Calcium blockers

Verapamil (Table 1), the first slow channel calcium blocker synthesized to selectively inhibit the transmembrane influx of calcium ions into cells, lowers blood pressure in hypertensive patients having good organ perfusion particularly with increased renal blood flow. Sustained-release verapamil for once a day dosing is available for the treatment of hypertension. Constipation is a prominent side effect. Headache, dizziness, and edema are frequent and verapamil can sometimes cause AV conduction disturbances and AV block. Verapamil should not be used in combination with -adrenoceptor blockers because of the synergistic negative effects on heart rate and contractile force. 

Despite the growth in interest in calcium blockers, there are comparatively few calcium channel blocking agents currently in clinical use. These drugs are characterised by the fact that they belong to classes of compounds which are chemically unrelated like Diltiazem , Nifedipine , Verapamil , Fluspirilene and some others (Scheme 1). 

One source of calcium ions, which cause contraction of smooth muscle in arterial walls, is inflow through ion-specific channels. So, the calcium blockers block the channels, limiting inflow of calcium and keeping muscle cells in relaxed states for a longer time. 

Napoli et al. [286] found that the nifedipine treatment of stroke-prone spontaneously hypertensive rats (SPSHR) suppressed the plasma and LDL oxidation and the formation of oxidation-specific epitopes and increased the survival of rats independently of blood pressure modification. Their results suggest that the protective effects of calcium blockers of dihydro-pyridine-type on cerebral ischemia and stroke may, at least in part, depend on their antioxidant activity. In vivo antioxidant effect of nilvadipine on LDL oxidation has been studied in hypertensive patients with high risk of atherosclerosis [287], It was found that there was a significant decrease in the level of LDL cholesterol oxidation in patients after nilvadipine treatment. 

Calcium antagonists are able to affect nitric oxide production and suppress the peroxyni-trite-induced damage. Thus, nifedipine enhanced the bioavailability of endothelial NO in porcine endothelial cell cultures supposedly through an antioxidative mechanism [288], Pretreatment with nisoldipine, a vascular-selective calcium blocker of dihydropyridine-type, of confluent bovine aortic endothelial cells suppressed the peroxynitrite-induced GSH loss and increased cell survival [289]. 

Similar to dihydropyridine calcium blockers, many 0-adrenoreceptor antagonists exhibit antioxidant activity. Mak and Weglinski [290] showed that the pretreatment of canine myocytic sarcolemmal membranes with 0-adrenoreceptor antagonists (propranolol, pindolol, metoprolol, atenolol, or sotalol) (Figure 29.15) inhibited superoxide-induced sarcolemmal... 

Amlodipine (Norvasc) Calcium-blocker Amoxapine (Asendin) Antidepressant Amoxicillin (Amoxil) Antibiotic... 

Isotretinoin (Accutane) Anti-acne Isradipine (DynaCirc, Calcium-blocker DynaCirc CR)... 

Propranolol has been studied most carefully in experiments and in clinics. It is used for ventricular tachycardia, arrhythmia caused by digitalis drug overdose, or as a result of thy-rotoxosis or excess catecholamine activity. Despite the fact that there are a number of )8-adrenoblockers, propranolol is considered the first choice of drugs although other blockers of calcium blockers can be just as effective. 

Drugs that may affect calcium blockers include amiodarone, antineoplastics, azole... 

Drugs that may affect beta blockers include aluminum salts, barbiturates, calcium salts, cholestyramine, cimetidine, colestipol, diphenhydramine, hydroxychloroquine, NSAIDs, penicillins (ampicillin), rifampin, salicylates, SSRIs, sulfinpyrazole, calcium blockers, oral contraceptives, flecainide, haloperidol, hydralazine, loop diuretics,... 

Drugs that may be affected by carvedilol include antidiabetic agents, calcium blockers, clonidine, cyclosporine, disopyramide, catecholamine depleting agents (eg, reserpine), and digoxin. 

Diuretics or beta blockers-- 2. ACE inhibitors, calcium blockers, alpha-] blockers, alpha-beta blocker ... 

Drugs that may be affected by itraconazole include alfentanil, almotriptan, alprazolam, amphotericin B, aripiprazole, benzodiazepines, buspirone, busulfan, calcium blockers, carbamazepine, cilostazol, cisapride, corticosteroids, cyclosporine, digoxin, disopyramide, docetaxel, dofetilide, eletriptan, epierenone, ergot alkaloids, haloperidol, HMG-CoA reductase inhibitors, hydantoins (phenytoin), hypoglycemic agents, oral midazolam, phosphodiesterase type 5 inhibitors, pimozide, polyenes, protease inhibitors, quinidine, rifamycins, sirolimus, tacrolimus, tolterodine, triazolam, trimetrexate, vinca alkaloids, warfarin, and zolpidem. 

Verapamil has been shown to block the P-glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells (see Chapter 1) other calcium channel blockers appear to have a similar effect. This action is not stereospecific. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Some clinical results suggest similar effects in patients (see Chapter 54). Animal research suggests possible future roles of calcium blockers in the treatment of osteoporosis, fertility disorders and male contraception, immune modulation, and even schistosomiasis. 

While they are often prescribed, the lower costs of codeine, ACE inhibitors, beta-blockers, thyroid hormones, calcium blockers, and benzodiazepines keep them off the list of top sales. Conversely, the higher cost of erythropoietins, antineo monoclonal antibodies, angiotensin II antagonists, antiarthritis drugs, and bisphosphonates put them on the list of top sales but not top prescriptions. 

Smidt and Langner111"1 in their synthesis of the natural calcium blocker leualacin utilized the Mitsunobu reaction for the construction of the linear depsipeptide N-(tert-but oxycarbony I) -(3-alanyl-O-D-leucic acid benzyl ester in 69% yield. Higher yields (94-96%) were reported for two didepsipeptide units N-(/er/-butoxycarbonyl)-./V-methylleucyl-D-lactic acid diphen-ylmethyl ester and iV-(/er/-butoxycarbonyl)-yV-methylleucyl-D-phenyllactic acid diphe-nylmethyl ester in the course of the total synthesis of the anthelmintic cyclooctadepsipeptide PF1022A based on the Mitsunobu reaction.1102 ... 

Hollt, V., M. Kouba, M. Dietel, and G. Vogt. 1992. Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. Biochem Pharmacol 43 2601. 

Ethanol is a vasodilator, probably as a result of both central nervous system effects (depression of the vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde. In cases of severe overdose, hypothermia—caused by vasodilation—may be marked in cold environments. Ethanol also relaxes the uterus and—before the introduction of more effective and safer uterine relaxants (eg, calcium blockers, magnesium ion, NSAIDs, and -adrenoceptor stimulants)—was used intravenously for the suppression of premature labor. 

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