a. General consideration:-
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 in to 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 115mmHg.
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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 out put (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).
b. Antihypertensive therapies.
- 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
53 - 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.
- 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:
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.
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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 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:
a) 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 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 hypersensitivety
reactions (fever, liver damage, thrombocytopenia).
b) 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 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.
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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) 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 out put and total peripheral resistance.
d) 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.
e) 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.
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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
57 - 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.
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