Nicorandil Vasodilators

Vasodilators (e.g. hydralazine) Beta blockers + Hydralazine Diazoxide + Hydralazine Guanethidine + Minoxidil Nicorandil + Vasodilators... 

There are at least 13 primary types of K+ channels known. In addition, within each type there are several subtypes. The best known chemical classes of potassium channel openers are nicorandil, piaacidil, and cromakalim. They are aU potent smooth muscle relaxants. PharmacologicaUy, they behave as classical vasodilators, lowering blood pressure and causiag tachycardia and fluid retention. 

Nicorandil. Nicorandil is a potassium channel opener that can lower blood pressure 21, 20, and 29 mm Hg after single oral doses of 10, 20, and 30 mg, respectively (250). There are no significant changes ia heart rate. Headache is the primary side effect. Nicorandil has potent coronary vasodilator effects. It causes sustained vasodilation of arteriolar resistance and venous capacitance blood vessels, thus reduciag cardiac preload and aftedoad. 

From a clinical perspective, some of these PCO classes have attracted initial attention. Diazoxide and minoxidil have been evaluated as antihypertensive agents. These PCOs open K+ channels in the plasma membranes of vascular smooth muscle cells, causing vascular vasodilation, thereby lowering blood pressure. Cromakalim has been investigated as a smooth muscle bronchodilator for the treatment of human asthma. Nicorandil was launched in Japan in 1984 for the treatment of angina because of its perceived ability to promote vasodilation of coronary arteries. Developmental work on these and other PCOs is continuing for indications ranging from hypertension, asthma, urinary incontinence, psychosis, epilepsy, pain, and alopecia (hair loss). 

Nicorandil is a potent vasodilator with anti-spasmodic properties. Its cardiovascular effects are mainly characterised by dilatation of large coronary arteries in combination with reduction of preload and afterload. It has a dual mode of action, activating ATP-dependent K+ channels and a nitrate-like effect. 

Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action, thus providing an additional mechanism for causing vasodilation. 

Diazoxide is chemically a thiazide but has no appreciable diuretic effect indeed, like other potent arterial vasodilators it causes salt and water retention. It reduces peripheral arteriolar resistance through activation of the ATP-dependent potassium channel (c.f. nicorandil and minoxidil), with little effect on veins. The t) is 36 h. 

Nicorandil is an effective vasodilator through two actions. It acts as a nitrate by activating cyclic GMP (see above) but also opens the ATP-dependent potassium channel to allow potassium efflux and h5rperpolarisation of the membrane which reduces calcium ion entry and induces muscular relaxation. It is indicated for use in angina, where it has similar efficacy to p-blockade, nitrates or calcium channel blockade. It is administered orally and is an alternative to nitrates when tolerance to these is a problem, or to the other classes when these are contraindicated by asthma or cardiac failure. Adverse effects to nicorandil are similar to those of nitrates, with headache reported in 35% of patients. It is the only antianginal drug for which at least one trial has demonstrated a beneficial influence upon outcome. ... 

The coronary vasodilator response of nicorandil is potentiated by dipjridamole (34). 

The potassium-channel openers are thought to work by opening a subset of K -channels, which leads to membrane stabilization. Agents such as this have so far been proposed as vasodilators for the treatment of hypertension or heart failure, e.g. nicorandil. They may, however, become used for their smooth muscle relaxant action at other sites, e.g. in the aihvays as ANTIASTHMATIC AGENTS, or for bladder hyperexcitability. Other examples of drugs that work at least partly by this mechanism are cromakalim, diazoxide, pinacidil and minoxidil. See POTASSIUM-CHANNEL ACTIVATORS. 

These are a relatively recent development and act by increasing the efflux of potassium ions in smooth muscle cells of blood vessels. This leads to hyperpolarization of vascular smooth muscle thereby reducing the excitability and bringing about vasodilation. The resulting vasodilation in coronary arterioles improves blood flow to the myocardium. This, in combination with a reduction in both afterload (dilation of arteries) and preload (dilation of veins), relieves the angina. Nicorandil is an example of a potassium channel activator. 

Nicotinic acid and its reduced form, nicotinyl alcohol, have been used for years in attempts to manage peripheral vascular disease. However, nicotinic acid and the alcohol (which is metabolized to the acid) have weak vasodilating activity. At tolerated doses they probably exhibit some activity on dermal blood vessels. The nitrate ester of N-(p-hydrox-yethyl)nicotinamide, nicorandil, was developed in Japan as an antianginal agent. The drug has coronary and peripheral vasodilating properties as well as spasmolytic effects. It thus acts as a classical nitrate. Whether the molecular mechanisms are the same has not been established. 

Nicorandil induces nitrate-like activation of soluble guanylate cyclase, increasing intracellular levels of cGMP with resultant dilation of venous capacitance vessels. Increases in cGMP are less than those observed with conventional nitrates, although the degree of vasodilation produced appears to be similar. Its oral bioavailability ranges from 75 to 80%. Food reduces the rate, but not the extent, of absorption. Nicorandil is extensively metabolized via denitration to inactive... 

Neither cimetidine nor rifampicin had any clinically relevant effect on the pharmacokinetics of nicorandil. Nicorandil did not alter the anticoagulant effects of acenocoumarol. Although animal studies surest antagonism of effects, a study in patients found no pharmacodynamic interaction between nicorandil and glibenclamide. Nicorandil may potentiate the hypotensive effects of other vasodilators, tricyclic antidepressants and alcohol. 

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