CARDIOVASCUL

AR DRUGS
Prepared by Joshua Gwaro
 Introduction
The most commonly encountered cardiovascular disorders
include;
• Hypertension,
• Congestive heart failure,
• Angina pectoris and
• Cardiac arrhythmias.
Most drugs available currently are able to reduce the
morbidity and mortality due to these disorders.
 Antihypertensive drugs
Hypertension is defined as an elevation of arterial blood pressure
above an arbitrarily defined normal value.
The American Heart Association defines hypertension as arterial blood
pressure higher than 140/90mmHg (based on three measurements at
different times).
Hypertension may be classified into three categories, according to the
level of diastolic blood pressure:
• Mild hypertension with a diastolic blood pressure between 95-105
mmHg
• Moderate hypertension with a diastolic blood pressure between 105
– 115mmHg
• Severe hypertension with a diastolic blood pressure above
• Sustained arterial hypertension damages blood vessels in
kidney, heart and brain and leads to an increased incidence
of renal failure, cardiac failure, and stroke.
• Effective pharmacologic lowering of blood pressure prevents
the damage to blood vessels and reduces the morbidity and
mortality rate.
• In order to understand the pathophysiology of hypertensive
states and, in turn, the underlying rationale of drug therapy,
an appreciation of the systems normally involved in
monitoring and regulating blood pressure is required.
• Two factors which determine blood pressure are cardiac
output (stroke volume x heart rate) and total peripheral
resistance of the vasculature.
• Blood pressure is regulated by an interaction between
nervous, endocrine and renal systems
• Elevated blood pressure is usually caused by a combination
of several abnormalities such as psychological stress, genetic
inheritance, environmental and dietary factors and others.
• Patients in whom no specific cause of hypertension can be
found are said to have essential hypertension or primary
hypertension (accounts for 80-90 % of cases).
• Secondary hypertension arises as a consequence of some
other conditions such as, atherosclerosis, renal disease,
endocrine diseases and others.
• The central issue of antihypertensive therapy is to lower
arterial blood pressure, irrespective of the cause.
• The choice of therapy of a patient with hypertension
depends on a variety of factors: age, sex, race, body build,
life-style of the patient, cause of the disease, other co-
existing disease, rapidity of onset and severity of
hypertension, and the presence or absence of other risk
factors for cardiovascular disease (e.g. smoking, alcohol
consumption, obesity, and personality type).
 Antihypertensive therapies.
1. Non pharmacological therapy of hypertension
Several non-pharmacological approaches to therapy of
hypertension are available. These include:
• Low sodium chloride diet
• Weight reduction
• Exercise
• Cessation of smoking
• Decrease in excessive consumption of alcohol
• Psychological methods (relaxation, meditation …etc)
• Dietary decrease in saturated fats.
• The sensitivity of patients differs to these non-
pharmacological approaches, but, on the average, only
modest reductions (5 to 10 mmHg) in blood pressure can be
achieved.
• This may be sufficient for the treatment of some mild
hypertensive cases.
• The major advantage of non-pharmacological approaches is
the relative safety and freedom from side effects, compared
with drug therapy.
2. Pharmacological therapy of hypertension.
• Most patients with hypertension require drug treatment to achieve
sustained reduction of blood pressure. Currently available drugs
lower blood pressure by decreasing either cardiac output (CO) or
total peripheral vascular resistance (PVR) or both although changes in
one can indirectly affect the other. However, physiological
mechanisms tend to oppose a drug – induced reduction of blood
pressure.
• Anti - hypertensive drugs are classified according to the principal
regulatory site or mechanism on which they act. They include:
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 include:
i) 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 (6-8 weeks), they decrease blood
pressure by decreasing peripheral vascular resistance as the
cardiac output 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.

ii) 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.
iii) 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 natriuretic 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:
i) Centrally acting antihypertensive agents e.g. methyldopa, clonidine
• Centrally acting sympathetic depressants act by stimulating α2-
receptors located in the vasomotor centre of the medulla. As a result,
sympathetic outflow from the medulla is diminished and either total
peripheral resistance or cardiac out put decreases.
• Methyldopa is useful in the treatment of 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).
ii) Adrenoceptor antagonists, e.g propranolol (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 output 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.

iii) Adrenergic neuron – blocking agents, e.g. guanethidine

• Guanethidine is an adrenergic neuron-blocking drug
recommended for treatment of severe forms of
hypertension.
• Guanethidine blocks adrenergic nerve transmission, preventing the
release of transmitter.
• It lowers blood pressure by reducing both cardiac output and total
peripheral resistance.
iv) Drugs which deplete catecholamine stores, e.g. reserpine.
• Reserpine interferes with the storage of endogenous
catecholamines in storage vesicles as a result of which little
neurotransmitter is released upon stimulation. It leads to reduction
of cardiac out put and peripheral vascular resistance. Reserpine is a
second-line drug for treatment of hypertension.
v) Ganglion blockers, e.g. trimethaphan
• Trimethaphan is ganglion blocking drug which is reserved for use in
hypertensive emergencies only.
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 metabolic acidosis,
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, 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 diazoxide, sodium
nitroprusside, hydralazine, trimethaphan, labetalol can be
indicated.