Calcium channel blockers pharmacological effects

C. Clinical Use and Toxicities Calcium channel blockers are effective for converting atrioventricular nodal reentry (also known as nodal tachycardia) to normal sinus rhythm. Their major use is in the prevention of these nodal arrhythmias in patients prone to recurrence. These drugs are orally active verapamil is also available for parenteral use (Table 14—2). The most important toxicity of verapamil is excessive pharmacologic effect, since cardiac contractility, AV conduction, and blood pressure can be significantly depressed. See Chapter 12 for additional discussion of toxicity. Amiodarone has moderate calcium channel-blocking activity. 

Other drugs such as the neuroleptic, haloperidol, inhibit the induction of hsp70 mRNA in rodent neurons (Sharp et al.. 1992). Although this observation needs to be confirmed in the human population, it raises the possibility that an age-dependent defect in the production of HS proteins is exacerbated by a drug which is commonly used in demented elderly patients. The potential for certain pharmacologic agents to inhibit the HS response could increase the risk for untoward effects of atherosclerosis and hypoxia. A similar concern may be raised with certain calcium channel blockers which also have been found to reduce the synthesis of HS proteins in cardiac myocytes (Low-Friedrich and Schoeppe, 1991). 

Pharmacology The calcium channel blockers share the ability to inhibit movement of calcium ions across the cell membrane. The effects on the cardiovascular system include depression of mechanical contraction of myocardial and smooth muscle and depression of both impulse formation (automaticity) and conduction velocity. 

The effects of the prototypical calcium channel blockers are seen most prominently in the cardiovascular system (Table 19.1), although calcium channels are widely distributed among excitable cells. The following calcium channel-blocking drugs are clinically the most widely used compounds in this very extensive class of pharmacological agents amlodipine, diltiazem, isradipine, nifedipine, nicardipine, nimodipine, and verapamil. 

The pharmacokinetic properties of these drugs are set forth in Table 12-5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with 3 blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients. 

Gurdal, H., Sara, Y., Tulunay, F.C. Effects of Calcium Channel Blockers on formalin-induced nociception and inflammation in rats, Pharmacology 1992, 44, 290-296. 

Although they are chemically heterogeneous, many adverse effects are common to all calcium channel blockers, predictable from their pharmacological actions. Calcium plays a role in the functions of contraction and conduction in the heart and in the smooth muscle of arteries drugs that interfere with its availability (of which there are many, the calcium channel blockers being the most specific) will therefore act in all these tissues. A few idiosjmcratic and hypersensitivity reactions have also been reported with individual calcium channel blockers. 

Once patients with angina develop symptoms sufficient for pharmacologic therapy on a daily basis, the initial prophylactic therapy recommended is a /3-blocker. There is a paucity of comparative, long-term clinical trials of 8-blockade versus calcium channel blockers to determine which is superior for survival benefit. /3-Blockers are recommended first-line therapy because of theirefficacy in post-MI patients and favorable adverse-effect profile. 

The calcium channel blockers have been found to affect several different subcellular processes (see Figure 7.2) and these effects may contribute to the pharmacological profile of the drugs. However, these actions are mainly seen at higher concentrations of the drugs than the concentrations required for calcium channel blockade. For example, high concentrations of D600, nitrendipine and verapamil have been shown to block the fast sodium channels present in cardiac tissue [44, 153-156], On the other hand, lower concentrations of verapamil do not decrease the maximum rate of depolarization of phase 0 of the action potential (Fmax) [156, 157], Neither diltiazem nor nisoldipine reduces Kmax [7,42]. Since influx of Na+ into the cell via the fast sodium... 

Thus, the individual pharmacological effects exerted by each calcium channel blocker may depend upon the extent to which the drug affects other intracellular systems as well as its potency at the calcium channel. Many of the effects described here would tend to increase the vasodilator action of the drugs, such as inhibition of calmodulin-dependent enzymes. However, these other effects are subsidiary to blockade of the calcium channel, as they occur mainly at concentrations higher than those required to block the channels therefore, at low concentrations the actions of the calcium channel blocking drugs are relatively specific. 

Nisoldipine. l,4-Dihydro-2,6-dimethyl-A.(2-ni. tmphenyl)-3,S-pyridinedicarboxylic acid methyl 2-methyl-propyl ester isobutyl methyl l,4-dihydro-2,6-dimethyl-4-(o-nitrophenyl)-3,5-pyridinedicarboxylate isobutyl 1,4-dihy-dto -5 -methox year bony] -2.6 -dimethyl -4 -(2 -nitroplienyl) -3 pyridinecar boxy late 2,6-dimethyl-3-car bomethoxy-4-(2-nitrOphenyl)-5 -carbisobutoxy 1,4-dihydropyridine Bay k 5552 Baymycard Syscor. C. HaNjO. mol wt 388.42. C 61.85%. H 6.23%. N 7.21%, O 24.71%. Dihydro pyridine calcium channel blocker. Prepn E. Wehinger et ah, Ger. pat. 2,549,568 eidem. U.S. pat. 4,154,839 (1977. 1979 both to Bayer). Pharmacology S. Kazda et ah, Arzneimittel-Forsch. 30, 2144 (1980). Preferential effect on vascular smooth muscle in humans A. Vogt el ah. ibid. 2162. 

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