Calcium antagonists hypertension treatment

Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST) A randomized, controlled trial. JAMA 2003 290 2805-2816. 

Data on the effect of calcium antagonists on cardiovascular disease risks in patients with hypertension are available from one moderate-to-large scale randomized, placebo-controlled trial. In the Systolic Hypertension in Europe (Syst-Eur) trial, nitrendipine-based therapy produced an approximate 10/5 mmHg reduction in SBP-DBP in patients with systolic hypertension and a 42% reduction in the risk of stroke. Similar results were observed in two large, nonrandomized, placebo-controlled trials (with alternate treatment assignment), i.e. the Shanghai Trial of Nifedipine in the Elderly and the Systolic Hypertension in China (Syst-China) trial. 

Konianim. C, and A.L. Tranquilli Calcium Antagonists in Ihe Treatment of Hypertension in Pregnancy. Parthenon Publishing Croup. New York. NY. 1999. 

In a new syntiiesis of diltiazem (98b R = Ac, X = CH2CH2NMe2), a calcium antagonist used in the treatment of hypertension, die key step is die diastereoselective reduction of a-ketolactam (97) to die alcohol precursor (98a R = X = H).158 The reduction of the 1,5-benzothiazepine (97) was achieved using an NaBH4-(5)-amino acid combination (,S)-f-leucine was most efficient, and was readily recovered unracemized. 

Essential hypertension all calcium antagonists, particular the dihydropyridine type, are widely used for the treatment of hypertension due to not only their strong effects on the reduction of peripheral resistances, but also their excellent safety profile. 

Isradipine (Fig. 7.5) is a further nifedipine analogue, which has been used in the treatment of hypertension either alone or in combination with diuretics. Isradipine possesses high calcium antagonist activity, which results in a peripheral vasodilatation without any detrimental effect on cardiac conduction. Its oral bioavailability is 90-95% of the administered dose, but the hepatic first-pass effect reduces this to 15-24%. Isradipine was shown to possess anti-atherosclerotic activity in a number of experimental models, but clinical studies (MIDAS) failed to confirm these findings in patients. 

Manidipine (Fig. 7.11) is a nifedipine analogue which shows a potent and selective calcium antagonist activity that translates into a potent antihypertensive and coronary vasodilatory activity. Manidipine shows some selectivity towards the renal vasculature, making it particularly useful for the treatment of renovascular hypertension. 

Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). It has generally been indicated for the treatment of angina and, more recently (2), hypertension. Diltiazem hydrochloride is a potent dilator of coronary arteries and has been shown to increase exercise tolerance in man. It is available for dosing as immediate release tablets and as extended or sustained release capsules and is usually well-tolerated. While some adverse reactions have been reported during diltiazem hydrochloride therapy, it is generally considered to be well-tolerated. In most cases, no causal relationship between the events and diltiazem hydrochloride use has yet to be established (1). 

Kiowiski N, Bolli P, Biihler FR, Ernep P, et al, 1985. Age, race, blood pressure, and renin predictions for hypertensive treatment with calcium antagonist . Am. J. Cardiol. 16 81H-85H. 

Finally, a comprehensive hemodynamic evaluation in IPAH patients should include assessment of pulmonary vasoreactivity with inhaled nitric oxide (10-40 ppm), inhaled iloprost, IV epoprostenol, or adenosine in patients with precapillary hypertension. If with these treatments mPAP decreases by 10 mm Hg to levels <40 mm Hg, IPAH patients are considered responders. This denotes a small but very important population (<15% of IPAH patients) with significantly improved outcomes when treated with high doses of calcium channel blockers (29,30). For the select patients who are deemed responders and are subsequently treated with calcium antagonists, close follow-up to confirm a sustained hemodynamic improvement is essential. 

Unlike skeletal muscles, which contain endogenons stores of calcium ions, both cardiac muscle and vascnlar smooth muscle require extracellular calcium for contractile function. Therefore, cardiac muscle and vascnlar smooth muscle are subject to regulation by calcium antagonists or calcium entry blockers (Figure 103 and Table 21), which are used in the treatment of hypertension, Raynand s disease, Prinzmetal s angina, and migraine syndromes. 

Calcium antagonists (Figure 4.3) are agents which block the flow of calcium ions into cardiac and vascular smooth muscle when they are stimulated to contract. They have value as vasodilators for use in hypertension and also reduce blood flow resistance and cardiac workload in the treatment of angina. Verapamil (Knoll Pfizer, 1967) is also used as an antiarrhythmic because of its effects on ion channels in the heart s electrical conduction system. Nifedipine (Bayer, 1977) is among the world s top 25 drugs and is the forerunner of several agents of the dihydropyridine class. 

In the treatment of hypertension, ACE inhibitors are as effective as diuretics, (3-adrenoceptor antagonists, or calcium channel blockers in lowering blood pressure. However, increased survival rates have only been demonstrated for diuretics and (3-adrenoceptor antagonists. ACE inhibitors are approved for monotherapy as well as for combinational regimes. ACE inhibitors are the dtugs of choice for the treatment of hypertension with renal diseases, particularly diabetic nephropathy, because they prevent the progression of renal failure and improve proteinuria more efficiently than the other diugs. 

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