Calcium antagonistic agents

Dihydropyrimidinones (DHPMs) are well-known calcium antagonistic agents and are most commonly prepared by acid-catalyzed cydocondensation of urea, p-ketoesters, and aromatic aldehydes. Ever since its discovery in 1893, this so-called Biginelli reaction (Scheme 17.19) has been subject of numerous optimization studies and many modified procedures have resulted [vide infra). The Biginelli reaction and its modifications are still popular tools for the preparation of DHPMs 26 and have been extensively reviewed by Kappe et al. [56],... 

Schmitz, G. Lepper, H. Estler, C. J. Failure of calcium antagonistic agents to prevent hepatotoxicity induced by diclofenac. Pharmacol. Toxicol. 1995, 77, 32-35. 

Calcium Antagonists. The potential use of antagonists as radioprotective agents has been suggested based on the importance of... 

The cardiac effects of the calcium antagonists, ie, slowed rate (negative chronotropy) and decreased contractile force (negative inotropy), are prominent in isolated cardiac preparations. However, in the intact circulation, these effects may be masked by reflex compensatory adjustments to the hypotension that these agents produce. The negative inotropic activity of the calcium antagonists may be a problem in patients having heart failure, where contractility is already depressed, or in patients on concomitant -adrenoceptor blockers where reflex compensatory mechanisms are reduced. 

In symptomatic patients, medical therapy can be tailored either to control ventricular response or to restore sinus rhythm. Nondihydropyridine calcium antagonists (e.g., verapamil) are considered first-line drug therapy for decreasing ventricular response. Type I agents (e.g., procainamide, quinidine) are only occasionally effective in restoring sinus rhythm. DCC is ineffective, and /3-blockers are usually contraindicated because of coexisting severe pulmonary disease or uncompensated HF. 

These drugs were developed as coronary vasodilating agents and were used for that purpose for some time, until it was discovered that they inhibit the contractile effect of calcium on smooth musculature and cardiac muscle, and that they affect calcium channels on the cell surface that permit calcium ions to enter. At first, they were called calcium antagonists however, later on this class of compounds was given the preferred name of calcium channel blockers. 

Concomitant therapy - Observe caution when terazosin is administered concomitantly with other antihypertensive agents (eg, calcium antagonists) to avoid the possibility of significant hypotension. When adding a diuretic or other antihypertensive agent, dosage reduction and retitration may be necessary. 

While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, use care because interference with cyclosporine metabolism may require a dosage adjustment. 

Beta-blockers interact with a large number of other medications. The combination of beta-blockers with calcium antagonists should be avoided, given the risk for hypotension and cardiac arrhythmias. Cimetidine, hydralazine, and alcohol all increase blood levels of beta-blockers, whereas rifampicin decreases their concentrations. Beta-blockers may increase blood levels of phenothiazines and other neuroleptics, clonidine, phen-ytoin, anesthetics, lidocaine, epinephrine, monoamine oxidase inhibitors and other antidepressants, benzodiazepines, and thyroxine. Beta-blockers decrease the effects of insulin and oral hypoglycemic agents. Smoking, oral contraceptives, carbamazepine, and nonsteroidal anti-inflammatory analgesics decrease the effects of beta-blockers (Coffey, 1990). 

Post and colleagues (252, 253) have suggested that voltage-gated calcium antagonists, such as nimodipine, may be more effective, especially in treatment-resistant and ultrarapid and ultradian cycling patients (i.e., cycles every several weeks or hours, respectively). This is in part because such agents may penetrate the blood—brain barrier more readily than verapamil. 

Antianginal agents derive from three drug groups, the pharmacological properties of which have already been presented in more detail the organic nitrates (p.124), the calcium antagonists (p. 126), and the p-blockers (P-96). 

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