Cardiovascular drugs by Mrinmalini

BY
Mrinmalini Priyadarshini
M.Pharm, B.P.U.T, Odisha.

 Drugs having their major action on heart or blood
vessels, or those used primarily for cardiovascular
disorders are designated cardiovascular drugs.
 They can act directly on the cardiovascular structures
or through autonomic/central nervous system, kidney,
autacoids or hormones which regulate cardiovascular
function.

 Myocardium: cardiac muscle fibers are arranged into
four chambers, 2 atria and 2 ventricles.
 Conduction system: specialized tissue that conducts
nerve impulses throughout the heart, SA and AV
node, bundle of His, bundle branches, and Purkinje
fibers
 Nerve supply: Nerve branches from both the
sympathetic and parasympathetic divisions of the
autonomic nervous system, regulate heart rate and
force of contraction.

 Cardiac Glycoside and CHF
 Angina Pectoris
 Cardiac arrhythmias
 Hypertension

 Congestive heart failure (CHF) is a chronic progressive
condition that affects the pumping power of our heart
muscles. While often referred to simply as “heart
failure”.
 CHF specifically refers to the stage in which fluid
builds up around the heart and causes it to pump
inefficiently.

 CHF develops when your ventricles can’t pump enough
blood volume to the body. Eventually, blood and other
fluids can back up inside our:
 lungs
 abdomen
 liver
 lower body
 CHF can be life-threatening. If you suspect you or
someone near you has CHF, seek immediate medical
treatment.

 There are two kinds of left-sided heart failure:
 Systolic heart failure occurs when the left ventricle
fails to contract normally. This reduces the level of
force available to push blood into circulation. Without
this force, the heart can’t pump properly.
 Diastolic failure, or diastolic dysfunction, happens
when the muscle in the left ventricle becomes stiff.
Because it can no longer relax, the heart can’t quite fill
with blood between beats.

 The cardiac glycosides are often called digitalis or digitalis glycosides.
 They are a group of chemically similar compounds that can increase the
contractility of the heart muscle and, therefore, are used in treating heart
failure.
 The digitalis glycosides have a low therapeutic index, with only a small
difference between a therapeutic dose and doses that are toxic or even fatal.
 The most widely used cardiac glycosides is digoxin.
Cardiac glycosides Mechanism of action :
Digoxin's primary mechanism of action involves inhibition of the sodium
potassium adenosine triphosphatase (Na+/K+ ATPase), mainly in
the myocardium. This inhibition causes an increase in
intracellular sodium levels, resulting in decreased activity of the sodium-
calcium exchanger, which normally imports three extracellular sodium
ions into the cell and transports one intracellular calcium ion out of the cell.

 The inaction of this exchanger causes an increase in the
intracellular calcium concentration that is available to the
contractile proteins.
 Increased intracellular calcium lengthens phase 4 and
phase 0 of the cardiac action potential, which leads to a
decrease in heart rate. Increased amounts of Ca2+ also
leads to increased storage of calcium in the sarcoplasmic
reticulum, causing a corresponding increase in the release
of calcium during each action potential.
 This leads to increased contractility (the force of
contraction) of the heart without increasing heart energy
expenditure.

Schematic diagram of a cardiac muscle sarcomere, with the sites of action of several drug classes that alter contractility (numbered structures).
Site 1 is Na+/K+–ATPase, the sodium pump. Site 2 is the Na-Ca2+ exchanger. Site 3 is the voltage-gated calcium channel. Site 4 is a calcium
transporter that pumps calcium into the sarcoplasmic reticulum (SR). Site 5 is a calcium channel in the membrane of the SR that is activated to
release stored calcium by an influx of calcium that enters the cell through calcium channels; i.e., “trigger” calcium. Site 6 is the actin-troponin-
tropomyosin complex at which “activator” calcium released from the sarcoplasmic reticulum brings about contractile interaction of actin and
myosin.

 Antianginal drugs are those that prevent, abort or
terminate attacks of angina pectoris.
 Angina pectoris Is a pain syndrome due to induction of
an adverse oxygen supply/demand situation in a portion
of the myocardium.

Two principal forms are recognized:
(a) Classical angina: (Stable angina)
Stable angina occurs when the heart has to work
harder than normal, for example: during exercise,
emotion, eating or coitus,. It has a regular pattern, and
if you already know that you have stable angina, you
will be able to predict the pattern. Once you stop
exercising, or take medication the pain goes away,
usually within a few minutes.

(b) Variant/Prinzmetal/Vasospastic angina:
 (uncommon form) Attacks occur at rest or during
sleep and are unpredictable. They are due to recurrent
localized (occasionally diffuse) coronary vasospasm
which may be superimposed on arteriosclerotic
coronary artery disease.
 Drugs are aimed at preventing and relieving the
coronary vasospasm.

Fig. Diagrammatic representation of coronary artery caliber changes in classical and variant
angina

1. Nitrates:
(a) Short acting: Glyceryl trinitrate (GTN,Nitroglycerine)
(b) Long acting: Isosorbide dinitrate (short acting by sublingual route),
Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate.
2. β Blockers :
Propranolol, Metoprolol, Atenolol and others.
3. Calcium channel blockers:
(a) Phenyl alkylamine: Verapamil
(b) Benzothiazepine: Diltiazem
(c) Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine,
Nimodipine,Lacidipine, Lercanidipine, Benidipine
4. Potassium channel opener :Nicorandil
5. Others :
Dipyridamole, Trimetazidine,Ranolazine, Ivabradine, Oxyphedrine

Mechanism of vascular smooth muscle relaxant action of nitrodilators like glyceryl trinitrate and calcium
channel blockers; (- - -→) Inhibition CAM—Calmodulin; NO—Nitric oxide; MLCK—Myosin light chain kinase; MLCK-
P—Phosphorylated MLCK; GTP—Guanosine triphosphate; cGMP—Cyclic guanosine monophosphate

 Organic nitrates are rapidly de-nitrated enzymatically in the
smooth muscle cell to release the reactive free radical nitric
oxide (NO) which activates cytosolic guanylyl cyclase →
increased cGMP → causes dephosphorylation of myosin
light chain kinase (MLCK) through a cGMP dependent
protein kinase.
 Reduced availability of phosphorylated (active) MLCK
interferes with activation of myosin → it fails to interact
with actin to cause contraction. Consequently relaxation
occurs. Raised intracellular cGMP may also reduce Ca2+
entry—contributing to relaxation.

Heart arrhythmia, also known as irregular heartbeat or cardiac
dysrhythmia, is a group of conditions where the heartbeat is
irregular, too slow, or too fast.
Arrhythmias are broken down into:
 Slow heartbeat: bradycardia.
 Fast heartbeat: tachycardia.
 Irregular heartbeat: flutter or fibrillation.
 Early heartbeat: premature contraction.
Most arrhythmias are not serious, but some can predispose the
individual to stroke or cardiac arrest.

Class-I: Block sodium channels
Membrane stabilizing agents
These classes of drugs are local anaesthetics acting on nerve and myocardial
membranes to slow conduction by inhibiting phase 0 of action potential
They decrease the maximal rate of depolarisation without changing the
resting potential.
Class I sub-classified into three classes.
Ia (quinidine, procainamide, disopyramide)
Ib. (Lignocain, phenytoin)
Ic (flecainide, propaferone)

Class II: (β-Blocker)
Block sympathetic activity; reduce rate and conduction.
(propranolol,atenolol,sotalol)
Class III: (Potassium channel blocker) prolong action
potential and prolong refractory period by blocking k+ channel
(supress re-entrant rhythms) (amiodarone, dronedarone)
Class IV : (Calcium channel blocker)Block L-type calcium-
channels; most effective at SA and AV nodes; reduce rate and
conduction. (verapamil, diltiazem).

 Hypertension is not a disease. It is an arbitrarily defined
disorder to which both environmental and genetic
factors contribute Hypertension - An increase in BP
such that systolic is > 140 mm/Hg & diastolic > 90
mm/Hg.

 Essential Hypertension= most common about 90% of
clients.
 Exact Origin unknown. Contributing Factors ‐ family
hx, hyperlipidemia, diabetes, obesity, aging, stress,
excessive Alcohol & smoking.
 ™Secondary Hypertension is about 10% , related to
endocrine or renal disorders.

Stage
Diastolic Range
(mm/Hg)
Systolic Range
(mm/Hg)
High Normal 85-89 130-139
Stage-1 90-99 140-159
Stage-2 100-109 160-179
Stage-3 >109 >179

1. Diuretics
Thiazides: Hydrochlorothiazide,
Chlorthalidone, Indapamide
High ceiling: Furosemide, etc.
K+ Sparing: Spironolactone, Amiloride
2. ACE inhibitors
Captopril, Enalapril, Lisinopril,
Perindopril, Ramipril, Fosinopril, etc.
3. Angiotensin (AT1 receptor) blockers
Losartan, Candesartan, Irbesartan, Valsartan,
Telmisartan

4. Calcium channel blockers
Verapamil, Diltiazem, Nifedipine, Felodipine,
Amlodipine, Nitrendipine, Lacidipine, etc.
5. β Adrenergic blockers
Propranolol, Metoprolol, Atenolol, etc.
6. β + α Adrenergic blockers
Labetalol, Carvedilol
7. α Adrenergic blockers
Prazosin, Terazosin, Doxazosin
Phentolamine, Phenoxybenzamine

8. Central sympatholytics
Clonidine, Methyldopa
9. Vasodilators
Arteriolar: Hydralazine, Minoxidil,
Diazoxide
Arteriolar + venous: Sodium nitroprusside
Adrenergic neurone blockers (Reserpine, Guanethidine, etc.)
and ganglion blockers (Pentolinium, etc.) are only of historical
importance, though reserpine is still marketed.

 Loop Diuretics
Loop diuretics, reversibly, inhibit the Na+⁄2Cl-⁄K+ co-transporter of the
thick ascending loop of Henle where one-third of filtered sodium is
reabsorbed. This causes decreased sodium and chloride reabsorption and
increased diuresis. which causes venous dilatation.
 Thiazide Diuretics
Thiazide diuretics inhibit the sodium–chloride transporter at the distal
portion of the ascending limb and the first part of the distal tubule. They
prevent maximal dilution of urine, thus increasing free water clearance and
excretion of sodium and chloride through the renal tubular epithelium.
 The increased delivery of sodium to the collecting ducts enhances the
exchange of sodium with potassium and, as a result, potassium depletion.as
a result decrease peripheral vascular resistance resulting in a decrease of
blood pressure.

 Potassium-sparing diuretics
These diuretics prevent K+ secretion by antagonizing the effects
of aldosterone at the late distal and cortical collecting tubules.
Inhibition may occur by direct pharmacologic antagonism of
mineralocorticoid receptors (spironolactone, eplerenone) or by
inhibition of Na+ influx through ion channels in the luminal
membrane (amiloride, triamterene).

 ACEIs inhibit the formation of angiotensin which is a potent
vasoconstrictor
 ACEIs decrease the release of aldosterone which retains
sodium and water.
 The ACEIs can be used with thiazide and organic acid
diuretics.

 These drugs block angiotensin receptors on blood
vessels and adrenal cortex
 Like the ACEIs, these drugs produce vasodilation and
decrease the activity of aldosterone
 The angiotensin receptor blockers generally produce
a lower incidence of adverse effects than the ACEIs

 Block the influx of calcium into the heart and arterial
blood vessels
 Verapamil and diltiazem act on both the heart and
blood vessels to lower BP
 Nifedipine and other calcium blockers lower BP only
by vasodilation
 Calcium antagonists are also used to treat angina
pectoris and cardiac arrhythmias

 Beta blockers bind to beta adrenorecepters located in
cardiac nodal tissue. The heart has both β1 and β2
adrenorecepter primarily bind norephineprene that is
released from sympathetic adrenergic nerves.
 Beta blockers prevents the normal ligant (epinephrine&
norepinephrine ) from binding to beta adrenocepter by
competing from the binding site.
 Therefore beta blockers cause decreases in heart rate.

 Alpha-adrenergic blockers are drugs used to lower blood
pressure. They work by relaxing the muscles in the walls of
blood vessels. With blood vessels open and relaxed, blood
flow improves and blood pressure lowers.
 Alpha-adrenergic blockers also lower blood pressure and
reduce stress on the heart by slowing the heart rhythm and
lessening the force of the heartbeat.
 These drugs are also called alpha blockers, alpha-adrenergic
antagonists and alpha-adrenergic blocking agents.
 This improves blood flow and lowers blood pressure.

 Central sympatholytic drugs reduce blood pressure
mainly by stimulating central α(2) -adrenergic receptors
in the brainstem centres, thereby reducing sympathetic
nerve activity and neuronal release of norepinephrine to
the heart and peripheral circulation.
 This class of drugs, however, is currently used mainly
as fourth-line (or beyond) drug therapy for
hypertension because of side effects of drowsiness,
fatigue, and dry mouth.

 Vasodilators are medications that open (dilate) blood
vessels. They affect the muscles in the walls of our
arteries and veins, preventing the muscles from
tightening and the walls from narrowing.
 As a result, blood flows more easily through our
vessels. our heart doesn't have to pump as hard,
reducing your blood pressure.

Cardiovascular drugs by Mrinmalini

Cardiovascular drugs by Mrinmalini

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Cardiovascular drugs by Mrinmalini