Antihypertensive Drugs

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.

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.

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.

• 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:

1. 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:

1. 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.

• 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.

• 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.

• Sympathoplegic agents (Depressants of sympathetic activity).

Based on the site or mechanism of action sympathoplegic drugs are divided into:

1. Centrally acting antihypertensive agents e.g. methyldopa, clonidine

Centrally acting sympathetic depressants act by stimulating a₂ – 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 a – 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).

• Adrenoceptor antagonists, e.g propranolol (beta blocker), prazosin (alpha blocker), labetalol (alpha and beta blocker).

b – 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.

• 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.

• 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.

• Ganglion blockers, e.g. trimethaphan

Trimethaphan is ganglion blocking drug which is reserved for use in hypertensive emergencies only.

• 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.

• 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.

• 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 mono- therapy 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.