General Introductory Pharmacology by Accra College students

General Introductory
Pharmacology
Basic concepts by
Yakubu Jibira

2
OBJECTIVES:
After attending lectures and studying this course you should
be able to:
• Define specific pharmacological terms.
• Know the difference between the Generic,
Official, Chemical & Trade Name of a drug.
• Know the processes by which a drug travels
from the point of delivery to its site of action
and out of the body
• Know the processes by which drugs alter body
function ( i.e. the effect of the drug on the
body)

3
PHARMACOLOGY:
• Defined as the study of the
interaction of substances (drugs),
other than foods, with living
systems

4
Terminologies
• Pharmakon-Drug or poison
• Drug: Any molecule, used to alter
body's physiology and function.
–Used to cure, treat or prevent
disease (therapeutics)

5
Changes in physiological functions
paralysis inhibition - + stimulation excitation
nonspecific
specific
according to interactions with targets, effects
of drugs are:

6
• Receptor: specific molecule that drug may
interact with that plays a regulatory role
– Many drugs work by interacting with
receptors, which can be divided into
several groups:
• intracellular receptors
• transmembrane enzymes
• receptors acting via G-protein
• ion channels
• o t h e r: enzymes (MAO), structural proteins
(tubulin),

• Indications
– Conditions that enable the appropriate
administration of the drug (as approved
by the FDA).
• Contraindications
– Conditions that make it inappropriate to
give the drug
• …..means a predictable harmful event will
occur if the drug is given in this situation
• Dosage
– The amount of the drug that should be
given

• Routes of Administration
– How the drug is given.
• Side Effects/Adverse Reactions
– The drug’s untoward or undesired effect
• Mechanism of Action
– The way in which a drug causes its
effects; its pharmacodynamics

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Medical pharmacology is studying processes
by which:
• a drug travels from the point of delivery to its
site of action and out of the body-
– Pharmacokinetics
• drugs alter body functions-
– Pharmacodynamics
• Pharmacology deals with the fate and actions
of drugs in the body

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Pharmacology:
• is a science based upon a sound
understanding of :
–organic chemistry
–biochemistry
–physiology
–pathology and
–microbiology.

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Pharmacology: Subdivisions of particular importance
include:
• Pharmacokinetics:
– a drug travels from the point of delivery to its site of
action and out of the body
• Pharmacodynamics
– drugs alter body functions-
• Pharmacotherapeutics (Therapeutics):
– The application of pharmacology to the problems of
clinical medicine.
• Chemotherapy:
– The use of drugs, which ideally have little effect on the
host (patient) but destroy or retard the growth of
invading cells and organisms.
• Toxicology:
– The pharmacology of poisons and the harmful effects
of any drug.
• Pharmacoeconomics

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• Chemical name:
• Any typical organic chemical name.
• Generic name:
• The assigned name of a drug, by which it
will be known throughout the world no
matter how many different companies
manufacture it. This name is usually
assigned and agreed upon by the World
Health Organization.
• Official name:
• This is the name by which a drug is listed
in one of the following official publications:
a) U.S. Pharmacopoeia, b) National
Formulary
• The official name is often the same as the
generic name.

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• Trade name:
• The name that is given by a particular
company that is manufacturing the drug.
• The company is the legal owner of the
name.
• Sometimes a single generic drug may be
sold under 5 or 10 different trade names.

Chemical Name
7-chloro-1, 3-dihydro-1,
methyl-5-phenyl-2h-1
Generic Name Diazepam
Official Name Diazepam, USP
Brand Name Valium®
Names of Drugs

Sources of Drug Information
• United States Pharmacopeia (USP)
• British Pharmacopeia (BP)
• British Pharmacopeia Codex (BPC)
• Physician’s desk reference (PDR)
• The National Formulary (NF)
–Ghana National Formulary (GNF)
• Monthly prescribing reference

17
References
• Rang, Dale & Ritter
• Katzung
• www.pharmacology2000.com

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All substances are poisons;
there is none that is not a
poison. The right dose
differentiates a poison from a
remedy.
Paracelsus, 1493-
1541

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FATE OF DRUGS IN THE BODY
Two fundamental processes that determine the
concentration of a drug in the body at any moment
and in any region of the body are:
▪ Movement of the drug molecules across
membranes (i.e. absorption and
distribution)
▪ Biotransformation and elimination from
the body (i.e. metabolism and excretion)
The distinguishing feature of one drug from the
other is its ability to cross non-aqueous (lipid)
barriers.

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Pharmacodynamics: Introduction
• Drug-Body Interactions (Overview)
– Pharmacodynamics: action of drug on the body
(MOA)
• A. Types of drug-receptor interactions
– Agonist drugs: bind to and activate the receptor
which directly or indirectly brings about the effect
– Some agonists inhibit their binding molecules to
terminate the action of endogenous agonists
» Ex: slowing the destruction of endogenous
acetylcholine by using acetylcholinesterase
inhibitors

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Introduction
• Antagonist drugs: bind to a receptor
to prevent binding of other molecules
• Ex: Atropine decreases Ach
effects
• Partial agonist drugs: acts as
agonist or antagonist depending on
the circumstance.
• Ex: Pindolol can act as an
antagonist if a “full agonist” like
Isoproterenol is present.

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Introduction
• B. Duration of Drug Action
– Dissociation (separation) of drug from
receptor can terminate effect
– If some coupling molecule is still present in
activated form, drug action will persist.
– When drug molecules continue to be
present for long periods of time, receptor-
effector systems incorporate
desensitization mechanisms for preventing
excessive activation

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Introduction
• C. Receptors and Inert Binding Sites
– To be a receptor in the body, the endogenous
molecule must be:
• Selective in choosing ligands (drug molecules) to
bind
• Must change its function upon binding so that the
function of the biologic system (cell, tissues, etc..) is
altered
– Inert binding site
• Ex: Plasma albumin - endogenous molecule that
can bind a drug molecule, however, will result in no
change of biologic function
• Significance of binding- will affect distribution of
drug in the body

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Binding -Focus on inert binding sites in plasma protein
Generally, acidic drugs bind to albumin, while bases bind
more avidly to α1 glycoprotein.
I m p o r t a n c e:
1. Drugs with high affinity for albumin can be divided into two
classes depending on the dose of drug (in clinical
conditions).
– Class I: the dose is less than the biding capacity of
albumin---the drug fraction bound is high:
• tolbutamide is normally 95% bound, and only
5%free
– Class II: the dose greatly exceeds the number of
albumin binding sites---relatively high proportion
of the drug exists in the free state
• sulfonamides.

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Binding -Focus on inert binding sites in plasma protein
If given simultaneously,
• sulfonamide displaces tolbutamide from
albumin, leading to a rapid increase in the
concentration of free tolbutamide in
plasma
Consequence?
–(hypoglycaemia)

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2. Plasma protein binding becomes clinically
important when, because of a disease state,
•plasma protein concentrations fall (albumin
concentrations in liver cirrhosis)
•or rise (α1-acid glycoprotein, which is an
acute phase reactant), in acute infection:
– total drug concentration in the plasma
may be unchanged from that recorded
in healthy subjects, but the drug is
more/less potent because a
greater/lower fraction is unbound.

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PHARMACOKINETICS
The therapeutic effect of a drug is determined by
the concentration of drug at the receptor site of
action.
Even though the concentration of drug that
reaches the target receptor is dependent upon
the dose of the drug, there are other factors that
influence the delivery of the drug to the target
site.
These include absorption, distribution,
metabolism, and (elimination) excretion.
The study of these variables is called
pharmacokinetics.

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• I. Principles which govern the
movement of drugs in the body
• II. Pharmacokinetic processes
• III. Pharmacokinetics in medical
practice

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I. Principles which govern the
movement of drugs in the body

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I. Principles which govern the movement of drug in the body
In order to reach the receptors and bring
about an effect, a drug molecule must
travel from the site of administration to the
site of action-the target organ, tissue)
3 principles govern the movement of drugs:
i. Physical and chemical properties
ii. Binding
iii. Permeation (movement of drug
molecules across cellular barriers)

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Principles which govern the movement of drug in the body
• Drugs vary widely in size, shape and
physico-chemical characteristics
• A. Physical Nature of Drugs
– Solid drugs -> oral route
aspirin
– Liquid drugs -> oral route, IM, SC
ethanol
– Gaseous drugs -> inhalation
nitrous oxide, halothane, amylnitrite

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▪ Most drugs dissolve readily in body water
or aqueous fluids.
• Chemical nature of drugs
▪ Many drugs are weak acids or bases
▪ pH differences in the body may alter
the degree of ionization of drug
▪ The action of any drug requires the
presence of adequate concentration in
the fluids surrounding the target tissues

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Principles which govern the
movement of drug in the body
• B. Drug Size
Most drugs have molecular
weights between 100 and 1,000
–Molecular weight (size)
• penicillin G, (334.39 g/mol)
• procaine-penicillin G- 570.7
• benzathin-penicillin G – 981.2

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D. Drug Shape
– Lock and Key phenomenon for the drug
and its receptor site
– More than half of all useful drugs are chiral
molecules and exist as enantiomeric pairs
Ex: Carvedilol has a single chiral center and two
enantiomers
S(-) isomer – potent Beta receptor blocker
R(+) isomer – 100-fold weaker at Beta
receptor

• One drug enantiomer is often more
susceptible than the other to drug-
metabolizing enzymes
• One enantiomer could have a longer
or shorter duration of action than the
other
• As of now, most clinical studies of
drugs have only tested racemic
mixtures (two enantiomer pairs)
• 55% of drugs are only available as
racemic mixtures where a patient is
receiving 50% inactive or actively
toxic drug
38

39
• E. Rational Drug Design
–Drugs are designed based on the
structure of the receptor site
–Computers help us do this (match
drug to receptor site to increase
selectivity)

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II. Binding (types/force/properties)
• Drug Reactivity and Drug Receptor Bonds
Covalent bond – very strong, not reversible
Electrostatic bond -- ionic molecules,
hydrogen bonds, dipole interaction (Van der
waals Forces)
Hydrophobic bonds – weak, highly lipid soluble
drugs, more selective

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VARIATION IN PLASMA PROTEIN
CONCENTRATION
A. High levels of
plasma
proteins.
B. Reduced levels of
plasma proteins.

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III.Permeation (movement of drug molecules across cellular
barriers)
Drug molecules move around the body in two ways:
✓ Transport in the bloodstream and other aqueous
fluid between the barriers.
✓ Diffusional transfer (i.e. molecule-by-molecule)
across various barriers in the body to the site of
action, metabolism and the excretory organs.
▪ Nature of drug makes no difference to its
transport in the systemic circulation.
▪ Diffusional characteristics and transport across
membranes however differ markedly between
different drugs.

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Permeation (movement of drug molecules across cellular barriers)
To cross cellular barriers i.e. G.I. mucosa, renal
tubules, blood-brain barrier, placenta etc.,
Drug molecules have to cross lipid membranes.
4 main ways by which drug molecules cross
membranes:
▪ Diffusing through the aqueous pores that crosses
the lipid membrane (aqueous diffusion)
▪ By diffusing through lipid of the membrane (lipid
diffusion)
▪ Combination with carrier molecules that
transports the drug across the membrane (active
transport)
▪ By Endocytosis, Exocytosis or Pinocytosis.

44
Permeation (movement of drug molecules
across cellular barriers)
Of the four ways, the most important routes are :
▪ diffusion through the lipid membranes
and
▪ carrier mediated transport mechanisms.
▪ Lipid solubility is a very important
determining factor for the transport of drug
molecules across non-aqueous barriers.

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• Aqueous diffusion: through the watery extracellular
and intracelluar spaces (is dependent of the size of
pores:4 nm in the renal glomerulus, 3 nm in
capillaries, 0.2-0.3 nm in cellular wall)
• For passage of large molecules (20,000-
30,000MW)
• Occurs in larger aqueous compartments in the
body (interstitial space, cytosol, etc..)
• Driven by concentration gradient of drug- downhill
movement- Ficks Law (molecules per unit time)
Permeation (movement of drug molecules across cellular
barriers)

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• Lipid diffusion through lipid structures: predicted
by Fick´s law:
– Large # of lipid barriers that separate
compartments
– Weak acids or bases (gain or lose electrical
charge bearing protons, depending on pH).
– Ability to move from aqueous to lipid or vice
versa varies with pH of medium because
charged molecules attract water molecules.
– Henderson-Hasselbalch equation is the ratio of
lipid soluble form to water soluble form for a
weak acid or base.
area
x
thickness
t
coefficien
ty
permeabili
x
Rate c
c )
( 2
1 −
=

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Permeation (lipid diffusion cont)
Other important factors in relation to membrane
permeability is:
▪ pH of the physiological environment,
▪ the degree of ionization of the drug
(pKa).
▪ Many drugs are either weak acids or weak
bases.
▪ Their degree of ionization varies with
the pH of the physiological fluid

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A weakly acidic or basic drug can exist in both
the ionized or unionized form depending on the
pH of the physiological environment.
▪ i.e. the ratio of the ionized and the unionized
forms varies with pH.
• Most drugs are weak acids or bases, and
their degree of ionization is determined by
the surrounding pH and their pKa

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• Lipid diffusion is dependent on lipid
solubility.
– The degree of lipid solubility of an
individual drug will vary with degree
of ionization
• Only unionized drug is lipid soluble.

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Lipid solubility : The Henderson-Hasselbach equation
allows the un-ionized fraction to be calculated
HA <==> H+ + A- B + HCl <==> BH+ + Cl-
[ UI ] [ I ] [ UI ] [ I ]
pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)
ASPIRIN pKa = 4.5 (weak acid)
100mg orally (proportions at
equilibrium)
99.9 = [ UI ] [ UI ]
Stomach
pH = 2
Blood
pH = 7.4
0.1 = [ I ]
Aspirin is reasonably absorbed Strychnine not absorbed until
from stomach (fast action) enters duodenum
0.1 = [ UI ] [ UI ]
Blood
pH = 7.4
99.9 = [ I ]
STRYCHNINE pKa = 9.5 (weak base)
100mg orally (proportions at equilibrium)
Stomach
pH = 2

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Lipid solubility :weak acids and weak bases
HA <==> H+ + A- B + HCl <==> BH+ + Cl-
[ UI ] [ I ] [ UI ] [ I ]
pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)
ASPIRIN pKa = 4.5 (weak acid)
(proportions at equilibrium)
0.1 = [ UI ] [ UI ] = 0.1
Stomach
pH = 2
Blood
pH = 7.4
0.0001 = [ I ] [ I ] = 99.8
Aspirin is expelled from acid Strychnine ion trapped in acid
stomach (ion trapped in more alkaline stomach compartment
blood compartment)
0.1 = [ UI ] [ UI ] = 0.1
Blood
pH = 7.4
99.8 = [ I ] [ I ] = 0.0001
STRYCHNINE pKa = 9.5 (weak base)
(proportions at equilibrium)
Stomach
pH = 2

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Permeation (lipid
diffusion cont)
So for aspirin, which is an acid with a pKa of 4.5,
• if the pH is 2.5 then the ratio of ionized to un-
ionized is 0.1, i.e. 90% of the drug is un-
ionized and it crosses membranes readily.
• If the pH were 5.5 then the same ratio is 100,
i.e. 1% of the drug is un-ionized and it
crosses membranes poorly.

Permeation (lipid diffusion cont
• For the two Compounds HA and B
above,
• The ionized forms (BH+ and A-) have
very low lipid solubility & therefore
unable to transport easily across lipid
membranes, except where a specific
transport mechanism is involved.

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The lipid solubility of HA or B (unionized) will
depend on the chemical nature of the drug.
• For most drugs, the uncharged species are
sufficiently lipid soluble and permit rapid transport
across the membranes.
• But for some drugs the unionized molecules may
be insufficiently lipid (are polar) and will not be
absorbed from the G.I. when given orally e.g.
Aminoglycosides
▪ Aminoglycosides and other polar drugs may have
hydrogen-bonding groups(–OH), which makes
them highly polar and hence not absorbed into
the systemic circulation, when administered
orally.

55
<
The distribution of a drug between its ionized and un-ionized form
depends on the ambient pH and pKa of the drug. For illustrative
purposes, the drug has been assigned a pKa of 6.5.
When pH = pKa
HA = A and
BH = B
-
+
When pH is less than pKa,
the protonated forms HA
and BH predominate.
+
pH pKa
When pH is greater than pKa,
the deprotonated forms A
and B predominate.
-
pH pKa
>
pKa
pH 3 4 5 6 7 8 9 10 11

56
Important effects of pH
partitioning
▪ Acidification of urine will accelerate the
excretion of weakly basic molecules and retard
that of weak acids and vice versa.
▪ Increasing the plasma pH will cause weakly
acidic drugs to be extracted from the CNS into
the plasma and accelerate their excretion.
• { NaHCO3 could be used for raising the
plasma pH.}
▪ Reducing the plasma pH will cause weakly
acidic drugs such as aspirin to be
concentrated in the CNS, leading to toxicity.

57
Clinical application
– Henderson-Hasselbalch Equation
• Equation is clinically important when it is necessary
to accelerate the excretion of drugs by the kidney –
in the case of an overdose.
• Can manipulate drug excretion by the kidney by
changing the pH of the urine – inc ionized state to
“trap” drug in urine
• When a pt takes an overdose of a weak acid drug,
its excretion may be accelerated by alkalinizing the
urine – giving bicarbonate I.V.
– Acidic drug is in the lipid soluble form at acidic
pH
• Excretion of a weak base may be accelerated by
acidifying the urine - giving ammonium chloride I.V.
– Basic drug is in the lipid soluble form at alkaline
pH

58
Rx of Aspirin poisoning
Choice of
• alkalinizing the urine (by giving
bicarbonate or acetazolamide) in
an overdose of a weak acid
(aspirin)?
–Both  urine pH
–Hence  salicylate elimination
• NaHCO3 preferred?

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CARRIER-MEDIATED TRANSPORT
(CMT)
• Many cell membranes possess specialized transport
mechanisms that regulate entry and exit of
physiologically important molecules such as sugars,
amino acids, neurotransmitters, metal ions etc.
• The carriers are mainly transmembrane proteins that
bind the drug and convey it to the other side of the
membrane.
• This system may operate passively without an energy
process, but they could also be coupled to an energy
source.(mostly requires energy, prevalent in neuronal
membranes, hepatocytes, renal tubules etc.)

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Carrier mediated transport
The difference between this system and
simple diffusion is that:
• the rate of transport increases directly in proportion
to the concentration gradient with simple diffusion;
• where as in the CMTS, the carrier sites could
become saturated at higher concentration of the
drug and reduce the rate of transport across
membranes.
• CMTS are particularly important for drugs that are
chemically related to endogenous substances.
(Probenecid vs penicillins, uric acid)
» For large or insoluble substances
» Ex: peptides, amino acids, glucose
» Movement: active transport or facilitated diffusion
» Saturable, inhibitable

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Endocytosis, exocytosis or
pinocytosis.
Endocytosis→ Plasma membrane pinches off
to form a vesicle, which internalizes the drug.
Exocytosis→ cytoplasmic vesicle fuses with
the plasma to release its contents.
Pinocytosis→ The process by which
macromolecules e.g. insulin crosses the
blood-brain barrier.
»For large substances to enter the
cells
»Ex: iron and vitamin B12
»Each complexed with appropriate
binding protein

62
Aqueous diffusion of a water-soluble
drug through an aqueous channel or pore.
Passive diffusion of a lipid-soluble
drug dissolved in a membrane.
Drug
Carrier-mediated active
transport of drug
SCHEMATIC REPRESENTATION OF DRUGS CROSSING CELL
MEMBRANE OF EPITHELIAL CELL OF GASTROINTESTINAL TRACT.
ATP

63
II. PHARMACOKINETIC PROCESSES
(ADME)
Absorption
Distribution
Metabolism and
Excretion
The Life Cycle of a Drug
(pharmacokinetics)
Elimination

64
Introduction
Most drugs :
enter the body (by mouth or injection or…) -
must cross barriers to entry (skin, gut wall,
alveolar membrane…..)
are distributed by the blood to the site of
action - intra- or extracellular - cross
barriers to distribution (capillaries, cell
wall….)
- distribution affects concentration at site of
action and sites of excretion and
biotransformation

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are biotransformed perhaps to several
different compounds by enzymes evolved
to cope with natural materials - this may
increase, decrease or change drug actions
are excreted (by kidney or …….) which
removes them and/or their metabolites
from the body
Pharmacokinetics is the quantification of
these processes
Introduction

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Why does this all matter?
• Relevant to ALL drugs - every drug you give
you should think ---->>>>>> ????
ADME????
–frequent cause of failure of treatment
• failure of compliance
• failure to achieve effective level
• produce toxic effects
• >>>> drug interactions <<<<
• can be manipulated to enhance patient satisfaction
• understand what is going on and the different
dosage forms available

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Case study 1
Your are a consultant psychiatrist treating patients
with moderate depression. You administer the
standard dose of nortryptyline (75-150 mg/d) to 100
patients:
All get worse for 2 weeks; then between 4-8 weeks:-
most respond and improve;
1 develops cardiac dysrhythmias and dies;
9 do not respond - 2 commit suicide in week 7
- the remaining 7 you change to paroxetine and they
respond
What is going on?

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Case studies 2
You are a GP. An 18 year old woman comes for help with
her hay-fever; getting worse over the last few years.
You give her chlorpheniramine (4mg 4xd) but a week later
she is back complaining of dry mouth and feeling tired
all the time. Wants it sorted out before going on
holiday.
You swap her to terfenadine 60mg/d. One week later she
reports treatment as successful.
On holiday she developed candidiasis (given
itraconazole) and on return goes on diet (grapefruit
juice)
Six weeks later having collapsed in the street she is
admitted as an emergency and dies.
What is going on?

69
Absorption, Distribution, Metabolism &
Excretion (ADME)
Learning Objectives
• know the main processes determining the
ADME drugs in the body;
• be able to exemplify how these processes can
be affected by disease, diet, drugs and other
factors;
• know how alterations in these processes can
affect the outcome of drug treatment.
• Appreciate how differences in these processes
between patients can affect therapy
• Know how these processes have been
exploited to improve therapy

71
Absorption
Generally defined as the passage of drug from
the site of administration into the plasma or the
systemic circulation
•Depends on
–patient compliance
–rate and extent of transfer from the site
of administration to the blood
•Rate and efficiency of absorption depends
on a drug´s route of administration

Slow Absorption
• Orally (swallowed)
• through Mucus
Membranes
– Oral Mucosa (e.g. sublingual)
– Nasal Mucosa (e.g. insufflated)
• Topical/Transdermal
(through skin)
• Rectally (suppository)

Faster Absorption
• Parenterally (injection)
– Intravenous (IV)
– Intramuscular (IM)
– Subcutaneous (SC)
– Intraperitoneal (IP)
• Inhaled (through lungs)

Fastest Absorption
• Directly into brain
– Intracerebral (into brain tissue)
– Intracerebroventricular (into brain ventricles)
General Principle: The faster the absorption, the quicker the
onset, the higher the addictiveness, but the shorter the duration

Absorption: Solubility
• Water-soluble
– Ionized (have electrical charge)
– Crosses through pores in capillaries, but not cell membranes
• Lipid(fat)-soluble
– Non-ionized (no electrical charge)
– Crosses pores, cell membranes, blood-brain-barrier
Dissociation constant or pKa → indicates the pH where 50% of the drug is ionized
(water soluble) and 50% non-ionized (lipid soluble);
pKeq = pH + log [X]ionized/[X]non-ionized
This affects a drug's solubility, permeability, binding, and other characteristics.

76
Drug Absorption :Routes of
Administration
The main routes of administration for drugs can be
categorized into four groups:
1. Enteral route
• oral ingestion, sub-lingual and rectal (into the GIT)
2. Parenteral route (by inj.)
• Intravenous (i.v.), intraarterial (i,a.), subcutaneous
(s.c.), intramuscular (i.m.), intraperitoneal (i.p.) and
intrathecal
3. Topical route (i.e. application to epithelial
surfaces or mucous membranes) → skin,
cornea (eye), vagina and nasal mucosa etc.),-usually
local effects
4. Inhalational (lungs)-

77
Drug Absorption :Routes of Administration
Other classification:
• Oral:
– Drugs administered by mouth and swallowed.
• Transcutaneous:
– Used when local effects on the skin is required e.g.
Topical creams, transdermal patches for nicotine
withdrawal symptoms, fentanyl for analgesia & GTNT
for angina.
• Transmucosal e.g. Sublingual,
– absorption directly from the oral cavity [drug must have
good taste], rectal (supp.) conj, vaginal (pess),nasal
adm,
• Inhalational
– Drugs administered this way to achieve much higher
concentrations in the lungs than elsewhere in the
body.e.g Inhalers, Inhalational anaesthethics etc.
Parenteral (by inj.)

78
• Depends on route of administration
– Oral (per os)
• A. Site of absorption
– 1. Oral mucosa – sublingual route
– Direct access to systemic veins - will avoid hepatic
first pass effect (direct absorption into systemic
venous circulation)
– (Drugs that are extensively metabolized.)
» Ex: nitroglycerin
– 2. Stomach
» Drugs that are weak acids tend to be absorbed
here. Ex: aspirin, ethanol
– 3. Small intestine
» Drugs that are weak bases tend to be absorbed
here

79
B. Advantages of oral route
»Most convenient
»Least unpleasant method for most
drugs
»No equipment required
»Safest (drug absorbed more slowly)

80
– C. Disadvantages of oral route
• 1. Certain drugs destroyed by pH and/or enzymes
» Ex: Insulin
• Some drugs metabolized in gut wall by Cyp3A4
• Bacterial metabolism in gut can affect
bioavailability
» Ex: so digoxin is only 70% bioavailable
• 2. Slow onset of action
• 3. Cannot give to unconscious patient
• 4. Irritating substances cause nausea and
vomiting, resulting in drug loss
• 5. Drug may have significant 1st pass effect from
stomach or intestine because of direct access to
portal veins
• 6. Liver can excrete drug into the bile

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Disadvantages of oral route
• 7. Irregular absorption may occur due to:
• a) Variation in process of solution
• b) pH variation
» If drug is too hydrophilic (i.e. atenolol), the drug cannot
cross the lipid cell membrane; if too lipophilic (i.e.
acyclovir), the drug is not soluble enough to cross the
water layer adjacent to the cell
• c). Binding to food (e.g. tetracycline chelated to Ca++ and
other heavy metals)
• d). Variation in motility and emptying time of GI
• e). Reverse transporter associated with P-glycoprotein
process actively pumps drug out of gut wall cells back into
the gut lumen
» Tx: grapefruit juice – will inhibit P-glycoprotein and gut
wall metabolism

82
Oral absorption
Drug absorption after oral
administration has two (2) components:
▪ The Rate of Absorption
▪ Bioavailability of the drug.

83
Oral absorption
THE RATE OF ABSORPTION
• The rate of absorption is partially controlled by
the physicochemical characteristics of the drug.
• This could be modified by formulation to
enhance or slow the rate of absorption.
• Reduction in the rate of absorption can lead to a
smoother concentration-time profile with a lower
potential for concentration-dependent adverse
effects. [may even allow less frequent dosing]

84
Oral absorption
BIOAVAILABILITY
Is the term used to describe the fraction of the
administered dose (free unchanged form) that is
absorbed into the systemic circulation.
– ( Differ from bioequivalence ▬drug products are
bioequivalent when the rate and extent of
bioavailability of the active ingredients do not
differ significantly)
Bioavailability ranges from 0 to1 or 0 to 100 %.
•i.v injection gives 100% bioavailability
– Calculated from comparison of the area under the
curve (AUC) relating plasma concentration to
time for i.v. dosage compared with other route.
Says nothing about effectiveness.

Bioavailability
It depends on a number of physico-chemical & clinical
factors.
• What determines bioavailability?
– Physical properties of the drug (hydrophobicity, pKa,
solubility)
– The drug formulation (immediate release, delayed release,
etc.)
– If the drug is administered in a fed or fasted state
– Gastric emptying rate
– Circadian differences
– Interactions with other drugs
– Age

86
Oral absorption
• Bioavailability may be altered:
• By low lipid solubility of the drug
• If drug is destroyed by the acid in the
stomach (e.g. X’Pen).
• By the presence of food in the G.I.T.
• Co-administration with other drugs.
»e.g. Heavy metals in antacids can
reduce the absorption of quinolones
(e.g. Ciprofloxacin) and tetracyclines
by binding them in the gut.

87
Bioavailability
• For drugs that are susceptible to extensive
first pass metabolism, a substantial portion
or almost all the drug could be metabolized
in the liver before it reaches the site of
action. E.g. GTNT, (low oral bioavailability 0
or<0.5)
• Drugs with very low lipid solubility such
as strong acids: pKa ≤ 3 or strong bases
pKa ≥ 10 (e.g.suxamethonium); are fully
ionized in the GIT, may not be absorbed
when administered orally.
• [administer parenterally]

88
Bioavailability
• Other highly polar molecules such as amino-
glycosides and vancomycin are also poorly
absorbed from the G.I. (Very low oral
bioavailability).
• These drugs are usually formulated as
injections.
• Drugs such as levodopa and others are
exceptions since they are absorbed by carrier
mediated mechanisms.

89
Bioavailability
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation

90
Oral absorption
Oral ingestion
• Absorption occurs via passive diffusion and is governed
by blood flow, surface area, drug concentration &
formulation.
• Theoretically drugs that are weak acids would be
optimally absorbed from the acid environment of the
stomach.
• And drugs that are weak bases from the alkaline
environment of the intestine.
• The small surface area of the stomach and its thick
mucosa limits absorption.
• In contrast, as a result of the huge surface area of the
intestines, the rate of absorption of ALL drugs is greater
in the intestines.
• Changes in the rate of gastric emptying influence
rate of presentation of drug to the intestine, and
therefore influence rate of absorption.

91
Oral absorption
Though the unionized form of a drug is
absorbed more rapidly than the ionized form
at any particular site in the GI tract,
the OVERALL RATE of absorption of a drug
from the intestine > that from the stomach
even if the drug is relatively more ionized in
the intestine than in the stomach.

92
Absorption
Prodrugs:
Chemical modification of the molecule to
form a compound that is better absorbed
and from which the active drug is liberated
(activated) after absorption
–enalapril-----enalaprilat
–levodopa-----dopamine

93
Absorption
2. Parenteral
– A. Advantages of parenteral route
» 1. More rapid and predictable absorption
» 2. Used to administer drugs that would be destroyed by
stomach acid or enzymes
» 3. Use with unconscious or uncooperative patient
» 4. More accurate dose selection
– B. Disadvantages of parenteral route
» 1. Strict asepsis must be maintained
» 2. Pain associated with injection
» 3. Self administration may be difficult
» 4. More expensive
» 5. Possibility of technical errors (rate of dosing, area
given)
» 6. Difficult to correct overdose or error
» 7. Risk of infection or local irritation

94
Absorption
• C. Parenteral routes
– 1. Subcutaneous (SC) – drug is injected beneath
the skin and permeates capillary walls to enter the
blood stream
– A. Advantages of subcutaneous route
– 1. Slow absorption
– 2. Smaller volume than IM
– 3. Rate of absorption may be altered by:
– a. Drug solution
– b. Local vasoconstriction
– c. Tourniquet or other manipulations altering
blood flow
– B. Disadvantages of subcutaneous route
– 1. Irritating drugs may result in severe pain and
local necrosis

95
Absorption
• 2. Intramuscular (IM) – drug passes through
capillary walls to enter the blood stream
• A. Advantages of intramuscular route
» 1. Generally more rapid absorption than SC
» 2. Larger volumes and relatively irritating substances
may be given
» 3. Absorption may be hastened or slowed by various
manipulation
» Rate of absorption depends on formulation: oil based
preparation has slow rate of absorption; aqueous
preparation has rapid rate of absorption
• B. Disadvantages of intramuscular route
» 1. Vasoconstriction (e.g. epinephrine) cannot be used
to slow absorption as in SC
» 2. More painful than SC

96
Absorption
– 3. Intravenous (IV) – agent injected directly into
blood stream
» A. Advantages of intravenous route
» 1. Rapid onset of action, controlled
» 2. Most irritating substances may be given. Have to
be soluble drugs
» 3. Large volumes may be given
» 4. Useful in emergency situations (i.e. when patient
is unconscious)
» 5. 100% bioavailability
» B. Disadvantages of intravenous route
» 1. Dangers associated with too-rapid delivery
of large volumes (embolisms, elevated blood
pressure, etc.) or with toxic doses of a drug
» 2. Technical difficulties of administering the
drug (getting the correct rate for dosing)

97
Absorption
• IA→ Localises drug effect to an organ/tissue.
Requires great care
• Intrathecal→Drug administered into
subarachnoid space. By- passes the bbb,
allows for local and rapid effect of drugs on
meninges and in the CNS.
– for drugs excluded by the blood-brain barrier
(methotrexate in childhood leukemias to
eliminate malignant cells from the CNS)
– - risks: neurotoxicity, death or permanent
neurological disability
– I.P→ common route in rodent laboratory
studies.

98
Absorption
P a r e n t e r a l administration the onset of action at
i n t r a v e n o u s
- instantaneous and complete absorption
- more dangereous (vancomycin)
1-2 min
i n t r a m u s c u l a r
- faster and more complete than per os, but in
severe hypotension blood flow may be low and
i.m. absorption slow, incomplete
- for larger size of particles (suspension), lipid
soluble ones
( injection of depot preparations results in very
slow absorption.)
10-15 min
s u b c u t a n e o u s 20 min

99
Absorption: Other routes of
administration
– A. Inhalation
– Rapid absorption due to large surface area and large #
of blood capillaries lining alveoli
• For gaseous/volatile drugs; Absorption rapid, local
application, avoids first-pass metabolism.
– - local: in the case of respiratory disease offers
delivery closest to the target tissue
– - systemic: rapid absorption (large alveolar
surface)
– Nasal→ (- for local effects ) Gonadotropin-releasing
hormone and calcitonin
- administered as nasal spray [quickly
destroyed in the G.I.T
- inactive when given orally]. Ephedrine nasal drops,
desmopressin for patients with diabetes insipidus)

100
Absorption
– B. Rectal (PR) – suppositories
» Useful for unconscious or vomiting patients or small
children
– Absorption is unreliable:
» Lower rectum – enter vessels that drain into inferior vena
cava and by-pass liver
» As a suppository moves upward in the rectum, access to
superior hemorrhoidal vein is more likely and this leads to
the liver
– C. Topical
» To maximize the drug concentration at the site of action
and minimize it elsewhere, particularly for those drugs
which have toxic effects if administered systemically
» Ex: dermatologic, ophthalmologic, nasal, vaginal, and otic
– D. Transdermal – drug seeps out of patch, through skin and
into capillary bed
» Slow absorption
» To prolong the duration of drug absorption
» Convenient for self administration – increases compliance

101
Absorption
– Mechanisms for drug transport across
membranes
• A. Passive (simple) diffusion
– 1. Rate of transfer of substances are directly proportional
to the concentration gradient on both sides of the
membrane
– 2. Rapid for lipophilic, nonionic, small molecules
– 3. No energy or carrier required
• B. Aqueous channels
– 1. Small hydrophilic drugs (<200 MW) diffuse along conc
gradient by passing through pores (aqueous channels)
– 2. No energy required

102
Absorption
• C. Specialized transport
– 1. Facilitated diffusion – drugs bind to carrier
noncovalently
» No energy is required
– 2. Active transport – identical to facilitated
diffusion except that ATP (energy) powers
drug transport against conc gradient
• D. Pinocytosis and phagocytosis
– Engulfing of drug
– Ex: Vaccines

103
Summary: Factors affecting oral
absorption
• Disintegration of dosage form
• Dissolution of particles
• Chemical stability of drug
• Stability of drug to enzymes
• Motility and mixing in GI tract
• Presence and type of food
• Passage across GI tract wall
• Blood flow to GI tract
• Gastric emptying time
• FORMULATION

105
DRUG DISTRIBUTION
Once the drug enters the blood stream, it may be
distributed into the body fluids (body water).
The extent of distribution depends on:
▪ Regional blood flow.
▪ Drug Binding to plasma proteins
(macromolecules in blood or tissues)
▪ Partition co-efficient into fatty tissues
(lipid solubility).
▪ The pKa of the drug
▪ Size of the organs (tissues)

106
Drug Distribution ; Regional blood
flow
• Blood flow - important for the rate of drug
uptake
– well-perfused tissues (heart, brain,
kidney, splanchnic organs) will achieve
high tissue concentration sooner than
poorly perfused tissues (adipose,
bones)
▪ The heart, Liver, kidney and the brain receive
most drugs after absorption ▬ more
perfused.
▪ Drug delivery to and from the muscle, skin
and adipose tissue is slower ▬ Less
perfused

107
Drug Distribution: Binding
• Binding –in the blood or tissue compartment will
tend to increase the drug’s conc. in that
compartment.
– Only a free (unbound drug) can be distributed
– 1. Protein binding
– Two factors determine degree of plasma
protein binding:
» 1. Affinity of drug for plasma protein
» 2. # of binding sites available
– Weak acid drugs bind to albumin (phenytoin,
salicylates, and disopyramide are extensively bound)
– Weak basic drugs bind to serum globulins → α1 acid
glycoprotein (quinidine, lidocaine, propranolol)

108
Drug Distribution
• Protein binding
– Limits the drug conc in tissues because
bound drug cannot enter tissues, as a
result, leads to high concs of drug in the
plasma (bound + free drug)
• Bound drug is NOT therapeutically active
–There is an equilibrium between the free
drug and the bound drug
»Drug is gradually released from the
protein (acts as storage for drug) as the
free drug is utilized and removed

109
Drug Distribution
• Protein binding
– Is non-selective
– The # of binding sites on plasma protein is limited
– Drugs will compete with other drugs, hormones, or
other endogenous substances for protein binding sites
• Ex: Glyburide (sulfonamide) can displace warfarin, phenytoin,
salicylates, etc.. and cause ↑ hypoglycaemic effects (more free
drug in body)
• Ex: Warfarin can be displaced by indomethacin, aspirin, etc..
which can ↑ bleeding.
• These interactions may necessitate a dosage
adjustment or discontinuation of the other drug

110
Distribution: BINDING TO PLASMA
PROTEINS
Quite a number of drugs bind to circulating plasma proteins.
mainly albumin but globulins, lipoproteins and acid
glycoprotein's can also bind to drugs.
The acidic drugs bind mainly to plasma albumin whilst the
basic drugs bind to 1-acid glycoprotein.
The amount of drug that binds the plasma proteins depends
on:
▪ The free drug concentration.
▪ Affinity of the drug for the binding sites.
▪ The protein concentration in the body.

111
Protein binding & drug distribution
• Usually it is the unbound or the free drug that distributes
into the tissues of the body, ▬ responsible for the
clinical effect or toxicity of drug.
NB:
• Only the unbound drug can
▪ bind to receptors to elicit Pharmacological
response
▪ cross tissue membranes, gain access to cellular
enzymes,
▪ be metabolized and excreted from the body
• Increased plasma concentration of free drug may be
clinically relevant if the drug is highly protein bound
OR
• not clinically relevant if the change in plasma
concentration is a transient increase.

112
Plasma binding of drugs
1000 molecules
high % bound lower
molecules free
99.9% 90.0%
100
1
Fewer free molecules means :
less drug in active form - therefore action smaller
lower concentration gradient of diffusable drug - slower onset
less at biotransformation & excretion sites - longer action
CHANGE in drug binding = possible serious interaction (eg.100-fold increase
in free pharmacologically active drug)
Effective TOXIC

2. Lipid solubility :Membrane
permeability
• Lipid solubility: in organs with a high lipid
content, a high concentration of lipid-soluble
agents is reached:
– a very lipid soluble anaesthetic agent will
transfer out of the blood more rapidly and to
a greater extent than a drug with a low lipid
solubility.
• Membrane permeability
– For a drug to enter an organ (tissue), it
must permeate all membranes that
separate the organ from the site of drug
administration

114
Drug Distribution
• A. Blood brain barrier (BBB) – lipid membrane located
between plasma and the extracellular space in the brain
Blood and brain are separated by
capillary cells packed tightly
together and by a fatty barrier
called a glial sheath, which is
made up of extensions (glial feet)
from nearby astrocyte cells. A
drug moving from blood to brain
must diffuse across the cells of
the capillaries and because there
are tight jxns rather than pores b/n
the cells, the drug must then move
through the fatty glial sheath

115
Drug Distribution: Blood brain
barrier (BBB)
– The entry of drugs is restricted into the CNS and
CSF (cerebrospinal fluid)
– Lipid solubility and cerebral blood flow limit
permeation of the CNS
– Highly lipophilic drugs can pass the BBB (i.e.
benzodiazepines)
– It is difficult to tx the brain or CNS, however, the
difficulty of passage into the brain can also serve
as a protective barrier when treating other parts
of the body
• Excludes ionized substances; Active transport
mechanisms;
• Not uniform – leaky (circumventricular areas)

116
Drug Distribution
• B. Blood-placenta barrier – the foetus is
exposed to most drugs the mother ingests at
anytime during the pregnancy.
Lipid soluble drugs may cross the
placenta and cause developmental toxicity.
▪ Nicotine withdrawal symptoms in
neonates,
▪ Down syndrome babies for alcoholic
mothers.

• C. Mammary transfer of drugs – breast
milk is acidic so basic drugs
concentrate in this fluid
– Non-electrolyte drugs (do not
depend on pH gradient – i.e.
alcohol) readily reaches the same
concentration as in the plasma,
independent of the pH of breast
milk

118
Drug Distribution
3. Storage Depots (Tissue/Depot binding)
•Drugs may collect in certain body tissues
– A. Fat – lipophilic drugs accumulate here and
are released slowly (due to low blood flow)
– Ex: thiopental (or other anesthetic) – causes ↑ sedation in
obese patients
• B. Bone – Ca++ binding drugs accumulate here
– Ex: tetracycline can deposit in bone and teeth → will cause
mottling or discoloration of teeth
• C. Liver – many drugs accumulate in the liver due to
an affinity for hepatic cells
• Ex: quinacrine (antimalarial agent) – has higher conc (22,000
times) in the liver than in plasma due to long term administration

119
Drug Distribution
– 3. Storage Depots
– D. Skin – some drugs accumulate here
» Ex: griseofulvin (antifungal of skin, hair, and nails)
binds to keratin protecting the skin from new infection
» Chloroquine, highly tissue bound and stays in the
body for a longer time.
• Drugs bind to “depot sites” or “silent receptors” (fat, muscle,
organs, bones, etc)
• Depot binding reduces bioavailability, slows elimination, can
increase drug detection window
• Depot-bound drugs can be released during sudden weight
loss – may account for flashback experiences?
• Redistribution – after a drug has accumulated in tissue,
i.e. thiopental in fatty tissues, drug is gradually returned
to the plasma

120
VOLUME OF DISTRIBUTION Vd
• Vd ▬ Defined as the volume of fluid into which
drug distributes based on the amount in the
body and the concentration in the plasma
(measured in l/kg)
–
• If the drug is wholly confined to the plasma,
the volume of distribution (vd) would be equal
to the plasma volume.
• If the drug is widely distributed through out
the body water, vd would be higher.
p
d
C
plasma
in
Conc
Q
body
in
Amount
Dose
V
)
(
=

121
Vd
• The amt of drug in a living tissue cannot be known
precisely but Vd gives an indirect measure of drug
distribution.
• Apparent volume of distribution
– is the theoritical volume of fluid required to
contain the total amount of drug in the body
at the same concentration as that in the
plasma.
• If the drug is tissue bound, the plasma
concentration will be low but the apparent
volume of distribution will be high.
• If the drug is highly bound to plasma proteins,
the concentration in the blood/plasma will be
high and the drug will have a low volume of
distribution.

122
Vd & Penetration into BBB
• The brain is inaccessible to many systemically
acting drugs including the aminoglycosides
▬insufficiently lipid soluble to allow
penetration into the blood-brain barrier.
–Inflammation of the meningis (as in
meningitis) disrupt the integrity of the
blood-brain barrier and allow such
substances to pass through.
• Lipid insoluble drugs are mainly confined
to the plasma or the interstitial fluids and
could hardly enter the blood-brain barrier
unless the meningis are inflamed.

123
Vd
Lipid soluble drugs can reach all the compartments
of the body and may accumulate in body fat.
Generally :
•Small volume of distribution occurs when:
o The Lipid solubility properties of the drug is
low.
o High degree of plasma protein binding
o Low level of tissue binding
•High Vd however occurs when:
o Lipid solubility properties of the drug is
high
o Low degree of plasma protein binding,

125
Transformation of Xenobiotics by Biological
Systems

126
IMPLICATIONS FOR DRUG METABOLISM
1. Termination Of Drug Action: Atropine
tropic acid & tropine
2. Activation Of Prodrug: L dopa
dopamine
3. Bioactivation And Toxication: Terfenadine
fexofenadine
Acetaminophen Reactive
Metabolite N-Acetylbenzoquinoneimine

4.Carcinogenesis: Metabolites of these agents
interact with DNA
• 3,4 Benzopyrene
• Aflatoxin
• N-Acetylaminofluorene
5.Teratogenesis
• THALIDOMIDE: Fetal malformations in humans,
monkeys, and rats occur due to metabolism of the
parent compound to a teratogen. This occurs very
early in gestation
IMPLICATIONS FOR DRUG METABOLISM

128
DRUG METABOLISM
Drugs are eliminated from the body by two principal
mechanisms:
– By liver metabolism and
– By renal excretion.
• NB metabolism and elimination occurs in other parts of the body e.g.
Billiary excretion, lungs etc.
•Drugs that are water soluble may be excreted
unchanged by the kidney.
•Lipid soluble drugs are not easily excreted by the
kidneys because they are largely reabsorbed from
the proximal tubules after glomerular filtration.
– such drugs have to undergo
biotransformation before they could be
excreted by the kidneys.

Degradation & Excretion
• Kidneys
– Traps water-soluble (ionized)
compounds for elimination via
urine (primarily), feces, air, sweat
• Liver
– Enzymes(cytochrome P-450)
transform drugs into more water-
soluble metabolites
– Repeated drug exposure increases
efficiency → tolerance

130
DRUG METABOLISM
• The first step in the elimination of lipid soluble drugs is
metabolism to more polar cpds that are water soluble and
excreted by the kidneys.
• Drug metabolism occurs mainly in the liver and generally
in 2 phases.
– But drugs like suxamethonium are metabolized in the plasma
( by P. cholinesterase);
– Vitamin D in the kidneys,
– some cytotoxic drugs e.g. Cyclophosphamide, Cytosine
arabinose etc.metabolized in the cells;
– Acetylcholine and other neurotransmitters ▬ at the synapses
and within the nerve endings etc.
– the G.I. and in the lungs.

131
DRUG METABOLISM
• Biotransformation
– Process of making a drug more polar and water
soluble to be excreted out of the body (lead to
termination)
– Drug metabolism often results in detoxification
or inactivation of drugs where the metabolites
are less active or inactive compared to the
parent drug
– Some metabolites may be equally or even more
active than the parent drug. Prodrug – inactive
drug that is activated by metabolism (ex:
enalapril)
– Some drugs can be metabolized to toxic
compounds
• Ex: When acetaminophen exceeds therapeutic doses, it
can deplete glutathione and accumulate a toxic metabolite
which causes hepatotoxicity. N-acetylcysteine is given

132
DRUG METABOLISM
• Biotransformation in the elderly
• Hepatic enzymes and other organs deteriorate
over time
• Biotransformation in the foetus or neonate
– These individuals are very vulnerable to the toxic
effects of drugs
– Their liver and metabolizing enzymes are under-
developed
– They also have poorly developed blood brain barrier
• Can get hyperbilirubinemia which leads to
encephalopathy
– Have poorly developed kidneys which can alter excretion
and cause jaundice

133
DRUG METABOLISM
• Biotransformation
– General pathways of drug metabolism
• Phase I reaction – (oxidation, reduction,
hydrolysis)
– Generally, the parent drug is oxidized or
reduced to a more polar metabolite by
introducing or unmasking a functional group
(-OH, -NH2, -SH)
– The more polar the drug, the more likely
excretion will occur
– This reaction takes place in the smooth (no
ribosomes) endoplasmic reticulum in liver
cells (hepatocytes)

134
DRUG METABOLISM
– Phase I reaction
• The smooth microsomes are relatively rich
in enzymes responsible for oxidative drug
metabolism
–Important class of enzymes – mixed
function oxidases (MFOs)
»The activity of these enzymes
requires a reducing agent, NADPH
and molecular oxygen (O2)
• Two microsomal enzymes play a key role:
» 1. NADPH-cytochrome P450 reductase, a
flavoprotein
» 2. Cytochrome P450, a hemoprotein, the terminal
oxidase

135
DRUG METABOLISM
–Phase I reaction
• Cytochrome P450
–Is a family of isoenzymes
–Drugs bind to this enzyme and are
oxidized or reduced
–Can be found in the GI epithelium,
lung and kidney
–Cyp3A4 alone is responsible for more
than 60% of the clinically prescribed
drugs metabolized by the liver

136
DRUG METABOLISM :Phase I
Rxns
The Phase 1 metabolites usually have only minor
structural differences from the parent compound but
may exhibit totally different pharmacological
actions.
– E.g. aromatic hydroxylation of
phenobarbitone abolishes its hypnotic
activity
– metabolism of azathioprine produces 6-
mercaptopurine, which is a powerful
antimetabolite with anticancer properties
– oxidation of ethanol to acetaldehyde.

137
DRUG METABOLISM :The 2
phases of liver metabolism:
TERM DEFINITION
Phase I Rxns that convert the parent drug to a more polar
(water-soluble), or a more reactive product
by unmasking or inserting polar functional group
as
OH, SH,NH2
more polar, less active:
deamination: diazepam -- nordiazepam
hydroxylation: phenytoin
activated:
O-dealkylation: codeine--morphine
The phase 1 metabolites are usually more reactive and
sometimes more toxic than the parent compound.

138
DRUG METABOLISM :2 phases
of liver metabolism
• The liver metabolic reactions are mostly
catalyzed by the mixed function oxidases
or the cytochrome P450 enzymes.
–( There are multiple iso-forms of the
P450 enzymes which can act on
numerous substrates)
• Different members of the iso-zymes have
distinct but often overlapping substrate
specificities.
• Some act on the same substrates as the
other but at different rates.

139
DRUG METABOLISM :2 phases of
liver metabolism
P450 iso-zyme Drug(s) or substrate(s)
Cyp 1A1 Theophylline
Cyp 1A2
Cyp 3A4
Caffeine, P’mol, Theophylline, ondansetron
Erythromyin, midazolam, nifedipine,
Cyp2C9 Warfarin, Tolbutamide, Ibuprofen, Phenytoin
Cyp2D6
Cyp 2E1
Debrisoquine, Codeine Metoprolol,
nortryptyline
Alcohol, Halothane

140
DRUG METABOLISM :Phase II
Metabolism
D+ENDOX DX+ENDO
A molecule endogenous to the body donates a
portion of itself to the foreign molecule
This almost always lead to abolition of p/cological
activity or produces a p/cologically inactive
compound that is more water soluble and readily
excreted in the urine mainly, or by the bile.
The liver is the major site for phase II conjugation
reactions but conjugation can also occur in the
gut.

141
DRUG METABOLISM
– Phase II reaction
• This involves coupling the drug or it’s polar metabolite
with an endogenous substrate (glucuronic acid,
sulfate, glycine, or amino acids)
• The endogenous substrates originate in the diet, so
nutrition plays a critical role in the regulation of drug
conjugation
• Drugs undergoing phase II conjugation reactions
(glucuronidation, acetylation, methylation, and
glutathione, glycine, and sulfate conjugation) may
have already undergone phase I transformation
• Some parent drugs may already possess a functional
group that may form a conjugate directly

142
DRUG METABOLISM :The 2
phases of liver metabolism:
Phase II Rxns that increase water solubility by
conjugation of the drug molecule
with a polar moiety:
glucuronidation: morphine
sulfate conjugation:
acetaminophen
acetylation: sulphonamides
all tend to be less lipid soluble and therefore better
excreted (less well reabsorbed)

143
Patterns of Drug Metabolism
• Parent molecule → Phase 1 metabolism
• Phase 1 metabolite → Phase 2 metabolism
• Parent molecule → Phase 2 metabolism
• Phase 2 metabolite → Phase 1 metabolism
Some drugs are not metabolized, for example, gallamine and
decamethonium. Atracurium undergoes spontaneous
hydrolysis.

144
DRUG METABOLISM
• Variations in drug metabolism:
• Generally, men metabolize faster than women (ex:
alcohol)
• Diseases can affect drug metabolism (ex: hepatitis,
cardiac (↓ blood flow to the liver), pulmonary disease)
• Genetic polymorphism.
• Differences in the metabolism of drugs in different races
or populations. E.g 50% of Caucasians are slow
acetylators of Isoniazid, Hydralazine and procainamide.
• Some individuals are poor metabolizers or extensive
metabolizers of debrisoquine, (i.e. hydroxylation of
debrisoquine via CYP 2D6)
– Other drugs metabolized by 2D6 are metoprolol and
nortriptyline.

145
Metabolism: Presystemic metabolism and
first-pass effect
• Following oral administration drugs gain access
to the systemic circulation via the portal vein, so
the entire absorbed dose is exposed first to the
intestinal wall and then to the liver before gaining
the access to the rest of the body.
• If the drug is rapidly metabolized, a
substantional fraction will be extracted and
metabolized before it reaches the systemic
circulation. This it known as presystemic
metabolism.
• Presystemic metabolism in the liver: in the gut:
lidocaine,morphine levodopa, salbutamol

• Pronounced first-pass metabolism
necessitates high oral doses by
comparison with the IV route.
• Alternative routes of drug delivery e.g.
• rectal,
• buccal,
• sublingual,
• inhalation or
• transdermal
• partly or completely bypass presystemic
metabolism (elimination).

147
DRUG METABOLISM
– First-pass effect – some drugs go straight from
the GI tract to the portal system where they
undergo extensive metabolism in the liver (ex:
morphine) before entering the systemic circulation
• This can limit the bioavailability of certain drugs
• It can be greatly reduced by giving drug by other route of
administration
– Extraction ratio – an expression of the effect of first-
pass hepatic elimination on bioavailability. ER =
Clliver/Q (hepatic blood flow)
• Highly extracted drugs: isoniazid, morphine, propranolol, verapamil,
and several TCAs
• Poorly extracted drugs: phenytoin, theophylline, warfarin, diazepam

148
DRUG METABOLISM :Factors
affecting Biotransformation
• Age (reduced in aged patients & children)
• Sex (women more sensitive to ethanol?)
• Species (phenylbutazone 3h rabbit, 6h horse,
8h monkey, 18h mouse, 36h man); route of
biotransformation can also change
• Race (fast and slow isoniazid acetylators, fast
= 95% Eskimo; 50% Brits; 13% Finns; 13%
Egyptians.
• Clinical or physiological condition
• First-pass (pre-systemic) metabolism

149
The enterohepatic shunt
Portal circulation
Liver
gall
bladder
Bile
duct
Drug
Biotransformation;
glucuronide produced
Bile formation
Hydrolysis by
beta glucuronidase
Gut
some drugs, or their metabolites, which are concentrated in the bile then
excreted into the intestines, can be reabsorbed into the bloodstream from the
lower GI tract

150
DRUG METABOLISM
• ENZYME INDUCTION & INHIBITION.

151
Enzyme Induction & Inhibition.
• The expression/production of the liver
metabolizing enzymes could be induced
or inhibited.
–Enzyme inhibitors or inducers may
be present in the diet or within the
environment.
–E.g. Grapefruit juice inhibits the
metabolism of terfenadine where as
cigarette smoke is an enzyme
inducer.

152
Enzyme induction
• results from increased synthesis of
CYP450-dependent drug-oxidizing
enzymes in liver
• autoinduction
• heteroinduction
• pl .concentrations, effects
• phenobarbital--warfarin
• phenytoin---digitoxin, theophylline
• rifampin--- methadone, metoprolol

153
Enzyme inhibition
decreases drug metabolizing capacity
pl .concentrations effects
cimetidine---warfarin,theophylline
erythromycin--- astemizole

154
Enzyme Induction.
• Cytochrome P450 enzyme induction
–Stimulation of hepatic drug
metabolism by some drugs
–Enzyme inducers stimulate their own
metabolism and also accelerate
metabolism of other drugs
–Ex of inducers: phenobarbital,
rifampin, phenytoin, carbamazepine,
griseofulvin, cigarette (nicotine)

155
ENZYME INDUCTION
• A number of drugs e.g. rifampicin, ethanol,
phenytoin, carbamazepine etc, increase
the activity of liver microsomal enzymes
by inducing the expression or synthesis of
the enzymes. Many carcinogenic
chemicals such as benzpyrene also have
this effect.
• This is one of the major causes of drug
interactions.
• Drugs such as alcohol, phenobarbitone
and rifampicin induce their own

156
ENZYME INDUCTION
• If two drugs which are metabolized by the same
enzymes are administered together, one can
influence the metabolism of the other
• eg. the anticonvulsants phenytoin,
carbamazepine, and phenobarbarbitone are all
metabolized by the same enzymes that
metabolizes oestrogens and progesterone of
oral contraceptives.
– If a woman taking an oral contraceptive
concurrently takes one of the drugs
mentioned above, the metabolism of the
oestrogen and the progesterone in the
contraceptive increases with the risk of
contraceptive failure.

157
ENZYME INDUCTION
• Nicotine in cigarette induces the expression of
the enzyme that metabolize theophyline, leading
to decreased theophylline levels in the body
when administered concurrently with nicotine.
Other examples of enzyme inducers include,
• alcohol,
• phenobarbitone,
• griseofulvin,
• DDT,
• sodium valproate etc.

158
Enzyme induction
• Enzyme induction by accelerating phase I
metabolism can increase or decrease drug
effect or drug toxicity.
• Phase I metabolites of paracetamol and some
polycyclic hydrocarbons are mainly responsible for
their toxicity.
• The toxic effects are increased following enzyme
induction.
• The carcinogenic action of some polycyclic
hydrocarbon compounds are associated with
increased formation of highly reactive oxidative
products from phase I metabolism, that can damage
DNA.

159
ACETAMINOPHEN AND ITS PHASE II METABOLITES
The sulfate and glucuronide conjugates of acetaminophen are the
major metabolites.
High doses of acetaminophen can exhaust the metabolic pathways
that produce these conjugates, allowing more of the parent drug to
undergo the phase I metabolic pathway which is involved in
bioactivation and toxication.

160
ACETAMINOPHEN AND ITS PHASE I METABOLITES

161
ACETAMINOPHEN AND ITS PHASE I METABOLITES-
The minor metabolite (4% of acetaminophen), N-
hydroxyacetaminophen, is always produced by microsomal
cytochrome P450.
It rearranges to the electrophile N-
acetylbenzoquinoneimine, which in turn reacts with the
sulfhydryl group of glutathione. Acetaminophen
mercapturic acid is the final metabolite.
If tissue glutathione stores are depleted as a result of
fasting, intake of excessive doses of acetaminophen or
through induction of CYP2E1 as a result of chronic intake
of ethanol, the quinone interacts with nucleophilic sites of
cellular macromolecules, such as proteins.

162
ACETAMINOPHEN AND ITS PHASE I METABOLITES-
• Liver necrosis is the result.
• Regular intake of acetaminophen during
fasting or chronic ethanol intake should be
avoided.
• N-acetylcysteine is the antidote for
acetaminophen poisoning. It reacts with the
electrophile.
• A small amount of acetaminophen is said to
undergo deacetylation to the phase 1
metabolite p-aminophenol.

163
ENZYME INHIBITION
Concurrent administration of some drugs could also lead to
inhibition of enzyme activity.
For e.g. cimetidine decreases the metabolism of theophylline,
leading to potentially dangerous adverse effects such as cardiac
arrythmias, seizures etc.
•Other examples of microsomal enzyme inhibitors include:
– Allopurinol
– Chloramphenicol
– Cimetidine
– Ketoconazole
– Erythromycin
– Ciprofloxacin
– Isoniazid
• NB Terfanidine + ketoconazole
• Cimetidine + Metronidazole

164
Enzyme Inhibition.
– Cytochrome P450 enzyme inhibition
• Some drugs may decrease the activity of hepatic drug-
metabolizing enzymes
• Could lead to increase levels of active drug in the body
– Ex of inhibitors:, allopurinol, grapefruit juice, cimetidine,
amiodarone, ciprofloxacin, clarithromycin, erythromycin,
fluoxetine, isoniazid, metronidazole, verapamil, omeprazole,
oral contraceptives
• Two different mechanisms, examples:
– Cimetidine binds tightly to Cyp450 and through competitive
inhibition reduces metabolism of other drugs
– Erythromycin is metabolized at Cyp3A, its metabolite forms
complex with enzyme and renders it catalytically inactive

165
DRUG METABOLISM
• Drug metabolism can alter the pharmacological action of a drug
qualitatively.
• E.g. Aspirin to salicylate – has anti-inflammatory effect
but no antiplatelet activity.
• Terfenidine causes serious cardiac arrhythmias but
fexofenadine, an active metabolite lacks cardio-toxic
effects. (Both are non- sedating anti histamines)
• Toxic metabolites: Acetaminophen, Phase I metabolite
is hepatotoxic.
• Acrolein is a toxic metabolite (Bladder toxicity) of
cyclophosphamide.
• Both methanol and Ethylene glycol exert their toxic
effect through their active metabolites (By alcohol
dehydrogenase)

Pharmacokinetics vs
Pharmacodynamics…concept
• Fluoxetine increases plasma
concentrations of amitriptyline. This is a
pharmacokinetic drug interaction.
• Fluoxetine inhibits the metabolism of
amitriptyline and increases the plasma
concentration of amitriptytline.

Pharmacokinetics vs
Pharmacodynamics…concept
• If fluoxetine is given with tramadol serotonin
syndrome can result. This is a pharmacodynamic
drug interaction.
• Fluoxetine and tramadol both increase availability
of serotonin leading to the possibility of “serotonin
overload” This happens without a change in the
concentration of either drug.

169
DRUG EXCRETION
Renal drug excretion:
• Drugs differ greatly in the way they are
cleared by the kidneys.
• For e.g. penicillins are almost completely
cleared on a single transit through the kidney
where as diazepam is cleared extremely slowly
by the kidneys.
• Most products of phase I and II metabolism
are more quickly cleared from the body by the
kidneys than the parent compounds.
• Urine is the principal but NOT the only route of
excretion
M i n o r r o u t es :

170
DRUG EXCRETION
• some drugs are mainly excreted by the kidney
without prior metabolism -digoxin,
gentamicin, lithium
• most drug metabolites are inactive and their
rate of renal excretion is usually without
clinical importance- neuroleptics
• if metabolites retain pharmacological activity,
drug action may be terminated by excretion
NOT by biotransformation- nordiazepam

171
Drug Clearance (Elimination)
• Clearance is the sum of all drug eliminating
processes.
• Principally determined by hepatic metabolism and
renal excretion.
• Renal Clearance
– Defined as the Volume of Plasma containing
the amount of drug that is removed by the
kidney in a given period of time.
•
• Cu=urinary concentration, Cp=Plasma conc.
• Vu= Rate of flow of urine.
p
u
u
r
C
V
C
Cl =

172
Half life (T1/2)
▪ The plasma-half life of a drug is the time required for
the plasma concentration of the drug to fall to ½ of its
original value.
▪ Whole body half-life: Time it takes to eliminate half of
the body content of a drug.
▪ 4 half-lives must elapse after starting a drug
dosing regimen before full effects will be seen
k = The elimination rate
constant
▪ The plasma t1/2 is directly proportional to the volume of
distribution and inversely proportional to the rate of
clearance.
▪ It can be used to determine dosage interval to
k
T
2
ln
2
/
1 =

173
Elimination: kinetics
• First-order elimination - implies that the rate of
elimination is proportionate to the concentration,
i.e., the higher the concentration, the greater the
amount of drug eliminated per unit time.
• When drug concentration is high, rate of
disappearance
is high.

174
Elimination”kinetics
• Zero-order elimination (saturation kinetics). Z-o
elim. implies elimination at a constant rate
regardless of concentration. As a result, the
drug´s concentration in plasma decreases in a
linear fashion over time.
• Constant amount eliminated per unit of time.
– This is typical of ethanol, and of phenytoin and aspirin at high
therapeutic or toxic concentration.

Comparison
• First Order Elimination
– [drug] decreases
exponentially w/ time
– Rate of elimination is
proportional to [drug]
– Plot of log [drug] or
ln[drug] vs. time are
linear
– t 1/2 is constant
regardless of [drug]
• Zero Order Elimination
– [drug] decreases
linearly with time
constant
independent of [drug]
– No true t 1/2

176
Overview - ADME
Most drugs :
enter the body (by mouth or injection or…) - must cross barriers
to entry (skin, gut wall, alviolar membrane…..)
are distributed by the blood to the site of action - intra- or extra-
cellular - cross barriers to distribution (capillaries, cell wall….)
- distribution affects concentration at site of action and sites
of excretion and biotransformation
are biotransformed perhaps to several different compounds by
enzymes evolved to cope with natural materials - this may
increase, decrease or change drug actions
are excreted (by kidney or …….) which removes them and/or
their metabolites from the body
Pharmacokinetics is the quantification of these processes

177
Pharmacokinetics
Study of ADME on a quantitative basis
In man study blood, urine, faeces, expired air.
Measure urine volume & concentration of
drug
If neither secreted nor reabsorbed then
CLEARANCE
RENAL
conc
Plasma
per
vol
X
urine
of
Conc
=
min

178
PHARMACOKINETICS
ABSORPTION
free drug
free drug free drug
bound drug
TISSUES BLOOD CIRCULATION EXCRETION
receptor
depo
metabolite
receptor
depo
organs for
BIOTRANSFORMATION
DISTRIBUTION
bound metabolite
free
metabolite
free
metabolite

180
Case studies
Your are a consultant psychiatrist treating patients
with moderate depression. You administer the
standard dose of nortryptyline (75-150 mg/d) to
100 patients:
all get worse for 2 weeks; then between 4-8
weeks:-
most respond and improve;
1 develops cardiac dysrhythmias and dies;
9 do not respond - 2 commit suicide in week 7 -
the remaining 7 are changed to paroxetine and
respond

181
Case studies 2
You are a GP. An 18 year old woman comes for help with her hay-fever; getting
worse over the last few years. You give her chlorpheniramine (4mg 4xd) but
a week later she is back complaining of dry mouth and feeling tired all the
time. Wants it sorted out before going on holiday. You swap her to
terfenadine 60mg/d. One week later she reports treatment as successful. Six
weeks later having collapsed in the street she is admitted as an emergency
and dies.
Terfenadine blocks cardiac K+channels and
prolongs QT. On holiday she developed
candidiasis (given itraconazole) and on return
goes on diet. Drinks grapefruit juice. Both
itraconazole and grapefruit juice inhibit CYP3A4.
This normally quickly biotransforms terfenadine

General Introductory Pharmacology by Accra College students

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