Nicorandil Nitrates

Despite these challenges, the area of K+ channel openers (PCOs) is emerging as an active area of drug design. Over the past 5-10 years, eight novel structural classes of PCOs have received systematic development benzopyrans (e.g., cromakalim, 7.27), cyanoguanidines (e.g., pinacidil, 7.28), thioformamides (e.g., aprikalim, 7.29), pyridyl nitrates (e.g., nicorandil, 7.30), benzothiadiazines (e.g., diazoxide, 7.31), pyrimidine sulphates (e.g., minoxidil sulphate, 7.32), tertiary carbinols, and dihydropyridines. These various classes have been subjected to analog preparation with compound optimization via structure-activity studies. 

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 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. ... 

These classes of drug complement each other and can be used together. The combined nitrate and potassium-channel activator, nicorandil, is an alternative when any of the other drugs is contraindicated. 

Nicorandil, a long-acting potassium-chaimel activator this does not cause tolerance like the nitrates. 

The arterial and venous vasodilatory properties of nicorandil precipitate postural hypotension, leading to dizziness, syncope, palpitation, and headache, through a mechanism similar to that of organic nitrates. Other minor gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and diarrhea have been reported, as has flushing... 

Food reduces the rate but not the extent of absorption of nicorandil after an oral dose (35). Its systemic availability is good and is generally greater than 75% in healthy volunteers, suggesting hmited first-pass hepatic metabo-hsm, unlike the organic nitrates (36). 

Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989 63(21) J18-24. 

Clinically important, potentially hazardous interactions with alpha-ll-blockers, doxazosin, ketoconazole, nicorandil, nitrates, ritonavir... 

In the patient with chronic angina, the drugs commonly used seem to offer important myocardial protection Thus, (3-blockers, ACE inhibitors and most probably angiotensin receptor blockers, statins, Ca2+ channel blockers, all are in their way cardioprotective. Nitrates and more importantly nicorandil are worthwhile options. Trimetazidine and drugs producing a shift towards preferential glucose oxidation would also be a consideration. A number of studies stress that they may produce an improvement in ischemic cardiomyopathy, probably through an anti-inflammatory action.261... 

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... 

The phosphodiesterase type-5 inhibitors potentiate the hypotensive effects of nitrates in a proportion of patients, which might re-suit in potentiaiiy serious hypotension or even precipitate myocardiai infarction. Therefore, the concurrent use of sildenafil, tadalafil or vardenafil with organic nitrates (glyceryl trinitrate (nitroglycerin), isosorbide dinitrate, isosorbide mononitrate, etc.) is contraindicated. The concurrent use of nicorandil and all phosphodiesterase type-5 inhibitors is also contraindicated. 

It is not yet known whether nicorandil interacts with the phosphodiesterase inhibitors to a clinically relevant extent or not, but because part of its vasodilatory actions are mediated by the release of nitric oxide (like conventional nitrates), the manufacturers of nicorandil contraindicate its use with all phosphodiesterase inhibitors. ... 

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