Vasodilator nifedipine

The vasodilator nifedipine (389) is photolabile because of the presence of an ortho-nitrobenzyl function its photostability in powders and tablet form has been examined. 

Another important reaction of diketene derivatives is the Hant2sch pyridine synthesis (101). This synthesis is the preparation of 1,4-dihydropyridines (14) starting either from two acetoacetic esters, which react with an aldehyde and ammonia or a primary amine or from 3-aminocrotonates and 2-alkyhdene acetoacetic esters, both diketene derivatives. Several such dihydropyridines such as nifedipine [21829-25-4] (102), nimodipine [66085-59-4] and nicardipine [55985-32-5] exhibit interesting pharmaceutical activity as vasodilators (blood vessel dilation) and antihypertensives (see Cardiovascularagents). 

Nifedipine (Table 3) is a potent vasodilator that selectively dilates resistance vessels and has fewer effects on venous vessels. It does not cause reflex tachycardia during chronic therapy. Nifedipine is one of the first-line choices for black or elderly patients and patients having concomitant angina pectoris, diabetes, or peripheral vascular diseases. Nifedipine, sublingually, is also suitable for the treatment of hypertensive emergencies. Nifedipine does not impair sexual function or worsen blood Hpid profile. The side effects are flushing, headache, and dizziness. 

Ca++-channel blockers. Verapamil has powerful effects on the heart, decreasing heart rate and myocardial contractility ( l CO) and causing some vasodilation. On the other hand, nifedipine is a more potent vasodilator (1 TPR) with weaker myocardial effects. The effects of diltiazem are somewhat intermediate, in that this drug has moderate inhibitory effects on the myocardium and vascular smooth muscle. 

The answer is d. (Hardman, pp 794-795.) Hydralazine, minoxidil, diazoxide, and sodium nitroprusside are all directly acting vasodilators used to treat hypertension. Because hydralazine, minoxidil, nifedipine, and diazoxide relax arteriolar smooth muscle more than smooth muscle in venules, the effect on venous capacitance is negligible. Sodium nitroprusside, which affects both arterioles and venules, does not increase cardiac output, a feature that enhances the utility of sodium nitroprusside in the management of hypertensive crisis associated with MI. 

Short-acting nifedipine may rarely cause an increase in the frequency, intensity, and duration of angina in association with acute hypotension. This effect may be obviated by using sustained-released formulations of nifedipine or other dihydropyridines. Other side effects of dihydropyridines include dizziness, flushing, headache, gingival hyperplasia, and peripheral edema. Side effects due to vasodilation such as dizziness, flushing, head-... 

Verapamil and diltiazem cause less peripheral vasodilation than dihydro-pyridines such as nifedipine but greater decreases in AV node conduction. They must be used with caution in patients with preexisting conduction abnormalities or in patients taking other drugs with negative chronotropic properties. 

Calcium-channel blockers interfere with the inward movement of calcium ions through the cell membrane channels. This results in reduction of myocardial contractility (hence negative inotropes), reduction of cardiac output and arteriolar vasodilatation. The dihydropyridine group, such as nifedipine and amlodipine, which may be used in the management of hypertension, are very effective as arterial vasodilators, whereas diltiazem and verapamil are very effective in reducing atrioventricular conduction. 

The choice between calcium antagonists must take into account the differential effect of nifedipine versus verapamil or diltiazem on cardiac performance (see above). When p-blockers are given, the potential consequences of reducing cardiac contractility (withdrawal of sympathetic drive) must be kept in mind. Since vasodilating P2-receptors are blocked, an increased risk of vasospasm cannot be ruled out Therefore, monotherapy with p-blockers is recommended only in angina due to coronary sclerosis, but not in variant angina. 

In multidrug therapy, it is necessary to consider which agents rationally complement each other. A p-blocker (bradycardia, cardiodepression due to sympathetic blockade) can be effectively combined with nifedipine (reflex tachycardia), but obviously not with verapamil (bradycardia, cardiodepression). Monotherapy with ACE inhibitors (p. 124) produces an adequate reduction of blood pressure in 50% of patients the response rate is increased to 90% by combination with a (thiazide) diuretic. When vasodilators such as dihydralazine or minoxidil (p. 118) are given, p-blockers would serve to prevent reflex tachycardia, and diuretics to counteract fluid retention. 

Edema Edema, mild to moderate, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in 10% to 30% of patients receiving nifedipine. It occurs primarily in the lower extremities and usually responds to diuretics. In patients with CHF, differentiate this peripheral edema from the effects of decreasing left ventricular function. 

Direct vasodilators reduce pressure by dilating resistance vessels (arteries) by vascular smooth muscle relaxation (e.g., Ca + channel blockers such as verapamil (4.133) or nifedipine (5.151) vasodilators such as dihydralazine (5.152))... 

Alcohol, antidepressants, hypnotics, sedatives, tranquillizers, fenfluramine, levodopa, vasodilators such as nitrates, nifedipine, verapamil Potentiation. 

Calcium channel blockers with vasodilator effects, such as nifedipine, nicardipine, and nimodipine, will potentiate the effect of vasodilator effects of, e.g. halothane or isoflurane, potentiating any hypotension. This is especially obvious in hypertensive patients and when combined with similarly acting agents, such as sodium nitroprusside or nitroglycerin. Similarly, they also enhance the tendency of volatile anaesthetics to reduce hypoxic pulmonary vasoconstriction, which might exacerbate ventilation/perfusion mismatching during anaesthesia. 

Nifedipine (a dihydropyridine) Block of vascular L-type calcium channels > cardiac channels Like verapamil and diltiazem less cardiac effect Prophylaxis of angina, hypertension Oral, duration 4-6 h Toxicity Excessive hypotension Interactions Additive with other vasodilators... 

Nitro compounds, in particular aromatic and heterocyclic derivatives, absorb strongly in the near UV. They have properties similar to ketones in their excited state. These compounds are characterized by an unpaired electron in the n0 orbital and thus by a radical character. A typical example of this radical character is the easy intramolecular hydrogen abstraction in nifedipine and related vasodilators (Sch. 7) (18). Another manifestation of the radical character of the nitro group is the rearrangement often observed with nitrated five-membered heterocycles, as in the case of metronidazole (Sch. 8) (19). 

Calcium antagonists can cause serious toxicity or death with relatively small overdoses. These channel blockers depress sinus node automaticity and slow AV node conduction (see Chapter 12 Vasodilators the Treatment of Angina Pectoris). They also reduce cardiac output and blood pressure. Serious hypotension is mainly seen with nifedipine and related dihydropyridines, but in severe overdose all of the listed cardiovascular effects can occur with any of the calcium channel blockers. 

The calcium channel blockers inhibit the entrance of calcium into cardiac and smooth muscle cells of the coronary and systemic arterial beds. All calcium channel blockers are therefore vasodilators that cause a decrease in smooth muscle tone and vascular resistance. (See p. 187 for a description of the mechanism of action of this group of drugs.) At clinical doses, these agents affect primarily the resistance of vascular smooth muscle and the myocardium. [Note Verapamil mainly affects the myocardium, whereas nifedipine exerts a greater effect on smooth muscle in the peripheral vasculature. Diitiazem is intermediate in its actions.]... 

Nifedipine [nye FED i peen] functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac conduction or heart rate. Nifedipine is administered orally and has a short half-life (about 4 hours) requiring multiple dosing. The vasodilation effect of nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm. Nifedipine can cause flushing, headache, hypotension, and peripheral edema as side effects of its vasodilation activity. The drug may cause reflex tachycardia if peripheral vasodilation is marked resulting in a substantial decrease in blood pressure. 

Verapamil [ver AP a mill] slows cardiac conduction directly and thus decreases heart rate and oxygen demand. Verapamil causes greater negative inotropic effects than does nifedipine, but it is a weaker vasodilator. Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. It also causes constipation. Verapamil should be used with caution in digitalized patients, since it increases digoxin levels (see p. 160). 

Owing to their large caliber, the proximal coronary segments do not normally contribute significantly to flow resistance. However, in coronary sclerosis or spasm, pathological obstruction of flow occurs here. Whereas the more common coronary sclerosis cannot be overcome pharmacologically, the less common coronary spasm can be relieved by appropriate vasodilators (nitrates, nifedipine). 

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