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Abstract

Hypertension remains one of the most comm only prevalent disease world wide. The physicians’ attitude towards raised blood pressure levels has changed progressively over the past two decades with growing awareness of the risks associated with even relatively minor increase in arterial pressures and the development of more acceptable and safe antthypertensive drugs.
Antihypertensive treatment like all other fields of cardiovascular medicine has undergone significant advancement in the past few years.
Since the introduction of drug therapy for hypertension several drugs have become obsolete. Alpha methyl dope was the major drug until recently. Then came the Beta adrenocepter blockers, vasodilators and more recently, angio. tensin converting enzyme inhibitors and calcium channel entry blockers. Thiazide diuretics have, however, remained a viable group throughout. The physician has a wide range of agents to choose for a particular patient situation. Useful combination therapies have emerged to deal with refractory, severe, accelerated/malignant hyperten­sion and the hypertensive emergencies. There is good evidence to suggest that effective blood pressure control has resulted in the decline of its complications.
The advent of calcium channel blockers for the control of hypertension has gained a lot of interest in the last few years. Today three pharmacological agents representing three classes
of calcium channel blockers are commercially available i.e.,Nifedipine, Verapamil and Diltiazem which are in use in USA and UK and available in Pakistan as well.
Belonging to same therapeutic group, the three have differences in their mechanism of action and clinical application. With the passage of time our understanding of their mechanism of action has improved and a number of new indi­cations for their use have emerged. In this article it is proposed to discuss the use of Calcium Blockers in hypertension.
MECHANISM OF ACTION
Ca+ + transport in the cardiovascular smooth muscles has three possible sites. The main pathway is perhaps the so called voltage dependent channel, controlled by a “gate “ that opens and closes in response to voltage gradient. Ca blockers close this gate and thus inhibit the entry of extra cellular Ca++ into this channel. This blockage results in the reduction of available Ca for contractile processes. Besides inhibiting the intracellular entry of Ca ions they also inhibit the rate of Ca binding1.
The second pathway is the Receptor Dependent Channel, normally activated by alpha agonist Norepinephrine and angiotensin and related endogenous substances. On interaction of agonist with the receptor this channel is opened and the extracellular Ca enters into the cells. This channel activation also mobilizes Ca from the inactive intracellular stores.
By their competitive blockade of the effects of Norepinephrine by an action on alpha adrenergic receptors some Ca blockers may block the receptor dependent channel2.
The third pathway is dependent on Na — Ca exchange across the cell membrane. This pathway is (somewhat) indirectly affected. The Ca blockers block the entry of ionic Calcium into the cells. This impedes the role of Ca as intracellular ionic messenger which initiates Na - Ca exchange. These drugs do not antagonize the effects of Ca; they merely prevent the ions from entering the intracellular site of action. Hence Ca channel blockers is the preferred term over Ca antagonist3. As mentioned earlier despite common biological and pharmacological properties there exist notable differences in the mechanism of action of three sub groups of Ca blockers. The three groups include Diphenyl alkylamines, Benzothia­zepines and Dihydropyridines represented commercially by Verapamil, Diltiazem and Nifedi. pine respectively.
It has been postulated that three specific receptor sites exist one each for Nifedipine, VerapLmil and Diltiazem.