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Anti-hypertensive agents

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Hypertension is usually asymptomatic. Although there is no cause for primary hypertension, in blacks, it has been found to be due to volume overload (hence, treatment is usually started with diuretics) and due to dysregulation of RAAS in Caucasians (hence, treatment is usually started with ACE inhibitors). Usually, hypertension is treated using combination therapy. Hypertension is a life-long condition except in secondary hypertension where when the cause is treated, the consequent hypertension is resolved. Habits, diet, civilisation and social behaviours/ status are implicated in hypertension. Salt consumption is also widely implicated in hypertension. Exogenous use of steroids, hyperaldosteronism, Cushing's syndrome, pheochromocytoma, renal vascular diseases are all causes of secondary hypertension (1 in 5)


There are four broad classes of anti-hypertensive agents

  1. Diuretics: they lower blood pressure by depleting body sodium and reducing blood volume
  2. Sympathoplegic agents: they reduce peripheral vascular resistance, inhibit cardiac function and increase venous pooling in capacitance vessels (veins).
  3. Vasodilators: they relax vascular smooth muscles thus dilating resistant vessels. They may also increase capacitance vessels too.
  4. Agents that block the production or action of angiotensing. ACE inhibitors (prevent conversion of angiotensin I to angiotensin II) and angiotensin receptor blockers.

Agents that alter sodium and water balance (Diuretics)

Diuretics generally lower blood pressure primarily by depleting the body 's sodium store. They have been found to also reduce the blood volume and cardiac output, but peripheral vascular resistance may increase. After 6-8 weeks of administration, cardiac output returns to normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity and this is assumed to be due to sodium-calcium exchange with a resultant increase in intracellular calcium. All of these effects can be reversed by sodium restriction or the use of diuretics.

Diuretics lower blood pressure by 10-15mmHg in most patients and so provide adequate treatment in mild to moderate essential hypertension, but in severe hypertension, they may need to be combined with other agents like vasodilators.


It is preferred to other diuretics because of evidences that abound that it improves and provides 24hr coverage for blood pressure control and also reduces cardiovascular events e.g. cardiac failure, left ventricular failure, etc. More powerful diuretics like the loop diuretics are reserved for use in severe hypertension.

Potassium sparing diuretics

They are useful both to avoid excessive potassium depletion and to enhance the natriuretic effect of other diuretics.

Side effects

The most common side effect of diuretics in the management of hypertension is potassium depletion except in the potassium sparing ones. Hypokalemia is dangerous in individuals taking digitalis, individuals with chronic arrhythmias, left ventricular failure and acute myocardial infarction. They may also cause magnesium depletion, impairment of glucose tolerance, increase serum lipid concentration and increase uric acid concentration and thus may precipitate gout. The use of low dose diuretics minimises all of these effects without impairing their antihypertensive property. It should be noted that potassium sparing agents may produce hyperkalemia particularly in patients with renal insufficiency or those taking Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers. Spironolactone is a steroid and it can cause gynaecomastia.

Those that alter sympathetic nervous system function (symphathoplegic agents)

1. Centrally acting sympathoplegic drugs

E.g. alpha-methyl dopa and clonidine. They reduce sympathetic outflow from the vasomotor center in the brain-stem.

Alpha-methyl dopa is an analogue of L-dopa and it is converted to alpha-methyl dopamine and alpha-methyl norepinephrine. This conversion is similar to the one seen in the synthesis of norepinephrine from dopa. It is stored in adrenergic vesicles and is released on nerve stimulation to interact with postsynaptic receptors. It serves as a false neurotransmitter in peripheral neurons. Its antihypertensive effect is due to stimulation of alpha adrenoceptors by alpha-methyl norepinephrine or alpha-methyl dopamine.

Clonidine is a 2-imidazole derivative and its antihypertensive effect was discovered when it was being used as a nasal decongestant. It produces a brief rise in blood pressure after intravenous injection and this is followed by a more prolonged hypotension. The pressor response is due to direct stimulation of alpha-receptors in the arterioles. It is classified as a partial agonist at alphareceptors because it also inhibits pressor effects of other alpha agonists. It reduces sympathetic and increases parasympathetic tone resulting in lowering of blood pressure and bradycardia. Other agents in this class include guanabenz, guanfacine

Methyl dopa

It was a popular antihypertensive but now primarily limited to treating hypertension in pregnancy. It lowers blood pressure by reducing peripheral vascular resistance with a variable reduction in heart rate and cardiac output. Most cardiovascular reflexes are unaffected and blood pressure reduction is not dependent on the posture even though postural or orthostatic hypotension may occur particularly in volume depleted patients. One of its notable advantage is that it causes reduction in renal vascular resistance.


It enters the brain via an aromatic amino acid transporter. In usual doses, it produces maximum antihypertensive effects in 4-6 hours and this effect can last up to 24 hours. The effect depends on accumulation and storage of its metabolite in the vesicles on nerve endings and the effects may persist after the parent drug has disappeared from the circulation.

Side effects

Sedation, particularly during the initiation of treatment. Others include nightmares, depression, vertigo, extrapyramidal side effects, lactation (occurs in both men and women due to inhibition of dopaminergic mechanisms in the hypothalamus), development of positive coomb's test (occurs in 10-20% of patients undergoing therapy for more than 12 months), hemolytic anemia, hepatitis and drug fever. Discontinuation of this drug results in prompt reversal of all the mentioned toxicities.


It lowers blood pressure by reduction in cardiac output due to a decrease in heart rate and relaxation of capacitance vessels. It has also been noted to decrease peripheral vascular resistance. Reduction in arterial blood pressure is accomplished by decreased renal vascular resistance and maintenance of renal blood flow. There are secondary causes of hypertension that are congenital diseases e.g. renal artery stenosis and coarctation of the aorta. It reduces renal blood pressure in the supine position and rarely causes postural hypotension.

Side effects

Dry mouth and sedation. Both side effects are centrally mediated and dose-dependent. It also causes depression and thus should not be given to patients with depressive episodes. Its concomitant use with tricyclic antidepressants (TCAs) may block its antihypertensive effects. This effect is believed to be due to alpha adrenergic blocking action of TCAs. Withdrawal of clonidine after use, particularly protracted use, can result in life threatening hypertensive crisis which is mediated by increased sympathetic nervous activity.

2. Ganglion blockers

Ganglion blockers competitively block nicotinic cholinoceptors on post-ganglionic neurons in both sympathetic and parasympathetic ganglia. They use to be first line agents in the treatment of hypertension but are no longer available for clinical use because of their intolerable toxicities. Their toxicities are direct extension of their pharmacologic effects. These effects include sympathoplegic effects (excessive orthostatic hypotension, sexual dysfunction) and parasypathoplegic effects (urinary retention, constipation, precipitation of glaucoma, blurry vision and dry mouth).

3. Adrenergic neuron blockers

They produce their blood lowering effects by preventing physiologic release of norepinephrine from post-ganglionic sympathetic neurones e.g. guanethidine: it produces all the toxic effects seen in pharmacologic sympathectomy which include marked postural hypotension, diarrhoea and impaired ejaculation and because of these effects, they are rarely used in clinical practice. They are polar agents and do not cross into the central nervous system meaning that they do not have the central effects seen with many other antihypertensives. Other examples include guanadrel, bethanidine, debrisoquin

Mechanism of action

Guanethidine inhibits release of norepinephrine from sympathetic nerve endings and this effect is responsible for the sympathoplegia that is seen in patients. It has a long half-life (about 5-days). The onset of sympathoplegia is gradual but maximum in one to two weeks and persists for a considerable period after cessation of treatment.

Side effects

Guanethidine is notorious for causing postural hypotension and hypotension following exercise. Sympathoplegia induced by guanethidine in men has been associated with delay or retrograde ejaculation. They also cause diarrhoea and this results from increased GI motility. They can also produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma. When it is co-administered with TCAs, the antihypertensive effect is attenuated and this can lead to hypertensive crisis.

4. Adrenoceptor antagonists (beta blockers)

These drugs are generally effective in lowering elevated blood pressure e.g. propanolol: it was the first beta blocker to be shown as being effective in hypertension and ischemic heart disease, but it has largely been replaced by cardio-selective beta blockers like metoprolol and atenolol. They are useful in lowering blood pressure in individuals with mild to moderate systemic hypertension. In severe hypertension, beta blockers are used to prevent reflex tachycardia that results from treatment with direct vasodilators. They also reduce mortality in patients that suffer myocardial infarction and also in some that suffer heart failure. They decrease cardiac output and these effects have also been found to result in a reduction in blood pressure. Propanolol inhibits the stimulation of renin production so its effect also includes in part, depression of RAAS. Resting bradycardia and reduction in heart rate during exercise are indicators of propanolol's beta blocking effect and changes in these parameters may be used as a guide for regulating dosage (popular ward round question). Other examples include nadolol & carteolol (non-selective beta blockers. They are not appreciably metabolized and are excreted in a considerable amount in urine) betaxolol & bisoprolol (beta-1 selective blockers also metabolized in the liver and have long half-lives that permit once daily administration). Acebutolol & penbutolol are partial agonists that block beta receptors with some intrinsic sympathomimetic activity. Labetalol, carvedilol and nebivolol (beta blockers with vasodilating effect); labetalol can be given as a repeated IV injection to treat hypertensive emergencies (severely elevated blood pressure with evidence of end-organ damage; bring down blood pressure quickly. In hypertensive urgency, there is no end-organ damage so blood pressure is reduced gradually over days). They can also be used in treating hypertension from pheochromocytoma.

5. Alpha blockers

E.g. prazosin, terazosin and doxazosin. They produce their effects by selectively blocking alpha 1 receptors in the arterioles and venules. They produce less reflex tachycardia.


They are metabolized in the liver, but undergo little or no first pass metabolism with a half-life of about 12 hours. Doxazosin has an intermediate bioavailability with a half-life of about 22 hours. Long term treatment with alpha blockers causes postural hypotension and in some patients, this can be dangerous. For this reason, the first dose should be small and given at bed-time. Others include phentolamine and phenoxybenzamine which are used in the treatment and diagnosis of pheochromocytomas.


E.g. Hydralazine, minoxidil. Both are oral vasodilators and they are used in long term outpatient treatment of hypertension. The parenteral vasodilators include nitroprusside and fenoldopam which are used in the treatment of hypertensive emergencies (cyanide toxicity is a side effect of nitroprusside administration). The nitrates are also potent vasodilators that can be used in the management of ischemic heart disease and sometimes in hypertensive emergencies. Oral vasodilators are useful in hypertension because they relax smooth muscles of arterioles thereby decreasing systemic vascular resistance. Sodium nitroprusside and the nitrates also relax the veins.


It dilates arterioles but not veins (T/F). It are not particularly effective because of tachyphylaxis to the antihypertensive effect and this develops rapidly.  Hydralazine is currently used only in patients with eclampsia or pre-eclampsia or in patients with renal defects. It is well absorbed where administered orally and rapidly metabolized in the liver due to first pass effect so the bioavailability is low (25%) and this usually varies among individuals. Metabolism in the liver is in part by acetylation; as a result of this, rapid acetylators have a greater first pass effect and this lowers the blood levels of the drug resulting in less antihypertensive benefit from a given dose than slow acetylators (this condition is genetically determined). In rapid acetylators, the drug can be completely metabolized.

Side effects

Headache, nausea, anorexia, palpitations, sweating and flushing. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation will provoke angina and ischemic arrythmias. Patients who are slow acetylators may develop a syndrome characterised by arthralgia, myalgia, skin rashes and fever and this is called lupus erythematosus-like syndrome; this syndrome is not associated with renal damage and is reversed by discontinuation of hydralazine. Other side effects include peripheral neuropathy and drug fever.