
● Long-term use may cause atypical fractures
● With high doses, osteonecrosis of the jaw has been reported

Indications:

The potency and indications of the different generations of bisphosphonates is summarized in

Table 1.

Table 1. Potency and indications of bisphosphonates

DRUG
GENERATION POTENCY INDICATIONS
NAME
First Etidronate 1 Hypercalcemia
Pamidronate 100
Osteoporosis
Second Alendronate 500
Paget’s disease
Ibandronate 500
Same as second-generation; when
Risedronate 1000 there is an increased severity of disease
Third
Zoledronate 5000 Hypercalcemia of malignancy
Bone metastases

ESTROGEN RECEPTOR MODULATORS

 ● In post-menopausal women, estrogen efficiency can increase osteoclastic activity and
decrease bone mass.
● Estrogen itself has several adverse effects. Therefore, drugs that interact with estrogen
receptors are used.
● Raloxifene is an estrogen receptor modulator. It has agonist effects on bone, but
antagonist effects on breast and endometrial tissue. Therefore, it can increase bone
mass with minimum adverse effects.
EXERCISES:
1. Which of the following is a physiological function of calcium?

a. Intracellular messenger

b. Bone mineral

c. Role in muscle contraction

d. All of the above

2. How much of dietary calcium is actually absorbed by the body?

a. One-fourth

b. One-thirds

c. Two-thirds

d. Five-eights

3. Which of the following is not a function of PTH?

a. Increasing plasma calcium level

b. Increasing osteoclastic activity in bone

c. Promoting calcium reabsorption in kidney

d. Promoting intestinal calcium absorption

4. Which of the following drugs is usually given in hypoparathyroidism?

a. Vitamin D

b. Parathormone

c. Calcitonin

d. Bisphosphonates
5. Which of the following endocrine glands secretes calcitonin?

a. Thyroid

b. Parathyroid

c. Pituitary

d. Thymus

6. Which of the following routes of administration is preferred for calcitonin?

a. Oral

b. Intranasal

c. Intramuscular

d. Rectal

7. Which of the following forms of vitamin D is synthesized in the skin?

a. Ergocalciferol

b. Calciferol

c. Cholecalciferol

d. Calcitriol

8. Which of the following bisphosphonate drugs is used for treatment of bone metastases?

a. Etidronate

b. Pamidronate

c. Alendronate

d. Zoledronate

9. What is the potency of risedronate as compared to etidronate?

a. 50

b. 100

c. 1000

d. 5000
10. On which of the following tissues does raloxifene have an agonist effect?

a. Breast

b. Bone

c. Endometrium

d. All of the above

 CHAPTER 6: INSULIN AND ORAL
HYPOGLYCEMIC DRUGS
Insulin is a hormone that is secreted by the beta cells of the islets of the pancreas. It is
primarily concerned with glucose metabolism.

Diabetes mellitus is a disease that is characterized by deficiency in the supply or functioning

of insulin. This is one of the most common diseases affecting people worldwide. Classically,
there are two types of diabetes:

● Type 1 diabetes: In this condition, the beta cells of the pancreatic islets are destroyed
due to viruses or toxins. This leads to an absolute lack of insulin, and can only be
treated by replacing insulin. This type affects children and adolescents and is therefore
called 'juvenile diabetes'.
● Type 2 diabetes: This disease commonly affects older adults. While the beta cells of the
pancreas are functioning, there is peripheral resistance to insulin and the target organs
fail to take up insulin. Over a period of time, the apparent decreased
requirement by the target organs cause the beta cell function to decline, and
may eventually result in an actual insulin deficit.

INSULIN AND INSULIN ANALOGS

Insulin is an anabolic hormone that converts glucose, amino acids, and fatty acids to
glycogen, proteins, and lipids.

Physiological functions:

● Promotes transport of glucose across the cell membrane of cells like skeletal muscle and
fat.
● It promotes glycogenesis in the liver, and inhibits gluconeogenesis.
● In adipose tissue, it promotes triglyceride synthesis and inhibits lipolysis. It also
increases levels of the enzyme lipoprotein lipase, which helps in clearing chylomicrons
and very low-density lipoprotein (VLDL).
● It promotes protein synthesis from amino acids and prevents protein breakdown.

To replace the deficiency of insulin in diabetes, synthetic insulin is used. This is obtained
from genetically altered strains of microorganisms like E.coli and yeast, using recombinant DNA
technology. Depending on the amino acid sequence used, insulins having different properties can
be produced.

Synthetic preparations of insulin:

Depending on the onset and duration of action, the preparations are classified as rapid-acting,
short-acting, intermediate-acting, and long-acting preparations. These drugs are summarized in
Table 1.

Table 1. Classification of different insulin preparations.

ONSET
OF DURATION
TYPE OF EXAMPLES ACTION OF ACTION INDICATIONS
PREPARATION (HOURS) (HOURS)

Insulin Control of postprandial

lispro glucose (functions like
Insulin 0.2 to mealtime insulin)
Rapid-acting 3 to 5
aspart 0.4 Emergency treatment of
Insulin uncomplicated diabetic
glulisine ketoacidosis
May be combined with
longer acting insulins to
Regular control fasting glucose levels
Short-acting 0.5 to 1 6 to 8
insulin Used for
emergency control of blood
glucose levels
Insulin zinc
suspension
(Lente insulin) Basal control of blood
Intermediate-
Neutral 1 to 2 8 to 10 glucose levels in Type I
acting
protamine diabetics
hagedorn (NPH
insulin)
Insulin
Basal control of blood
glargine
Long-acting 2 to 4 20 to 24 glucose levels in Type I
Insulin
diabetics
detemir

Pharmacokinetics:

Synthetic insulin cannot be given orally as it gets degraded in the GIT. It is usually
administered as subcutaneous injections. Both natural and synthetic insulin are metabolized
largely in the liver. Some metabolism also occurs in the skeletal muscle and kidney.

Adverse effects:

● Hypoglycemia
● Lipodystrophy at the injection site
● Weight gain
 ORAL HYPOGLYCEMIC DRUGS

These drugs are used for the management of Type 2 diabetes. They are more popular for
management as they can be taken orally, unlike insulin, which must be injected.

Sulfonylureas

These drugs promote the release of insulin from the pancreas. They are classified as first-
generation drugs (tolbutamide, chlorpropamide) and second-generation drugs (glimepiride,
glipizide, glyburide). The second-generation drugs are more potent, and have a better
pharmacological profile. They have completely replaced first-generation drugs.

Mechanism of action:

These drugs block ATP-sensitive potassium channels in the islet cells. This causes
depolarization, which in turn leads to calcium influx, and exocytosis of insulin. They also
improve the sensitivity of the target cells to insulin.

Pharmacokinetics:

These drugs are well absorbed by the oral route, and are highly bound to plasma proteins.
Metabolism occurs in the liver, and the drug is excreted in urine and feces. The half-life of
different sulfonylureas is as follows:

● Glyburide – 2 to 4 hours
● Glipizide – 3 to 5 hours
● Glimepiride – 5 to 7 hours
● Gliclazide – 8 to 20 hours

Adverse effects:

● Hypoglycemia: Patients with liver and kidney dysfunction, and elderly patients are
especially susceptible.
● Renal dysfunction: The risk is especially high with glyburide.
● Hypersensitivity reactions: May cause flushing and skin rashes.

Meglitinide analogs

These drugs have a quick onset and short duration of action. The drugs repaglinide and
nateglinide belong to this category.

Mechanism of action:

Like sulfonylureas, these drugs also act on ATP-sensitive potassium channels and stimulate
insulin secretion. As compared to sulfonylureas, they act quickly and for a short period of time.
They stimulate insulin in response to food, and are effective at postprandial blood glucose
control.
 Pharmacokinetics:

They are well absorbed orally, and must be taken prior to meals for effective glucose control.
Metabolism occurs through the cytochrome P450 system of the liver, and excretion occurs
through bile.

Adverse effects:

● Hypoglycemia: they must never be combined with sulfonylureas as this potentiates

the risk.
● Minor side effects: headache, arthralgia, weight gain

Biguanides

The only biguanide that is therapeutically used today is metformin. It is the drug of choice
for initial therapy in Type 2 diabetes. Apart from diabetes, it is also used to improve insulin
sensitivity in polycystic ovary disease.

Mechanism of action:

Metformin increases the sensitivity of target organs to insulin. It reduces intestinal absorption
of glucose and inhibits hepatic gluconeogenesis. It also improves utilization of glucose by
peripheral tissues.

Pharmacokinetics:

The drug is well absorbed through the oral route. It does not bind to any plasma proteins, and
does not undergo metabolism. It is excreted unchanged through the urine.

Adverse effects and contraindications:

● Minor GIT effects: Abdominal pain, metallic taste, bloating, anorexia, and
diarrhea.
● Contraindicated in patients with renal dysfunction as they can develop lactic
acidosis.
● It must be discontinued if the patient develops conditions that predispose to renal failure,
such as myocardial infarction, cardiac failure, and sepsis. It must also be temporarily
withdrawn in patients receiving contrast dye for CT scans, as the dye is nephrotoxic.

Thiazolidinediones:

Pioglitazone and rosiglitazone are the drugs in this category. They are also used in the
treatment of polycystic ovary disease.

Mechanism of action
 These drugs are agonists for a specific nuclear receptor called peroxisome proliferator-
activated receptor-γ (PPAR-γ). Binding to this receptor stimulates the transcription of genes that
increase insulin sensitivity. This action takes place in the adipose tissue, liver, and skeletal
muscle.

Pharmacokinetics:

These drugs are well absorbed through the oral route, and are highly bound to serum
albumin. Metabolism occurs in the liver through the cytochrome P450 system. While
pioglitazone is largely excreted through the feces, rosiglitazone is excreted through urine.

Adverse effects:

● Has the potential to cause liver toxicity.

● Minor side effects: Weight gain due to increase in subcutaneous fat and fluid retention.

● Long-term pioglitazone use may increase the risk of bladder cancer.

● Rosiglitazone is banned in a few countries because of the high risk of myocardial
infarction and stroke.

α-Glucosidase inhibitors

These drugs, including acarbose, voglibose, and miglitol, are used for the control of
postprandial blood glucose levels.

Mechanism of action:

As the name suggests, these drugs inhibit the enzyme α-glucosidase. They retard the
digestion of carbohydrates. This prevents glucose absorption and lowers blood glucose levels.

Pharmacokinetics:

Acarbose is poorly absorbed through the oral route, while miglitol is well absorbed. The
drugs are metabolized by intestinal bacteria, and metabolites are excreted through urine.

Adverse effects:

● They can cause abdominal cramps, flatulence, and diarrhea.

● These drugs are not indicated in patients with pre-existing GIT conditions like ulcers,
inflammatory bowel disease, or intestinal obstruction.

Dipeptidyl-peptidase inhibitors:

These drugs stimulate secretion of insulin and include the drugs sitagliptin, saxagliptin,
alogliptin, and linagliptin.
 Mechanism of action:

Dipeptidyl peptidase is an enzyme that degrades an incretin hormone, GLP-1, which

increases insulin secretion in response to meals. By inhibiting the degrading enzyme, the life of
GLP-1 is prolonged, and this enhances insulin secretion.

Pharmacokinetics:

They are well absorbed through the oral route, and are unaffected by food intake. Saxagliptin
undergoes metabolism in the liver through the cytochrome P450 system, and is excreted in the
urine. Sitagliptin and alogliptin are excreted unchanged in the urine, while linagliptin is excreted
out through the enterohepatic system.

Adverse effects:

● Minor effects: Headache, nasopharyngitis

● Pancreatitis is a rare but serious adverse effect.

Sodium glucose cotransporter-2 inhibitors

This is a newer category of drugs, and had two important agents – canagliflozin and
dapagliflozin.

Mechanism of action:

The sodium glucose cotransporter-2 system is responsible for reabsorbing glucose into the
blood at the proximal tubule of the kidney. Inhibiting this transporter system results in
glycosuria, and decrease in blood glucose levels. This drug, however, also decreases sodium
reabsorption, and may cause osmotic diuresis.

Pharmacokinetics:

Absorption is through oral route and is optimal on an empty stomach. They are metabolized
in the liver by glucuronide conjugation. Excretion occurs through urine and feces.

Adverse effects:

● Increases susceptibility to genital fungal infections and urinary tract infections,

particularly in women.
● Increased frequency of urination
● Hypotension may occur due to an increased urine output.
EXERCISES:

1. What is the duration of action of insulin glulisine?

1. 3 to 5 hours
2. 6 to 10 hours
 3. 10-14 hours
4. 20 to 24 hours
2. What is the preferred route of administration of insulin?
1. Oral
2. Intramuscular
3. Subcutaneous
4. Rectal
3. Which ion channels are blocked by the use of sulfonylureas?
1. Sodium
2. Potassium
3. Calcium
4. Chloride
4. Which of the following sulfonylureas has the longest plasma half-life?
1. Glyburide
2. Glipizide
3. Glimepiride
4. Gliclazide
5. Which of the following sulfonylureas has the highest risk of renal dysfunction?

1. Glyburide
2. Glipizide
3. Glimepiride
4. Gliclazide
6. Which of the following oral hypoglycemic drugs has a high risk of bladder cancer?

1. Repaglinide
2. Pioglitazone
3. Rosiglitazone
4. Metformin
7. Which of the following drugs is the first-line drug in diabetes mellitus?
1. Acarbose
2. Sitagliptin
3. Canagliflozin
4. Metformin
8. Which of the following oral hypoglycemic drugs acts by preventing digestion of
carbohydrates?
1. Sitagliptin
2. Miglitol
3. Tolbutamide
4. Nateglinide
9. Which of the following drugs can cause nasopharyngitis?
1. Acarbose
2. Sitagliptin
3. Metformin
4. Pioglitazone
10. Which of the following oral hypoglycemic drugs promote diuresis?
1. Acarbose
2. Sitagliptin
3. Canagliflozin
4. Metformin
 CHAPTER 7: CORTICOSTEROIDS
The adrenal gland secretes two main kinds of hormones. The inner adrenal medulla secretes
catecholamines, namely adrenaline and noradrenaline. These have already been discussed in the
chapter on adrenergic drugs. The outer adrenal cortex secretes corticosteroids and adrenal
androgens. The current chapter focuses on corticosteroids.

There are two types of corticosteroids, glucocorticoids and mineralocorticoids. The outer part
of the adrenal cortex, called the zona glomerulosa, secretes mineralocorticoids. The middle part,
zona fasciculata, synthesizes glucocorticoids. The inner part of the adrenal cortex, called the
zona reticularis, secretes adrenal androgens.

MINERALOCORTICOIDS

The main mineralocorticoid in the body is aldosterone.

Physiological functions:

● Enhances reabsorption of sodium in the distal convoluted tubule of the kidney.

● Enhances concomitant excretion of potassium and hydrogen ions.
● It also enhances reabsorption of sodium from other parts of the body such as the
gastrointestinal mucosa, sweat and salivary glands.

GLUCOCORTICOIDS

The main glucocorticoid produced in the human body is cortisol. It is produced upon
stimulation from corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone
(ACTH) from the hypothalamus and pituitary gland, and has a negative feedback relationship
with these structures.

Physiological functions:

● They promote catabolism of proteins and lipolysis. They also promote gluconeogenesis
from amino acids and fatty acids.
● They provide excess glucose needed in cases of stress, trauma, and infection.
● They increase blood levels of red blood cells, neutrophils, and platelets. They decrease
blood levels of eosinophils, basophils, lymphocytes, and monocytes. The overall effect
is immunosuppression.
● They exert anti-inflammatory activity by inhibiting the enzyme phospholipase A2. This
enzyme is responsible for the release of arachidonic acid, which is the precursor of pro-
inflammatory prostaglandins and leukotrienes.
● They decrease blood calcium levels by inhibiting intestinal absorption and promoting
renal excretion of calcium ions.
● Glucocorticoids help maintain normal glomerular filtration in the kidney and enhance
tubular secretion.
 SYNTHETIC CORTICOSTEROIDS

Synthetic corticosteroids have different levels of mineralocorticoid and glucocorticoid

activity. The commonest steroid used is hydrocortisone, and it is taken as a reference drug
against which the potency of other drugs is compared.

Table 1: Potency and indications of different corticosteroids.

POTENCY - POTENCY -
DURATION
CATEGORY DRUG NAME MINERALOCORTICOID GLUCOCORTICOID
OF ACTION
FUNCTION FUNCTION

Reference Short-acting Hydrocortisone 1 1

Mostly
Prednisolone 0.8 4
glucocorticoid Intermediate-
Methylprednisolone 0.5 5
function acting drugs
Triamcinolone 0 5
Mostly Long-acting Dexamethasone 0 25
mineralocorticoid drugs Betamethasone 0 25
function

Desoxycorticosterone 100 10
acetate
Fludrocortisone 150 0.3

Pharmacokinetics:

Most synthetic corticosteroids are well absorbed orally. Some are also available for
intramuscular or intravenous injection. Corticosteroids are also available as topical ointments and
intranasal sprays, and some amount gets absorbed systemically through this route. More than
90% of absorbed corticosteroids are bound to plasma albumin or globulin. They are metabolized
in the liver through oxidation and glucuronide conjugation. Excretion occurs through the urine.

Therapeutic indications:

● Primary adrenal insufficiency (Addison’s disease): Fludrocortisone is the preferred

drug.
● Secondary and tertiary adrenal insufficiency: It can occur due to ACTH and CRH
suppression. This is often seen in patients who take long-term steroids. Hydrocortisone
is preferred.
● Inflammation: They are useful in reducing swelling due to surgery in the postoperative
 period. They are also used for long-term management in inflammatory conditions like
arthritis.
● Allergic conditions: Asthma, allergic rhinitis benefit from intranasal inhalation of
steroids.
● Lung maturation: In the fetus, cortisol promotes lung maturation. Steroids are used to
accelerate lung maturation in premature infants.

Adverse effects:

These are dose-dependent and are more common in patients who are on long-term therapy.

● Osteoporosis: Due to decreased calcium levels

● Hyperglycemia: Glycemic control is worsened in diabetics
● Impaired wound healing and increased risk of infection
● Minor effects: Increased appetite, emotional disturbances, and weight gain in the central
region of the body.
● Secondary adrenal insufficiency: This can develop if the patient abruptly discontinues
the drugs, or there is an increased steroid requirement in times of stress. Endogenous
steroid production is suppressed due to exogenous suppression of CRH and ACTH.

GLUCOCORTICOID INHIBITORS:

Certain drugs can suppress the synthesis and function of glucocorticoids. These are drugs that
were primarily developed for other purposes, and their properties are discussed in detail in the
relevant chapters.

Ketoconazole:

● This is an antifungal agent.

● It inhibits synthesis of hormones both from the adrenal gland and gonadal hormones.
● It is used in therapy of Cushing’s syndrome (excess steroid production by the adrenal
gland).

Spironolactone:

● This is a competitive antagonist for the mineralocorticoid receptor in the kidney. It also
antagonizes the synthesis of aldosterone and testosterone. Therefore, it reduces
reabsorption of sodium in the kidney.
● It is used in congestive heart failure, and to manage hirsutism in women.
● Adverse effects include skin rashes, gynecomastia, dysmenorrhea, and rarely,
hyperkalemia.

Eplerenone:

● This is also an aldosterone antagonist, and binds to the mineralocorticoid receptor.

● Also used in heart failure and hypertension. Unlike spironolactone, it does not cause
gynecomastia.
EXERCISES:
1. Which part of the adrenal gland is responsible for the release of glucocorticoids?
1. Adrenal medulla
2. Zona glomerulosa
3. Zona fasciculata
4. Zona reticularis
2. Sodium reabsorption occurs from all the following body parts except:
1. Proximal convoluted tubule
2. Distal convoluted tubule
3. Salivary glands
4. Gastrointestinal mucosa
3. Which of the following is not an indication for corticosteroid therapy?
1. Allergic rhinitis
2. Rheumatoid arthritis
3. Osteoporosis
4. Addison’s disease
4. Which of the following corticosteroids is indicated for treatment of Addison’s disease?
1. Hydrocortisone
2. Fludrocortisone
3. Prednisolone
4. Dexamethasone
5. Which of the following corticosteroids is preferred in management of acute asthmatic
attacks?
1. Hydrocortisone
2. Fludrocortisone
3. Prednisolone
4. Dexamethasone
6. Which of the following corticosteroids has the maximum potency?
1. Hydrocortisone
2. Fludrocortisone
3. Prednisolone
4. Dexamethasone
7. As compared to hydrocortisone, what is the potency of prednisolone?
1. 3 times
2. 4 times
3. 5 times
4. 6 times
8. Which of the following antifungal agents inhibits corticosteroid synthesis?
1. Fluconazole
2. Ketoconazole
3. Miconazole
4. Itraconazole
9. What is the risk of giving corticosteroids in the postoperative period?
1. Impaired pain tolerance
2. Increase of swelling
3. Impaired wound healing
 4. Increased bleeding from wound
10. Which of the side effects of spironolactone is eliminated by the use of eplerenone?
1. Skin rashes
2. Dysmenorrhea
3. Gynecomastia
4. Hyperkalemia
 CHAPTER 8: ANDROGENS, ESTROGENS AND
PROGESTINS
These hormones are also referred to as gonadal or sex hormones. They are primarily involved
in pubertal maturation and reproduction.

ANDROGENS

Androgens are a group of sex hormones that have masculinizing effects. In the males, the
predominant androgenic hormone is testosterone, which is secreted by the Leydig cells of the
testes. In females, some secretion occurs in the ovaries, and some secretion occurs from adrenal
gland in both genders.

Synthetic androgens include methyltestosterone and fluoxymesterone. They are not as

effective as testosterone, but have better bioavailability. Certain synthetic androgens have higher
anabolic and lower androgenic activity. They are referred to as anabolic steroids, and include
drugs like oxymetholone, methandienone, and nandrolone.

Physiological actions:

● Promotes growth of male genital organs during puberty.

● Promotes development of male secondary sexual characteristics, including facial, pubic,
and axillary hair growth. This also includes growth of larynx and deepening of voice.
● Induces pubertal growth spurt, which allows for growth of the skeleton and skeletal
muscles.
● Promotes erythropoiesis, which increases the hematocrit of men relative to women.

Pharmacokinetics:

Natural testosterone undergoes high first-pass metabolism in the liver. They must be
combined with esterified lipids to increase the bioavailability and duration of action. However,
synthetic androgens are metabolized slowly and have a much longer duration of action. In
plasma, androgens are highly bound to plasma proteins. Metabolism occurs in the liver, mostly
through glucuronide conjugation. Excretion occurs through the urine.

Adverse effects:

● In females, androgens can cause hirsutism, deepening of voice, and male pattern
baldness.
● In males, excessive use of androgens can cause priapism, gynecomastia, and impotence.
● Anabolic steroid use can cause premature closure of epiphyseal plates, causing stunted
growth. They can also cause mood disturbances and aggression.

Therapeutic uses:
 ● Testosterone is usually used for the treatment of primary or secondary hypogonadism.
● Anabolic steroids are used to treat muscle wasting in conditions like AIDS or cancer.
Moreover, they may also be used to treat senile osteoporosis and severe burns.
● Androgens can be used to enhance skeletal growth in prepubertal boys with pituitary
dwarfism.

ANTI-ANDROGENS

● These are a group of drugs that block the synthesis or actions of androgens.
● Finasteride and dutasteride block synthesis of testosterone by inhibiting the enzyme 5-α-
reductase.
● Flutamide, nilutamide, and related drugs compete with androgens for their receptors and
block their effects.
● These drugs find application in treatment of benign prostate hyperplasia, or in prostate
cancer.

ESTROGENS

Estrogens are a group of hormones that are secreted by the ovary. The principal estrogen is
estradiol. Estrone and estriol are metabolites of estradiol and are less potent.

Physiological functions:

● Brings about pubertal changes in women such as growth of uterus, ovaries, and fallopian
tubes.
● Confers secondary sexual characteristics, such as development of breasts, pubic and
axillary hair.
● Maintains bone mass by preventing bone resorption and increasing the expression of
bone matrix proteins.
● Metabolic effects: Estrogens decrease plasma low-density lipoprotein (LDL) and
cholesterol, and increase high-density lipoprotein (HDL) and triglyceride levels. They
may slightly impair glucose tolerance.
● Blood vessels: They increase blood coagulability and fibrinolytic activity. They also
relax vessel wall musculature and cause vasodilation.

Types of therapeutic estrogens:

● Natural: Estradiol is predominantly used. It is not very effective when taken orally.
● Synthetic estrogens: These include steroidal derivatives like ethinyl estradiol, and non-
steroidal derivatives like diethylstilbestrol.

Pharmacokinetics:

Estradiol is rapidly absorbed through the skin, mucous membranes, and GIT. However, from
the GIT, it is immediately metabolized by the liver. Synthetic compounds are well absorbed
orally, and are stored in the adipose tissue, from which they are released slowly. They are
metabolized both in the liver and peripheral tissues. They are excreted in the bile, and active
metabolites are reabsorbed through enterohepatic circulation. Inactive metabolites are eventually
excreted through the urine.

Adverse effects:

● Minor effects – Nausea, breast tenderness, migraine

● Increased risk of breast and endometrial cancer, especially with unopposed use (without
progestin).
● Increased risk of thromboembolic events such as myocardial infarction.

Therapeutic uses:

● Post-menopausal hormonal replacement therapy: Menopause may cause unpleasant

symptoms such as hot flushes, cognitive changes, and urogenital atrophy. Hormone
replacement therapy can suppress these effects. However, due to the risk of adverse
effects, the minimum possible dose of estrogen must be used.
● Contraception: For this purpose, it is usually used in combination with progesterone.

ESTROGEN RECEPTOR MODULATORS

These are drugs that have either agonist or antagonist effects on estrogen receptors.

Clinical actions:

● Antagonist effects in breast tissue: Tamoxifen, toremifene, and raloxifene are

competitive antagonists for estrogen in the breast tissue.
● Agonist effect on bone: Raloxifene acts similar to estrogen in preserving bone mass.
● Endometrium: Tamoxifen can act like estrogen and predispose to endometrial cancer.
Raloxifene does not have agonist activity in this region.
● Metabolic effects: Like estrogen, raloxifene lowers LDL and cholesterol levels in
plasma.
● Influence on pituitary: Some drugs like clomiphene are only partial agonists, and
interfere with the negative feedback mechanism on the pituitary. This increases
secretion of gonadotropin-releasing hormone, which in turn stimulates gonadotropin
secretion and stimulates ovulation.

Pharmacokinetics:

These drugs are absorbed orally. Metabolism occurs in the liver through cytochrome P450
system and glucuronide conjugation. Metabolites are excreted in the bile, undergo enterohepatic
circulation, and are finally excreted through feces.

Adverse effects:

Estrogen modulator inhibitor Adverse effects

Hot flashes, nausea,
Tamoxifene endometrial hyperplasia and malignancy
Hot flashes, nausea
Raloxifene
Increased risk of thromboembolic events
 Clomiphene Headache, nausea, hot flushes
Ovarian enlargement, risk of multiple births

Therapeutic uses:

● Tamoxifen – Metastatic breast cancer to reduce malignancy size

● Raloxifene – Prevention of osteoporosis in post-menopausal women
● Clomiphene – Infertility due to anovulation
● Ospemifene – Treatment of dyspareunia

PROGESTOGENS

This hormone is secreted in response to stimulation from luteinizing hormone. It is secreted

from the corpus luteum in the second half of the menstrual cycle, and also from the placenta.
Small amounts are also secreted from the adrenal cortex, in both men and women.

Physiological functions:

● Progesterone basically primes the body for pregnancy.

● Uterus: It prepares the uterus for implantation. When progesterone levels decrease,
menstruation occurs.
● Vagina and cervix: It thickens secretions, increases leukocyte infiltration.
● Breast: Prepares breast for lactation. Proliferation of acinar cells occurs.
● Synthetic progesterones: Natural progestin is not suitable for metabolic use, as it is
metabolized rapidly. Some of the common synthetic progesterone derivatives include
desogestrel, norethindrone, and medroxyprogesterone.

Pharmacokinetics:

Natural progesterone is metabolized rapidly when taken orally, and has a very short half-life.
Synthetic progesterones can mostly be taken orally. They are metabolized slowly in the liver, and
excreted in urine as inactive metabolites.

Adverse effects:

● Headache, breast tenderness, amenorrhea

● Long-term use can predispose to diabetes and breast cancer.

Therapeutic uses:

● Along with estrogen, it may be used in:

○ Hormone replacement therapy for post-menopausal women
○ For contraception
● Dysmenorrhea
● Endometriosis: prevents bleeding from ectopic sites
● To prevent abortion in high-risk cases
ANTI-PROGESTINS

● Mifepristone, an anti-progestin, has partial agonist-antagonist activity.

● It inhibits progesterone, and can thus be used to induce abortion in early pregnancy.
● Adverse effect: It can cause severe uterine bleeding.
EXERCISES
1. What is the main reason for using synthetic androgens and estrogens for therapeutic use?

a. Natural forms are difficult to obtain

b. Natural forms get metabolized very fast

c. Natural forms are not absorbed well orally

d. Natural forms may be toxic

2. Which drug is used in muscle wasting conditions?

a. Mifepristone

b. Desogestrel

c. Nandrolone

d. Tamoxifene

3. Which of the following drugs inhibits the synthesis of androgens?

a. Finasteride

b. Flutamide

c. Mifepristone

d. Raloxifene

4. Which of the following drugs is used to reduce the size of breast malignancies?

a. Mifepristone

b. Desogestrel

c. Nandrolone

d. Tamoxifene

5. Which of the following drugs is used for prevention of abortion?

 a. Mifepristone

b. Desogestrel

c. Nandrolone

d. Tamoxifene

6. Which of the following drugs carries the risk of inducing multiple births?

a. Tamoxifen

b. Raloxifene

c. Clomiphene

d. Ospemifene

7. Which of the following drugs does not compete for estrogen in the breast tissue?

a. Tamoxifen

b. Raloxifene

c. Clomiphene

d. Ospemifene

8. Which of the following drugs is used for the treatment of dyspareunia?

a. Tamoxifen

b. Raloxifene

c. Clomifene

d. Ospemifene

9. Which of the following hormones primes the body for pregnancy?

a. Estrogen

b. Prolactin

c. Progesterone

d. Oxytocin

10. Which of the following drugs is used to induce abortion?

a. Mifepristone

b. Desogestrel

c. Nandrolone

d. Tamoxifene
 UNIT VI – THE CARDIOVASCULAR SYSTEM
CHAPTER 1: DRUGS USED IN HYPERTENSION
Antihypertensives are a group of drugs that are used to manage high blood pressure. Any
patient who has systolic blood pressure above 140mmHg, or diastolic pressure above 90mmHg is
considered to be hypertensive. Most patients suffer from primary or ‘essential’ hypertension,
where the cause is not known. While hypertension itself does not cause any symptoms, it is a
major risk factor in the development of other morbid conditions such as heart disease, stroke, and
kidney failure.

There are several different categories of anti-hypertensive agents based on their mechanism
of action. These drugs are chosen based on the degree of hypertension and other medical
comorbidities present.

DIURETICS

The exact mechanism and pharmacology of diuretics is discussed in detail in Unit X.

Basically, by promoting urinary excretion, diuretics decrease blood volume, which in turn lowers
the blood pressure. Given in low doses, diuretics are the initial drug of choice for hypertension in
most patients. The following forms of diuretics are used in the management of hypertension:

Thiazide diuretics:

● These include the drugs hydrochlorothiazide and chlorthalidone.

● These drugs lower blood pressure by increasing sodium and water excretion.
● Long-term use tends to normalize plasma volume. However, the hypotensive effect
continues because of lowered peripheral vascular resistance.
● Adverse effects: Hypokalemia, hyperuricemia, hyperglycemia
● Indications: As monotherapy in patients with mild hypertension. May be combined with
other drugs for moderate to severe hypertension.
● Contraindications: Cannot be used in patients with renal dysfunction (efficacy is
reduced).

Loop diuretics:

● These include the drugs furosemide, bumetanide, and ethacrynic acid.

● They block sodium and chloride reabsorption in the kidney. They also increase renal
blood flow and decrease renal peripheral vascular resistance.
● Adverse effects: Hypokalemia, fluid imbalance, hypercalcemia
● Indications: For management of hypertension in patients with
○ Congestive cardiac failure – decreases fluid load in these patients
○ Renal dysfunction

Potassium-sparing diuretics:
 ● These include the drugs triamterene, amiloride, and spironolactone.
● The first two drugs prevent sodium reabsorption, while spironolactone acts as an
antagonist for aldosterone.
● They reduce potassium loss in urine and are therefore combined with the previous
diuretics to prevent hypokalemia.

ACE INHIBITORS

The first angiotensin-converting enzyme inhibitor to be used was captopril. Today,

commonly used drugs include enalapril and lisinopril.

Mechanism of action:

An important factor in the determination of blood pressure is the renin-angiotensin-

aldosterone mechanism:

● The kidneys respond to decreased blood arterial pressure by releasing an enzyme called
renin.
● Renin acts on angiotensinogen to convert it into angiotensin I.
● Angiotensin I is converted into angiotensin II in the presence of angiotensin converting
enzyme (ACE).
● Angiotensin II causes vasoconstriction, which increases the blood pressure. It also
stimulates secretion of aldosterone, which reabsorbs sodium and water, and increases
the blood volume, thereby contributing to a rise in blood pressure.

ACE inhibitors prevent conversion of angiotensin I into angiotensin II. They reduce
peripheral vascular resistance. Decreasing sodium and water retention also decreases the blood
volume, which decreases the preload and after-load on the heart.
 Figure 9 The renin-angiotensin-aldosterone system is a hormone system within the body that is essential for the regulation
of blood pressure and fluid balance. Kidneys respond to decreased blood pressure by releasing renin, which acts on
angiotensinogen and converts it into angiotensin I. Angiotensin I is converted into angiotensin II in the presence of ACE.
Angiotensin II causes vasoconstriction, thereby increasing blood pressure; it also stimulates secretion of aldosterone from the
adrenal glands, which reabsorbs sodium and water, also contributing to the rise in blood pressure.

Pharmacokinetics:

All ACE inhibitors can be taken orally. Metabolism generally occurs in the liver. For
captopril and lisinopril, even the metabolites are active, so they may be preferred in patients with
renal impairment. Most drug metabolites are excreted in the urine. The metabolites of fosinopril
may be partly excreted through bile. The t1/2 of some ACE inhibitors is summarized in Table 1.

Table 1. Elimination half-life of ACE inhibitors

DRUG ELIMINATION HALF-LIFE
Captopril 2 hours
Enalapril 11 hours
Lisinopril 12 hours
Fosinopril 12 hours
Perindopril 24 hours
Ramipril 48 hours

Adverse effects:

● Minor: Dry cough, fever, altered taste, headache, nausea

● Hypotension
● Rash, urticaria, angioedema: Due to increases bradykinin levels
● Hyperkalemia: Must not be combined with potassium-sparing diuretics
● Teratogen

Indications:

● Hypertension: May be used as first-line drugs for management of hypertension.

● Congestive cardiac failure: They decrease blood volume and reduce the workload on
the heart.
● Myocardial infarction: ACE inhibitors reduce mortality following MI, if they are
administered when MI is evolving, and are continued for up to six weeks.
● Diabetic nephropathy: It can prevent or delay end stage renal disease in diabetics.

ANGIOTENSIN II RECEPTOR BLOCKERS

● This category includes drugs such as losartan, candesartan, and olmesartan. These drugs
block angiotensin II from binding to its receptors, thus inhibiting its functions.
● Like ACE inhibitors, they reduce blood volume by preventing salt and water
reabsorption. They also lower peripheral vascular resistance.
● They do not decrease bradykinin levels and thus have a low risk of urticaria and
angioedema.
● Their other adverse effects, and indications are similar to ACE inhibitors.
● They must not be combined with ACE inhibitors because of a similar adverse effect
profile, which can be potentiated.

RENIN INHIBITOR

● Aliskiren is a drug that inhibits renin. It thus functions similar to ACE inhibitors and
angiotensin receptor blockers. It should not be combined with these drug categories.
● It may be administered orally, but has low bioavailability. It is excreted in feces. Plasma
half-life is 24 hours.

CALCIUM CHANNEL BLOCKERS

 Mechanism of action:

Calcium basically mediates action potential development, and muscle contraction in smooth
muscles and cardiac muscles. Calcium channel blockers (CCBs) prevent intracellular influx of
calcium, which decreases the intracellular calcium and prevents action potential.

Clinical actions:

● Smooth muscle relaxation: This includes smooth muscle of the vascular walls, which
causes vasodilation. This effect is mainly seen in arterioles, and not the veins.
● Negative inotropic, chronotropic, and dromotropic action on the heart: This means a
decrease in the force of contraction, heart rate, and conduction velocity of the heart.

Pharmacokinetics:

Based on their chemical structure and pharmacokinetics, CCBs are divided into three
categories:

● Diphenylalkylamines: Verapamil is the main drug in this category. It is well absorbed

orally, and has a bioavailability of 15-30% due to high first-pass metabolism. It is
metabolized in the liver and excreted in the urine. Plasma half-life is 4 to 6 hours.
● Benzothiazepines: This consists of one drug, diltiazem. It is well absorbed orally, has a
bioavailability of 40% to 60%, and is 80% bound to plasma proteins. It is metabolized
in the liver and excreted through urine. Plasma half-life is 5 to 6 hours.
● Dihydropyridines: This consists of several useful drugs, including nifedipine,
amlodipine, and nicardipine. The pharmacokinetics are similar to the above drugs.
Plasma half-life differs, with nifedipine having a short half-life of 2 to 5 hours, and
amlodipine having the longest, ranging from 25 to 35 hours.

Adverse effects:

● Verapamil – Can cause constipation. It can also aggravate first degree AV block and is
contraindicated in these conditions.
● Dihydropyridines- Dizziness, headache, fatigue, and peripheral edema. They can also
cause gingival hyperplasia.

Indications:

● Hypertension: May be used both as first-line or add-on therapy. They are indicated in
patients who suffer from asthma, diabetes, and peripheral vascular disease, as they do
not adversely affect these conditions.
● Angina: Their vasodilating effect reduces workload on the heart.

ADRENERGIC BLOCKERS:

These drugs have been discussed in detail in Unit III. Both α and β blockers are used in the
management of hypertension
β blockers:

● They act in two ways to reduce blood pressure. Firstly, they act directly on the heart to
reduce cardiac output. Secondly, they reduce sympathetic stimulation to the kidney,
which inhibits the release of renin.
● Selective β1 blockers, including metoprolol and atenolol are commonly prescribed. Non-
selective blockers must be avoided in asthmatics, as they can cause
bronchoconstriction.
● Adverse effects include bradycardia, hypotension, fatigue, and lethargy. Abrupt
withdrawal of these drugs can induce angina or myocardial infarction. If discontinued,
these drugs must always be tapered off.
● They are useful for primary treatment of hypertension, especially in patients with
concomitant heart disease.

α blockers:

● These include the drugs prazocin, terazocin, and doxazocin.

● They reduce blood pressure by relaxing the smooth muscles of the vascular walls, which
lowers peripheral vascular resistance.
● Adverse effects include postural hypotension and tachycardia. Long-term use can lead to
congestive heart failure due to sodium and water retention.
● They are not used for initial treatment owing to their adverse effects, and are reserved for
refractory cases.

Combined α/β blockers:

● These include the drugs labetalol and carvedilol.

● They produce pharmacological effects of both α and β blockers, resulting in a profound
fall in blood pressure.
● Labetalol is indicated during hypertension of pregnancy, and hypertensive emergencies.
Carvedilol is generally not used as an anti-hypertensive agent.

CENTRALLY ACTING α2 AGONISTS

● These drugs decrease sympathetic outflow to the periphery, resulting in fall in blood
pressure and bradycardia. The drugs in this category are discussed completely in Unit
III.
● Clonidine is indicated in patients with renal disease as it does not compromise renal
blood flow. Methyldopa is indicated for hypertension in pregnancy.

VASODILATORS

● These include the drugs hydralazine, dihydralazine, and minoxidil.

● As the name suggests, these drugs cause vasodilation by relaxing the smooth muscles in
the walls of arteries and arterioles.
● These agents tend to cause reflex stimulation of the heart. This leads to tachycardia,
increased myocardial contractility, and increased workload and oxygen consumption.
This can predispose to angina and myocardial infarction.
 ● They also increase renin secretion, and can cause sodium and water retention.
● For these reasons, vasodilators are always combined with beta blockers and diuretics.
● Hydralazine is used to manage hypertension in pregnancy. Topical minoxidil is used to
treat alopecia and male pattern baldness.

EXERCISES:
1. Hypertension is a risk factor for development of all of the following diseases except:

a. Heart disease

b. Diabetes
 c. Stroke

d. Kidney failure

2. Which of the following diuretics does not cause hypokalemia?

a. Furosemide

b. Hydrochlorothiazide

c. Spironolactone

d. Bumetanide

3. ACE inhibitors decrease the levels of which of the following?

a. Renin

b. Angiotensin I

c. Angiotensin II

d. None of the above

4. Which of the following ACE inhibitors has the longest plasma half-life?

a. Captopril

b. Lisinopril

c. Enalapril

d. Ramipril

5. Which of the following is not indicated as a primary drug for hypertension?

a. Losartan

b. Metoprolol

c. Prazosin

d. Chlorthalidone

6. Which of the following antihypertensives does not work on the renin-angiotensin system?

a. Lisinopril

b. Candesartan
 c. Atenolol

d. Alisartan

7. Which of the following drugs can cause gingival hyperplasia?

a. Verapamil

b. Nifedipine

c. Diltiazem

d. Enalapril

8. Which of the following antihypertensives can cause AV heart block?

a. Verapamil

b. Nifedipine

c. Diltiazem

d. Enalapril

9. Which of the following anti-hypertensives is preferred for patients with renal disease?

a. Minoxidil

b. Methyldopa

c. Clonidine

d. Hydralazine

10. Which of the following drugs is indicated in male pattern baldness?

a. Minoxidil

b. Methyldopa

c. Clonidine

d. Hydralazine
 CHAPTER 2: DRUGS USED FOR MYOCARDIAL
ISCHEMIA
Myocardial ischemia is a condition of reduced blood flow to the myocardium. Blood to the
heart usually comes from coronary arteries, so if there is a reduction in the diameter of these
arteries, the blood flow can be compromised. The most common cause is atherosclerotic disease,
where there is deposition of plaque on the walls of the coronary arteries. Uncommonly, other
causes, such as vascular smooth muscle spasm, can also lead to myocardial ischemia.

Myocardial ischemia can lead to angina, or myocardial infarction. There are three types of
angina – stable, unstable, and variant (or Prinzmetal) angina.

The drugs that are commonly used in the management of angina are summarized in Table 1.

Table 1. Drugs used in the management of angina

DRUG CATEGORY EXAMPLE PURPOSE

Glyceryl trinitrate, isosorbide To abort an established
Nitrates
dinitrate attack
Beta blockers Propranolol, metoprolol, atenolol Prophylaxis
Calcium channel
Verapamil, diltiazem, nifedipine Prophylaxis
blockers
Potassium channel
Nicorandil Prophylaxis
openers
Miscellaneous drugs Ranolazine, trimetazidine Prophylaxis

NITRATES

These are the first-line drugs used for relief from angina. Based on their onset and duration of
action, they are classified as:

● Short-acting: e.g., Glyceryl trinitrate or nitroglycerin

● Long-acting: e.g., Isosorbide dinitrate

Mechanism of action:

● Organic nitrates are converted into nitrates, which in turn is converted into nitric oxide
(NO).
● NO is a powerful vasodilator and acts by increasing the levels of cyclic GMP within
cells.
● Elevated cGMP causes dephosphorylation of the myosin light chain, which causes
relaxation of smooth muscles in the blood vessel walls.
 Clinical actions:

Nitrates basically reduce the demand for oxygen from the myocardium. It does this by the
following methods:

● Reducing the preload: Nitrates cause venous dilation, which decreases venous return to
the heart and workload of the heart.
● Reducing the afterload: There is also arteriolar dilation, which decreases the peripheral
resistance and afterload.
● Improved coronary blood flow: Direct dilation of coronary vasculature improves blood
flow to the ischemic regions of the myocardium.
● Other systemic effects: Cutaneous vasodilation can cause flushing of skin. Bronchi and
esophageal smooth muscles are relaxed slightly. There is decreased renal and
splanchnic blood flow to compensate for the vasodilation in other areas.

Pharmacokinetics:

Nitroglycerin has high first-pass metabolism and is therefore not administered orally. The
most preferred route is sublingual, from which it is quickly absorbed and acts within one minute.
Longer acting drugs have better oral bioavailability, and their onset of action may take up to 30
minutes.

Adverse effects:

● Most common is headache due to vasodilation.

● Other effects include hypotension, tachycardia, and facial flushing.

Indications:

● Angina: Including stable, unstable, and variant angina. Short-acting nitrates are used to
obtain immediate relief, while long-acting nitrates are used to reduce the frequency of
anginal attacks.
● Myocardial infarction and acute coronary syndromes: It improves outcomes in these
patients.
● Esophageal spasm and achalasia: Relieves spasm and promotes swallowing of food.

BETA BLOCKERS

● Beta adrenergic blockers block the β1 receptors of the heart. This decreases the heart
rate, force of contraction, and cardiac output. All this serves to reduce the workload and
oxygen demand of the myocardium.
● In patients with angina, they have the following therapeutic effects:
○ They decrease the frequency and severity of anginal attacks.
○ In stable angina, they improve exercise tolerance.
○ They improve mortality rates in patients who have had MI before, or who have cardiac
failure.
○ Non-selective beta blockers must be avoided in patients with asthma.
 CALCIUM CHANNEL BLOCKERS

● Calcium channel blockers cause vascular smooth muscle relaxation. Their main effect is
on the coronary vessels. They also reduce the afterload on the heart by vasodilation of
arterioles.
● They are used as prophylaxis in all three forms of angina. However, they are not
recommended for use in myocardial infarction.

POTASSIUM CHANNEL OPENERS

● Nicorandil causes an influx of potassium into the cells. This causes hyperpolarization of
vascular smooth muscle, resulting in vasodilation.
● There is arterial and venous dilation, as well as increase in coronary blood flow.
● It decreases the frequency of anginal attacks and improves exercise tolerance. It is also
believed to have a ‘cardioprotective effect’ which prevents vascular occlusion.
● Adverse effects include headache, flushing, dizziness, nausea, and vomiting

MISCELLANEOUS DRUGS

Ranolazine:

● This drug is a sodium channel blocker. It prevents intracellular entry of sodium, which
indirectly prevents calcium entry into cells. It thus functions similar to CCBs.
● It is reserved for patients in whom traditional antianginal therapy does not work.
● This drug can be administered orally. It has a bioavailability of 30 to 50%, and the onset
of action takes 4 to 6 hours. It is metabolized in the liver, through the cytochrome P450
system, and is excreted out through the urine. The elimination half-life is about 7 hours.

Trimetazidine:

● The exact mechanism of action of this drug is uncertain, but it acts by non-hemodynamic
mechanisms.
● It is useful in patients who are not responding to long-acting nitrates and CCBs.

PHARMACOTHERAPY IN MYOCARDIAL INFARCTION

Myocardial infarction (MI), or heart attack, is a condition where there is irreversible necrosis
(infarction) of the cardiac muscle. This occurs secondary to prolonged ischemia. Once MI
occurs, the goals of drug therapy are:

● To manage the patient’s pain and anxiety

● To limit the spread and extent of the infarct
● To reduce the workload on the heart
● To reverse the cause. For instance, a blocked coronary artery must be recannulated to
restore circulation to the myocardium.

Prehospital care: Along with providing supplemental oxygen, the following drugs are
indicated:
 ● Non-enteric coated aspirin: This has antiplatelet actions that prevent initiation of blood
clotting and help limit the infarct size.
● Nitroglycerin: This improves oxygen supply to the myocardium, and provides
symptomatic relief from pain. However, it does not improve mortality rates.

In-hospital care:

● Antithrombotic drugs: This includes heparin and related drugs. These potentiate the
action of anti-platelet drugs and prevent the formation of thrombi associated with MI.
● Beta blockers: These drugs reduce the workload of the heart and reduce its oxygen
demand. They also have antiarrhythmic properties, and prevent ventricular ectopy
following MI.
● ACE inhibitors or angiotensin receptor blockers: They also reduce cardiac workload,
especially in patients with ventricular dysfunction.
● Thrombolytic drugs: These are meant to dissolve the blood clot in the occluded vessels
and restore circulation. Fibrinolytic drugs, including streptokinase, urokinase, and
alteplase are used for this purpose.
● Analgesics: During this episode, it is essential to ensure that the patient has relief from
pain and anxiety. Morphine sulphate is the drug of choice.
EXERCISES:
1. Which of the following drugs is used to abort an established anginal attack?

a. Glyceryl trinitrate

b. Isosorbide dinitrate

c. Propranolol

d. Verapamil

2. Which of the following compounds is increased within the cell by the action of nitrates?

a. ATP

b. cAMP

c. GTP

d. cGMP

3. What is the most common side effect of nitrate drugs?

a. Headache

b. Nausea and vomiting

c. Renal dysfunction
 d. Tachycardia

4. Which of the following drugs has a cardioprotective effect on the heart?

a. Atenolol

b. Nicorandil

c. Isosorbide dinitrate

d. Diltiazem

5. Which of the following anti-anginal drugs does not have a hemodynamic mechanism of
action?

a. Verapamil

b. Metoprolol

c. Trimetazidine

d. Nicorandil

6. Which of the following drugs must not be used for angina patients who have asthma?

a. Verapamil

b. Propranolol

c. Trimetazidine

d. Nicorandil

7. What is the bioavailability of ranolazine?

a. 10-20%

b. 20-40%

c. 30-50%

d. 50-70%

8. Which is the analgesic drug of choice during a myocardial infarction?

a. Codeine

b. Tramadol

c. Morphine
 d. Ketorolac

9. Which of the following drugs does not improve mortality rates after myocardial
infarction?

a. Propranolol

b. Aspirin

c. Nitroglycerin

d. Enalapril

10. Which of the following drugs is used to lyse the blood clot after an MI?

a. Aspirin

b. Alteplase

c. Atenolol

d. Heparin
 CHAPTER 3: DRUGS USED IN ARRHYTHMIAS
The cardiac muscle is specialized in that it does not require external stimulus to facilitate
contraction. The heart contains a special group of ‘pacemaker’ cells that automatically generate
action potentials in a rhythmic fashion. Any defect in the generation or conduction of this action
potential can result in arrhythmias. The different kinds of arrhythmias that can commonly occur
are summarized in Table 1.

Table 1. Types of arrhythmias

CATEGORY OF ARRHYTHMIA TYPES

Atrial flutter
Atrial Arrhythmias
Atrial fibrillation
AV nodal entry
Supraventricular tachycardias Acute supraventricular tachycardia
Paroxysmal supraventricular tachycardia
Acute ventricular tachycardia
Ventricular tachycardias Ventricular fibrillation
Torsades de pointes
Disorders of conduction A-V block: first, second, and third degree block

Antiarrhythmic drugs prevent arrhythmias by modifying impulse generation or impulse

conduction, or they reduce symptoms associated with arrhythmias. To achieve this, these drugs
must act at some phase of the action potential. Antiarrhythmic drugs may be classified based on
the specific phase of the action potential at which they act. This is summarized in Table 2.

Table 2, Classification of antiarrhythmic drugs

DRUG PHASE OF ACTION POTENTIAL DRUG

EXAMPLES
CLASS BLOCKED CATEGORY
Class Phase 0 depolarization in ventricular Quinidine,
IA muscle fibers- slows procainamide
Class Phase 3 repolarization in ventricular Sodium Lidocaine,
IB muscle fibers - shortens channel blockers mexiletine
Class Phase 0 depolarization in ventricular Flecainide,
IC muscle fibers- greatly slows propafenone
Phase IV depolarization in SA and AV β adrenergic Metoprolol,
Class II
nodes blocker esmolol
Class Phase 3 repolarization in ventricular Potassium Amiodarone,
III muscle fibers - prolongs channel blocker dronedarone
Class Inhibits action potential generation in Calcium Verapamil,
IV SA and AV nodes channel blocker diltiazem

CLASS I ANTIARRHYTHMIC DRUGS

These are sodium channel blockers. They prevent sodium ions from entering the cell, thereby
preventing depolarization.

Class IA drugs

They bind to open and inactivated sodium channels, and act during phase 0 of depolarization.

Quinidine:

● This drug also blocks α-adrenergic receptors and cholinergic receptors. Other class I
drugs do not possess this activity.
● It is rapidly absorbed after oral administration. It is metabolized by the cytochrome P450
system. Metabolites are active.
● Adverse effects: Blurred vision, tinnitus, headache, disorientation, and psychosis. There
is also a high risk of cardiac arrest, and other arrhythmias like torsades de pointes.
● Indications: Quinidine may be used for all types of arrhythmias such as atrial, AV-
junctional, and ventricular tachyarrhythmias.

Procainamide:

● Procainamide is used to treat acute atrial and ventricular arrhythmias.

● It is short-acting and the effect lasts for about 2 to 3 hours.

Disopyramide:

● It has cardiac depressant effects, and mild anticholinergic actions.

● Disopyramide is used in atrial fibrillation and flutter, to maintain normal sinus rhythm.
● It is well absorbed orally. About 50% of the drug is metabolized in the liver through the
cytochrome P450 system and the rest is excreted unchanged in urine.
● Anticholinergic adverse effects: Dry mouth, blurred vision, constipation, and urinary
retention.

Class IB Antiarrhythmic drugs:

These drugs rapidly bind to and rapidly dissociate from the sodium channels. They tend to
function when the channels are in an inactivated state, and are useful when the heart ‘fires’
rapidly.

Lignocaine:

● Primarily a local anesthetic, it suppresses spontaneous firing from ectopic foci.

● It is commonly employed in ventricular fibrillation and pulseless ventricular tachycardia.
● It is given intravenously to avoid high first-pass metabolism. The other details of this
 drug are discussed in Unit IV.

Mexiletine:

● This drug is pharmacologically similar to lignocaine and functions in a similar manner.

● It is completely absorbed through the oral route, metabolized in the liver, and excreted
through urine. The plasma half-life is about 9 to 12 hours.
● It is indicated for chronic treatment of ventricular arrhythmias.

Class IC antiarrhythmic drugs

This is the most potent category in this class. They act on sodium channels in the open state
and markedly delay conduction.

Propafenone:

● Slows conduction in all cardiac pathways. In addition, it has some β-blocking action.
● Adverse effects: Bitter taste, nausea, vomiting, blurred vision, constipation.
● It is indicated for atrial arrhythmias and paroxysmal supraventricular tachycardias.

Flecainide:

● This drug also blocks potassium channels, which further prolongs the action potential.
● It is absorbed orally, metabolized in the liver by cytochrome P450 system, and excreted
in urine.
● It can cause dizziness, nausea, and blurred vision. It may aggravate chronic heart failure
due to its negative inotropic effect.
● It is indicated in resistant cases of atrial fibrillation, and life-threatening ventricular
tachycardia in patients who do not have congestive cardiac failure.

CLASS II ANTIARRHYTHMIC DRUGS

● These are beta blockers, which work by suppressing sympathetic activity.

● They slow the phase 4 of depolarization, which helps to prolong AV conduction, and
decreases the heart rate and force of contraction.
● Metoprolol is most commonly used. Esmolol, which is short-acting, is preferred for acute
arrhythmias that require immediate management.
● The main antiarrhythmic indications of beta blockers are:
○ Atrial flutter and atrial fibrillation
○ AV nodal reentrant tachycardia
○ Following MI, they prevent ventricular arrhythmias, which can be fatal.

CLASS III ANTIARRHYTHMIC DRUGS

These are potassium channel blockers. They prevent the outflow of potassium from the cells
during the repolarization phase. Thus, they prolong the refractory period that immediately
follows the action potential.
 Amiodarone:

Amiodarone and dronedarone are potassium channel blockers that exhibit some degree of
Class I, II, and IV activity as well. They also block α-adrenergic receptors to some extent.

Pharmacokinetics:

On oral administration, the drug is absorbed slowly and incompletely. Therefore, onset of
action may take days to weeks. Intravenous injection of the drug can produce rapid onset. It is
stored in adipose tissue and skeletal muscle, from where it is slowly released. The plasma half-
life is 3 to 8 weeks. Metabolism occurs in the liver, through the cytochrome P450 system.

Adverse effects:

● Corneal deposits, optic neuritis, bluish-grey discoloration of skin.

● Nausea, vomiting, hepatotoxicity
● Can cause hypothyroidism or hyperthyroidism.
● Prolonged use may cause pulmonary alveolitis and fibrosis.

Indications:

● Drug of choice for atrial fibrillation and flutter

● Supraventricular tachycardias, ventricular tachyarrhythmias.

Sotalol:

● This is a Class III agent that also has properties of non-selective β blockers.
● It is preferred for patients with left ventricular hypertrophy or atherosclerotic heart
disease. In these patients, it is indicated for atrial fibrillation, atrial flutter, or
supraventricular tachycardia.

CLASS IV ANTIARRHYTHMIC DRUGS

● These are calcium channel blockers and include the drugs verapamil and diltiazem.
● These drugs bind selectively to the open, depolarized, voltage-sensitive calcium
channels, and prevent inward movement of calcium. This prevents repolarization from
occurring until the drug dissociates from the channel.
● The SA nodes and AV nodes are dependent on calcium to generate current, and these
drugs can inhibit this process.
● They reduce ventricular rate in atrial flutter and fibrillation. They are also used for the
management of supraventricular tachycardia.

OTHER DRUGS USED IN ARRHYTHMIA

Adenosine:

● This is a naturally occurring nucleoside, which forms an important component of DNA,

RNA, and energy compounds.
 ● At high doses, it can inhibit automatic firing of the AV node, can decrease conduction
velocity, and can prolong the refractory period.
● It has a short onset of action (10 to 15 seconds) and is ideal for use in acute
supraventricular tachycardia.
● Adverse effects: Hypotension, chest pain, flushing.

Magnesium sulfate:

● Magnesium is a dietary mineral. In the body, one of its main functions is to facilitate
transport of ions such as sodium, potassium, and calcium across cell membranes.
● When administered intravenously, it can retard impulse generation from the SA node. It
can also prolong conduction.
● It is indicated for life threatening arrhythmias, including digoxin-induced arrhythmias
and torsades de pointes.
EXERCISES:
1. Which class of antiarrhythmic drugs does lignocaine belong to?

a. Class IA

b. Class IB

c. Class II

d. Class IC

2. Which ion channel is blocked by Class I antiarrhythmic agents?

a. Sodium

b. Potassium

c. Calcium

d. Chloride

3. Which of the following drugs had anticholinergic effects?

a. Quinidine

b. Procainamide

c. Disopyramide

d. Lignocaine

4. What is the plasma half-life of mexiletine?

a. 2 to 3 hours
 b. 4 to 5 hours

c. 7 to 8 hours

d. 9 to 12 hours

5. Which of the following drugs has potassium channel blocking, as well as β blocking
effects?

a. Atenolol

b. Propranolol

c. Sotalol

d. Esmolol

6. Which of the following drugs can cause pulmonary fibrosis?

a. Quinidine

b. Sotalol

c. Amiodarone

d. Magnesium sulfate

7. What is the drug of choice for atrial fibrillation and flutter?

a. Digoxin

b. Amiodarone

c. Metoprolol

d. Adenosine

8. What is the mechanism of action of potassium channel blockers?

a. Prevent generation of impulse

b. Retard depolarization

c. Prolong refractory period

d. Inhibit impulse conduction

9. Which nucleoside is used as an antiarrhythmic agent?

a. Guanosine
 b. Adenosine

c. Thymidine

d. Inosine

10. When used for management of arrhythmias, what route must magnesium sulfate be
administered?

a. Oral

b. Sublingual

c. Intramuscular

d. Intravenous
 CHAPTER 4: DRUGS USED IN HEART FAILURE
Heart failure is a condition where the heart fails to pump enough blood to meet the needs of
the body. While the body initially tries to compensate, ultimately, a lot of pathological changes
occur in the heart. A short summary of pathological changes that occur in heart failure is given
below:

● Initially, low cardiac output results in a drop in blood pressure. This is detected by the
baroreceptors, which in turn cause sympathetic stimulation.
● Sympathetic activity stimulates the beta-adrenergic receptors. This increases the force of
contraction of the heart. However, β stimulation also causes vasoconstriction. This
increases venous return, and the pre-load. The workload of the heart increases.
● Low cardiac output also decreases renal perfusion, which stimulates renin release. The
renin-angiotensin-aldosterone system causes sodium and water retention, increasing the
blood volume. This further increases cardiac workload.
● To compensate for the excess workload, there is hypertrophy of cardiac muscle. While
initially this may increase the force of contraction, ultimately the fibers elongate,
weaken, and the force of contraction lessens.
● Therefore, although the heart can initially compensate, over time, there is decompensated
heart failure. In decompensated heart failure, there is edema due to fluid retention,
dyspnea, and fatigue.

AIMS OF THERAPY IN HEART FAILURE

The therapeutic aims in heart failure are as follows:

● Improve inotropic effect on the heart, without increasing the workload

● Decrease fluid retention and promote excretion of sodium and water
● Inhibition of the sympathetic nervous system

Drugs that improve force of contraction:

Certain drugs are used to improve the force of contraction of the heart, which in turn
improves the cardiac output. These are referred to as inotropic drugs.

CARDIAC GLYCOSIDES

Cardiac glycosides are drugs that increase the inotropic activity of the heart by influencing
the flow of sodium and calcium ions. They come from the foxglove plant and are collectively
referred to as digitalis. The main cardiac glycoside in use today is digoxin.

Mechanism of action:

● This drug inhibits the enzyme Na+/K+ ATPase, which is responsible for pumping
sodium out of the cell.
 ● The increased intracellular sodium increases the concentration gradient, which stimulates
the Na+/Ca2+ exchanger pump. This drives calcium into the cell. The increased
calcium is available for the next excitation-contraction coupling, and increases the
force of contraction.

Clinical actions:

● Heart: It has the following effects

○ Positive inotropic effect: increases force of contraction of the heart. It shortens systole
and prolongs diastole.
○ Decreases heart rate, causing bradycardia
○ Depresses generation and conduction of the action potential
● Kidney: Causes diuresis due to increased circulation and renal perfusion
● CNS: Stimulates chemoreceptor trigger zone, leading to nausea and vomiting. Can cause
some amount of mental confusion, disorientation, and visual disturbances.

Pharmacokinetics:

It is available in both oral and intravenous forms. On oral administration, bioavailability is

about 60-80%. After absorption, 25% of it is bound to plasma proteins, and the rest is widely
distributed. It gets concentrated in the heart, skeletal muscle, liver, and kidney.

The onset of action occurs in 15 to 30 minutes. It does not undergo metabolism, and is
excreted unchanged in the urine. Plasma half-life is about 40 hours.

Adverse effects:

● Blurred or yellowish vision

● Anorexia, nausea, and vomiting
● Can induce different kinds of arrhythmias.

Indications:

● Congestive cardiac failure

● Cardiac arrhythmias: Including atrial fibrillation, and paroxysmal supraventricular
tachycardias.

BETA-ADRENERGIC AGONISTS

● The commonly used inotropic drugs in this category are dobutamine and dopamine.
● These drugs increase cyclic AMP levels, which activate protein kinase. This in turn
causes phosphorylation of slow calcium channels, and increases calcium entry into the
myocardial cells, this enhances muscle contraction.
● They are used intravenously for management of acute heart failure in the hospital setting,
and cannot be used for long-term.

Drugs that decrease fluid retention

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS:

● These drugs inhibit angiotensin II and aldosterone. This prevents sodium and water
retention. They also cause vasodilation. Both these effects reduce the preload and
afterload on the heart.
● They are indicated in all stages of left ventricular failure, and in heart failure with
reduced ejection fraction.
● ACE inhibitors increase bradykinin levels, and may predispose to angioedema. In
patients who cannot tolerate them, angiotensin-receptor blockers may be used instead.

DIURETICS:

● Diuretics promote excretion of sodium and water by the kidneys. This relieves the
congestion and edema that occurs in heart failure.
● Loop diuretics such as furosemide are the most effective diuretics. Thiazide diuretics are
not useful.
● They promptly relieve symptoms of heart failure, such as dyspnea and orthopnea.
However, they do not improve mortality rate, and must be used with other agents such
as beta blockers or ACE inhibitors.

Drugs that inhibit the sympathetic nervous system

● Beta adrenergic blockers are the main class of drugs that are used to suppress the
sympathetic overactivity that occurs in heart failure.
● Beta-blockers are actually known for their negative inotropic effect. However, they do
have more benefit in patients with heart failure, as they reduce the oxygen demand and
consumption by the myocardium.
● These drugs also inhibit release of renin from the kidneys.
EXERCISES:
1. Which of the following is not a primary management goal in heart failure?

a. Decrease fluid retention

b. Inhibit sympathetic activity

c. Inhibit electrical activity

d. Improve force of contraction

2. Which enzyme is inhibited by digoxin?

a. Kinase

b. Na+/K+ ATPase

c. Angiotensin converting enzyme

 d. Phosphorylase

3. Which of the following ions promotes cardiac muscle contraction?

a. Sodium

b. Calcium

c. Potassium

d. Chloride

4. What is the bioavailability of digoxin when administered by oral route?

a. 10-20%

b. 20-40%

c. 40-60%

d. 60-80%

5. What is the time of onset of action of digoxin?

a. 10-15 minutes

b. 15-30 minutes

c. 30-45 minutes

d. 45-60 minutes

6. Which drug is preferred for the management of acute heart failure in the hospital setting?

a. Adrenaline

b. Dopamine

c. Digoxin

d. Adenosine

7. What compound is increased by beta adrenergic agonists?

a. ATP

b. cAMP

c. GTP
 d. cGMP

8. Which of the following classes of diuretics is preferred for symptomatic relief in heart
failure?

a. Loop diuretics

b. Thiazide diuretics

c. Osmotic diuretics

d. Potassium sparing diuretics

9. Which of the following drugs does not improve mortality rates in heart failure?

a. Metoprolol

b. Digoxin

c. Enalapril

d. Furosemide

10. What is the reason for using beta-blockers in heart failure?

a. Negative inotropic effect

b. Vasodilation

c. Inhibition of sympathetic activity

d. Bradycardia effect
 UNIT VII: HEMATOPOIETIC SYSTEM
CHAPTER 1: HEMATINICS AND DRUGS AFFECTING
BLOOD CLOTTING
The hematopoietic system consists of the red blood cells, white blood cells, and platelets.
The most common diseases that affect this system are anemia, thrombotic diseases, and bleeding
disorders.

DRUGS USED TO TREAT ANEMIAS

Anemia is a condition where there is a decrease in concentration of circulating plasma

hemoglobin. It occurs due to a wide variety of causes. Broadly, anemia may be genetic or
acquired. Acquired anemia can be due to nutritional deficiencies, chronic blood loss, infections,
and other conditions. Accordingly, a wide variety of drugs are available to treat anemia, which
are described in this chapter.

Iron:

● The heme component of hemoglobin consists of four molecules of iron. Apart from this,
iron is also combined with storage proteins (as ferritin), or with transport proteins (as
transferrin). Iron is largely obtained from the diet. If nutritional intake is not adequate,
or if there is excessive blood loss, iron deficiency anemia may occur. This may be
corrected by taking supplements of elemental iron.
● Pharmacokinetics: Iron is usually absorbed from the intestine in the ferrous form. Hence
it is administered orally as ferrous sulphate, ferrous gluconate, or ferrous aluminum
citrate. Parenteral preparations are also available as iron dextran or iron sucrose.
● Adverse effects: Abdominal pain, constipation, diarrhea, and black stools can occur with
oral administration. Parenteral administration can cause anaphylaxis.

Folic acid:

● Like iron, this is primarily used to address deficiency states. This can occur during
pregnancy, alcoholism, small intestine diseases, or during therapy with certain drugs
that inhibit the enzyme dihydrofolate reductase (e.g. Methotrexate).
● It is indicated for treatment and prophylaxis against megaloblastic anemia, caused due to
folate deficiency.
● It is absorbed from intestinal jejunum, and excess is excreted unchanged. No side effects
are reported.

Cyanocobalamin:

● This is vitamin B12. It is deficient in pernicious anemia, a condition where the gastric
parietal cells fail to produce the ‘intrinsic factor’ required for its absorption. Dietary
deficiency may also occur, and megaloblastic anemia may require combination
 treatment with vitamin B12 and folate. Other conditions, like malabsorption syndromes
and gastric resection may contribute to deficiency.
● It is administered parenterally in pernicious anemia. For other types of deficiency, it may
be administered orally along with folate. It does not have adverse effects.

Erythropoietin:

● This is a glycoprotein that is synthesized in the kidney. It stimulates differentiation of

proerythroblasts and release of reticulocytes into the bloodstream.
● Human erythropoietin, called epoetin alfa, produced by recombinant DNA technology, is
indicated for anemia secondary to bone marrow disorders and end-stage renal disease.
● Adverse effects usually occur due to sudden increase in hematocrit. This increases risk of
clot formation, especially around the A-V shunts in patients on dialysis.

Hydroxyurea:

● This is largely used in sickle cell anemia. It reduces the frequency of sickle crises.
● This increases the levels of fetal hemoglobin and dilutes the abnormal hemoglobin.
However, it can cause bone marrow suppression and cutaneous vasculitis.
● It is also used in chronic myeloblastic anemia and polycythemia vera.

Pentoxifylline:

● This drug improves the flexibility of erythrocytes and reduces blood viscosity.
● Its clinical effects are to improve blood flow, enhance tissue oxygenation, and reduce
systemic vascular resistance.
● It is indicated in conditions where there is reduced blood flow to the tissues, such as
intermittent claudication, diabetic angiopathies, osteoradionecrosis, and leg ulcers.

DRUGS AFFECTING BLOOD COAGULATION

Blood coagulation is a normal physiological response to insult or injury. While this is

beneficial after injury, sometimes intrinsic coagulation can cause thrombus formation which can
lead to ischemic conditions. There are two phases of blood coagulation - the initial phase in
which platelet aggregation occurs, and the final phase marked by the coagulation cascade. Drugs
are categorized based on the phase on which they act.

Antiplatelet drugs

These drugs inhibit the formation of the initial blood clot, or the platelet plug.

Aspirin:

● Aspirin inactivates the cyclo-oxygenase enzyme-1, which in turn inhibits the formation
of thromboxane A2 which is responsible for platelet aggregation. Thus, aspirin inhibits
platelet aggregation.
● For antiplatelet action, the recommended dose is around 75mg a day. It is well absorbed
from the oral route, and is converted to salicylic acid in the liver. The half-life of
 salicylic acid lasts up to 12 hours, after which it is metabolized and excreted in the
urine.
● Aspirin prolongs bleeding time. It can also cause occult GI bleeds.

Ticlopidine, clopidogrel, and prasugrel:

● These compounds prevent binding of ATP to platelet surface receptors, thereby

inhibiting platelet aggregation.
● These agents can be taken orally. Food interferes with absorption of only ticlopidine.
After absorption, these drugs bind to plasma proteins, and are metabolized in the liver.
Excretion occurs through urine and feces.
● Ticlopidine can cause serious adverse reactions such as agranulocytosis, aplastic anemia,
and purpura. All these drugs can cause prolonged bleeding.

Glycoprotein receptor antagonists:

● Drugs such as abciximab, eptifibatide, and tirofiban act by inhibiting glycoprotein

IIb/IIIa receptors, which usually facilitates binding of fibrinogen and von Willebrand
factor, and leads to platelet aggregation.
● These drugs are usually given intravenously, and act within 30 minutes. They are rapidly
cleared from plasma and excreted in urine. However, the antiplatelet effect of a single
dose can act up to 48 hours.

Dipyridamole:

● This drug inhibits the enzyme cyclic nucleotide phosphodiesterase. This reduces
intracellular cAMP levels and suppresses thromboxane A2 formation.
● It is used from oral route, is highly bound to plasma proteins, undergoes glucuronide
conjugation in the liver, and is excreted in feces.
● It can cause vasodilation and is contraindicated in patients with unstable angina, as this
can get worsened.

Indications of antiplatelet drugs:

● Patients with evidence of coronary artery disease

● Acute coronary syndromes, including unstable angina and myocardial infarction
● Cerebrovascular disease
● Patients with prosthetic heart valves and AV shunts
● Venous thromboembolism, for prophylaxis and treatment

Antithrombotic drugs:

These drugs inhibit the coagulation cascade, or the formation of the final blood clot.

Heparin and heparin analogues:

● Heparin is an anticoagulant that occurs naturally in the body in the lungs, liver, and
intestinal mucosa. It is present along with histamine in the mast cells. For
 pharmacotherapy, heparin derived from porcine sources are produced in two forms:
○ Unfractionated heparin (UFH)
○ Low-molecular-weight heparins (LMWH) – enoxaparin, dalteparin, and tinzaparin
● Mechanism of action: Heparin binds with antithrombin III, and this complex inactivates
factors II and X of the clotting cascade.
● Pharmacokinetics: UFH is administered intravenously, while LMWH may be
administered subcutaneously. It binds to several proteins and is metabolized by the
monocyte macrophage system. Metabolites are excreted in urine.
● Adverse effects:
○ Excessive bleeding. This may be reversed by using the antidote protamine sulfate.
○ Allergic reactions, including anaphylaxis
○ Thrombocytopenia
● Indications: Prevention and management of venous thromboembolism.

Synthetic anticoagulants:

● Fondaparinux binds to antithrombin III and selectively inhibits factor Xa.

● It is administered subcutaneously, and has a more predictable pharmacokinetic profile
than heparin. It is eliminated unchanged in urine. Plasma t1/2 is 17 to 21 hours.

Directly acting oral anticoagulants:

● These are drugs which do not need to bind to antithrombin III, and instead, directly act to
inactivate clotting factors. Dabigatran directly inhibits thrombin formation, while
rivaroxaban and apixaban directly inhibit factor Xa.
● All these drugs are taken orally. Rivaroxaban and apixaban are highly bound to plasma
proteins and are metabolized in the liver by the cytochrome P450 system. All these
drugs are substrates for glycoprotein P, with which they bind before being eliminated
through urine and feces.
● These drugs have the potential to cause severe bleeding, and unlike heparin, they do not
have approved antidotes. Dabigatran is contraindicated in patients with prosthetic heart
valves.
● These drugs are used for prophylaxis against venous thromboembolism, and against
stroke in patients with atrial fibrillation.

Warfarin:

● This is the only clinically used coumarin anticoagulant; related compounds are used as
pesticides.
● Warfarin and other coumarin compounds decrease the regeneration of vitamin K from
vitamin K epoxide. This decreases available levels of vitamin K. Vitamin K activates
clotting factors II, VII, IX, and X, and this process is inhibited when warfarin is
administered.
● Warfarin may be taken orally. It binds to plasma albumin, and can cross the placenta but
not other barriers. It is contraindicated in pregnancy. It is metabolized in the liver by
cytochrome P450 system and glucuronide conjugation, and is excreted in the urine. Its
half-life is 40 hours.
 ● Warfarin therapy requires frequent monitoring of International Normalized Ratio (INR),
which must be maintained in the range of 2 to 3. It is primarily used for prevention of
stroke and venous thromboembolism.
● The main adverse effect is hemorrhage. Mild bleeding may be reversed by administration
of vitamin K, while major bleeding may require transfusion with whole blood, plasma,
or plasma concentrate. Another adverse effect is ‘purple toe syndrome’ where there is
discoloration of the toes due to cholesterol plaque deposits.

Fibrinolytic drugs

● These are drugs that act to destroy existing blood clots. These agents promote the
conversion of plasminogen to plasmin. Plasmin hydrolyzes fibrin and dissolves blood
clots. The commonly used fibrinolytic drugs include streptokinase, urokinase, and
alteplase.
● Fibrinolytic therapy is mainly used to lyse clots after myocardial infarction, to establish
reperfusion. These drugs must be administered early, within 2-6 hours, as the clot
becomes difficult to disintegrate as it ages. When the clot is broken down, the small
fragments may stimulate platelet aggregation and further thrombosis. To prevent this, it
is best to use these drugs along with antiplatelet and antithrombotic drugs.
● Alteplase is a ‘fibrin selective’ drug and acts locally at the site of blood clots. It binds
only to plasminogen in blood clots, but not to tissue plasminogen.

DRUGS USED FOR BLEEDING TENDENCIES

Vitamin K

● This is a fat-soluble vitamin. Its main site of action is in the liver, where it acts as a
cofactor for synthesis of four clotting factors – II, VII, IX, and X. Any deficiency of
vitamin K can lead to bleeding tendencies. This may manifest as GI bleeds, hematuria,
nasal bleeds, and skin ecchymosis.
● Vitamin K therapy is indicated in the following cases:
○ True deficiency due to poor diet, prolonged antimicrobial therapy, and malabsorption
syndromes
○ Liver diseases
○ Deficiency in the newborn child
○ Overdose of oral anticoagulants such as warfarin

Local hemostatic agents

● Hemostatic agents, or styptics are drugs that act locally at the site of injury to stop
bleeding. These substances work by different mechanisms.
● Gelatin foam, oxidized cellulose, and fibrin usually provide a mesh framework for the
clot to form. Thrombin powder directly stimulates clot formation, and is useful in
patients with bleeding disorders.
● Vasoconstrictors such as adrenaline may also be applied locally. However, once the
effect wears off, there may be reactionary bleeding.

Anti-fibrinolytic drugs
 ● Contrary to fibrinolytics, these drugs inhibit the conversion of plasminogen into plasmin.
They usually bind to the lysine binding site on plasminogen and prevent its conversion.
● Aminocaproic acid and tranexamic acid are two commonly used antifibrinolytics.
Tranexamic acid is 7-10 times more potent than aminocaproic acid. Both are
administered via the oral route, and are excreted in urine. They can also be used
topically for control of bleeding.
● It is used to control bleeding in patients with bleeding disorders, following trauma or
minor procedures such as tooth extraction.
EXERCISES:

1. Which of the following forms of anemia requires parenteral therapy?

1. Microcytic anemia
2. Megaloblastic anemia
3. Pernicious anemia
4. Sickle cell anemia
2. Which of the following drugs is preferred in sickle cell anemia?
1. Iron
2. Cyanocobalamin
3. Erythropoietin
4. Hydroxyurea
3. Which of the following drugs prevents binding of ATP to platelet receptors?
1. Tirofiban
2. Aspirin
3. Clopidogrel
4. Dipyridamole
4. What is the dose of aspirin for antiplatelet therapy?
1. 50mg
2. 75mg
3. 100mg
4. 325mg
5. What is the antidote for heparin-induced bleeding?
1. Vitamin K
2. Tranexemic acid
3. Protamine sulfate
4. Oxidised cellulose
6. Which of the following drugs selectively inhibits factor II?
1. Enoxaparin
2. Dabigatran
3. Fondaparinux
4. Rivaroxaban
7. What is the plasma half-life of warfarin?
1. 10 hours
2. 20 hours
3. 30 hours
4. 40 hours
 8. What is the period within which fibrinolytic drugs must be administered after an MI?
1. 2 hours
2. 3 hours
3. 5 hours
4. 6 hours
9. Which of the following drugs inhibits the conversion of plasminogen into plasmin?
1. Streptokinase
2. Tranexemic acid
3. Adrenaline
4. Warfarin
10. Which of the following drugs acts ‘locally’ on the blood clot?
1. Streptokinase
2. Urokinase
3. Alteplase
4. Tranexemic acid
 UNIT VIII – RESPIRATORY SYSTEM
CHAPTER 1: DRUGS USED IN COUGH AND
BRONCHIAL ASTHMA
Respiratory disorders can involve the upper or lower respiratory tract. This chapter discusses
two important conditions - cough and bronchial asthma.

DRUGS USED TO MANAGE COUGH

Cough is a defense mechanism of the respiratory tract against irritants. This is usually
secondary to infection or allergy. Whenever possible, the underlying etiology of the cough must
be ascertained and treated, along with treatment for cough itself. The following categories of
drugs are used to manage cough.

Antitussives:

● Antitussives directly control the cough reflex mechanism by working at the central or
peripheral part of the cough reflex arc.
● Opioids: These increase the stimulus threshold in the central cough center. Codeine and
ethylmorphine are commonly used opioids. They have the potential for respiratory
depression and must not be used in asthmatics. They can also cause constipation.
● Non-opioids: Dextromethorphan is a synthetic NMDA antagonist and works similar to
opioids. It has a lower addictive profile, and does not cause respiratory depression.
● Benzonatate: This works peripherally to suppress the cough reflex receptors that are
located in the lungs and respiratory passages. It may cause numbness of the tongue,
mouth and throat, especially if the active drug comes in direct contact with the mucosa.
● Indications for anti-tussives: Dry, non-productive cough; especially cough that disturbs
sleep, or may be detrimental to health (e.g. in patients with hernia, or who have had
ocular surgery).

Pharyngeal demulcents:

● These are marketed as cough lozenges or syrups.

● They contain a combination of active ingredients, including honey, peppermint oil,
anesthetics such as benzocaine, or dextromethorphan.
● They decrease afferent impulses sent from inflamed pharyngeal mucosa, by soothing the
throat.

Expectorants:

● These drugs either increase bronchial secretions, or reduce their viscosity, thus
facilitating their expulsion.
● Guaifenesin is a plant product which enhances mucociliary function and decreases the
viscosity of secretions.
 ● Bromhexine is also a mucolytic and mucokinetic. It breaks down sputum by enhancing
release of lysosomal enzymes and depolymerizing mucopolysaccharides. Adverse
effects include nausea, gastric irritation, lacrimation, and rhinorrhea. Its metabolite,
ambroxol, has similar effects.
● Carbocisteine and acetylcysteine: These drugs also liquify sputum, by breaking down
disulphide bonds of proteins in mucous. However, it may also break down the gastric
mucosal barrier, and must be avoided in patients prone to peptic ulcer.

DRUGS FOR BRONCHIAL ASTHMA

Asthma is a disease characterized by chronic inflammation of the bronchial airway, which

leads to bronchoconstriction and increased bronchial secretions. Therapy is aimed at providing
symptomatic relief, as well as reducing inflammation in the long-term.

Bronchodilators

These drugs provide symptomatic relief by causing relaxation of the bronchial smooth
muscles. The drugs used are β-2 agonists, methylxanthines, or anticholinergic drugs.

β-2 agonists:

These drugs directly act on the bronchial smooth muscle to relax it. There are two types of
drugs used for asthma:

● Short acting β-2 agonists:

○ These drugs are used for quick relief of acute bronchoconstriction. They do not have any
anti-inflammatory effect, and must not be used as monotherapy in chronic asthma.
They may be used alone only in intermittent asthma and in patients with exercise-
induced bronchospasm.
○ The onset of action is 15 to 30 minutes and the effects last for 4 to 6 hours.
○ Drugs in this category include albuterol, levalbuterol, and terbutaline.
● Long acting β-2 agonists:
○ These drugs have a longer duration of action for at least 12 hours. As the onset is slow,
they are not preferred for acute relief.
○ Salmeterol and formoterol are the drugs used in this category.
○ These drugs are not preferred as monotherapy. They may be used in combination with
other drugs for management of moderate and severe persistent asthma.

Methylxanthines:

● Methylxanthines include the drugs caffeine, theophylline, and theobromine. Of these,

theophylline has been used for the management of asthma and COPD.
● Theophylline causes bronchial smooth muscle relaxation. It also decreases the release of
histamine from mast cells, and thereby exerts an anti-inflammatory effect.
● It has a narrow therapeutic window and several adverse effects. These include headache,
nervousness, nausea, and gastric pain. Due to this, it is no longer considered as a first-
line drug to treat asthma.
Anticholinergics:

● Anticholinergic drugs block M3 receptors which mediate bronchoconstriction.

● The commonly used drug is ipratropium bromide. It can be used for asthmatic
exacerbations when short-acting β-2 agonists are not tolerable.
● Adverse effects include dry mouth and altered taste.

Anti-inflammatory drugs

These drugs reduce the inflammation of the bronchial mucosa.

Corticosteroids:

● This is the drug of choice in all patients with persistent asthma, either with or without
long-acting β-2 agonists. These drugs exert an anti-inflammatory effect by inhibiting
the enzyme phospholipase-A2, which plays a key role in prostaglandin synthesis.
● Usually, steroids are administered via the inhalation route. Beclomethasone, fluticasone,
and budesonide are the most commonly used inhalational drugs.
● Severe cases of asthma, which do not respond to inhaled steroids, may require
administration of oral corticosteroids, such as prednisolone or methylprednisolone.
This will require tapering prior to switching to inhaled steroids. Oral steroids are also
used in status asthmaticus.

Leukotriene antagonists:

● As the name suggests, these drugs exert an anti-inflammatory effect by blocking the
leukotriene pathway. The mechanism of action varies. Drugs like montelukast and
zafirlukast act by binding to the leukotriene receptor and exerting antagonist effect.
Zileuton inhibits the enzyme lipoxygenase.
● Inhibition of leukotrienes suppresses inflammation and also promotes bronchodilation.
● These drugs are absorbed from the oral route and are highly bound to plasma proteins.
They are metabolized in the liver. Zileuton is excreted in the urine and the other two
undergo biliary excretion. The plasma half-life is short for montelukast (3-4 hours) and
longer for zafirlukast (8-12 hours).
● They can be used as alternatives to glucocorticoids in mild-to-moderate asthma. In severe
asthma, they can be added to glucocorticoids and can facilitate dose reduction.
● Adverse effects include headache, rashes, eosinophilia, and neuropathy.

Mast cell stabilizers:

● Cromolyn sodium is a drug that prevents degranulation of mast cells. This in turn
prevents release of histamine, interleukins, and leukotrienes, thus exerting an anti-
inflammatory effect.
● It does not have bronchodilator activity. It can be used as a long-term prophylactic agent
in asthma.

Anti-IgE antibody:
 ● Omalizumab is an IgE antibody derived from recombinant DNA. By binding to IgE, it
decreases antigen binding to mast cells and basophils, thus limiting the allergic and
inflammatory response.
● It is used in moderate to severe asthma that does not respond to steroid therapy.
● Adverse effects include fever, rashes, arthralgia, and sometimes, anaphylaxis.
EXERCISES:

1. Which of the following antitussives acts at the peripheral nervous system?

1. Codeine
2. Ethylmorphine
3. Dextromethorphan
4. Benzonatate
2. Which expectorant liquefies mucus by breaking disulfide bonds?
1. Guaifenesin
2. Ambroxol
3. Acetylcysteine
4. Bromhexine
3. Which of the following is usually not a component of pharyngeal demulcents?
1. Benzocaine
2. Codeine
3. Peppermint oil
4. Dextromethorphan
4. Which of the following drugs is used for acute symptomatic relief from asthma?
1. Albuterol
2. Salmeterol
3. Theophylline
4. Budesonide
5. Which of the following bronchodilators has an antiinflammatory effect?
1. Theophylline
2. Ipratropium bromide
3. Albuterol
4. Formoterol
6. What is the first choice of drug therapy for maintenance in a patient with persistent
asthma?
1. Beta agonists
2. Methylxanthines
3. Corticosteroids
4. Leukotriene antagonists
7. Which of the following drugs inhibits the enzyme lipoxygenase?
1. Zafirlukast
2. Zileuton
3. Montelukast
4. Cromolyn sodium
8. What is the half-life of montelukast?
1. 1-2 hours
2. 3-4 hours
 3. 5-6 hours
4. 7-8 hours
9. Which of the following drugs inhibits degranulation of mast cells?
1. Budesonide
2. Cromolyn sodium
3. Montelukast
4. Omalizumab
10. Which of the following drugs acts by decreasing antigen binding to mast cells?
1. Budesonide
2. Cromolyn sodium
3. Montelukast
4. Omalizumab
 UNIT IX – GASTROINTESTINAL SYSTEM
CHAPTER 1: DRUGS USED FOR DISEASES OF THE GI TRACT
Diseases of the gastrointestinal tract fall under four main categories – gastric ulcer disease,
emesis, diarrhea, and constipation.

DRUGS USED FOR PEPTIC ULCER AND GASTRO-ESOPHAGEAL REFLUX

DISEASE

Gastric or peptic ulcers are formed when the gastric mucosa is directly exposed to acidic
secretions. This can occur when there is an increase in aggressive factors, including acid, pepsin,
bile, and the micro-organism Helicobacter pylori; or a decrease in defensive factors, including
gastric mucous, bicarbonate, and prostaglandins. Gastric acid secretion is usually stimulated by
histamine, acetylcholine, and gastrin, and inhibited by prostaglandins. To address these factors,
various drugs are used in the management of peptic ulcer disease.

H2 antagonists:

● These drugs block histamine type 2 receptors in the stomach, and decrease gastric acid
production.
● They are indicated for gastric and duodenal ulcers, as well as gastritis.
● The four main drugs in this category are cimetidine, ranitidine, famotidine, and
nizatidine.

Proton pump inhibitors:

● As the name suggests, these drugs covalently bind to the proton pump (H+/K+ ATPase
system) and inactivate it. The proton pump secretes hydrogen ions into the gastric
lumen, for acid secretion. Therefore, these drugs ultimately suppress gastric acid
secretion.
● The various drugs used in this category include omeprazole, lansoprazole, rabeprazole,
and pantoprazole.
● These drugs are effective when taken orally, however, they are usually enteric coated to
avoid transformation in the gastric juice. They must preferably be taken 30 to 60
minutes before meals. They are metabolized quickly in the liver and excreted in urine.
Although the plasma t ½ is only 1-2 hours, the effect lasts for 2-3 days because of
covalent binding to the enzyme.
● PPIs are the preferred drug of choice for management of ulcers, GERD, esophagitis, and
hypersecretory conditions like Zollinger-Ellison syndrome.
● Adverse effects include vitamin B12 deficiency, hypomagnesemia, diarrhea, and Cl.
difficile colitis. Long-term use may increase the risk of fractures. PPIs must never be
given to patients taking clopidogrel, as it can increase the risk of cardiovascular events.

Prostaglandin analogues:
 ● Misoprostol is a synthetic analogue of PGE1.
● It stimulates gastric mucous and bicarbonate secretion, inhibits gastric acid secretion, and
therefore exerts a protective effect on gastric mucosa.
● It is indicated as prophylaxis for ulcers in patients taking NSAIDS. It is contraindicated
in pregnant patients as it can induce uterine contractions.
● Adverse effects include nausea and diarrhea.

Antacids:

● These are substances with high pH (bases) that work by neutralizing gastric acid. They
neutralize existing acid and do not prevent secretion of new acid. Over time, excess
acid may be produced to compensate for the neutral effect, leading to an acid rebound.
They are mostly used to provide immediate symptomatic relief.
● Magnesium hydroxide (milk of magnesia), aluminum hydroxide, and calcium carbonate
are commonly used antacids. They must ideally be taken after meals as they act
immediately, and are effective for 2-3 hours.

Cytoprotective agents:

These drugs reduce inflammation, prevent injury to gastric mucosa, and promote ulcer
healing.

Sucralfate

● This is an aluminum salt of sucrose. It has a local mechanism of action. It binds to

normal and necrotic epithelial cells, forming a gel that acts as a physical barrier
between the gastric mucosa and acidic secretion.
● It only acts at acidic pH and must not be combined with PPIs, H2 blockers, or antacids.
● It may be used for patients with peptic and duodenal ulcers. However, it does not prevent
NSAID-induced ulcers.

Bismuth subsalicylate

● This drug also forms a barrier by binding with tissue glycoproteins. Apart from this, it
has antimicrobial activity, inhibits pepsin activity, and increases mucous secretion.

Antimicrobial therapy:

● Several patients with gastritis and ulcers show infection with H.pylori. H.pylori plays an
important role in pathogenesis of peptic ulcer, and its eradication improves prognosis
for patients.
● Commonly used antibiotics include amoxicillin, clarithromycin, metronidazole, and
tetracycline.
● Generally, H.pylori eradication uses triple therapy (Metronidazole or amoxicillin,
clarithromycin, and PPI), or quadruple therapy (Metronidazole, tetracycline, PPI, and
bismuth subsalicylate).

ANTIEMETIC DRUGS
 Emesis, or vomiting occurs when the vomiting center, located in the medulla, is stimulated.
Impulses to this center are relayed by two important areas of the brain - the chemoreceptor
trigger zone (CTZ), and nucleus tractus solitarius (NTS). The CTZ and NTS communicate with
the vomiting center through a variety of neurotransmitters, namely, histamine (H1 receptors),
dopamine (D2 receptors), serotonin (5HT-3), neurokinin, and cholinergic (M) receptors.
Antiemetic drugs, therefore, address one of these areas.

Anticholinergic drugs:

● Hyoscine and dicyclomine are usually used. They act by blocking cholinergic receptors.
● They are effective in preventing motion sickness, but do not have any effect on
chemotherapy-induced emesis, if the drugs directly act on the CTZ.

H1 antihistamines:

● Promethazine, diphenhydramine ,and dimenhydrinate are useful in controlling motion

sickness.
● Doxylamine is used along with pyridoxine for management of emesis during pregnancy.
● Meclizine is long-acting and is preferred for sea-sickness.

Neuroleptics (Phenothiazines):

● Prochlorperazine is the main drug used in this category. It blocks dopamine receptors in
the CTZ.
● It is useful in emesis due to chemotherapeutic agents. However, it can cause
extrapyramidal side effects like muscle dystonia.

Serotonin receptor blockers:

● They block 5-HT3 receptors both in the brain and periphery. These drugs have a longer
duration of action and are commonly used antiemetics.
● Ondansetron and granisetron block emesis due to cisplatin therapy.
● They are also used in management of post-anesthesia nausea and vomiting.

Prokinetic drugs (Benzamides):

● Metoclopramide is a prokinetic drug that antagonizes both dopamine and 5HT-3

receptors. It also speeds gastric emptying by increasing gastric peristalsis and relaxing
the pylorus and duodenum.
● It is useful in postoperative emesis and emesis due to cisplatin and other chemotherapy
drugs.
● Domperidone also blocks D2 receptors, but it's extrapyramidal side effects are low as it
does not effectively penetrate the blood-brain barrier.

Neurokinin receptor antagonists:

● Aprepitant is a new drug that blocks the neurokinin receptors and substance P. It is useful
when highly emetogenic chemotherapy drugs are used.
 ● It may cause weakness, fatigue, and flatulence.

Corticosteroids:

● Some corticosteroids, like dexamethasone and methylprednisolone, can have an

antiemetic effect against chemotherapy drugs.
● They are usually not used alone, but combined with other agents.

Benzodiazepines:

Lorazepam and alprazolam have weak anti-emetic effects. They are more useful in treating
anticipated vomiting, where they might be beneficial due to their sedative effect.

DRUGS USED TO TREAT DIARRHEA

Diarrhea is defined as the passage of three or more loose, watery stools in a 24-hour period.
It can occur due to decreased absorption of electrolyte and water from the GI tract, inflammation
of GI mucosa, or increased motility of the GI tract. The following categories of drugs are used to
manage diarrhea:

Antimotility drugs:

● These drugs are opioid derivatives. They stimulate opioid receptors in the enteric system,
which reduces propulsive movements of the intestine, increase absorption, and
diminish intestinal secretions.
● Common drugs used are loperamide and diphenoxylate, which are derivatives of
meperidine.
● This can cause abdominal cramps, rashes, and intestinal paresis. There is a risk of toxic
megacolon in patients who have colitis.

Adsorbents:

● Drugs like aluminum oxide and methylcellulose act locally by absorbing toxins and
micro-organisms, and by coating the intestinal mucosa.
● They can improve consistency of the stools and ease abdominal pain.

Agents to improve fluid and electrolyte transport:

● Bismuth subsalicylate decreases fluid secretion in the bowel. It is also useful in

management of traveler’s diarrhea.

DRUGS USED FOR THE MANAGEMENT OF CONSTIPATION

Drugs that are used to treat constipation are referred to as laxatives. Several classes of drugs
may be used as laxatives:

Stimulant drugs:

● These drugs act by irritating the intestinal mucosa and stimulating motility.
 ● Diphenyl methanes such as bisacodyl and phenolphthalein act by increasing nitric oxide
secretion, which acts on nerve fibers in the colon. They cause evacuation in 3 to 4
hours.
● Senna is a plant product derived from the cassia plant. It can cause evacuation in 8 to 10
hours. It is useful in opioid-induced constipation.
● Castor oil is a natural laxative. It is broken down in the small intestine to ricinoleic acid,
which is a powerful irritant and stimulates bowel movements in 2-3 hours.
● Irritant laxatives can cause cramping and abdominal pain.

Bulk laxatives:

● These are hydrophilic colloids which react with water in the large intestine to form gels.
This increases the bulk of stools and promotes evacuation.
● Bran, psyllium husk, and methylcellulose are examples of bulk laxatives. These
compounds must be taken with plenty of water, otherwise they have the potential to
cause intestinal obstruction. They may cause flatulence.

Stool softeners and lubricants:

● These are detergent like substances that react with the stools to make them softer. This
eases their passage through the digestive tract.
● Docusate sodium and docusate calcium are commonly used stool softeners. They may
cause nausea, cramps, and abdominal pain.
● Liquid paraffin, mineral oils, and glycerin are lubricants, which ease the passage of stools
through the intestine.

Chloride channel activators:

● Drugs such as lubiprostone activate chloride channels, which increases fluid secretion
into the intestinal lumen.
● It is quickly metabolized in the stomach and jejunum.
● Tolerance usually does not develop to this drug, and hence it is useful in chronic
constipation.
EXERCISES:

1. Which of the following drugs must not be used in patients taking PPIs to avoid
cardiovascular events?
1. Aspirin
2. Clopidogrel
3. Digoxin
4. Amiodarone
2. Sucralfate is a combination of sucrose and salt of which of the following metals?
1. Sodium
2. Potassium
3. Aluminum
4. calcium
 3. Which of the following is a prostaglandin analogue?
1. Ondansetron
2. Misoprostol
3. Meperidine
4. Lubiprostone
4. Which of the following antihistamines is preferred for morning sickness?
1. Doxylamine
2. Promethazine
3. Meclizine
4. Cetirizine
5. Which of the following drugs are effective in nausea against cisplatin therapy?
1. Diphenhydramine
2. Ondansetron
3. Domperidone
4. Dexamethasone
6. Which of the following drugs is an antagonist for neurokinin?
1. Metoclopramide
2. Granisetron
3. Aprepitant
4. Lorazepam
7. Which of the following drugs is not a part of triple therapy?
1. Amoxicillin
2. Clarithromycin
3. Omeprazole
4. Bismuth subsalicylate
8. Which of the following drugs is used in the management of traveler’s diarrhea?\
1. Loperamide
2. Bismuth subsalicylate
3. Meperidine
4. Aluminum oxide
9. Which of the following drugs stimulates intestinal motility?
1. Bisacodyl
2. Psyllium
3. Docusate
4. Lubiprostone
10. Which of the following drugs is most useful for chronic constipation?
1. Ondansetron
2. Misoprostol
3. Meperidine
4. Lubiprostone
 UNIT X: GENITOURINARY SYSTEM
CHAPTER 1: DIURETICS
Diuretics are drugs which increase urine output. Usually, these drugs cause a net loss of both
sodium and water in urine. Based on their efficacy, they may be categorized as high ceiling,
medium efficacy, and weak diuretics.

Figure 10 Nephrons are functional units within the kidney, and are the structures that produce urine in the process of
removing waste and excess substances from the blood.

HIGH CEILING DIURETICS/LOOP DIURETICS:

● These drugs have maximum diuretic effect and produce large amounts of urine. Diuresis
increases with increasing dose, and the drug is effective in patients with renal failure.
● Mechanism of action: These drugs act at the loop of Henle. They inhibit the co-transport
of Na+/K+/2Cl- in this region. These ions are not reabsorbed, and are excreted along
with water. They also improve renal blood flow.
● Pharmacokinetics: These drugs are usually taken orally, and have a bioavailability
ranging from 60% for furosemide, to 100% for bumetanide. They are highly bound to
plasma proteins, and are metabolized in the liver by glucuronide conjugation. The
drugs are mostly excreted in urine, but small amounts may also be excreted in bile.
● Indications:
● To reduce edema of hepatic, renal, or cardiac origin. It is used to manage heart failure.
● Acute pulmonary edema
● Cerebral edema
 ● To manage hypertension in patients with renal insufficiency
● To manage hypercalcemia and hyperkalemia
● Adverse effects: They have the potential to cause ototoxicity. They can cause
hypokalemia, hypomagnesemia, and even acute hypovolemia. Hyperuricemia may also
occur, which may lead to gout.

MEDIUM EFFICACY DIURETICS

These include thiazide and thiazide-like diuretics

Thiazide diuretics:

● Thiazide diuretics include the drugs chlorothiazide and hydrochlorothiazide. There is a

separate group of drugs, called thiazide-like diuretics, which have a different chemical
structure, but have the same clinical actions and adverse effect profiles. This group
includes the drugs chlorthalidone, metolazone, and indapamide.
● Mechanism of action: These drugs act on the ascending loop of Henle and the distal
convoluted tubule. They inhibit the Na+/Cl- cotransporter, and inhibit sodium
reabsorption. Excretion of sodium and chloride is increased. With prolonged use,
potassium ions may be exchanged for sodium, leading to potassium loss as well.
However, there is reabsorption of calcium ions.
● Initially, thiazide diuretics decrease blood pressure by increasing urine output and
thereby reducing blood volume. Over time, the body compensates and there is volume
recovery. However, they also cause arteriolar smooth muscle relaxation and decrease in
peripheral vascular resistance. Therefore, the anti-hypertensive effect is maintained.
● Pharmacokinetics: These drugs are well absorbed through the oral route. The onset of
action starts in one hour, and can last up to 48 hours. They undergo very little hepatic
transformation and are usually excreted unchanged.
● Indications:
○ Hypertension: Mild to moderate hypertension can be managed with thiazides alone.
○ May be added to loop diuretics to manage heart failure.
○ Diabetes insipidus: They promote excretion of hyperosmolar urine.
○ Hypercalciuria: They prevent excess excretion of calcium in urine.
● Adverse effects: Potassium depletion, hyponatremia, and volume depletion may occur. It
can also cause hyperuricemia, hypercalcemia, and hyperglycemia.

WEAK DIURETICS

There are three categories of drugs which are weak diuretics – potassium-sparing diuretics,
carbonic anhydrase inhibitors, and osmotic diuretics.

Potassium-sparing diuretics:

● These drugs act at the site of the collecting ducts, where they inhibit sodium reabsorption
and potassium excretion. As the name suggests, they tend to retain potassium, and
therefore carry the risk of hyperkalemia. Patients using these drugs must be carefully
monitored for their potassium levels.
● Mechanism of action: Based on their mechanism of action, there are two distinct classes
 of potassium-sparing diuretics:
○ Aldosterone antagonists: Spironolactone and eplerenone act as antagonists to the
aldosterone receptor and prevent its binding.
○ Sodium channel blockers: These drugs block sodium channels, which decreases the
exchange of sodium with potassium. This causes excretion of sodium and retention of
potassium. The drugs in this category are triamterene and amiloride.
● Pharmacokinetics: All potassium-sparing drugs are taken orally, and bind significantly
to plasma proteins. They are metabolized in the liver, and metabolites are also active.
● Adverse effects:
○ Spironolactone can cause gynecomastia and menstrual irregularities.
○ All potassium-sparing diuretics have the potential to cause hyperkalemia.
● Indications:
○ Diuretics: They are used in conjunction with thiazide and loop diuretics.
○ Spironolactone is used in secondary hyperaldosteronism.
○ Heart failure: They prevent remodeling of the heart and decrease mortality.
○ Used in ascites and polycystic ovary syndrome
○ Used in hypertension resistant to other medications.

Carbonic anhydrase inhibitors:

● These drugs inhibit the enzyme carbonic anhydrase. Carbonic anhydrase converts water
and carbon dioxide into carbonic acid, which breaks down into hydrogen and
bicarbonate ions. These drugs inhibit availability of hydrogen ions in the proximal
convoluted tubule, which cannot be exchanged for sodium ions.The main drug in this
category is acetazolamide.
● Pharmacokinetics: It is well absorbed from oral routes. It is highly bound to plasma
proteins and does not undergo metabolism. It is excreted unchanged in urine.
● Adverse effects: Metabolic acidosis can occur due to bicarbonate excretion.
● Indications:
○ Prophylaxis of acute mountain sickness
○ To reduce intraocular pressure in glaucoma

Osmotic diuretics:

● Mannitol is a drug that increases the osmolarity of the renal tubular fluid. This prevents
further reabsorption of water. It does not affect sodium excretion, and is therefore not
useful in conditions with sodium retention.
● It can only be administered intravenously. It is excreted unchanged in 1.5 hours.
● Indications:
○ Acute renal failure due to trauma, drugs etc.
○ Increased intracranial pressure and intraocular pressure e.g. following trauma, stroke,
cavernous sinus thrombosis etc.
● Contraindications: Anuria and acute tubular necrosis, cerebral hemorrhage, acute left
ventricular or congestive cardiac failure.
 EXERCISES:

1. What is the bioavailability of bumetanide?

1. 50%
2. 70%
3. 90%
4. 100%
2. Which of the following is not an adverse effect of loop diuretics?
 1. Ototoxicity
2. Hyperkalemia
3. Hyperuricemia
4. Hypomagnesemia
3. Which of the following diuretics does not affect the Na+/Cl- cotransporter?
1. Chlorothiazide
2. Metolazone
3. Furosemide
4. Chlorthalidone
4. How long does the effect of thiazide diuretics last?
1. 12 hours
2. 24 hours
3. 48 hours
4. 72 hours
5. Which of the following drugs is an antagonist to aldosterone?
1. Chlorthalidone
2. Spironolactone
3. Triamterene
4. Amiloride
6. Which of the following drugs can cause metabolic acidosis?
1. Furosemide
2. Acetazolamide
3. Spironolactone
4. Amiloride
7. Which of the following drugs does not affect sodium excretion?
1. Mannitol
2. Spironolactone
3. Triamterene
4. Amiloride
8. In which of the following conditions is mannitol contraindicated?
1. Stroke
2. Drug induced renal failure
3. Congestive cardiac failure
4. Cavernous sinus thrombosis
9. Which of the following drugs is indicated for acute mountain sickness?
1. Chlorothiazide
2. Furosemide
3. Mannitol
4. Acetazolamide
10. Which of the following drugs is indicated for diabetes insipidus?
1. Chlorothiazide
2. Furosemide
3. Mannitol
4. Acetazolamide
 UNIT XI – ANTIMICROBIALS
CHAPTER 1: ANTIBACTERIAL DRUGS
Infections are diseases that are caused by microorganisms – bacterial, viral, protozoal, or
fungal. Drugs used in antimicrobial therapy have the capacity to kill microorganisms without
damaging host cells.

Antibacterial drugs, or antibiotics, are the most common form of antimicrobial therapy used.
Different antibiotics are effective against a different range of microorganisms. Antibiotics may
be selected empirically, based on previous knowledge of similar infections, or after sensitivity
testing, in which infectious material (such as pus or sputum) is grown along with antibiotic discs,
and the most effective one is chosen based on inhibition of bacterial growth. The usual
antimicrobial spectrum of commonly used antibiotics is summarized in Table 1.

Based on their mechanism of action, there are several different kinds of antibiotics. These are
described below.

CELL WALL INHIBITORS

These drugs act by inhibiting cell wall synthesis. This results in exposure of the underlying
cell membrane. The cell membrane is not osmotically stable and cell lysis can occur due to raised
osmotic pressure. All cell wall inhibitors are bactericidal drugs. Most of these drugs have a beta-
lactam ring in their structure, and are hence referred to as beta-lactam antibiotics.

Penicillins:

In addition to inhibiting cell wall synthesis, these drugs also bind to proteins on the surface of
the cell membrane, called penicillin-binding proteins (PBPs). This can alter bacterial morphology
and lead to lysis. Penicillins are classified into the following categories:

● Natural penicillin: Penicillin G

● Acid-resistant penicillin: Penicillin V is not destroyed by gastric acids, unlike penicillin
G.
● Extended-spectrum penicillins: Ampicillin, amoxicillin, carbenicillin, piperacillin
● Penicillinase-resistant penicillins: Staphylococcus produces the enzyme penicillinase
which normally inactivates this drug. Methicillin, cloxacillin, dicloxacillin are resistant
to this enzyme.

Pharmacokinetics:

● Some penicillins, such as amoxicillin, dicloxacillin, and Penicillin V are taken by oral
route, while penicillin G and combination drugs, such as ampicillin-sulbactam and
piperacillin/tazobactam are used only through the intravenous route. Oral drugs can
affect intestinal flora, and their absorption may be delayed by food.
● They can cross the placenta, but do not penetrate bone or enter CSF. They do not
 undergo significant metabolism.
● Excretion occurs through urine.

Adverse effects:

● Can cause severe hypersensitivity reactions, including anaphylaxis, in 5% of all patients.

Cross-allergy is common among all beta-lactam antibiotics.
● Diarrhea due to altered intestinal flora.
● In high doses, neurotoxicity can occur. Piperacillin and ticarcillin may also cause
decreased blood coagulation.
● Methicillin has been linked to interstitial nephritis.

Cephalosporins:

These are structurally similar to penicillins. Based on their antimicrobial spectrum, four
generations of cephalosporins have been introduced:

● First generation: Cefazolin, Cefalexin

● Second generation: Cefuroxime, Cefoxitin
● Third generation: Cefixime, Cefotaxime, Cefoperazone, Ceftriaxone
● Fourth generation: Cefepime, Cefpirome

Pharmacokinetics:

Only a few drugs like cephalexin and cefixime are administered orally, while the rest are
administered intravenously. They can cross the placenta. Few drugs such as cefotaxime and
ceftriaxone can penetrate CSF as well. They are usually eliminated through urine, except for
ceftriaxone, which is eliminated through bile and feces.

Adverse effects:

Allergic reactions; cross-reactivity with penicillins may occur.

Carbapenems:

● These are synthetic beta-lactam antibiotics. They include imipenem, meropenem,

doripenem, and ertapenem.
● These drugs are administered intravenously. They have good penetration into the CSF
even during inflammation. They are usually excreted through urine.
● Imipenem is metabolized in the kidney to an inactive form that may be nephrotoxic.
When combined with another drug, cilastatin, this is prevented.
● Adverse effects include nausea, vomiting, and diarrhea. Higher doses may cause seizures.

Monobactams:

● Aztreonam is the only clinically useful monobactam. It is administered parenterally and

is excreted through urine.
● Adverse effects include phlebitis, skin rash, and sometimes, liver dysfunction.
 BETA-LACTAMASE INHIBITORS

● Certain enzymes called beta-lactamases may destroy the beta-lactam ring of these
antibiotics and remove the antimicrobial effect. Specific drugs called beta-lactamase
inhibitors bind to these enzymes, inactivating them. This protects the antibiotics.
● Clavulanic acid, sulbactam, and tazobactam are usually used for this purpose.

VANCOMYCIN

● This drug is effective against methicillin-resistant Staphylococcus aureus, and

Clostridium difficile.
● It is usually given intravenously. It penetrates serous cavities and CSF. It is not
metabolized and is excreted in urine. The plasma t1/2 is around 6 hours.
● Adverse effects include dose-related ototoxicity and nephrotoxicity, skin allergy, and
hypotension.

PROTEIN SYNTHESIS INHIBITORS

Certain drugs target the bacterial ribosomes, and prevent protein synthesis. These drugs can
bind to either the 30S subunit (tetracyclines, aminoglycosides), or 50S subunit of the ribosome
(macrolides, chloramphenicol). These drugs are usually bacteriostatic.

Tetracyclines:

These drugs include tetracycline, doxycycline, and minocycline. They have a unique
antibacterial spectrum that allows them to be used for the treatment of specific infections,
including cholera, rocky mountain spotted fever, chlamydia, and Lyme disease.

Pharmacokinetics:

They are taken by oral or intravenous route. Simultaneous intake of antacids or dairy
products may also be absorbed from oral routes. They penetrate CSF, saliva and tears, as well as
calcified tissues such as bones and teeth. They can cross the placenta and enter fetal bones and
teeth. Only minocycline undergoes hepatic metabolism, while the others are unchanged.
Excretion occurs through urine, and for doxycycline, through feces.

Adverse effects:

● Gastric discomfort, esophagitis. Higher doses may cause hepatotoxicity.

● If taken by pregnant women or growing children, it can cause discoloration of primary or
permanent tooth buds.
● Phototoxicity, vestibular dysfunction, and benign intracranial hypertension may occur.

Aminoglycosides:

They are most effective against gram-negative bacilli and are reserved for treating serious
infections such as Pseudomonas infections.
 Pharmacokinetics:

All aminoglycosides are given parenterally, except neomycin, which is reserved for topical
use. They poorly penetrate CSF, but can cross the placenta. They are not metabolized and are
excreted unchanged in urine.

Adverse effects:

● Ototoxicity: The antibiotic accumulates in the endolymph and perilymph of the inner ear,
and can lead to deafness and vertigo.
● Nephrotoxicity: Can cause acute tubular necrosis.
● Neuromuscular paralysis: The risk is higher in patients with myasthenia gravis.
● Topical application of neomycin can cause contact dermatitis.

Macrolides:

These include the drugs erythromycin, clarithromycin, and azithromycin.

Pharmacokinetics:

All drugs can be taken orally, erythromycin alone needs to be taken as enteric-coated
preparations, as it is susceptible to gastric acid. These drugs tend to concentrate in the liver and
tissues. Azithromycin concentrates into macrophages, neutrophils, and fibroblasts. However,
there is poor penetration into CSF. These drugs undergo hepatic metabolism, and are excreted
through urine.

Adverse effects:

● Gastric distress and cholestatic jaundice

● Transient deafness or irreversible sensorineural hearing loss can occur
● May be hepatotoxic in patients with liver dysfunction

Chloramphenicol:

This has the same antimicrobial spectrum as tetracyclines, but is reserved for life-threatening
infections when these are ineffective.

Pharmacokinetics:

It is administered through the intravenous route. It can penetrate the CSF and is also secreted
in breast milk. It is metabolized in the liver and excreted in urine.

Adverse effects:

● Anemias – aplastic and hemolytic anemia

● Can cause ‘gray baby syndrome’ when administered to neonates.

Clindamycin:
 ● This is structurally different from erythromycin but has the same mechanism of action.
● It is administered orally as well as intravenously. It penetrates all body fluids except
CSF, but enters into bone. It is metabolized in the liver and excreted into the bile.
● Its main adverse effect is the development of potentially fatal pseudomembranous
enterocolitis, due to infection with C. difficile following alteration of intestinal flora.

Linezolid:

● Linezolid is a synthetic drug which is primarily useful against resistant microbes, such as
methicillin-resistant Staphylococcus aureus (MRSA), and penicillinase-resistant
streptococci.
● It is given both orally and intravenously. Its exact metabolic pathway is unknown, but its
oxidized metabolites are excreted through urine and feces.
● Adverse effects include nausea, diarrhea, headache, rash, and thrombocytopenia.

DRUGS THAT PROMOTE DNA LYSIS

These drugs enter the bacteria and inhibit two enzymes. Inhibition of DNA gyrase causes
breakage of DNA strands, while inhibition of bacterial topoisomerase prevents release of new
DNA. These drugs are bactericidal.

Fluoroquinolones:

These include the drugs norfloxacin, ciprofloxacin, moxifloxacin, and levofloxacin.

Moxifloxacin alone exhibits some activity against anaerobes.

Pharmacokinetics:

These drugs may be administered orally or intravenously. They are also available as
ophthalmic preparations. They are partially bound to plasma proteins, and distribute into all
tissues including bone, lungs, kidney, and prostate. They are excreted in urine.

Adverse effects:

● Nausea, vomiting, diarrhea

● Headache, dizziness, light-headedness
● Phototoxicity, arthropathy, and glucose dysregulation have also been reported.

FOLATE ANTAGONISTS

Tetrahydrofolate, a folic acid derivative, is essential for cell growth and division.
Sulfonamides prevent bacterial synthesis of folate, by inhibiting the enzyme p-aminobenzoic
acid. Trimethoprim prevents the conversion of dihydrofolate into tetrahydrofolate.

Sulfonamides:

These were the earliest used antibiotics and are often still employed owing to their low cost.
Silver sulfadiazine cream is often employed to prevent burn-related sepsis.
 Pharmacokinetics:

These drugs are well absorbed through oral routes. They bind to serum albumin and
distribute throughout the body, including CSF. They also cross the placenta. They are
metabolized in the liver and excreted in the kidney and breast milk.

Adverse effects:

● The drug metabolites can precipitate at neutral or acidic pH and cause crystalluria (stone
formation) in the kidney.
● Hypersensitivity can occur in patients with sulfa allergies.
● Hemolytic anemia and aplastic anemia can occur in patients with glucose-6-phosphate
dehydrogenase deficiency.

Trimethoprim:

● This has actions similar to sulfonamides. This drug is usually combined with
sulfonamides to potentiate antimicrobial effects. The combined product is called
cotrimoxazole.
● Both trimethoprim and cotrimoxazole can be taken orally. They are widely distributed,
and penetrate CSF, placenta, and prostate fluid. They are excreted unchanged in urine.
● Trimethoprim may produce folic acid deficiency and megaloblastic anemia.
Cotrimoxazole may cause nausea, vomiting, glossitis, stomatitis, and rarely,
hypokalemia.

Table 1. Antimicrobial spectrum of commonly used antibacterial agents

AEROBES ANAEROBES
GRAM
GRAM GRAM GRAM GRAM POSITIVE
DRUG NEGATIVE
POSITIVE COCCI POSITIVE BACILLI NEGATIVE BACILLI COCCI
COCCI
Neisseria
Streptococci Bacillus,
gonorrhoeae,
Penicillin G/V (except viridans), Corynebacterium, - -
N.
staphylococci Listeria,
meningitidis
Same as above, and S.viridans H. influenzae,
Extended
E.coli, Salmonella, -
spectrum penicillins
Shigella, H. pylori
Cephalosporins – Proteus, E.coli,
Same as Penicillin G -
1st generation Klebsiella

Cephalosporins – Same as 1st gen,

Same as Penicillin G H. influenzae, -
2nd generation
Enterobacter

Cephalosporins – Less sensitive Same as 2nd

Same as Penicillin G generation, plus Serratia -
3rd generation to S.aureus
and Pseudomonas
Cephalosporins – Same as 3rd
Same as Penicillin G, including S. aureus. -
4th generation generation
Enterobacteriaceae,
Streptococcus, Pseudomonas, H.
Carbapenems Listeria Neisseria Peptostreptococcus
Staphylococcus influenzae, Klebsiella.
 Proteus

Enterobacteriaceae,
Monobactams - - - -
Pseudomonas;
MRSA,
Vancomycin Corynebacterium - - -
enterococcus

S.aureus
Brucella, Vibrio,
Tetracyclines including MRSA, Bacillus anthracis - -
Yersinia
Streptococci,

Pseudomonas,
Streptococcus,
Klebsiella, Enterobacter
Aminoglycosides Enterococcus (with - - -
(especially multidrug
beta-lactams)
resistant forms)
H. influenzae,
Neisseria,
Macrolides Streptococcus Corynebacterium Bordetella, Legionella, -
Moraxella
Campylobacter
Enterobacter, H.
influenzae, Klebsiella,
Strep.
Fluoroquinolones B. anthracis - Legionella, Proteus, -
pneumoniae
Pseudomonas, Serratia,
Shigella
MRSA, VRE,
Streptococcus Corynebacterium,
Linezolid - - -
viridans and Listeria
pneumoniae
Sulfonamides/
- Nocardia - Enterobacter -
Trimethoprim

EXERCISES:

1. Which of the following penicillins is not administered by oral route?

1. Penicillin G
2. Penicillin V
3. Amoxicillin
4. Dicloxacillin
2. Which component of the bacterium is affected by beta-lactam antibiotics?
1. Cell membrane
2. Cell wall
3. Ribosomes
4. Mitochondria
3. Which of the following antibiotics is not bactericidal?
1. Penicillin
2. Ceftriaxone
3. Doxycycline
4. Moxifloxacin
4. Which of the following drugs can affect blood coagulation?
1. Ampicillin
 2. Methicillin
3. Piperacillin
4. Penicillin
5. Which generation of drugs does cefoperazone belong to?
1. 1st
2. 2nd
3. 3rd
4. 4th
6. Which drug is combined with imipenem to prevent nephrotoxicity?
1. Cisplatin
2. Cilastatin
3. Cefixime
4. Cetirizine
7. Which subunit of the ribosome does erythromycin inhibit?
1. 30S
2. 40S
3. 50S
4. 60S
8. Which of the following drugs is likely to cause tooth discoloration?
1. Methicillin
2. Minocycline
3. Gentamicin
4. Levofloxacin
9. Which of the following drugs can cause pseudomembranous enterocolitis?
1. Clarithromycin
2. Clindamycin
3. Cloxacillin
4. Cefixime
10. Which class of drugs does trimethoprim combine to maximize antimicrobial effects?
1. Fluoroquinolones
2. Sulfonamides
3. Macrolides
4. Aminoglycosides
 CHAPTER 2: ANTIVIRALS
Treatment of viral infections is more complicated than bacterial infections. While bacteria are
separate cells on their own, viruses are intracellular parasites which use the host cell’s metabolic
machinery to survive. So, killing viruses may not be possible without causing damage to host
cells. Antiviral drugs may only be effective during the incubation period. After clinical
symptoms set in, usually the replication and dissemination of viruses may exceed the efficacy of
the drug.

Antiviral drugs are classified based on the type of infection they are used to treat.

DRUGS AGAINST INFLUENZA

This group of drugs is effective against influenza viruses A and B, and respiratory syncytial
virus.

Amantadine and Rimantadine:

● These drugs are effective against influenza A virus. They inhibit the M2 protein of the
virus, which prevents viral release inside the cells.
● These drugs are well absorbed orally. Amantadine penetrates into the CNS, while
rimantadine does not. Rimantadine alone is metabolized in the liver, and both drugs are
excreted in urine.
● Amantadine can cause dizziness, insomnia, and ataxia. Both drugs can cause GI
intolerance.

Oseltamivir and Zanamivir:

● These drugs act against both influenza A and B viruses. They inhibit the enzyme
neuraminidase, which is responsible for releasing newly formed virions.
● Oseltamivir is administered orally. It is hydrolyzed to its active form in the liver, and
thereafter excreted unchanged in urine. Zanamivir is administered through inhalation
and is also excreted unchanged in urine.
● Oseltamivir can cause nausea and GI discomfort. Zanamivir can cause irritation of the
respiratory tract. It must be avoided in patients with bronchospasm and COPD.

DRUGS AGAINST HEPATITIS

Interferons:

● These are naturally occurring glycoproteins synthesized in the body. They activate host
enzymes, which inhibit translation of viral RNA, and ultimately degrade both viral
DNA and RNA. Interferon α is available for clinical use.
● It cannot be used by oral route, and is usually administered intravenously or
subcutaneously. It may also be given directly into the lesion. It is taken up by the liver
 and kidney cells and metabolized.
● Adverse effects include fever, chills, myalgia, arthralgia, and GI disturbances. Tolerance
to these effects soon develops. However, long-term therapy can lead to bone marrow
suppression, weight loss, and neurotoxicity.

Adefovir:

● This drug gets incorporated into viral DNA and terminates DNA chain elongation. It thus
prevents replication of hepatitis B virus.
● It is phosphorylated to its active form and is usually excreted in urine.
● Discontinuation may cause exacerbation of hepatitis. Long-term use can lead to
nephrotoxicity.

Entecavir:

● This drug competes with deoxyguanosine triphosphate and prevents transcription of viral
RNA.
● It is taken orally and is excreted unchanged in the urine.

Telbivudine:

● This drug competes with endogenous thymidine triphosphate and gets incorporated into
viral DNA. This prevents its replication.
● It is administered orally and excreted unchanged in urine.

Boceprevir and telaprevir:

● These drugs are used for management of chronic hepatitis C infection. These drugs
inhibit serine protease enzymes, which stop viral replication.
● Both drugs can be taken orally, and are metabolized by the cytochrome P450 system in
the liver.
● Adverse effects include anemia, dysgeusia, and rashes.

DRUGS AGAINST HERPES

Acyclovir and Ganciclovir:

● These drugs are phosphorylated by the enzyme thymidine kinase, which is secreted by
herpes viruses only in virus infected cells. The active form competes with
deoxyguanosine triphosphate for viral DNA polymerase, and gets incorporated into
viral DNA, resulting in strand termination.
● Acyclovir is available through oral, intravenous, and topical routes. Ganciclovir is
available only through intravenous routes. Both drugs penetrate the CSF, are partially
metabolized and excreted in urine.
● Adverse effects of acyclovir include nausea, vomiting, diarrhea, and headache. Topical
application may cause some local irritation. Ganciclovir can cause neutropenia, and is
reserved for cytomegalovirus infections.
 Cidofovir:

● This is an analog of cytosine, and inhibits viral DNA synthesis.

● It is approved for treatment of cytomegalovirus retinitis in patients with AIDS.
● It is available as intravenous and intravitreal injections. It can also be applied topically. It
can cause nephrotoxicity, neutropenia, and metabolic acidosis.

Foscarnet:

● This inhibits viral DNA and RNA polymerases. It is used for cytomegalovirus, and
herpes simplex that does not respond to acyclovir.
● It is available only through intravenous route and is excreted unchanged in urine.
● It can cause nausea, fever, anemia, and nephrotoxicity.

Trifluridine:

● It is an analog of thymidine and gets incorporated into viral DNA, which prevents its
replication.
● It is highly toxic for systemic use. It is only used topically in ophthalmic preparations, for
treating keratoconjunctivitis caused by herpes simplex.

ANTI-RETROVIRAL DRUGS

The HIV infection is a serious infection that renders the host susceptible to a variety of
opportunistic diseases. Antiretroviral drugs do not cure the disease, but can allow the host to
develop a reasonable amount of immunocompetence. The process of viral replication may be
halted at five different stages, and based on this, there are five classes of antiretroviral drugs.

Table 2. Drugs used in therapy of HIV

TYPE OF
MECHANISM ADVERSE
ANTIRETROVIRAL EXAMPLES PHARMACOKINETICS
OF ACTION EFFECTS
DRUG
These drugs
are nucleoside
analogs. They get
Lactic
phosphorylated
Zidovudine into triphosphates Administered orally, and acidosis,
Nucleoside
Didanosine within infected can cross the blood-brain hepatomegaly,
reverse transcriptase
Stavudine barrier. Intracellular half life bone marrow
inhibitors cells. They get
is 3 hours. toxicity,
incorporated into
headache
viral DNA and
prevent chain
elongation
Dizziness,
They bind headache, loss
Non-nucleoside Administered orally,
Efavirenz directly to reverse of
reverse transcriptase Nevirapine transcriptase and metabolized in the liver, and concentration,
inhibitors inhibit the enzyme excreted in urine. hypersensitivity
reactions

Nausea,
vomiting,
diarrhea,
altered lipid
Administered orally.
Inhibit HIV and glucose
Atazanavir They bind to plasma
Protease aspartyl protease. metabolism,
Darunavir proteins, are metabolized in
inhibitors This prevents redistribution
Ritonavir the liver, and excreted in
virus maturation. of fat leading to
urine.
breast
enlargement,
and buffalo
hump.
These drugs
bind to
At the
glycoproteins on
Enfuvirtide is given injection site,
the host cell
Enfuvirtide subcutaneously. Maraviroc is pain, erythema,
Entry inhibitors surface, and
Maraviroc given orally and metabolized and nodule
prevent HIV from
in the liver formation may
fusing with these
occur.
proteins and
entering the cell.
Nausea,
They inhibit
These drugs are given diarrhea,
Integrase Dolutegravir integration of viral
orally, metabolized in the elevation in
inhibitors Elvitegravir DNA into the host
liver, and excreted in feces. creatinine
cell genome.
levels.

NON-SPECIFIC ANTIVIRAL DRUGS

Lamivudine:

● This drug acts on two viruses – Hepatitis B and HIV. It inhibits the enzymes HBV DNA
polymerase and HIV reverse transcriptase.
● It can be taken orally and is excreted unchanged in urine. Its plasma t ½ is 6-8 hours,
while intracellular t1/2 can be up to 12 hours.
● It is usually well tolerated. It can cause headache, rashes, nausea, anorexia, and
abdominal pain.

Tenofovir:

● This is another drug which is effective against both HBV and HIV.
● It is a nucleoside analog of adenosine monophosphate. It inhibits the reverse transcriptase
 enzyme.
● It may be given orally and it has a long half life. It is excreted unchanged in urine.
● Adverse effects include nausea, bloating, and increase in serum creatinine.

Ribavirin:

● This drug is effective against several DNA and RNA viruses. Its oral form is commonly
used in chronic hepatitis C. Inhalational form is used for management of respiratory
syncytial bronchiolitis in children.
● It inhibits formation of GTP, which is essential for viral replication. It is converted to its
active form by phosphorylation. Thereafter, the drug and its metabolites are excreted in
urine.
● Adverse effects include anemia and elevated bilirubin. Monitoring of respiratory function
is necessary as it can sometimes cause deterioration.
EXERCISES:

1. Which of the following drugs is effective against Influenza B?

1. Amantadine
2. Oseltamivir
3. Acyclovir
4. Rimantadine
2. Which form of interferon is available for clinical use?
1. ��
2. Β
3. Ɣ
4. δ
3. Which of the following substrates does entecavir compete with?
1. ATP
2. Deoxy ATP
3. GTP
4. Deoxy GTP
4. Which of the following drugs is preferred for chronic hepatitis C?
1. Acyclovir
2. Adefovir
3. Telaprevir
4. Entecavir
5. Which of the following drugs is not a nucleoside reverse transcriptase inhibitor?
1. Zidovudine
2. Stavudine
3. Nevirapine
4. Didanosine
6. Which of the following drugs causes redistribution of body fat?
1. Stavudine
2. Ritonavir
3. Maraviroc
4. Elvitegravir
 7. Which of the following drugs prevents entry of HIV into cells?
1. Stavudine
2. Ritonavir
3. Maraviroc
4. Elvitegravir
8. Lamivudine is effective against HIV and which other virus?
1. Herpes simplex
2. Hepatitis A
3. Hepatitis B
4. Cytomegalovirus
9. Which drug is used to manage respiratory syncytial bronchiolitis?
1. Lamivudine
2. Zidovudine
3. Ribavirin
4. Ritonavir
10. Which of the following drugs must not be used systemically?
1. Foscarnet
2. Trifluridine
3. Ritonavir
4. Stavudine
 CHAPTER 3: ANTIFUNGAL DRUGS
Mycoses are infectious diseases caused by fungi. These infectious diseases are of two kinds –
superficial conditions that mostly affect the skin, and systemic infections that can affect the
internal organs. Accordingly, antifungal drugs may be administered systemically, or topically.

DRUGS FOR SYSTEMIC MYCOSES

Amphotericin B:

● This is the drug of choice for serious mycotic infections. It binds to a compound called
ergosterol on the cell membrane of sensitive fungal cells, and creates pores in the
membrane. This disrupts electrolyte balance and causes cell death.
● It is administered intravenously. It is a lipophilic drug and is therefore complexed with
sodium deoxycholate. It binds to plasma proteins and is distributed to most body fluids
except CSF. It does not cross the placenta. It is excreted in urine and bile.
● It has a low therapeutic index and has several adverse effects. Fever and chills may
develop a few hours after administration. It can cause nephrotoxicity, hypotension,
hypokalemia, and thrombophlebitis.

Flucytosine: (5-FC)

● 5-FC is a pyrimidine analog, which enters the fungal cell after binding to a specific
enzyme called permease. Within the cell, it can disrupt synthesis of nucleic acid and
proteins. It is more effective when combined with amphotericin B, as that drug
increases its penetration into the cell.
● It is well absorbed from oral routes. It can penetrate CSF, and some amount is
metabolized to 5-fluorouracil by intestinal bacteria. It is excreted through urine.
● Adverse effects include bone marrow suppression, neutropenia, and thrombocytopenia. It
can also cause nausea, vomiting, diarrhea, and enterocolitis.

Azole antifungals:

● These are of two types – imidazoles and triazoles. Only the triazoles are used for
systemic mycoses. The drugs in this category are fluconazole, posaconazole,
itraconazole, and voriconazole.
● These drugs inhibit a cytochrome P450 enzyme, C-14 α demethylase, which blocks the
demethylation of lanosterol to ergosterol. Ergosterol is an important component of the
cell membrane and without it, cell growth is inhibited.
● Fluconazole is taken orally or intravenously, and is excreted unchanged in urine.
Itraconazole is available for oral use, and is metabolized extensively by the liver. It is
excreted in urine or feces. Posaconazole is taken orally and undergoes glucuronide
conjugation in the liver. Voriconazole is available for both oral and intravenous use,
and is metabolized in the liver.
● Adverse effects include nausea, vomiting, diarrhea, and headache. Hypertension and
 hypokalemia can occur. Fluconazole and itraconazole may cause hepatotoxicity.

Echinocandins:

● This includes the drugs caspofungin and micafungin. They prevent cell wall synthesis by
inhibiting the enzyme β-D-glucan.
● They are available for intravenous use. Adverse effects include fever, rash, flushing,
nausea, and phlebitis.

Table 1. Indications for systemic antifungal agents.

DRUG MYCOTIC INFECTION

Invasive candidiasis, cryptococcosis, histoplasmosis, coccidioidomycosis,
Amphotericin
paracoccidioidomycosis, blastomycosis, disseminated sporotrichosis,
B
aspergillosis, mucormycosis
Oral or vaginal candidiasis, histoplasmosis, coccidioidomycosis,
Itraconazole blastomycosis, sporotrichosis, paracoccidioidomycosis, aspergillosis,
chromomycosis
Candidiasis, cryptococcosis, histoplasmosis, coccidioidomycosis,
Fluconazole
paracoccidioidomycosis, blastomycosis
Posaconazole Invasive candidiasis, aspergillosis, chromomycosis
Voriconazole Invasive candidiasis, aspergillosis
Clotrimazole Candidiasis
5-Flucytosine Cryptococcosis
Caspofungin Invasive candidiasis, aspergillosis

DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS

Terbinafine:

● This drug inhibits the enzyme squalene epoxidase, which inhibits ergosterol synthesis. It
is useful for fungal nail infections, tinea capitis, tinea pedis, tinea corporis, and tinea
cruris.
● It is available for oral use. It binds to plasma proteins and gets deposited in the skin,
adipose tissue, and nails. It is metabolized in the liver and excreted through urine. It is
also available for topical use.

Griseofulvin:

● It inhibits mitosis by disrupting the fungal mitotic spindle. It is effective against

onychomycosis, and dermatophytosis of the scalp and hair.
● From the oral route, it is absorbed and stored in the skin, nails, hair, and adipose tissue.
● It must not be given to pregnant patients and patients with porphyria.
 Nystatin:

● The structure and mechanism of action are similar to amphotericin B, but the drug is
reserved for topical use.
● It is effective in all forms of superficial candidiasis – oropharyngeal, vulvovaginal, and
cutaneous forms. Topical application may lead to skin irritation.

Imidazoles:

● These are azole derivatives which are reserved for topical use. They include the drugs
ketoconazole, miconazole, and clotrimazole.
● They are used in tinea corporis, cruris and pedis, and oropharyngeal and vulvovaginal
candidiasis.
● They may produce irritation, edema and contact dermatitis.

Ciclopirox:

● This drug disrupts the transport of essential elements into the fungal cell. This in turn
prevents synthesis of DNA, RNA, and proteins.
● It is effective against several fungal infections including candidiasis, tinea versicolor,
tinea corporis, tinea cruris, tinea pedis, and seborrheic dermatitis.

Tolnaftate:

● It stunts fungal growth by distorting fungal hyphae. It is effective against tinea corporis,
tinea pedis, and tinea cruris.

EXERCISES:

1. Which of the following drugs is the drug of choice for serious mycotic infections?
1. Itraconazole
2. Amphotericin B
3. Caspofungin
4. 5-fluorocytosine
2. Which of the following azoles is not a triazole?
1. Fluconazole
2. Itraconazole
3. Miconazole
4. Posaconazole
3. Which of the following drugs inhibits the enzyme β-D-glucan?
1. Itraconazole
2. Amphotericin B
3. Caspofungin
4. 5-fluorocytosine
4. Which of the following drugs can cause both bone marrow suppression and
enterocolitis?
 1. Itraconazole
2. Amphotericin B
3. Caspofungin
4. 5-fluorocytosine
5. Which of the following drugs undergoes glucuronide conjugation in the liver?
1. Fluconazole
2. Posaconazole
3. Itraconazole
4. Voriconazole
6. Which of the following drugs is a squalene epoxidase inhibitor?
1. Terbinafin
2. Griseofulvin
3. Nystatin
4. Ciclopirox
7. Which of the following drugs is a topical drug similar to Amphotericin B?
1. Terbinafin
2. Griseofulvin
3. Nystatin
4. Ciclopirox
8. Which of the following drugs is effective against tinea versicolor?
1. Terbinafin
2. Griseofulvin
3. Nystatin
4. Ciclopirox
9. Which of the following drugs disrupts the fungal mitotic spindle?
1. Terbinafin
2. Griseofulvin
3. Nystatin
4. Ciclopirox
10. Which of the following drugs distorts fungal hyphae?
1. Griseofulvin
2. Tolnaftate
3. Nystatin
4. Ketoconazole
 CHAPTER 4: ANTIPROTOZOAL AND
ANTHELMINTIC DRUGS
Protozoal and helminthic diseases mostly occur in tropical and developing countries. Most of
these are associated with improper hygiene practices. This chapter discusses the drugs used in
management of these diseases.

ANTI-AMOEBIC DRUGS

These drugs are effective against Entamoeba histolytica, which infects the intestinal tract and
can cause dysentery.

Metronidazole:

This was primarily developed as an anti-amebic drug, but its versatile antimicrobial spectrum
has led to its use in several other infections.

Mechanism of action:

Metronidazole enters microbial cells by diffusion. Anaerobic microbes possess redox

proteins, which react with the nitro group on the drug to form nitro radicals. The nitro radical is
cytotoxic, and destroys proteins and DNA.

Pharmacokinetics:

It is well absorbed orally. The drug distributes to all body tissues and fluids including vaginal
and seminal fluids, saliva, and CSF. It is metabolized in the liver through oxidation and
glucuronide conjugation. It is excreted in urine. Plasma t ½ is about 8 hours.

Adverse effects:

● Metallic taste, nausea, vomiting, abdominal cramps

● Sometimes neurotoxicity can occur.

Indications:

● Amebiasis – both intestinal and extraintestinal

● Giardiasis
● Trichomonas vaginitis
● Anaerobic bacterial infections, including acute necrotizing ulcerative gingivitis and
dental infections
● H. pylori eradication treatment
● Pseudomembranous enterocolitis caused by C. difficile.

Tinidazole:
 ● This is similar to metronidazole in terms of mechanism of action and indications.
● It has a longer half life of 12 hours, and lower incidence of adverse effects like metallic
taste.

Dehydroemetine:

● This was previously used to treat amebiasis, but has largely been replaced by
metronidazole.
● It is administered as an intramuscular injection. It acts by blocking chain elongation and
inhibiting protein synthesis.
● Adverse effects include pain at the injection site, neuromuscular weakness, dizziness,
cardiotoxicity, and rash.

Luminal amebicides:

● These drugs are used for the management of asymptomatic carriers.

● Iodoquinol kills the trophozoite and cyst forms of entamoeba within the intestinal lumen.
It can cause rashes, diarrhea, and peripheral neuropathy.
● Paromomycin directly reduces the population of all intestinal flora. It may cause GI
distress and diarrhea. Apart from amoebiasis, it may also be used for giardiasis and
cryptosporidiosis.

ANTIMALARIAL DRUGS

Malaria is a protozoal infection caused by Plasmodium falciparum and vivax. It is

transmitted to humans through the female anopheles mosquito.

Primaquine:

● Primaquine is effective only against the exo-erythrocytic forms of malaria. It is not

effective on microbes located within the red blood cells.
● It is administered orally and is metabolized by oxidation. The oxidized forms are active
and destroy the microorganism. Small amounts are excreted in urine.
● It must not be used in patients with glucose-6-phosphate dehydrogenase deficiency, as it
can lead to hemolytic anemia in these patients. It may cause abdominal discomfort.

Chloroquine:

● Chloroquine is the antimalarial drug of choice. The malarial parasite usually converts
heme to hemozoin. Chloroquine prevents this conversion, and the heme destroys the
parasite as well as the red blood cell.
● It is administered orally. The drug concentrates in red and white blood cells, spleen, liver,
and lung. It crosses the blood-brain barrier and placenta. It is metabolized in the liver
and excreted in urine.
● It can cause headache, blurred vision, and gastrointestinal upset. It can also cause
discoloration of nails and skin and pruritus

Atovaquone/Proguanil:
 ● This combination is used for malarial strains that are resistant to chloroquine.
Atovaquone inhibits the mitochondrial processes of the parasite. Proguanil is converted
into cycloguanil, which inhibits dihydrofolate reductase in the parasite and blocks DNA
synthesis.
● The adverse effects of this combination include nausea, anorexia, diarrhea, abdominal
pain, headache, and dizziness.

Artemisinin:

● This is used to treat multidrug-resistant malaria. This drug produces free radicals that are
toxic to the microorganism. The free radicals bind to malarial proteins and damage
them.
● They are available through oral or rectal routes. Adverse effects include hypersensitivity
reactions, nausea, and diarrhea.

Pyrimethamine:

● It inhibits the enzyme dihydrofolate reductase in the plasmodium. The drug concentrates
in blood and is ingested by the mosquito when it sucks blood. It can thus prevent
transmission of the disease as well.

DRUGS AGAINST TRYPANOSOMIASIS

Trypanosomiasis is characterized by two major conditions – African sleeping sickness and

Chagas’ disease (American sleeping sickness). The Trypanosoma parasite initially multiplies in
the blood, and then invades the CNS, causing inflammation of the brain and spinal cord.

Pentamidine:

● This drug is taken up within the protozoan cell, where it interferes with synthesis of
essential components, including DNA, RNA, proteins, and phospholipids.
● It is administered intramuscularly or intravenously. It concentrates in the liver, kidney,
lungs, and spleen, but does not penetrate CSF. It is excreted slowly in urine,
unchanged.
● It may cause renal dysfunction, altered glucose metabolism, pancreatitis, hyperkalemia,
and hypotension.
● Apart from trypanosomiasis, it is also used for management of Leishmaniasis and
infections by Pneumocystis jirovecii.

Melarsoprol:

● This drug penetrates the CSF and can be used for the second stage of trypanosomiasis. It
is administered intravenously, has a short half-life, and is excreted in urine.
● It can cause encephalopathy. It may also produce peripheral neuropathy, hypertension,
and hypersensitivity reactions.

Nifurtimox:
 ● This drug gets reduced and generates oxygen radicals, which are toxic to the
microorganism.
● It is administered orally. It is metabolized and excreted in urine.
● Adverse effects include hypersensitivity reactions, gastrointestinal problems, and
peripheral neuropathy.

DRUGS AGAINST LEISHMANIASIS

Leishmaniasis is transmitted through sandflies. It may be restricted to cutaneous or

mucocutaneous forms, or may invade viscera. Amphotericin B, pentamidine, and paromomycin
may be used for management.

Sodium stibogluconate:

● This drug is administered parenterally, and undergoes minimal metabolism before

excretion in urine.
● It can cause pancreatitis, liver dysfunction, cardiac arrhythmias, arthralgias, and
myalgias.

Miltefosine:

● This is available for oral administration. It reacts with cell membrane phospholipids, and
causes apoptosis of the microorganism.
● Adverse effects include nausea and vomiting. It is teratogenic.

ANTHELMINTIC DRUGS

Helminths are ‘worms’ that infest the human body. These drugs kill and expel not only the
worms, but their eggs and larvae. These drugs are summarized in Table 1.

Table 1. Anthelmintic drugs and their indications

DRUG MECHANISM ADVERSE

DRUG INDICATIONS
CATEGORY OF ACTION EFFECTS
Enterobiasis
Blocks glucose
ascariasis,
uptake and inhibits Abdominal
Mebendazole trichuriasis,
microtubules in pain, diarrhea
ancylostomiasis,
the parasite
trichinosis
It inhibits
cholinesterase and
Nausea, Enterobiasis,
releases
Pyrantel pamoate vomiting, ascariasis,
acetylcholine,
Drugs diarrhea ancylostomiasis
leading to
against muscular paralysis
nematodes
(roundworms) Increases Mazotti
chloride influx reaction – fever,
 Ivermectin into the parasite,headache, Onchocerciasis,
leading to dizziness, strongyloidiasis
hyperpolarization somnolence,
and paralysis hypotension
Nausea,
Kills vomiting,
Diethylcarbamazine Filariasis
microfilariae arthralgia,
headache
Increases Dizziness, Paragonimiasis,
Drugs
permeability of the malaise, schistosomiasis,
against
Praziquantel cell membrane to headache, clonorchiasis,
trematodes
calcium, which gastrointestinal taeniasis,
(flatworms)
leads to paralysis. upset cysticercosis
Inhibits Rare –
phosphorylation of malaise,
Niclosamide Diphyllobothriasis
ADP in the lightheadedness,
Drugs mitochondria pruritus.
against
cestodes Headache,
Inhibits
(tapeworms) nausea, Echinococcosis,
glucose uptake
Albendazole hepatotoxicity cysticercosis,
and microtubule
on long-term trichinosis
synthesis
use

EXERCISES:

1. Which group of metronidazole reacts with the proteins of microorganisms?

1. Hydroxyl
2. Nitro
3. Carboxyl
4. Sulfuric
2. What is the half-life of tinidazole?
1. 6 hours
2. 8 hours
3. 10 hours
4. 12 hours
3. Which of the following drugs is not effective for extraluminal microorganisms?
1. Metronidazole
2. Paromomycin
3. Tinidazole
4. Dehydroemetine
4. Which of the following antimalarials cause discoloration of the skin and nails?
1. Primaquine
2. Chloroquine
3. Proguanil
 4. Artemisinin
5. Which of the following drugs is used to treat multidrug-resistant malaria?
1. Primaquine
2. Chloroquine
3. Proguanil
4. Artemisinin
6. Which of the following drugs may be used for the second stage of trypanosomiasis?
1. Pentamidine
2. Melarsoprol
3. Nifurtimox
4. Miltefosine
7. Which of the following drugs is effective in filariasis?
1. Niclosamide
2. Albendazole
3. Diethylcarbamazine
4. Ivermectin
8. Which drug increases chloride influx into the cell?
1. Niclosamide
2. Albendazole
3. Diethylcarbamazine
4. Ivermectin
9. Which drug is used to treat diphyllobothriasis?
1. Niclosamide
2. Albendazole
3. Diethylcarbamazine
4. Ivermectin
10. Which drug inhibits microtubule synthesis in the parasite?
1. Niclosamide
2. Albendazole
3. Diethylcarbamazine
4. Ivermectin
 UNIT XII - IMPORTANT MISCELLANEOUS
DRUGS
CHAPTER 1: ANTICANCER DRUGS AND
IMMUNOSUPPRESSANTS
ANTIMETABOLITES

These drugs have a chemical structure that is similar to normal cellular compounds, which
allows them to interfere with normal cellular metabolism.

Methotrexate/Pralatrexate:

● These drugs are structurally similar to folic acid, and inhibit the enzyme dihydrofolate
reductase.
● They can be administered orally, intramuscularly, or intravenously. Since they do not
penetrate the blood-brain barrier, intrathecal route is employed for CNS cancers. It
undergoes metabolism by hydroxylation, and it is excreted via urine and feces.
● Adverse effects include nausea, vomiting, diarrhea, and stomatitis. Rash and alopecia
may occur. They can also cause myelosuppression and renal dysfunction in high doses.
● They are employed in acute lymphocytic leukemia, Burkitt lymphoma in children, breast
and bladder cancers, and head and neck cancer.

6-Mercaptopurine (6-MP):

● This is an analog of hypoxanthine. It penetrates cells and is converted to 6-MP ribose

phosphate. This compound inhibits purine synthesis, and itself gets incorporated into
RNA and DNA, rendering them non-functional. Its analog, azathioprine, acts in a
similar manner.
● It is administered orally and undergoes first-pass metabolism. It does not penetrate CSF.
Following metabolism in the liver, the drug and its metabolites are excreted in urine.
● Adverse effects include nausea, vomiting, diarrhea, anorexia, myelosuppression, and
hepatotoxicity.
● It is used for maintaining remission in acute lymphocytic leukemia. It is also used for
management of Crohn’s disease.

5-Fluorouracil:

● This is a pyrimidine analog, which enters the cell and is converted into its deoxy form.
The deoxy form inhibits thymidine synthesis, which in turn decreases synthesis of
DNA.
● It is administered intravenously. It is distributed to the liver, lung and kidney and is
metabolized in these tissues. Excretion occurs through urine.
● Adverse effects include mucositis, diarrhea, alopecia, myelosuppression, and coronary
vasospasm.
 Cytarabine:

● This is an analog of 2-deoxycytidine. Within the cell, it is converted into cytosine

arabinoside triphosphate, which inhibits the enzyme DNA polymerase. It is also
incorporated into DNA and causes chain termination.
● It is given intravenously or intrathecally. It is metabolized by oxidative deamination, and
is excreted in the urine.
● Adverse effects include nausea, vomiting, diarrhea, myelosuppression, hepatotoxicity,
neurotoxicity, and conjunctivitis.

ANTITUMOR ANTIBIOTICS

These are cytotoxic drugs that primarily interact with DNA and disrupt their function.

Anthracyclines:

● This category includes the drugs doxorubicin, daunorubicin, idarubicin, epirubicin, and
mitoxantrone. These drugs release free radicals, which can damage DNA, oxidize
nucleosides, and cause membrane lipid peroxidation.
● They are administered intravenously. They bind to plasma proteins, and do not enter the
CNS. Metabolism occurs in the liver and drugs are excreted through bile. Minimal
amounts may be excreted through urine, which can cause discoloration.
● They can cause cardiotoxicity and congestive cardiac failure.
● Doxorubicin is used for management of sarcomas, breast and lung carcinomas, acute
lymphoblastic leukemia and lymphomas. Mitoxantrone is used for management of
prostatic carcinoma. The other drugs in this category are mostly employed for
leukemias.

Bleomycin:

● This is a copper-chelating agent which cleaves DNA through oxidative processes. It is

administered either orally or parenterally, and is excreted unchanged in urine.
● Adverse effects include fever, chills, mucocutaneous reactions, and alopecia. Pulmonary
toxicity may also occur in the form of cough, rales, and pulmonary fibrosis.
● It is used in the management of Hodgkin’s lymphoma and testicular cancers.

ALKYLATING AGENTS

These agents covalently bind to nucleophilic groups on cells and alkylate DNA, destroying
the cell.

Cyclophosphamide/Ifosfamide:

● These drugs are initially hydroxylated in the liver. The hydroxylated form breaks down
to phosphoramide mustard and acrolein, which are cytotoxic. The metabolites are
excreted in urine. Both cyclophosphamide and ifosfamide are preferentially
administered orally.
 ● It can cause nausea, vomiting, diarrhea, alopecia, and amenorrhea. It can also lead to
myelosuppression, hemorrhagic cystitis, and secondary malignancies.
● They are used in several neoplastic diseases including breast cancer, non-Hodgkin’s
lymphoma, and sarcomas.

Nitrosoureas:

● These drugs, carmustine and lomustine, inhibit RNA and protein synthesis. They also
inhibit other enzymatic processes within the cell.
● Carmustine is given intravenously, while lomustine is given orally. These drugs
distribute widely and can penetrate the CNS. They are metabolized in the liver and
excreted through urine.
● Adverse effects include nausea, vomiting, and facial flushing. They can also cause
myelosuppression, impotence and infertility, pulmonary toxicity, and neurotoxicity.
● These drugs are primarily used in the management of brain tumors.

Temozolomide:

● It methylates the guanine part of the DNA chain, leading to termination. It also inhibits
the DNA repair enzyme, O-guanine-DNA-alkyltransferase.
● It is administered either orally or intravenously. It can enter the CNS, is metabolized in
the liver, and is excreted in urine.
● Adverse effects include headache, nausea, vomiting, myelosuppression, and
photosensitivity.
● It is used for CNS tumors such as glioblastomas and astrocytomas.

MICROTUBULE INHIBITORS

The microtubules, along with chromatin, make up the mitotic spindle of the cells. Inhibiting
the microtubules prevents cell replication and can be cytotoxic.

Vincristine/Vinblastine:

● Also known as vinca alkaloids, these drugs bind to the protein tubulin, and prevent its
polymerization to microtubules. This results in a dysfunctional spindle, which prevents
chromosomal segregation and cell division.
● These drugs are given intravenously. They are metabolized in the liver through the
cytochrome P450 system, and are excreted in bile and feces.
● Adverse effects include nausea, vomiting, diarrhea, alopecia, myelosuppression, and
peripheral neuropathy.
● They are used for the management of acute lymphoblastic leukemia, lymphomas, and
soft tissue sarcomas.

Paclitaxel/Docetaxel:

● These drugs promote the polymerization of tubulin, leading to accumulation of

microtubules. However, these are non-functional, and chromosomal segregation is
prevented.
● These drugs are given intravenously, and are metabolized in the liver through the
cytochrome P450 system. Excretion occurs through bile.
● Alopecia, neutropenia, and leukopenia may occur. These drugs are used for management
of ovarian and breast cancers.

MONOCLONAL ANTIBODIES

● Monoclonal antibodies are hybrid forms of B-lymphocytes, and they produce antibodies
against specific tumor antigens. This category includes drugs like cetuximab,
rituximab, and bevacizumab.
● These drugs are usually administered intravenously. They can cause fever and chills
during infusion, neutropenia, cardiotoxicity, pulmonary toxicity, and mucocutaneous
reactions.

PLATINUM COMPLEXES

● This class includes drugs such as cisplatin, carboplatin, and oxaliplatin. They release a
chloride group within the cell, and bind to guanine in DNA. This inhibits polymerases
involved in DNA replication and RNA synthesis.
● They are administered intravenously or intraperitoneally. It distributes to the liver,
kidney, intestine, testes, and ovary, but does not penetrate CSF.
● It can cause severe vomiting, myelosuppression, ototoxicity, neurotoxicity, and
hepatotoxicity.
● These are used for solid tumors, such as testicular, bladder, and ovarian carcinomas.

TOPOISOMERASE INHIBITORS

● Topoisomerases are enzymes which prevent supercoiling of DNA and reduce torsional
strain. These drugs, including camptothecins (such as irinotecan and topotecan) and
etoposide, inhibit this enzyme and make DNA brittle and prone to breakage.
● Myelosuppression and diarrhea can occur with camptothecins. Etoposide can also cause
hypotension and alopecia.
● Irinotecan is used in treating colorectal carcinoma, while topotecan is used for metastatic
ovarian cancer and small-cell lung cancer. Etoposide is used in lung and testicular
cancer.

TYROSINE KINASE INHIBITORS

● This category includes drugs such as imatinib, erlotinib, and sunitinib. These drugs
inhibit tyrosine kinase, which regulates signal transduction and cell division. They are
available as oral formulations, and undergo metabolism in the liver.
● Adverse effects include fluid retention, and QT interval prolongation. Erlotinib can cause
interstitial lung disease. Diarrhea, fatigue, hypertension, and hand-foot-mouth
syndrome can also occur.
● Imatinib is used in chronic myelogenous leukemia, and GI stromal tumors. Erlotinib is
used in treatment of non-small-cell lung cancer and pancreatic cancer. Sunitinib has
been used in GI stromal cell and pancreatic cancers.
 STEROID HORMONES AND ANTAGONISTS

● Prednisolone is used to induce remission in patients with acute lymphocytic leukemia,

and lymphomas.
● Tamoxifen is used in prophylaxis and management of breast cancer.
● Fulvestrant and raloxifene, which are estrogen receptor antagonists, are employed to treat
breast cancer in patients who have hormone positive tumors.
● Progestins are used for breast and endometrial neoplasms.
● Estrogens are used in the management of prostatic cancer.
● Flutamide and nilutamide are androgen antagonists used in the management of prostatic
cancer.

AGENTS USED FOR IMMUNOSUPPRESSION IN TRANSPLANT PATIENTS

These drugs are generally used in patients who have undergone renal, cardiac, or hepatic
transplants. Their function is to suppress immunity, to increase the chances of acceptance of the
transplanted organ. Some of the more commonly used immunosuppressants are given below:

Cytokine inhibitors:

● Cytokines are signaling proteins that play an important role in immune reactions. This
class of drugs inhibit cytokines, and therefore, decrease immune reactions. Important
drugs in this category include cyclosporine, tacrolimus, and sirolimus.
● Cyclosporine and tacrolimus are given either orally or intravenously. They are
metabolized by the cytochrome P450 system, and are excreted in bile and feces.
Sirolimus is given orally, and metabolism is similar.
● Due to immune suppression, viral infections may occur, including herpes and
cytomegalovirus infections. Hypertension, hyperlipidemia, and hyperkalemia may
occur. Cyclosporine can cause nephrotoxicity and hepatotoxicity.

Antimetabolites:

● Azathioprine is the prodrug that first converts to 6-mercaptopurine, and then to the
nucleotide thioinosinic acid.
● Mycophenolate mofetil is an inhibitor of inosine monophosphate dehydrogenase, and
blocks guanosine phosphate production. It is taken orally, undergoes glucuronide
conjugation, and is excreted in urine. It can cause nausea, vomiting, diarrhea, and
abdominal pain.

Antibodies:

● Antibodies produced by recombinant DNA technology may be injected at the time of

transplantation. They help to prolong graft survival. Antithymocyte globulins, which
bind to T lymphocytes, can cause lymphopenia and impaired immune response.

Steroids:

● Prednisolone and methylprednisolone are commonly used as immunosuppressants.

EXERCISES

1. Which of the following substrates is methotrexate structurally similar to?

1. Niacin
2. Riboflavin
3. Folic acid
4. Ascorbic acid
2. Which of the following compounds has synthesis inhibited by 5-fluorouracil?
1. Cytosine
2. Thymidine
3. Adenine
4. Guanine
3. Which type of lymphoma is bleomycin indicated for?\
1. Hodgkin’s
2. Non-hodgkins
3. Mixed
4. None of the above
4. Which of the following is not an example of an alkylating agent?
1. Cyclophosphamide
2. Carmustine
3. Doxorubicin
4. Temozolomide
5. Which of the following is an example of microtubule inhibitor?
1. Methotrexate
2. Lomustine
3. Paclitaxel
4. Cisplatin
6. Which of the following is an adverse effect associated with all anti-cancer drugs?
1. Nausea
2. Alopecia
3. Myelosuppression
4. All of the above
7. Which of the following hormones is not used for the management of breast cancer?
1. Raloxifene
2. Progestins
3. Estrogens
4. Tamoxifen
8. What viral infections are common after immunosuppressant therapy?
1. Herpes
2. HIV
3. Rotavirus
4. Influenza
9. Which of the following proteins is suppressed by cyclosporine?
1. Prostaglandins
2. Cytokines
3. Leukotrienes
 4. histamines
10. Which of the following steroids is most commonly used as an anti-cancer drug and
immunosuppressant?
1. Dexamethasone
2. Hydrocortisone
3. Prednisolone
4. Mometasone
APPENDIX
 APPENDIX I: IMPORTANT DRUG
INTERACTIONS

DRUG NAME OF CONCOMITANT EFFECT IF

CATEGORY DRUG DRUGS TO AVOID COMBINED
Anti-hypertensives Clonidine Propranolol Hypertension
Anti-anginal and Increased digoxin
Digoxin Quinidine
cardiac drugs levels and toxicity
Antibiotics –
Warfarin effect is
Clarithromycin,
potentiated because
erythromycin,
they inhibit gut flora,
ciprofloxacin,
Anticoagulants Warfarin which produce vitamin
metronidazole,
K.
cotrimoxazole
Aspirin, NSAIDS, Increased bleeding
paracetamol and INR
Additive platelet
Aspirin, Methicillin,
Antiplatelet drugs action, increased
Clopidogrel carbenicillin
bleeding risk
Inhibition of
Oral hypoglycemic
Sulfonylureas Sulfonamides metabolism,
drugs
hypoglycemia
Decreases
Most Antibiotics,
Oral contraceptives effectiveness of
Rifampicin, troglitazone
contraception
Cimetidine,
Carbamazepine,
erythromycin, Increases drug
phenytoin,
clarithromycin, levels
phenobarbitone
Antiepileptic fluconazole.
Carbamazepine,
Decreased drug
phenytoin, Rifampicin
levels
phenobarbitone
NSAIDS, diuretics, Increased drug
Lithium
metronidazole, tinidazole levels
Anti-Parkinsonism Peripheral
vasoconstriction,
Bromocriptine Pseudoephedrine
seizures, ventricular
tachycardia
Potentiates action
Tricyclic
 SSRIs antidepressants of tricyclic
Antidepressants antidepressants
MAO inhibitors Hypertensive crisis
Other SSRIs, SNRIs, Serotonin
tramadol syndrome, seizures
Ciprofloxacin, Increase in
Drugs for asthma Theophylline
norfloxacin, pefloxacin theophylline levels
Can cause
Diuretics Thiazides Sulfonamides
thrombocytopenia
Penicillin,
Prolonged
ampicillin, Probenecid
antibiotic action
cephalosporins
Antibiotics Ampicillin Allopurinol Can cause rashes
Metronidazole,
Disulfiram-like
tinidazole, Alcohol
reactions
cefoperazone
Erythromycin, Metabolism is
clarithromycin, azole inhibited, which can
Cisapride antifungals, antivirals, lead to prolonged QT
Immunosuppressant Class I and II anti- interval and
drugs arrhythmic agents arrhythmias
6-
Increased drug
mercaptopurine, Allopurinol
levels
azathioprine
 APPENDIX IIA: PREGNANCY
CLASSIFICATION OF DRUGS

DRUG
DESCRIPTION
CATEGORY
Adequate and well-controlled studies have failed to demonstrate a risk to the
A fetus in the first trimester of pregnancy. There is no evidence of risk in later
trimesters.
Animal reproduction studies have failed to demonstrate a risk to the fetus and
B
there are no adequate and well-controlled studies in pregnant women.
Animal reproduction studies have shown an adverse effect on the fetus and
C there are no adequate and well-controlled studies in humans, but potential
benefits may warrant use of the drug in pregnant women despite potential risks.
There is positive evidence of human fetal risk based on adverse reaction data
D from investigational or marketing experience or studies in humans, but potential
benefits may warrant use of the drug in pregnant women despite potential risks.
Studies in animals or humans have demonstrated fetal abnormalities and/or
there is positive evidence of human fetal risk based on adverse reaction data from
X
investigational or marketing experience, and the risks involved in use of the drug
in pregnant women clearly outweigh potential benefits

Source: Content and Format of Labeling for Human Prescription Drug and Biological
Products; Requirements for Pregnancy and Lactation Labeling (Federal Register/Vol. 73, No.
104/Thursday, May 29, 2008
 APPENDIX IIB: EXAMPLES OF COMMONLY
USED DRUGS CLASSIFIED ACCORDING TO
PREGNANCY CATEGORIES
COMMON
TYPES OF
DRUGS
A B C D X
PRESCRIBED
DURING
PREGNANCY
Metoclopramide,
Doxylamine,
Antiemetics ondansetron,
dextromethorphan
dimenhydrinate
Loperamide,
Other GI pantoprazole, psyllium
Bisacodyl
drugs husk, ranitidine,
cimetidine
Most beta-lactam
antibiotics,
erythromycin,
azithromycin, Aminoglycosides,
Antibiotics
clindamycin, tetracyclines
metronidazole,
aztreonam, meropenem

Acyclovir,
Antivirals, famciclovir, Fluconazole,
antifungal, Amphotericin B, voriconazole, Ribavirin,
anthelmintic Clotrimazole, hydroxychloroquine, griseofulvin
drugs Terbinafine, primaquine
Praziquantel
Drugs that
affect endocrine Levothyroxine Hydrocortisone
system
Ibuprofen, most
Paracetamol,
Analgesics NSAIDS* (only in
Indomethacin, ketamine,
and antipyretics third trimester, else
meperidine
Category C)
Hydrochlorothiazide, ACE inhibitors,
Anti-
amiloride, sotalol, angiotensin receptor
hypertensives
epoprostenol blockers, amiodarone
 Antiplatelets Clopidogrel, Warfarin,
and fondaparinux, apixaban, Edoxaban
anticoagulants enoxaparin
Ipratropium,
Drugs for
budesonide,
asthma
montelukast,
Oral
hypoglycemic Metformin
drugs
Antiepileptic, Sodium
other CNS drugs valproate

*Category C includes many of the drugs not mentioned above.

 REFERENCES
UNIT I - THE BASICS

CHAPTER 1 - ROUTES OF DRUG ADMINISTRATION

1. Whalen K. Lippincott illustrated reviews: pharmacology. Lippincott Williams &

Wilkins; 2018 Aug 14.
2. Tripathi KD. Essentials of medical pharmacology. JP Medical Ltd; 2013 Sep 30.
3. Verma P, Thakur AS, Deshmukh K, Jha AK, Verma S. Routes of drug administration.
International Journal of Pharmaceutical Studies and Research. 2010 Nov;1(1):54-9.
4. Gould T, Roberts RJ. Therapeutic problems arising from the use of the intravenous
route for drug administration. The Journal of pediatrics. 1979 Sep 1;95(3):465-71.
5. Gonda I. Systemic delivery of drugs to humans via inhalation. Journal of aerosol
medicine. 2006 Mar 1;19(1):47-53.

CHAPTER 2 - PHARMACOKINETICS AND PHARMACODYNAMICS

6. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications.

Philadelphia: Lea & Febiger; 1989.
7. Dresser MJ, Leabman MK, Giacomini KM. Transporters involved in the elimination of
drugs in the kidney: organic anion transporters and organic cation transporters. Journal
of pharmaceutical sciences. 2001 Apr 1;90(4):397-421.
8. Kenakin TP. The classification of drugs and drug receptors in isolated tissues.
Pharmacological reviews. 1984 Sep 1;36(3):165-222.
9. Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-
protein-coupled receptors. Nature. 2009 May;459(7245):356-63.
10. Dean PM. Molecular foundations of drug-receptor interaction. Cambridge: Cambridge
University Press; 1987 Jul.

UNIT II - CENTRAL NERVOUS SYSTEM

CHAPTER 1 - GENERAL ANESTHETICS

11. Morgan GE, Mikhail MS, Murray MJ, Larson CP. Clinical anesthesiology. New York:
Lange Medical Books/McGraw-Hill; 2006 Sep 20.
12. Chu LF, Fuller A. Manual of clinical anesthesiology. Lippincott Williams & Wilkins;
2012 Feb 20.
13. Ray DC, Drummond GB. Halothane hepatitis. British Journal of Anaesthesia. 1991 Jul
1;67(1):84-99.
14. Gupta A, Stierer T, Zuckerman R, Sakima N, Parker SD, Fleisher LA. Comparison of
recovery profile after ambulatory anesthesia with propofol, isoflurane, sevoflurane and
 desflurane: a systematic review. Anesthesia & Analgesia. 2004 Mar 1;98(3):632-41.
15. Grounds RM, Twigley AJ, Carli F, Whitwam JG, Morgan M. The haemodynamic
effects of intravenous induction: Comparison of the effects of thiopentone and
propofol. Anaesthesia. 1985 Aug;40(8):735-40.

CHAPTER 2 - SEDATIVE-HYPNOTIC DRUGS

16. Hollister LE, Müller-Oerlinghausen B, Rickels K, Shader RI. Clinical uses of

benzodiazepines. Journal of clinical psychopharmacology. 1993 Dec.
17. Weitzel KW, Wickman JM, Augustin SG, Strom JG. Zaleplon: a pyrazolopyrimidine
sedative-hypnotic agent for the treatment of insomnia. Clinical therapeutics. 2000 Nov
1;22(11):1254-67.
18. Forster A, Gardaz JP, Suter PM, Gemperle M. Respiratory depression by midazolam
and diazepam. Anesthesiology. 1980 Dec;53(6):494-7.
19. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P,
Margolis BD, Byrne DW, Ely EW, Rocha MG. Dexmedetomidine vs midazolam for
sedation of critically ill patients: a randomized trial. Jama. 2009 Feb 4;301(5):489-99.
20. Maxwell LG, Yaster M. The myth of conscious sedation. Archives of pediatrics &
adolescent medicine. 1996 Jul 1;150(7):665-7.

CHAPTER 3 - OPIOID ANALGESICS

21. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annual review of
biochemistry. 2004 Jul;73(1):953-90.
22. Yaster M, Kost-Byerly S, Maxwell LG. Opioid agonists and antagonists. Pain in
infants, children, and adolescents. Philadelphia: Lippincott Williams and Wilkins.
2003:181-224.
23. Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide-a potent antagonist of
morphine analgesia. Life sciences. 1990 Jan 1;47(6):579-85.
24. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain physician. 2008
Mar;11(2 Suppl):S133-53.
25. Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clinical
neuropharmacology. 1993 Feb;16(1):1-8.

CHAPTER 4 - ANTIDEPRESSANTS AND ANTI-MANIC DRUGS

26. Khushboo SB, Sharma B. Antidepressants: mechanism of action, toxicity and possible
amelioration. J. Appl. Biotechnol. Bioeng. 2017;3:1-3.
27. Frazer A. Antidepressants. Journal of Clinical Psychiatry. 1997;58(SUPPL. 6):9-25.
28. Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic
antidepressants. The British Journal of Psychiatry. 1994 Apr;164(4):549-50.
29. Jefferson JW. A review of the cardiovascular effects and toxicity of tricyclic
antidepressants. Psychosomatic Medicine. 1975 Mar.
30. Shaldubina A, Agam G, Belmaker RH. The mechanism of lithium action: state of the
art, ten years later. Progress in neuro-psychopharmacology & biological psychiatry.
 2001 May;25(4):855-66.

CHAPTER 5 - ANTIPSYCHOTIC DRUGS

31. Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein H-G, Steiner J, Bogerts B, Braun K,
Jankowski Z, Kumaratilake J, Henneberg M, Gos T (2014) The role of dopamine in
schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but
still in vogue. Front Psychiatry 5:47. doi: 10.3389/fpsyt.2014.00047.
32. Miller R. Mechanisms of action of antipsychotic drugs of different classes,
refractoriness to therapeutic effects of classical neuroleptics, and individual variation in
sensitivity to their actions: Part I. Curr Neuropharmacol. 2009;7(4):302–314.
doi:10.2174/157015909790031229
33. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe
RS, Davis SM, Davis CE, Lebowitz BD, Severe J. Effectiveness of antipsychotic drugs
in patients with chronic schizophrenia. New England journal of medicine. 2005 Sep
22;353(12):1209-23.
34. Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical
overview. Cmaj. 2005 Jun 21;172(13):1703-11.
35. Caroff SN, Mann SC. Neuroleptic malignant syndrome. The Medical clinics of North
America. 1993 Jan;77(1):185-202.

CHAPTER 6 - DRUGS USED IN NEURODEGENERATIVE DISEASES

36. Lang AE, Lozano AM. Parkinson's disease. New England Journal of Medicine. 1998
Oct 15;339(16):1130-43.
37. Calne D, Langston JW. Aetiology of Parkinson's disease. The Lancet. 1983 Dec
31;322(8365-8366):1457-9.
38. Senek M, Aquilonius SM, Askmark H, Bergquist F, Constantinescu R, Ericsson A,
Lycke S, Medvedev A, Memedi M, Ohlsson F, Spira J. Levodopa/carbidopa
microtablets in Parkinson’s disease: a study of pharmacokinetics and blinded motor
assessment. European journal of clinical pharmacology. 2017 May 1;73(5):563-71.
39. Gupta S, Jhawat V. Pathophysiology of Alzheimer Disease: Current Drug Therapy.
Frontiers in Clinical Drug Research-Alzheimer Disorders. 2017 Jul 31;6:87.
40. Vargas AP, Vaz LS, Reuter A, Couto CM, Cardoso FE. Impulse control symptoms in
patients with Parkinson's disease: The influence of dopaminergic agonist.
Parkinsonism & Related Disorders. 2019 Nov 1;68:17-21.

CHAPTER 7 - ANTI-EPILEPTIC DRUGS

41. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nature Reviews
Neuroscience. 2004 Jul;5(7):553-64.
42. Dichter MA, Brodie MJ. New antiepileptic drugs. New England Journal of Medicine.
1996 Jun 13;334(24):1583-90.
43. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. The Lancet Neurology.
2012 Sep 1;11(9):792-802.
44. Landmark CJ. Antiepileptic drugs in non-epilepsy disorders. CNS drugs. 2008 Jan
1;22(1):27-47.
45. Czapinski P, Blaszczyk B, Czuczwar SJ. Mechanisms of action of antiepileptic drugs.
Current topics in medicinal chemistry. 2005 Jan 1;5(1):3-14.

UNIT III - AUTONOMIC NERVOUS SYSTEM

CHAPTER 1 - CHOLINERGIC AND ANTICHOLINERGIC DRUGS

46. McCorry LK. Physiology of the autonomic nervous system. American journal of
pharmaceutical education. 2007 Aug 15;71(4).
47. Gotti C, Fornasari D, Clementi F. Human neuronal nicotinic receptors. Progress in
neurobiology. 1997 Oct 1;53(2):199-237.
48. Caulfield MP. Muscarinic receptors—characterization, coupling and function.
Pharmacology & therapeutics. 1993 Jan 1;58(3):319-79.
49. Pascuzzi RM. The edrophonium test. InSeminars in neurology 2003 (Vol. 23, No. 01,
pp. 083-088). Copyright© 2002 by Thieme Medical Publishers, Inc., 333 Seventh
Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662.
50. Ali–melkkilä T, Kanto J, Iisalo E. Pharmacokinetics and related pharmacodynamics of
anticholinergic drugs. Acta Anaesthesiologica Scandinavica. 1993 Oct;37(7):633-42.

CHAPTER 2 - ADRENERGIC AND ANTI-ADRENERGIC DRUGS

51. Berthelsen S, Pettinger WA. A functional basis for classification of α-adrenergic

receptors. Life sciences. 1977 Sep 1;21(5):595-606.
52. Kamibayashi T, Maze M. Clinical uses of α2-adrenergic agonists. Anesthesiology: The
Journal of the American Society of Anesthesiologists. 2000 Nov 1;93(5):1345-9.
53. Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter release
by amphetamines: a review. Progress in neurobiology. 2005 Apr 1;75(6):406-33.
54. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta‐blockers for
hypertension. Cochrane database of systematic reviews. 2017(1).
55. Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta‐blockers for chronic
obstructive pulmonary disease. Cochrane database of systematic reviews. 2005(4).

UNIT 4: PERIPHERAL NERVOUS SYSTEM

CHAPTER 1: LOCAL ANESTHETICS

56. Heavner JE. Local anesthetics. Current opinion in anesthesiology. 2007 Aug
1;20(4):336-42.
57. Haas DA. An update on local anesthetics in dentistry. Journal-Canadian Dental
Association. 2002 Oct;68(9):546-52.
58. Becker DE, Reed KL. Local anesthetics: review of pharmacological considerations.
Anesthesia progress. 2012 Jun;59(2):90-102.
59. Malamed SF. Handbook of local anesthesia. Elsevier Health Sciences; 2004 Jun 8.
60. Odedra D, Lyons G. Local anaesthetic toxicity. Current anaesthesia &
critical care. 2010 Feb 1;21(1):52-4.

CHAPTER 2: SKELETAL MUSCLE RELAXANTS

61. Beebe FA, Barkin RL, Barkin S. A clinical and pharmacologic review of skeletal
muscle relaxants for musculoskeletal conditions. American Journal of Therapeutics.
2005 Mar 1;12(2):151-71.
62. See S, Ginzburg R. Skeletal muscle relaxants. Pharmacotherapy: The Journal of
Human Pharmacology and Drug Therapy. 2008 Feb;28(2):207-13.
63. Harden RN, Argoff C. A review of three commonly prescribed skeletal muscle
relaxants. Journal of back and musculoskeletal rehabilitation. 2000 Jan 1;15(2-3):63-6.
64. Naguib M, Samarkandi A, Riad W, Alharby SW. Optimal dose of succinylcholine
revisited. Anesthesiology-Philadelphia Then Hagerstown-. 2003 Nov 1;99(5):1045-9.
65. McManus MC. Neuromuscular blockers in surgery and intensive care, Part 1.
American journal of health-system pharmacy. 2001 Dec 1;58(23):2287-99.

UNIT 5: DRUGS ACTING ON THE PARACRINE AND ENDOCRINE SYSTEM

CHAPTER 1: HISTAMINE AND ANTIHISTAMINES

66. Parsons ME, Ganellin CR. Histamine and its receptors. British journal
of pharmacology. 2006 Jan;147(S1):S127-35.
67. Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Progress in
neurobiology. 2001 Apr 1;63(6):637-72.
68. Simons FE, Simons KJ. Histamine and H1-antihistamines: celebrating
a century of progress. Journal of Allergy and Clinical Immunology. 2011 Dec
1;128(6):1139-50.
69. Golightly LK, Greos LS. Second-generation antihistamines. Drugs.
2005 Feb 1;65(3):341-84.
70. Church MK, Church DS. Pharmacology of antihistamines. Indian journal of
dermatology. 2013 May;58(3):219.

CHAPTER 2: PROSTAGLANDINS AND PROSTAGLANDIN INHIBITORS

71. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arteriosclerosis,

thrombosis, and vascular biology. 2011 May;31(5):986-1000.
72. Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of
immunity. Trends in immunology. 2002 Mar 1;23(3):144-50.
73. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000 Mar 14;101(10):1206-18.
74. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with
selective COX-2 inhibitors. Jama. 2001 Aug 22;286(8):954-9.
75. Green GA. Understanding NSAIDs: from aspirin to COX-2. Clinical cornerstone. 2001
Jan 1;3(5):50-9.
 CHAPTER 3: DRUGS ACTING ON THE HYPOTHALAMUS AND PITUITARY
GLAND

76. Kazlauskaite R, Evans AT, Villabona CV, Abdu TA, Ambrosi B, Atkinson AB, Choi
CH, Clayton RN, Courtney CH, Gonc EN, Maghnie M. Corticotropin tests for
hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. The Journal of Clinical
Endocrinology & Metabolism. 2008 Nov 1;93(11):4245-53.
77. Newman CB, Melmed S, George A, Torigian D, Duhaney M, Snyder P, Young W,
Klibanski A, Molitch ME, Gagel R, Sheeler L. Octreotide as primary therapy for
acromegaly. The Journal of Clinical Endocrinology & Metabolism. 1998 Sep
1;83(9):3034-40.
78. Molitch ME, Elton RL, Blackwell RE, Caldwell B, CHANG RJ, Jaffe R, Joplin G,
Robbins RJ, Tyson J, Thorner MO. Bromocriptine as primary therapy for prolactin-
secreting macroadenomas: results of a prospective multicenter study. The Journal of
Clinical Endocrinology & Metabolism. 1985 Apr 1;60(4):698-705.
79. Paradisi RO, Frank GI, Magrini OT, Capelli MA, Venturoli ST, Porcu EL, Flamigni
CA. Adeno-pituitary hormones in human hypothalamic hypophysial blood. The
Journal of Clinical Endocrinology & Metabolism. 1993 Aug 1;77(2):523-7.
80. Brownstein MJ, Russell JT, Gainer H. Synthesis, transport, and
release of posterior pituitary hormones. Science. 1980 Jan 25;207(4429):373-8.

CHAPTER 4: THYROID HORMONES AND INHIBITORS

81. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-

triiodothyronine combination therapy versus thyroxine monotherapy for clinical
hypothyroidism: meta-analysis of randomized controlled trials. The Journal of Clinical
Endocrinology & Metabolism. 2006 Jul 1;91(7):2592-9.
82. Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid
disease. Annals of Internal Medicine. 1993 Sep 15;119(6):492-502.
83. Sawka AM, Thephamongkhol K, Brouwers M, Thabane L, Browman G, Gerstein HC.
A systematic review and metaanalysis of the effectiveness of radioactive iodine
remnant ablation for well-differentiated thyroid cancer. The Journal of Clinical
Endocrinology & Metabolism. 2004 Aug 1;89(8):3668-76.
84. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. The Journal of
Clinical Endocrinology & Metabolism. 2009 Jun 1;94(6):1881-2.
85. Chiha M, Samarasinghe S, Kabaker AS. Thyroid storm: an updated review. Journal of
intensive care medicine. 2015 Mar;30(3):131-40.

CHAPTER 5: DRUGS USED IN CALCIUM METABOLISM

86. Peacock M. Calcium metabolism in health and disease. Clinical

Journal of the American Society of Nephrology. 2010 Jan 1;5(Supplement 1):S23-30.
87. Strewler GJ. The physiology of parathyroid hormone–related protein. New England
Journal of Medicine. 2000 Jan 20;342(3):177-85.
88. Austin LA, Heath III H. Calcitonin: physiology and pathophysiology. New England
 Journal of Medicine. 1981 Jan 29;304(5):269-78.
89. Lips P. Vitamin D physiology. Progress in biophysics and molecular
biology. 2006 Sep 1;92(1):4-8.
90. Coleman RE. Bisphosphonates: clinical experience. The Oncologist.
2004 Sep 1;9(suppl_ 4):14-27.

CHAPTER 6: INSULIN AND ORAL HYPOGLYCEMIC DRUGS

91. Hirsch IB. Insulin analogues. New England Journal of Medicine. 2005 Jan
13;352(2):174-83.
92. Zimmerman BR. Sulfonylureas. Endocrinology and metabolism clinics of North
America. 1997 Sep 1;26(3):511-22.
93. Waugh J, Keating GM, Plosker GL, Easthope S, Robinson DM. Pioglitazone. Drugs.
2006 Jan 1;66(1):85-109.
94. Hamnvik OP, McMahon GT. Balancing risk and benefit with oral hypoglycemic drugs.
Mount Sinai Journal of Medicine: A Journal of Translational and Personalized
Medicine: A Journal of Translational and Personalized Medicine. 2009 Jun;76(3):234-
43.
95. Ferner RE. Oral hypoglycemic agents. Medical Clinics of North America. 1988 Nov
1;72(6):1323-35.

CHAPTER 7 - CORTICOSTEROIDS

96. Tsigos C, Chrousos GP. Hypothalamic–pituitary–adrenal axis,

neuroendocrine factors and stress. Journal of psychosomatic research. 2002 Oct
1;53(4):865-71.
97. Wagner CA. Effect of mineralocorticoids on acid-base balance. Nephron Physiology.
2014;128(1-2):26-34.
98. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular
mechanisms. Clinical science. 1998 Jun;94(6):557-72.
99. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y.
Corticosteroids for severe sepsis and septic shock: a systematic review and meta-
analysis. Bmj. 2004 Aug 26;329(7464):480.
100. Poetker DM, Reh DD. A comprehensive review of the adverse effects of
systemic corticosteroids. Otolaryngologic Clinics of North America. 2010 Aug
1;43(4):753-68.

CHAPTER 8 - ANDROGENS, ESTROGENS AND PROGESTINS

101. Mooradian AD, Morley JE, Korenman SG. Biological actions of

androgens. Endocrine reviews. 1987 Feb 1;8(1):1-28.
102. Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and
actions of estrogens. New England Journal of Medicine. 2002 Jan 31;346(5):340-52.
103. Feigelson HS, Henderson BE. Estrogens and breast cancer.
Carcinogenesis. 1996 Nov 1;17(11):2279-84.
104. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR,
Schweppe KW, Thijssen JH. Reprint of classification and pharmacology of progestins.
Maturitas. 2008 Sep 1;61(1-2):171-80.
105. Jordan VC, Morrow M. Tamoxifen, raloxifene, and the prevention of
breast cancer. Endocrine Reviews. 1999 Jun 1;20(3):253-78.

UNIT VI - THE CARDIOVASCULAR SYSTEM

CHAPTER 1- DRUGS USED IN HYPERTENSION

106. Antonaccio MJ. Angiotensin converting enzyme (ACE) inhibitors. Annual review
of pharmacology and toxicology. 1982 Apr;22(1):57-87.
107. Burnier M. Angiotensin II type 1 receptor blockers. Circulation. 2001
Feb 13;103(6):904-12.
108. Elliott WJ, Ram CV. Calcium channel blockers. The Journal of Clinical
Hypertension. 2011 Sep;13(9):687-9.
109. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta‐
blockers for hypertension. Cochrane database of systematic reviews. 2017(1).
110. Ernst ME, Moser M. Use of diuretics in patients with hypertension.
New England Journal of Medicine. 2009 Nov 26;361(22):2153-64.

CHAPTER 2 - DRUGS FOR MYOCARDIAL ISCHEMIA

111. Abrams J. Pharmacology of nitroglycerin and long-acting nitrates. The American

journal of cardiology. 1985 Jul 10;56(2):A12-8.
112. Shu DF, Dong BR, Lin XF, Wu TX, Liu GJ. Long-term beta blockers for stable
angina: systematic review and meta-analysis. European journal of preventive
cardiology. 2012 Jun;19(3):330-41.
113. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute
myocardial infarction and unstable angina: an overview. Bmj. 1989 Nov
11;299(6709):1187-92.
114. Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina.
Cochrane Database of Systematic Reviews. 2005(4).
115. Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F,
Chalmers TC. Cumulative meta-analysis of therapeutic trials for myocardial infarction.
New England Journal of Medicine. 1992 Jul 23;327(4):248-54.

CHAPTER 3 - DRUGS USED IN ARRHYTHMIAS

116. Nattel S. Antiarrhythmic drug classifications. Drugs. 1991 May 1;41(5):672-701.

117. Anderson JL, Harrison DC, Meffin PJ, Winkle RA. Antiarrhythmic
drugs: Clinical pharmacology and therapeutic uses. Drugs. 1978 Apr 1;15(4):271-309.
118. Yang F, Hanon S, Lam P, Schweitzer P. Quinidine revisited. The
American journal of medicine. 2009 Apr 1;122(4):317-21.
119. Roden DM. Current status of class III antiarrhythmic drug therapy.
 American Journal of Cardiology. 1993 Aug 26;72(6):B44-9.
120. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated
receptor mechanism of action of sodium and calcium channel-blocking drugs. Annual
review of pharmacology and toxicology. 1984 Apr;24(1):387-423.

CHAPTER 4 - DRUGS USED IN HEART FAILURE

121. Jackson G, Gibbs CR, Davies MK, Lip GY. ABC of heart failure:
Pathophysiology. BMJ: British Medical Journal. 2000 Jan 15;320(7228):167.
122. Digitalis Investigation Group. The effect of digoxin on mortality and
morbidity in patients with heart failure. New England Journal of Medicine. 1997 Feb
20;336(8):525-33.
123. Brophy JM, Joseph L, Rouleau JL. β-Blockers in congestive heart
failure: a Bayesian meta-analysis. Annals of internal medicine. 2001 Apr 3;134(7):550-
60.
124. Akhtar N, Mikulic E, Cohn JN, Chaudhry MH. Hemodynamic effect of
dobutamine in patients with severe heart failure. The American journal of cardiology.
1975 Aug 1;36(2):202-5.
125. Faris RF, Flather M, Purcell H, Poole‐Wilson PA, Coats AJ. Diuretics
for heart failure. Cochrane Database of Systematic Reviews. 2012(2).

UNIT VII - HEMATOPOIETIC SYSTEM

CHAPTER 1 - HEMATINICS AND DRUGS AFFECTING BLOOD CLOTTING

126. Schafer AI. Antiplatelet therapy. The American journal of medicine. 1996 Aug
1;101(2):199-209.
127. Hirsh J. Low molecular weight heparin. Thrombosis and haemostasis. 1993
Jan;69(01):204-7.
128. Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants:
their advantages and disadvantages compared with vitamin K antagonists in the
prevention and treatment of patients with thromboembolic events. Therapeutics and
clinical risk management. 2015;11:967.
129. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D,
Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D. Thrombolysis with
alteplase 3 to 4.5 hours after acute ischemic stroke. New England journal of medicine.
2008 Sep 25;359(13):1317-29.
130. Couturier R, Grassin-Delyle S. Tranexamic acid: more than inhibition of
fibrinolysis?. Anesthesia & Analgesia. 2014 Aug 1;119(2):498-9.

UNIT VIII - RESPIRATORY SYSTEM

CHAPTER 1 - DRUGS USED IN COUGH AND BRONCHIAL ASTHMA

131. Rubin BK. Mucolytics, expectorants, and mucokinetic medications. Respiratory

 Care. 2007 Jul 1;52(7):859-65.
132. Schuh S, Canny G, Reisman JJ, Kerem E, Bentur L, Petric M, Levison
H. Nebulized albuterol in acute bronchiolitis. The Journal of pediatrics. 1990 Oct
1;117(4):633-7.
133. Barnes PJ. Efficacy of inhaled corticosteroids in asthma. Journal of
allergy and clinical immunology. 1998 Oct 1;102(4):531-8.
134. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus
higher-dose corticosteroid in asthma patients with symptoms on existing inhaled
corticosteroid. The Lancet. 1994 Jul 23;344(8917):219-24.
135. Van Noord JA, De Munck DR, Bantje TA, Hop WC, Akveld MM,
Bommer AM. Long-term treatment of chronic obstructive pulmonary disease with
salmeterol and the additive effect of ipratropium. European Respiratory Journal. 2000
May 1;15(5):878-85.

UNIT IX - GASTROINTESTINAL SYSTEM

CHAPTER 1 - DRUGS USED FOR DISEASES OF THE GI TRACT

136. Sachs G, Shin JM, Howden CW. The clinical pharmacology of proton pump
inhibitors. Alimentary pharmacology & therapeutics. 2006 Jun;23:2-8.
137. Tang OS, Schweer H, Seyberth HW, Lee SW, Ho PC.
Pharmacokinetics of different routes of administration of misoprostol. Human
reproduction. 2002 Feb 1;17(2):332-6.
138. Saad RJ, Schoenfeld P, Kim HM, Chey WD. Levofloxacin-Based Triple Therapy
versus Bismuth-Based Quadruple Therapy for Persistent Helicobacter pylori Infection:
A Meta-Analysis: CME. American Journal of Gastroenterology. 2006 Mar
1;101(3):488-96.
139. Gralla RJ, Osoba D, Kris MG, Kirkbride P, Hesketh PJ, Chinnery LW,
Clark-Snow R, Gill DP, Groshen S, Grunberg S, Koeller JM. Recommendations for
the use of antiemetics: evidence-based, clinical practice guidelines. Journal of Clinical
Oncology. 1999 Sep 1;17:2971-94.
140. Baker DE. Loperamide: a pharmacological review. Reviews in
gastroenterological disorders. 2007;7:S11-8.

UNIT X - GENITOURINARY SYSTEM

CHAPTER 1 - DIURETICS

141. Brater DC. Clinical pharmacology of loop diuretics. Drugs. 1991 Jun 1;41(3):14-
22.
142. Sica DA, Carter B, Cushman W, Hamm L. Thiazide and loop diuretics.
The journal of clinical hypertension. 2011 Sep;13(9):639-43.
143. Loriaux DL, MENARD R, TAYLOR A, PITA JC, SANTEN R.
Spironolactone and endocrine dysfunction. Annals of internal Medicine. 1976 Nov
1;85(5):630-6.
144. Forwand SA, Landowne M, Follansbee JN, Hansen JE. Effect of
 acetazolamide on acute mountain sickness. New England Journal of Medicine. 1968
Oct 17;279(16):839-45.
145. Wakai A, Roberts IG, Schierhout G. Mannitol for acute traumatic brain
injury. Cochrane database of systematic reviews. 2006(3).

UNIT XI - ANTIMICROBIAL DRUGS

CHAPTER 1 - ANTIBACTERIALS

146. KONG KF, Schneper L, Mathee K. Beta‐lactam antibiotics: from antibiosis to

resistance and bacteriology. Apmis. 2010 Jan;118(1):1-36.
147. Levine DP. Vancomycin: a history. Clinical Infectious Diseases. 2006
Jan 1;42(Supplement_1):S5-12.
148. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a
systematic review. Clinical therapeutics. 2005 Sep 1;27(9):1329-42.
149. Nightingale CH. Pharmacokinetics and pharmacodynamics of newer
macrolides. The Pediatric infectious disease journal. 1997 Apr 1;16(4):438-43.
150. Begg EJ, Barclay ML. Aminoglycosides--50 years on. British journal of
clinical pharmacology. 1995 Jun;39(6):597.

CHAPTER 2 - ANTIVIRALS

151. De Clercq E. Antiviral drugs in current clinical use. Journal of clinical

virology. 2004 Jun 1;30(2):115-33.
152. De Clercq E. Antiviral agents active against influenza A viruses. Nature
reviews Drug discovery. 2006 Dec;5(12):1015-25.
153. Whitley RJ, Gnann Jr JW. Acyclovir: a decade later. New England
Journal of Medicine. 1992 Sep 10;327(11):782-9.
154. Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM. Antiviral strategies in
hepatitis C virus infection. Journal of hepatology. 2012 Jan 1;56:S88-100.
155. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC,
Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV.
Prevention of HIV-1 infection with early antiretroviral therapy. New England journal
of medicine. 2011 Aug 11;365(6):493-505.

CHAPTER 3 - ANTIFUNGALS

156. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical
experience. Reviews of infectious diseases. 1990 Mar 1;12(2):308-29.
157. Zonios DI, Bennett JE. Update on azole antifungals. InSeminars in
respiratory and critical care medicine 2008 Apr (Vol. 29, No. 02, pp. 198-210).
Published by Thieme Medical Publishers.
158. Graybill JR, Craven PC. Antifungal agents used in systemic mycoses.
Drugs. 1983 Jan 1;25(1):41-62.
159. Gupta AK, Einarson TR, Summerbell RC, Shear NH. An overview of
 topical antifungal therapy in dermatomycoses. Drugs. 1998 May 1;55(5):645-74.
160. Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of
onychomycosis: an overview of current strategies for monotherapy and combination
therapy. Journal of the European Academy of Dermatology and Venereology. 2005
Jan;19(1):21-9.

CHAPTER 4 - ANTIPROTOZOAL AND ANTHELMINTIC DRUGS

161. Gonzales ML, Dans LF, Sio‐Aguilar J. Antiamoebic drugs for treating amoebic
colitis. Cochrane Database of Systematic Reviews. 2019(1).
162. Baird JK. Effectiveness of antimalarial drugs. New England Journal of
Medicine. 2005 Apr 14;352(15):1565-77.
163. Kennedy PG. Clinical features, diagnosis, and treatment of human
African trypanosomiasis (sleeping sickness). The Lancet Neurology. 2013 Feb
1;12(2):186-94.
164. Tiuman TS, Santos AO, Ueda-Nakamura T, Dias Filho BP, Nakamura
CV. Recent advances in leishmaniasis treatment. International Journal of Infectious
Diseases. 2011 Aug 1;15(8):e525-32.
165. Holden-Dye L, Walker RJ. Anthelmintic drugs. WormBook. 2007:1.

UNIT XII - IMPORTANT MISCELLANEOUS DRUGS

CHAPTER 1 - ANTICANCER DRUGS AND IMMUNOSUPPRESSANTS

166. DeVita VT, Chu E. A history of cancer chemotherapy. Cancer research.

2008 Nov 1;68(21):8643-53.
167. Peters GJ, Van der Wilt CL, Van Moorsel CJ, Kroep JR, Bergman AM,
Ackland SP. Basis for effective combination cancer chemotherapy with
antimetabolites. Pharmacology & therapeutics. 2000 Aug 1;87(2-3):227-53.
168. Goding JW. Monoclonal antibodies: principles and practice. Elsevier;
1996 Feb 26.
169. Mijatovic T, Van Quaquebeke E, Delest B, Debeir O, Darro F, Kiss R.
Cardiotonic steroids on the road to anti-cancer therapy. Biochimica et Biophysica Acta
(BBA)-Reviews on Cancer. 2007 Sep 1;1776(1):32-57.
170. McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K,
MacDonald AS. Sirolimus-tacrolimus combination immunosuppression. The Lancet.
2000 Jan 29;355(9201):376-7.
 ANSWERS TO EXERCISES
UNIT 1 - THE BASICS
CHAPTER 1- ROUTES OF DRUG ADMINISTRATION
1. c
2. c
3. a
4. b
5. d
6. b
7. c
8. b
9. a
10. b
CHAPTER 2 - PHARMACOKINETICS AND PHARMACODYNAMICS
1. b
2. c
3. c
4. d
5. d
6. a
7. c
8. b
9. d
10. b

UNIT 2 - CENTRAL NERVOUS SYSTEM

CHAPTER 1 - GENERAL ANESTHETICS
1. b
2. c
3. a
4. d
5. b
6. a
7. b
8. a
9. d
10. c
CHAPTER 2 - SEDATIVE-HYPNOTICS
1. d
2. c
3. a
4. b
5. c
 6. c
7. a
8. b
9. b
10. c
CHAPTER 3 - OPIOID ANALGESICS
1. c
2. c
3. c
4. c
5. d
6. b
7. b
8. b
9. c
10. b
CHAPTER 4 - ANTI-DEPRESSANTS AND ANTI-MANIC DRUGS
1. d
2. b
3. a
4. d
5. c
6. c
7. b
8. d
9. b
10. c
CHAPTER 5 - ANTIPSYCHOTICS
1. b
2. b
3. a
4. c
5. b
6. d
7. d
8. b
9. a
10. a
CHAPTER 6 - DRUGS USED IN NEURODEGENERATIVE DISEASES
1. c
2. a
3. d
4. b
5. b
6. d
7. c
 8. d
9. b
10. d
CHAPTER 7 - ANTI-EPILEPTIC DRUGS
1. a
2. a
3. a
4. b
5. d
6. c
7. a
8. a
9. a
10. b

UNIT III - AUTONOMIC NERVOUS SYSTEM

CHAPTER 1 - CHOLINERGIC AND ANTICHOLINERGIC DRUGS

1. a
2. a
3. c
4. b
5. b
6. c
7. a
8. b
9. c
10. a
CHAPTER 2 - ADRENERGIC AND ANTIADRENERGIC DRUGS
1. b
2. b
3. c
4. b
5. d
6. b
7. c
8. b
9. b
10. a

UNIT 4: PERIPHERAL NERVOUS SYSTEM

CHAPTER 1: LOCAL ANESTHETICS

1. c
2. a
3. c
 4. a
5. a
6. b
7. d
8. a
9. d
10. c

CHAPTER 2: SKELETAL MUSCLE RELAXANTS

1. c
2. b
3. b
4. c
5. b
6. b
7. c
8. c
9. d
10. c

UNIT 5: DRUGS ACTING ON THE PARACRINE AND ENDOCRINE SYSTEM

CHAPTER 1: HISTAMINE AND ANTIHISTAMINES

1. c
2. b
3. c
4. d
5. b
6. a
7. b
8. a
9. c
10. d

CHAPTER 2: PROSTAGLANDINS AND PROSTAGLANDIN INHIBITORS

1. c
2. b
3. c
4. d
5. b
6. c
7. a
 8. b
9. c
10. c

CHAPTER 3: DRUGS ACTING ON THE HYPOTHALAMUS AND PITUITARY

GLAND

1. b
2. a
3. b
4. b
5. b
6. d
7. c
8. d
9. c
10. b

CHAPTER 4: THYROID HORMONES AND INHIBITORS

1. b
2. c
3. b
4. c
5. c
6. b
7. d
8. d
9. a
10. c

CHAPTER 5: DRUGS INVOLVED IN CALCIUM AND BONE METABOLISM

1. d
2. b
3. d
4. a
5. a
6. b
7. c
8. d
9. c
10. b

CHAPTER 6: INSULIN AND ORAL HYPOGLYCEMIC DRUGS

 1. a
2. c
3. b
4. d
5. a
6. b
7. d
8. b
9. b
10. c

CHAPTER 7: CORTICOSTEROIDS

1. d
2. a
3. c
4. b
5. a
6. d
7. b
8. b
9. c
10. C

CHAPTER 8: ANDROGENS, ESTROGENS AND PROGESTINS

1. b
2. c
3. a
4. d
5. b
6. c
7. b
8. d
9. c
10. a

UNIT 6: THE CARDIOVASCULAR SYSTEM

CHAPTER 1: DRUGS USED IN HYPERTENSION

1. b
2. c
3. c
 4. d
5. c
6. c
7. b
8. a
9. c
10. a

CHAPTER 2: DRUGS FOR MYOCARDIAL ISCHEMIA

1. a
2. d
3. a
4. b
5. c
6. b
7. c
8. c
9. c
10. b

CHAPTER 3: DRUGS USED IN ARRHYTHMIAS

1. b
2. a
3. c
4. d
5. c
6. c
7. b
8. c
9. b
10. d

CHAPTER 4: DRUGS USED IN HEART FAILURE

1. c
2. b
3. b
4. d
5. b
6. b
7. b
8. a
9. d
10. C
 UNIT 7 - HEMATOPOIETIC SYSTEM
CHAPTER 1 - HEMATINICS AND DRUGS AFFECTING BLOOD CLOTTING

1. c
2. d
3. c
4. b
5. c
6. b
7. d
8. d
9. b
10. c

UNIT 8 - RESPIRATORY SYSTEM

CHAPTER 1 - DRUGS USED IN COUGH AND BRONCHIAL ASTHMA

1. d
2. c
3. b
4. a
5. a
6. c
7. b
8. b
9. b
10. d

UNIT 9 - GASTROINTESTINAL SYSTEM

CHAPTER 1 - DRUGS USED FOR DISEASES OF THE GI TRACT

1. b
2. c
3. b
4. a
5. b
6. c
7. d
8. b
9. a
10. d

UNIT 10 - GENITOURINARY SYSTEM

 CHAPTER 1 - DIURETICS

1. d
2. b
3. c
4. c
5. b
6. b
7. a
8. c
9. d
10. a

UNIT 11 - ANTIMICROBIAL DRUGS

CHAPTER 1 - ANTIBACTERIALS

1. a
2. b
3. c
4. c
5. c
6. b
7. c
8. b
9. b
10. b

CHAPTER 2 - ANTIVIRALS

1. b
2. a
3. d
4. c
5. c
6. b
7. c
8. c
9. c
10. b

CHAPTER 3 - ANTIFUNGAL DRUGS

1. b
2. c
 3. c
4. d
5. b
6. a
7. c
8. d
9. b
10. b

CHAPTER 4 - ANTIPROTOZOAL AND ANTHELMINTIC DRUGS

1. b
2. d
3. b
4. b
5. d
6. b
7. c
8. d
9. a
10. b

UNIT 12 - IMPORTANT MISCELLANEOUS DRUGS

CHAPTER 1 - ANTICANCER DRUGS AND IMMUNOSUPPRESSANTS

1. c
2. b
3. a
4. c
5. c
6. d
7. c
8. a
9. b
10. c