Nifedipine types

A variation of an approach developed by Meyers was used to prepare nifedipine-type 1,4-dihydropyridines 35 from pyridine 34 using an oxazoline-directed aryllithium 1,4-addition reaction <96H(43)2425>. 

The reaction of ethyl acetoacetate, benzaldehyde, and urea leads to ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-5-pyrimidinecarboxylate. This reaction (the so called Biginelli reaction) was discovered over 100 years ago [93T6937], Interest in these dihydropyrimidines has increased rapidly mainly due to their close structural relationship to the pharmacologically important dihydropyridine calcium channel blockers of the nifedipine-type [93T6937], The dibromo (51) and monobromo derivatives (55) of the most simple Biginelli compounds mentioned above are readily obtained by bromination [93T6937], and the reactions of these derivatives with sodium azide have been studied recently [90LA505] [91 JCS(P1)1342],... 

Meyer H, et al. Bayer-Symposium, 9th Cardiovascular Eff. Dihydropyridine-Type Calcium Antagonists Agonists, Rigid Calcium Agonists of the Nifedipine Type Geometric Requirements for the Dihydropyridine Receptor 1985 90-103. 

Kappe, C. 0.4-Aryldihydropyrimidines via the Biginelli condensation aza analogs of nifedipine-type calcium channel modulators. 

Seidel W, Meyer H, Born L, Kazda K, Dompert W. Rigid calcium antagonists of the nifedipine type Geometrical requirements for the dihydropyridine receptor. In Seydel J, editor, QSAR and strategies in the design of bioactive compounds. Weinheim VCH, 1985. p. 366-9. 

Theoretically it should be possible to classify the slow channel blockers according to whether or not they affect the kinetics of slow channel transport. In this way we could readily separate the nifedipine type of drugs from those that are more like verapamil. Alternatively can these drugs be subgrouped according to their chemistry This possibility seems to be remote. Thus diltiazem is a benzothiazepine derivative (Figure 1 nifedipine is derived from dihydropyridine whilst verapamil has some structural features in common with papaverine. 

The most common type of Ca channel in smooth muscle is the L-channel. It belongs, as do all known channels, to the same family of channels as the Na channel of nerve and skeletal muscle, and has a conductance of about 20pS. A cardinal characteristic of the L-channel is its affinity for and sensitivity to a number of dihydropyridine compounds. These drugs can affect the probability of L-chan-nels being open. The inhibitory members (e.g., nifedipine) of this group of drugs decrease the L-channel open-time probability, while the excitatory members, (e.g., BAY-K 8644), increase the open-time probability. The implication here is that the... 

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]. 

Ca44 channel-blockers Nifedipine Inhibits voltage-dependent L-type Ca44 channels. 

The answer is d. (Hardman, pp 767—775.) Ca channel blockers, of which nifedipine is a prime example, are now considered to be more effective than nitrates in relieving variant angina This is because this type of angina is believed to be caused by vasospasm, which is best antagonized by slow-channel Ca blockers. Such blockers appear to have a relative selectivity for coronary arteries. 

Curtis TM, Scholfield CN 2001 Nifedipine blocks Ca2+ store refilling through a pathway not involving L-type Ca2+ channels in rabit arteriolar smooth muscle. J Physiol 532 609-623... 

Taylor I should have said at the outset that all of these experiments are done with the L-type channels deliberately blocked by nifedipine or verapamil. 

Drugs that affect all phosphodiesterase type 5 inhibitors include the following alcohol, amlodipine, angiotensin II receptor blockers, antacids, bendroflumethiazide, beta blockers, cimetidine, diuretics, enalaphl, metoprolol, nifedipine, rifampin, tacrolimus. 

Fig. 3. Haemodynamic effects of different types of calcium antagonists. Drawn lines nifedipine and other rapidly an short-acting dihydropyridines. Dotted lines verapamil and diltiazem. MAP = mean arterial pressure HR = heart rate CO = cardiac output TPR = total peripheral resistance UE = urinary excretion of Na and H2O. Note the reflex tachycardia, provoked by nifedipine.

Diltiazem, a benzothiazepine, has a pharmacodynamic and side-effect profile that is intermediary between those of nifedipine and verapamil. Diltiazem is mostly used in the treatment of stable angina. It also displays antihypertensive activity, although it is not widely used in antihypertensive treatment. In certain countries diltiazem is used as an antiarrhyth-mic agent with the same type of applications as verapamil. 

C. The available blockers act primarily at voltagegated calcium channels of the L type. The three prototypes, verapamil, nifedipine, and diltiazem, act at three discrete sites at this channel. 

Julie Singer is a 55-year-old white woman who was admitted to the emergency department in acute distress. A previous physical examination showed hypertension and diabetes mellitus type 2. The patient s present medications include enalapril 40 mg, nifedipine 60 mg, and 100 U insulin. A physical examination revealed prominent ankle edema, a palpable spleen, and hepatomegaly. Chest radiography revealed diffuse cardiac enlargement and left ventricular hypertrophy. Based upon the history and clinical hndings, what is your diagnosis and what treatment do you recommend ... 

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