In this essay we will discuss about the drugs used for the treatment of hypertension.
Thiazide diuretics in low doses (e.g. 2.5 mg bendrofluazide) produce a maximal or near maximal blood pressure lowering effect, with very little metabolic disturbances and are considered to be the drugs of first choice because of their safety and benefit in reducing the incidence of stroke and cardiovascular events. Thiazides are particularly effective in elderly patients for whom they remain the drugs of choice.
The fall in blood pressure is due to a reduction in blood volume, natriuretic and mild vasodilatation by inhibiting sodium entry in the vascular smooth muscle cells. Indapamide in particular has a pronounced vasodilating effect. Diuretics are more effective than α adrenergic antagonist (doxazosin) in the treatment of hypertension. The only compelling contraindication to thiazides is gout.
b. β Blockers:
All β blockers are effective antihypertensive agents and are part of medical regimens that has been proven to decrease the incidence of stroke, myocardial infarction and heart failure. There mode of action is not clearly understood, but several factors probably play a role in their overall hypotensive effects which includes, decrease in heart rate, alteration of baroreceptor reflex sensitivity, reduction in plasma renin and aldosterone activity, decrease in plasma volume, release of vasodilatory prostaglandins, and probably a CNS-mediated antihypertensive effect.
β blockers are very suitable antihypertensive drugs in myocardial infarction and angina. Cardio-selective β blockers, e.g. atenolol, metoprolol and acebutolol are commonly used. β blockers are contraindicated in bronchial asthma, chronic obstructive pulmonary disease and heart block.
c. ACE Inhibitors:
ACE inhibitors are considered to be the drugs of choice for hypertension when diuretics and β blockers are contraindicated or fail to control blood pressure. Unlike β blockers, ACE inhibitors improve the “quality of life” and do not interfere with the patient’s lifestyle.
An ACE inhibitor can be used as a single drug to lower blood pressure or combined with other hypotensive drugs such as diuretics where it can reduce hypokalemia, hypercholesterolemia, hyperglycemia and hyperuricemia caused by diuretic therapy. Long acting ACE inhibitors such as enalapril, fosinopril, ramipril are prodrugs and have the advantage of single dose administration.
As antihypertensives, the compelling indications of ACE inhibitors are heart failure, left ventricular dysfunction and diabetic nephropathy. They are absolutely contraindicated in renovascular disease and pregnancy.
Angiotensin-II receptor antagonists (losartan and valsartan) do not inhibit the breakdown of bradykinin and thus do not appear to cause the persistent dry cough or angioedema which complicates ACE inhibitor therapy. Angiotensin II receptor antagonists are only indicated in patients who are intolerant to ACE inhibitors.
d. Calcium Antagonists:
Calcium channel blocking drugs are effective agents in the treatment of hypertension, particularly in patients with coexistent angina pectoris or in isolated systolic hypertension in the elderly, when a low dose thiazide is contraindicated or not tolerated.
The dihydropyridine group of calcium antagonists is used for the treatment of hypertension and amongst them the choice lies with newer second generation drugs like amlodipine, felodipine, isradipine and lacidipine, which are more Vaso-selective and have longer half-life requiring single dose administration. Calcium antagonists should not be used in heart failure and heart block.
e. α1 Blockers:
Prazosin, doxazosin and terazosin have a selective postsynaptic α1 adrenergic receptor blocking property and cause vasodilatation of both the arteries and veins. These drugs cause a fall of blood pressure with very little compensatory rise in pulse rate or cardiac output. Unlike β blockers, these drugs do not adversely affect insulin sensitivity or blood lipids and can improve the negative effects on lipids induced by thiazides and β blockers.
α1 blockers are less effective than first-line antihypertensive drugs, when used as mono-therapy. They may be used with other antihypertensive drugs in the treatment of mild to moderate hypertension, but cause postural hypotension.
α1blockers also relax smooth muscle tone in the bladder neck, prostatic capsule and prostatic urethra and are used for benign prostatic hyperplasia, but may cause urinary incontinence, particularly in women. Side effects of α1 blockers include ‘first dose effect’ (increased fall in blood pressure, syncope, dizziness and headache), which are self-limited and do not occur with continued therapy.
f. Centrally Acting Sympatholytics:
These are potent antihypertensive agents that act by stimulating the presynaptic α2 adrenergic receptors in the CNS. This simulation leads to a decrease in peripheral sympathetic tone, which reduces systemic vascular resistance. Also, it causes a modest decrease in cardiac output and heart rate.
The only indication of methyldopa is in the treatment of pregnancy-related hypertension, where it serves as first-line therapy because of its proven safety. Other commonly used antihypertensive drugs in pregnancy carry the risk of fetal morbidity or mortality. Hydralazine, a direct-acting vasodilator, is an alternative agent, and both of these drugs can be given IV for treatment of eclampsia.
Side effects include drowsiness, dry mouth, postural hypotension and sexual dysfunction. Rarely, it may cause hemolytic anemia and hepatitis. Clonidine is another centrally acting sympatholytic, which is mainly used to prevent the rise of noradrenalin in the brain that occurs during the withdrawal of opioids and accounts for the withdrawal symptoms during treatment of opioid addiction.
g. Direct-Acting Vasodilators:
These are potent antihypertensive agents that act by causing dilation of the arterioles, but not of veins and are reserved for refractory hypertension. They cause salt and water retention and reflex sympathetic stimulation of heart. Therefore, treatment with direct- acting vasodilators is always combined with a diuretic and β blocker.
These drugs should be used with caution or avoided in patients with ischemic heart disease because of the reflex sympathetic hyperactivity, which may precipitate angina or ischemic arrhythmias. Hydralazine has been largely replaced by other safer hypotensive drugs, but is still used in serious hypertension during pregnancy.
The disadvantages of hydralazine include:
i. Tachyphylaxis limits the sole use of the drug
ii. Rapidly metabolised during first pass metabolism leading to considerable reduction of its bioavailability
iii. Adverse effects, which include peripheral neuropathy, arthralgia, myalgia, and development of a lupus-like syndrome.
Minoxidil is a potent direct vasodilator, but rarely used because of potentially serious adverse effects, which include weight gain, hypertrichosis, hirsutism, ECG abnormalities, and pericardial effiisions. Topical preparations of minoxidil have been used to stimulate scalp hair growth in baldness.
h. Parenteral Antihypertensive Agents:
These are indicated for the immediate reduction of blood pressure in patients with hypertensive emergencies. Great care must be taken when lowering a very high blood pressure, as a precipitate fall may cause renal failure or cerebral damage due to a sudden reduction in the blood supply to the kidney and brain.
The aim of treatment should be to reduce the diastolic blood pressure slowly to around 100 mm Hg. Patients should be monitored very closely to avoid an exaggerated hypotensive response.
Sodium nitroprusside, a direct-acting arterial and venous vasodilator, is the drug of choice. It reduces blood pressure rapidly and is easily titratable, and its action is short lived when discontinued. It may cause nausea and vomiting. In presence of renal and hepatic insufficiency, it carries the risk of thiocyanate and cyanide toxicity.
A large number of other drugs are available for IV administration either as a bolus or by infusion and include nitroglycerin, labetalol, esmolol, nicardipine, enalapril, diazoxide and hydralazine; the choice of the drug must be individualized.
a. Antihypertensive regimen should include a low dose thiazide diuretic or at least a low-sodium diet.
b. Antihypertensive therapy should include at least two medications of different classes for mild hypertension and three or four different medication for more difficult and severe cases.