L-Type Calcium Channels for the Treatment of Hypertension - Case Study Example

Why are L-type calcium channels valid targets for the treatment of hypertension? Hypertension is a common problem world wide with devastating complications. Several classes of antihypertensives are available for use and they include ACE inhibitors, thiazide diuretics, beta blockers, angiotensin II receptor antagonists and calcium channel blockers. Which is the most ideal antihypertensive agent has been the subject of several large studies and to date, no ideal antihypertensive agent has been declared. The main goal of antihypertensive therapy is to decrease the risk of endpoints of hypertension, namely stroke, heart failure and myocardial ischemia. The type of medication administered depends on the age of the person and comorbid conditions. Other influencing factors include cost of medicines and tolerance to medications. For several years, L-calcium channel blockers have been the first line antihypertensive drugs for hypertensive patients (Klabunde, 2008). Calcium channel blockers are those drugs which prevent the entry of calcium into the cells of the heart and the blood vessels. By doing so, the muscles of the heart and blood vessels relax, resulting in dilatation of blood vessels and lowering of blood pressure. Some calcium channel blockers cause decrease the heart rate, thus further reducing the blood pressure. Calcium channel blockers not only reduce blood pressure, but also relieve angina and irregular heart beat. The calcium channel blockers which are currently approved bind to the L-type calcium channels that are located on the cardiac myocytes, vascular smooth muscle and cardiac nodal tissue, the atrioventricular and sinoatrial nodes. The channels regulate the influx of calcium into the muscle cells and in turn stimulate the contraction of the smooth muscles and the cardiac myocyte. In the nodal tissues of the heart, the L-type channels have major role to play in the pacemaker currents and in the phase 0 of action potentials. Thus, blocking of calcium entry into the cells causes vasodilation, negative ionotropy, negative dromotropy at the atrioventricular node, and negative chronotropy (Klabunde, 2008). Calcium channels are voltage dependent and opening of these channels permits influx of the calcium ions across the plasma membrane, thus triggering various physiological processes. The channels are distributed widely in the cardiovascular system, constituting main routes for entry of the calcium ions essential for excitation and contraction. In this regard, as of now, ten unique alpha-1 subunits have been identified and these are groups in 3 families: CaV1, CaV2, and CaV3. These encode the low-voltage–activated T-type and the high-voltage–activated L-, N-, P/Q- and R-type Ca2+ channels (Ge and Ren, 2009). The most common of these are the L-type and they are abundant in the peripheral vasculature and heart, constituting preferred target for initial calcium channel antagonists in antihypertensive treatment. T-channels are present in various cells like cardiomyocytes, neurons, endocrine cells and vascular smooth muscle cells. They have a role in several physiological processes (Ge and Ren, 2009). There is some evidence that T-channel blockade also is useful in the management of hypertension. The drugs developed for this purpose are dihydropyridines like benidipine, efonidipine, nilvadipine, manidipine and benzimidazole mibefradil (Ge and Ren, 2009). These drugs have vasodilatory properties similar to L-channel blockers and some of them may antagonise both L-channels and T-channels. However, there is yet uncertainity about the exact role of T-channel blockers in controlling vascular tone and decreasing hypertension (Toba et al, 2011). There are basically 3 classes of calcium channel blockers and they are: 1. Dihydropyridines: These are selective to smooth muscles of the blood vessels. Hence, they are mainly used to decrease systemic vascular resistance and arterial pressure. They are also primarily used to treat hypertension. They are not useful in the treatment of angina because reflex cardiac stimulation can occur due to their powerful systemic vasodilation and this can lead to increased myocardial oxygen demand and worsen angina. Eamples of dihydropyridines are nifedipine, nicardipine, amlodipine, felodipine, isradipine, nitrendipine and nimodipine. 2. Phenylalkylamines: These drugs are selective for myocardium. They do not have systemic action. The drug belonging to this category is verapamil. It reduces the myocardial oxygen demand and causes reversal of coronary vasospasm. Hence it is very useful in treating angina and arrhythmias. It is not useful for hypertension. 3. Benzothiazepines. The drug belonging to this group is diltiazem. It has both vasodilator acitions and cardiac depression actions. It decreases arterial pressure without causing much reflex cardiac stimulation. Of these, dihydropyridines are the most commonly used drugs for hypertension. These drugs are associated with some side effects which are tolerable, like head ache, flushing, excessive hypotension, reflex tachycardia and edema. It is yet unclear whether L-channel blockers are the best way to decrease the risk of adverse cardiac events. According to a study by Chen et al (2011) published in the cochrane database, calcium channel blockers are as effective as other classes of antihypertensives in decreasing blood pressure. However, diuretics seem to be better in terms of reducing the risk of cardiac events. The authors of the study concluded that for optimization of cardiovascular events, diuretics are thr first line antihypertensive agents. The review however does not distinguish between calcium channel blockers and diuretics and supports the use of calcium channel blockers over beta-blockers. According to the recent cochrane review (Wright and Musini, 2009), thiazide diuretics are the first line drugs for antihypertensive management. Other than L-calcium channel blockers, currently, combined L-/T-type Ca2+ channel blockers are also available and have been found to inhibit contraction in small vessels when compared to L-type Ca2+ channel blockers alone. Microvessels have an important role in blood pressure regulation, perfusion of the kidneys and coronary blood flow. Thus, combined channel blockage may provide addition benefits with regard to cardiovascular and renal diseases beyond the primary antihypertensive effects of L-type calcium channels. There is also evidence to suggest that L-/T-type Ca2+ blockers are superior to L-type Ca2+ channel blockers alone in kidney microcirculation. This is because; L-channel blocker causes only afferent arterioles dilation and not dilation of efferent arterioles, resulting in glomerular hypertension. On the contrary, combined L-/T-type Ca2+ channel blockers like mibefradil and efonidipine dilate both the arterioles and thus are renal protective (Ge and Ren, 2009). Based on the above discussion, L-channel blockers are ideal for antihypertensive management because of their efficacy in preventing cardiovascular complications, but as of now, thiazide diuretics are the first line drugs for hypertension. References Chen, N., Zhou, M., Yang, M., et al. (2010). Calcium channel blockers versus other classes of drugs for hypertension. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD003654. Ge, W., and Ren, J. (2009). Combined L-/T-Type Calcium Channel Blockers. Hypertension, 53, 592. Klabunde, R.E. (2008). Calcium-Channel Blockers. Cardiovascular Pharmacology Concepts. Retrieved from http://www.cvpharmacology.com/vasodilator/CCB.htm Toba, H., Yoshida, M., Tojo, C., et al. (2011). L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats. Hypertension Research (2011) 34, 521–529 Wright, J.M., Musini, V.M. (2009). First-line drugs for hypertension. Cochrane Database Syst Rev 8 (3): CD001841. doi:10.1002/14651858.CD001841.pub2. PMID 19588327. Read More