Discuss the pharmacology of two classes of antihypertensive drugs.

Outline:

·        Role in hypertension.

·        Beta-blockers.

·        Alpha-blockers.

Suggested Answer:

Beta-blockers are commonly employed clinically as antihypertensives in the management of hypertension, usually in combination with a diuretic.

Beta-blockers selectively block the beta-receptor effects of noradrenaline and adrenaline. The cardiovascular effects of beta-adrenoceptor block depend on the amount of sympathetic tone present. The chief cardiac effects result from reduction of sympathetic drive are reduced automaticity (heart rate) and reduced myocardial contractility. With reduced rate the cardiac output / min is reduced and the overall cardiac oxygen consumption falls. It also decreases the velocity of conduction through the sinoatrial (SA) and atrioventricular (AV) nodes.

With acute administration of a pure beta-blocker, peripheral vascular resistance rises (as the alpha-adrenoceptor vasoconstrictor effects are no longer opposed by beta-adrenoceptor dilator effects). With long-term use the resting blood pressure falls because cardiac output falls and the normal physiological reflex response passes off. Most of the blood pressure effect occurs quickly (hours, days) but there is often a modest further decrease over several weeks. A substantial advantage of beta-blockade in hypertension is that physiological stresses such as exercise, upright posture and high environmental temperature are not accompanied by hypotension as they are with the agents that interfere with alpha-adrenoceptor-mediated homeostatic mechanisms.

First-order kinetics applies to elimination from plasma, but receptor block follows a zero-order decline. Most beta-adrenoceptor blockers can be given orally once daily in either ordinary or sustained-release formulations because the half-life of pharmacodynamic effect exceeds the elimination half-life of the substance in the blood. Lipid-soluble agents such as propranolol, labetalol and metoprolol are extensively metabolized (hydroxylated, conjugated) to water-soluble compounds that can be eliminated by the kidney. They are subject to hepatic first-pass metabolism after oral administration, especially propranolol (up to 80% metabolized). Lipid-soluble agents readily cross cell membranes into and inside the body, and so have a high apparent volume of distribution; they readily enter the CNS. Water-soluble agents such as atenolol and sotalol show more predictable plasma concentrations because they are less subject to liver metabolism, being excreted unchanged by the kidney; thus their half-lives are much prolonged in renal failure.

The most common adverse cardiovascular effect of propranolol is bradycardia, especially in patients with digitalis intoxication. Bradycardia is occasionally severe and may be accompanied by hypotension, syncope, shock, or angina pectoris. Severe bradycardia should be treated with IM or IV administration of atropine sulfate. In patients with congestive heart failure, sympathetic stimulation is vital for the support of circulatory function. In patients with inadequate cardiac function, congestive heart failure may be precipitated as a result of removal of beta-adrenergic stimulation when propranolol therapy is initiated. Adverse CNS effects usually occur after long-term treatment with high doses of propranolol and range from lightheadedness, giddiness, ataxia, dizziness, irritability, sleepiness, hearing loss, and visual disturbances to vivid dreams, hallucinations, and confusion. Insomnia, lassitude, weakness, fatigue, and mental depression progressing to catatonia have been reported. Adverse GI effects such as nausea, vomiting, diarrhea, epigastric distress, abdominal cramping, constipation, and flatulence may occur in patients receiving propranolol and occasionally necessitate reduction of dosage or withdrawal of the drug. Hypoglycaemia can occur, especially with non-selective members, which block beta2-receptors, and especially in diabetes and after substantial exercise, due to impairment of the normal sympathetic-mediated homeostatic mechanism for maintaining the blood glucose. Bronchoconstriction occurs, especially in asthmatics. In elderly chronic bronchitis there may be gradually increasing bronchoconstriction over weeks. Abrupt withdrawal of therapy can be dangerous in angina pectoris and after myocardial infarction and withdrawal should be gradual. It is inadvisable to initiate an alpha-blocker at the same time as withdrawing a beta-blocker in patients with ischaemic heart disease. Overdose, including self-poisoning, causes bradycardia, heart block, hypotension and low output cardiac failure that can proceed to cardiogenic shock. Rational treatment includes atropine, glucagon and isoprenaline.

Most NSAIDS attenuate the antihypertensive effect of beta-blockers due to inhibition of formation of renal vasodilator prostaglandins. Nonselective beta-blockers potentiate the hypoglycaemia of insulin and sulphonylurea and diminish the response to both the latter. Concurrent use with calcium channel blockers in a patient with heart disease can lead to bradycardia, heart block and cardiac failure. Severe hypertension may occur upon abrupt discontinuation of clonidine in patients receiving both clonidine and beta-blockers. Rifampicin is an enzyme inducer and may increase the metabolism of beta-blockers resulting in reduced clinical efficacy. Some beta-blockers like propranolol may inhibit the metabolism of warfarin leading to increased plasma concentrations of warfarin and consequent greater anticoagulant effect.

Besides hypertension, beta-blockers are also indicated in the treatment of angina pectoris by reducing cardiac work and oxygen consumption; cardiac tacydysrhythmias by reducing drive to cardiac pacemakers; myocardial infarction where it has ‘cardioprotective effect’ – early use within 6 hours of onset can reduce infarct size by up to 25% and protection against cardiac rupture. Beta-blockers are used in aortic dissection and after subarachnoid haemorrhage, hepatic portal hypertension and esophageal variceal bleeding, hyperthyroidism to reduce unpleasant symptoms of sympathetic overactivity, phaeochromocytoma and glaucoma by altering production and outflow of aqueous humor.

Alpha-blockers are the other class of drug used in hypertension of which the prototype is prazosin. Prazosin reduces peripheral vascular resistance and blood pressure as a result of its vasodilating effects; the drug produces both arterial and venous dilation. Prazosin’s effects appear to result principally from its selective, competitive inhibition of alpha₁-adrenergic receptors which mediate vasoconstriction. Prazosin reduces blood pressure in both supine and standing patients; the effect is most pronounced on diastolic blood pressure. The drug may cause postural hypotension. Prazosin generally causes no change in heart rate or cardiac output in the supine position. Cardiovascular responses to exercise (e.g., increased heart rate and cardiac output) are maintained during prazosin therapy.

Prazosin is well absorbed orally. It has an oral bioavailability of 60% and a half-life of 3h. It is widely distributed in body tissues and is metabolized extensively in the liver principally by demethylation and conjugation and excreted as unchanged drug and metabolites.

Within 2h of the first dose of prazosin, there may be brisk hypotension sufficient to cause loss of consciousness. Nausea, palpitation and dizziness are common adverse effects of prazosin. Other adverse effects reported to occur with prazosin include urinary frequency, incontinence, impotence, priapism, blurred vision, epistaxis, tinnitus, reddened sclera, dry mouth, nasal congestion, liver function test result abnormalities, pancreatitis, diaphoresis, fever and arthralgia.

Alpha-blockers have few drug interactions. Following the first dose of prazosin, compensatory tachycardia helps to prevent or limit syncope. Beta-blockers may inhibit this tachycardia, thereby worsening prazosin-induced hypotension. The bioavailability of prazosin and terazosin are increased in the presence of calcium channel blockers and these may potentiate the hypotensive effects of both drugs.