DRUGS USED IN HYPERTENSION

DRUGS USED IN HYPERTENSION

Hypertension is described as a persistent elevated rise in blood pressure. It is basically of two types, primary and secondary. The actual level of pressure that can be considered hypertensive is difficult to define; it depends on a number of factors, including the patient’s age, sex, race, and lifestyle. As a working definition, a diastolic pressure of 90 mm Hg or higher or a systolic pressure of 140 mm Hg or higher represents hypertension.

Hypertension is considered to be stage I, or mild, if diastolic pressure is 90 to 99 mm Hg and/or systolic pressure is 140 to 159 mm Hg. Stage II, or moderate, hypertension is diastolic pressure of l00 to 109 mm Hg and/or systolic pressure of 160 to 179 mm Hg. Stage III, or severe, hypertension exists when diastolic pressure is 110 mm Hg or greater and/or systolic pressure is 180 mm Hg or greater.

There are three general approaches to the pharmacological treatment of primary hypertension. The first involves the use of diuretics to reduce blood volume. The second employs drugs that interfere with the renin–angiotensin system, and the third is aimed at a drug-induced reduction in peripheral vascular resistance, cardiac output, or both. A reduction in peripheral vascular resistance can be achieved directly by relaxing vascular smooth muscle with drugs known as vasodilators or indirectly by modifying the activity of the sympathetic nervous system. Therefore, the classes of drugs used include the following:

·         Diuretics

·         Angiotensin converting enzyme inhibitors

·         Calcium channel blockers

·         Vasodilators

Drugs that impair sympathetic nervous system------ β-adrenoceptor antagonist, α-adrenoceptor antagonist, drugs that interfere with norepinephrine synthesis, release and storage.

Centrally acting sympathoplegics. Of the above drugs, first line regimen include the use of diuretics (thiazides in particular), ACEIs and β-adrenoceptor antagonists.

N.B  -- It should be noted that blood pressure is mathematically defined as the product of cardiac output and peripheral resistance i.e B.P = C.O × P.R . This informs the fact that any factor that either increases C.O or P.R or both will lead to an increase in blood pressure. Therefore, pharmacological therapy is usually directed towards the reduction / elimination of these factors.

Diuretics

The value of diuretics lies in their ability to reverse the Na_ retention commonly associated with many antihypertensive drugs that probably induce Na_ retention and fluid volume expansion as a compensatory response to blood pressure reduction. The type (s) of diuretics used include thiazides, loop diuretics and potassium sparing diuretics.

Angiotensin converting enzyme inhibitors

As discussed above, these drugs prevent the conversion of angiotensin I to angiotensin II ( a potent arterial vasoconstrictor which increases peripheral resistance) by blocking the activity of the enzyme, angiotensin converting enzyme. Therefore, the absence of adequate amounts of angiotensin II to stimulate increased peripheral resistance leads to reduced blood pressure. Examples already discussed above.

Calcium channel blockers

Also called calcium entry blockers, the available Ca²⁺ channel blockers exert their effects primarily at voltage-gated Ca²⁺ channels of the plasma membrane. It should be recalled that Ca²⁺  influx occurs during membrane  depolarisation, making Ca²⁺  ion a very important ion and second messenger that underlies the process of excitation- contraction coupling in the cardiovascular system. Calcium currents in cardiac tissues serve the functions of inotropy, pacemaker activity (sinoatrial (SA) node), and conduction at the atrioventricular (A-V) node. In essence, calcium channel blockers prevents influx of Ca²⁺ into the myocardial cells leading to slowing of the heart rate, strong depression of conduction at the A-V node, and inhibition of contractility.

These drugs also exert vascular effects. Vascular tone and contraction are determined largely by the availability of calcium from extracellular sources (influx via calcium channels) or intracellular stores.

Drug-induced inhibition of calcium influx via voltagegated channels results in widespread dilation and a decrease in contractile responses to stimulatory agents. Ingeneral, arteries and arterioles are more sensitive tothe relaxant actions of these drugs than are the veins.

Examples include nifedipine and its analogues( e.g amlodipine, isradipine, felodipin), verapamil and diltiazem.

NIFEDIPINE

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VERAPAMIL

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Vasodilators

These drugs produce a direct relaxation of vascular smooth muscle and thereby their actions result in vasodilation. This effect is called direct because it does not depend on the innervation of vascular smooth muscle and is not mediated by receptors, such as adrenoceptors, cholinoreceptors, that are acted on by classical transmitters and mediators such as norepinephrine and acetylcholine. The vasodilators decrease total peripheral resistance and thus correct the hemodynamic abnormality that is responsible for the elevated blood pressure in primary hypertension. In addition, because they act directly on vascular smooth muscle, the vasodilators are effective in lowering blood pressure, regardless of the etiology of the hypertension. Unlike many other antihypertensive agents, the vasodilators do not inhibit the activity of the sympathetic nervous system; therefore, orthostatic hypotension and impotence are not problems. Also, they mediate decreased preload and afterload as discussed above.

However, the lack of sympathetic nervous system inhibition produced by the vasodilators, which is advantageous in some ways ( absence of orthostatic hypotension and impotence), can also be a disadvantage in that reflex increases in sympathetic nerve activity will lead to hemodynamic changes that reduce the effectiveness of the drugs. Therefore, the vasodilators are generally inadequate as the sole therapy for hypertension. However, many of the factors that limit the usefulness of the vasodilators can be obviated when they are administered in combination with a β-adrenoceptor antagonist, such as propranolol, and a diuretic. Propranolol reduces the cardiac stimulation that occurs in response to increases in sympathetic nervous activity, and the large increase in cardiac output caused by the vasodilators will be reduced. Propranolol also reduces plasma renin levels, and that is an additional benefit. The reduction in Na⁺ excretion and the increase in plasma volume that occurs with vasodilator therapy can be reduced by concomitant treatment with a diuretic.

Examples of vasodilators include hydralazine and minoxidil ( both are effective when administered orally) and are used for the chronic treatment of primary hypertension. Other drugs, diazoxide and sodium nitroprusside, are effective only when administered intravenously. They are generally used in the treatment of hypertensive emergencies or during surgery. All these drugs exert their effect primarily on arteries/arterioles except sodium nitroprusside  which exerts its effect on arteries and  veins.

SODIUM NITROPRUSSIDE

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Drugs that impair sympathetic nervous system

β-adrenoceptor antagonist – Discussed above

α-adrenoceptor antagonist- Examples include phenoxybenzamine, phentolamine, doxazosin and prazosin. These drugs block α-adrenoceptors on cardiac and smooth muscle thereby preventing norepinephrine from stimulating these receptors, the resultant effect of which is reduced blood pressure.

Drugs that interfere with norepinephrine storage e.g reserpine. Reserpine is the prototypical drug interfering with norepinephrine storage. Reserpine lowers blood pressure by reducing norepinephrine concentrations in the noradrenergic nerves in such a way that less norepinephrine is released during neuron activation.

Drugs that interfere with norepinephrine release. Also called adrenergic neuron-blocking drugs, these drugs are antihypertensives because they prevent the release of transmitters from peripheral postganglionic sympathetic nerves. The contraction of vascular smooth muscle due to sympathetic nerve stimulation is thereby reduced, and blood pressure decreases. Guanethidine is the prototypical member of this class.

Drugs that interfere with norepinephrine synthesis. Metyrosine is an example of this class of drugs. Chemically, metyrosine is α-methyl tyrosine. The drug blocks the action of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. The ultimate action of the drug is to decrease the production of catecholamines.

Centrally acting sympathoplegics.

Two important antihypertensive agents, α-methyldopa and clonidine, act predominantly in the brain. Although the details of their actions may differ in some respects, their antihypertensive activity is ultimately due to their ability to decrease the sympathetic outflow from the brain to the cardiovascular system.

           

α-METHYLDOPA

Current evidence suggests that for α-methyldopa to be an antihypertensive agent, it must be converted to α-methylnorepinephrine; however, its primary site of action appears to be in the brain rather than or to a lesser extent, in the periphery. Systemically administered α-methyldopa rapidly enters the brain, where it accumulates in noradrenergic nerves, is converted to α-methylnorepinephrine, and is released. Released α-methylnorepinephrine activates CNS α- adrenoceptors whose function is to decrease sympathetic outflow.

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