Chapter four:

CARDIOVASCULAR DRUGS

Dr Zakerie Hussein
 I. Antihypertensive drugs
A) Diuretics: which lower blood pressure by
depleting the body sodium and reducing blood
volume. Diuretics are effective in lowering blood
pressure by 10 – 15 mmHg in most patients.
 Diuretics
a) Thiazides and related drugs, e.g.
hydrochlorthiazide, bendrofluazide,
chlorthalidone, etc. Initially, thiazide diuretics
reduce blood pressure by reducing blood
volume and cardiac out put as a result of a
pronounced increase in urinary water and
electrolyte particularly sodium excretion.
• With chronic administration (6-8weeks), they
decrease blood pressure by decreasing
peripheral vascular resistance as the cardiac
out put and blood volume return gradually to
normal values.
• Thiazides are appropriate for most patients
with mild or moderate hypertension and
normal renal and cardiac function.
b) Loop diuretics, e.g. furosemide, ethacrynic
acid, etc.
• Loop diuretics are more potent than thiazides
as diuretics.
• The antihypertensive effect is mainly due to
reduction of blood volume.
• Loop diuretics are indicated in cases of severe
hypertension which is associated with renal
failure, heart failure or liver cirrhosis.
c) Potassium sparing diuretics, e.g.
spironolactone.
• They are used as adjuncts with thiazides or
loop diuretics to avoid excessive potassium
depletion and to enhance the effect of others.
• The diuretic action of these drugs is weak
when administered alone
B) Sympathoplegic agents (Depressants of
sympathetic activity).
• Based on the site or mechanism of action
sympathoplegic drugs are divided into
subgroups
a) Centrally acting antihypertensive agents e.g.
methyldopa, clonidine
• Centrally acting sympathetic depressants act by
stimulating α2 - receptors located in the
vasomotor center of the medulla. As a result,
sympathetic out flow from the medulla is
diminished and either total peripheral resistance
or cardiac out put decreases. Methyldopa is
useful in the treatment mild to moderately
severe hypertension.
• Methyldopa is a prodrug and must be
converted in the CNS to active α -
methylnorepinephrine to exert the effect on
blood pressure.
• The side effects of methyldopa include:
sedation, vertigo, dry mouth, nausea,
vomiting, diarrhea, postural hypotension,
impotence, haemolytic anemia, weight gain
and hypersensitivity reactions (fever, liver
damage, thrombocytopenia).
b) Adrenoceptor antagonists, e.g. propranolol,
atenolol (beta blocker), prazosin (alpha blocker),
labetalol (alpha and beta blocker).
• β – Blockers antagonize beta, receptors
located on the myocardium and prevent the
cardio acceleration, which follows
sympathetic stimulation.
• The rate and force of myocardial contraction
is diminished, decreasing cardiac out put and
thus, lowering blood pressure.
• An additional effect which can contribute to a
reduction of blood pressure is that renin
release is mediated by β receptors.
• Therefore, receptor blockade prevents
angiotensin II formation and associated
aldosterone secretion, resulting in a decrease
in total peripheral resistance and blood
volume.
• The principal action of alpha adrenergic
blocking drugs is to produce peripheral
vasodilation.
• Alpha blockers reduce arterial pressure by
dilating both resistance and capacitance
vessels.
• Treatment with prazosin should be initiated
with low dose (1mg 3 times daily) to prevent
postural hypotension and syncope or be given
at bed time.
C) Direct vasodilators.
• These include:-
✔ Arterial vasodilators, e.g. hydralazine
✔ Arteriovenous vasodilators, e.g. sodium
nitroprusside
• Hydralazine: It dilates arterioles but not veins.
It is used particularly in severe hypertension.
• The most common adverse effects are
headache, nausea, anorexia, palpitations,
sweating and flushing which are typical to
vasodilators.
• Sodium nitroprusside: It is a powerful vasodilator
that is used in treating hypertensive emergencies
as well as severe cardiac failure. It dilates both
arterial and venous vessels, resulting in reduced
peripheral vascular resistance and venous return.
Nitroprusside rapidly lowers blood pressure and it
is given by intravenous infusion. The most serious
toxicities include, arrhythmias, excessive
hypotension and death.
D) Angiotensin converting enzyme inhibitors,
e.g. captopril, enalapril, etc. The prototype is
captopril. Captopril inhibits angiotensin
converting enzyme that hydrolyzes angiotensin I
(Inactive) to angiotensin II (Active), a potent
vasoconstrictor, which additionally stimulates
the secretion of aldosterone.
• It lowers blood pressure principally by
decreasing peripheral vascular resistance.
• The adverse effects include maculopapular
rash, angioedema, cough, granulocytopenia
and diminished taste sensation.
• Enalapril is a prodrug with effects similar to
those of captopril.
E) Calcium channel blockers, e.g. nifedipine,
amilodipine, verapamil, nicardipine, etc. The
prototype is verapamil.
• The mechanism of action in hypertension is
inhibition of calcium influx in to arterial smooth
muscle cells, resulting in a decrease in peripheral
resistance.
• Verapamil has the greatest cardiac depressant
effect and may decrease heart rate and cardiac
out put as well.
• The most important toxic effects for calcium
channel blockers are cardiac arrest, bradycardia,
atrioventricular block and congestive heart
failure.
 Lines of treatment of primary
hypertension
• The initial step in treating hypertension may
be non-pharmacologic. Dietary salt restriction
may be effective treatment for about half of
the patients with mild hypertension. Weight
reduction even without salt restriction
normalizes blood pressure in up to 70% of
obese patients with mild to moderate
hypertension. Regular exercise may also be
helpful in some hypertensive patients.
• When non-pharmacologic approaches do not
satisfactorily control blood pressure, drug
therapy begins in addition to
non-pharmacological approaches.
• The selection of drug(s) depends on various
factors such as the severity of hypertension,
patient factors (age, race, coexisting diseases,
etc.).
 • For most patients with mild hypertension and
some patients with moderate hypertension
monotherapy with either of the following
drugs can be sufficient.
✔ Thiazide diuretics
✔ Beta blockers
✔ Calcium channel blockers
✔ Angiotensin converting enzyme inhibitors
✔ Central sympathoplegic agents
• Beta-blockers are preferred in young patients,
high renin hypertension and patients with
tachycardia or angina and hypertension. Black
patients respond well to diuretics and calcium
channel blockers than to beta-blockers and
ACE inhibitors.
• If mono-therapy is unsuccessful, combination
of two drugs with different sites of action may
be used.
• Thiazide diuretics may be used in conjunction
with a beta-blocker, calcium channel blocker
or an angiotensin converting enzyme inhibitor.
• If hypertension is still not under control, a
third drug e.g. vasodilator such as hydralazine
may be combined.
• When three drugs are required, combining a
diuretic, a sympathoplegic agents or an ACE
inhibitor, and a direct vasodilator or calcium
channel block is effective.
• The treatment of hypertensive emergencies is
usually started with furosemide given by
parenteral route at dose of 20-40mg.
• In addition, parenteral use of sodium
nitroprusside, hydralazine, labetalol can be
indicated.
 II. Drug used in heart failure
• Congestive heart failure occurs when there is an
inability of the heart to maintain a cardiac out put
sufficient to meet the requirements of the
metabolizing tissues.
• Heart failure is usually caused by one of the
following: ƒ
▪ Ischaemic heart disease, ƒ
▪ Hypertension, ƒ
▪ Heart muscle disorders, and ƒ
▪ Valvular heart disease.
• Drugs used to treat heart failure can be
broadly divided into:
A. Drugs with positive inotropic effect.
B. Drugs without positive inotropic effect.
 A. Drugs with positive inotropic
effect:-
• Drugs with positive inotropic effect increase
the force of contraction of the heart muscle.
These include:
I. Cardiac glycosides,
II. Bipyridine derivatives,
III. Sympathomimetics, and
IV. Methylxanthines
 1. Cardiac glycosides
• Cardiac glycosides comprise a group of steroid
compounds that can increase cardiac out put
and alter the electrical functions.
• Commonly used cardiac glycosides are digoxin
and digitoxin.
• The mechanism of inotropic action of cardiac
glycosides is inhibition of the
membrane-bound Na+ /K+ ATPase often
called the “Sodium Pump”.
• This results in an increased intracellular
movement of sodium and accumulation of
sodium in the cells.
• As a consequence of the higher intracellular
sodium, decreased transmembrane exchange
of sodium and calcium will take place leading
to an increase in the intracellular calcium that
acts on contractile proteins.
 • All cardiac glycosides exhibit similar
pharmacodynamic properties but do differ in
their pharmacokinetic properties. For
example, digitoxin is more lipid soluble and
has long half-life than digoxin. Therapeutic
uses of cardiac glycosides include:
I. Congestive heart failure
II. Atrial fibrillation,
III. Atrial flutter, and
IV. Paroxysmal atrial tachycardia.
 • Toxicity of cardiac glycosides include:
✔ Gastrointestinal effects such as anorexia,
nausea, vomiting, diarrhoea
✔ Cardiac effects such as bradycardia, heart
block, arrhythmias
✔ CNS effects such as headache, malaise,
hallucinations, delirium, visual disturbances
(yellow vision)
• Mild toxicities such as gastrointestinal and
visual disturbance can be managed by
reducing the dose of the drug.
• For the management of arrhythmias or
serious toxicity, potassium supplementation,
administration of anti-arrhythmic drugs (e.g.
lidocaine).
 2. Bipyridine derivatives, e.g. amrinone,
milrinone.
• These drugs possess both positive inotropic
effect and vasodilator effects.
• Bipyridine derivatives are used in cases of
heart failure resistant to treatment with
cardiac glycosides and vasodilators.
 3. Beta - adrenergic stimulants e.g. dobutamine,
dopamine
• The increase in myocardial contractility by beta
stimulants increase the cardiac out put. However,
positive chronotropic effect of these agents
minimizes the benefit particularly in patients with
ischaemic heart disease.
• The positive inotropic effect of dobutamine is
proportionally greater than its effect on heart
rate.
• It is reserved for management of acute failure or
failure refractory to other oral agents.
 4. Methylxanthines
• Methylxanthines e.g. theophylline in the form
of aminophylline
• Aminophylline has a positive inotropic effect,
bronchodilating effect and a modest effect on
renal blood flow.
• It is used for management of acute left
ventricular failure or pulmonary edema
 B. Drugs without positive
inotropic effect.
• These include:
I. Diuretics, e.g. hydrochlorothiazide,
furosemide
II. Vasodilators, e.g. hydralazine, sodium
nitroprusside
III. Angiotensin converting enzyme inhibitors
e.g. captopril, enalapril
 III) Pharmacotherapy of Angina
pectoris
• Angina pectoris develops as a result of an
imbalance between the oxygen supply and the
oxygen demand of the myocardium. It is a
symptom of myocardial ischemia. When the
increase in coronary blood flow is unable to
match the increased oxygen demand, angina
develops. It has become apparent that spasm
of the coronary arteries is important in the
production of angina.
 • Drugs used in angina pectoris
I. Organic nitrates e.g. nitro-glycerine,
isosorbide dinitrate, etc.
II. Beta adrenergic blocking agents e.g.
propranolol, atenolol, etc.
III. Calcium channel blocking agents e.g.
verapamil, nifedipine, etc.
IV. Miscellaneous drugs e.g. aspirin, heparin,
dipyridamole.
 1. Organic nitrates:
• organic nitrates are potent vasodilators.
• Nitrates release nitric oxide which is a
powerful muscle relaxant, so they produce
vasodilation, decreases preload and after
load, reduce myocardial oxygen consumption .
• The action of nitrates begins after 2-3 minutes
when chewed or held under tongue and
action lasts for 2 hours.
• The onset of action and duration of action
differs for different nitrates and varying
pharmaceutical preparations.
• Adverse effects include: flushing, weakness,
dizziness, tachycardia, palpitation, vertigo,
sweating, syncope, localized burning with
sublingual preparation and contact dermatitis
with ointment.
• Therapeutic uses: prophylaxis and treatment
of angina pectoris, post myocardial infarction,,
acute LVF (left ventricle failure)
 2. Miscellaneous drugs,
• Miscellaneous drugs, e.g. Acetylsalicylic acid
Acetylsalicylic acid (aspirin) at low doses given
intermittently decreases the synthesis of
thromboxne A2 without drastically reducing
prostacylin synthesis.
• Thus, at the doses of 75 mg per day it can
produce antiplatelet activity and reduce the
risk of myocardial infarction in anginal
patients.