Diets rich in inorganic nitrates are known to have a small blood pressure–lowering action but are of no value in angina. The agents useful in angina are simple organic nitric and nitrous acid esters of polyalcohols. Nitroglycerin may be considered the prototype of the group and has been used in cardiovascular conditions for over 160 years. Although nitroglycerin is used in the manufacture of dynamite, the formulations used in medicine are not explosive.
The conventional sublingual tablet form of nitroglycerin may lose potency when stored as a result of volatilization and adsorption to plastic surfaces. Therefore, it should be kept in tightly closed glass containers. Nitroglycerin is not sensitive to light.
All therapeutically active agents in the nitrate group appear to have identical mechanisms of action and similar toxicities, although development of tolerance may vary. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates.
The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is low (typically < 10–20%). For this reason, the sublingual route, which avoids the first-pass effect, is preferred for achieving a therapeutic blood level rapidly. Nitroglycerin and isosorbide dinitrate both are absorbed efficiently by the sublingual route and reach therapeutic blood levels within a few minutes. However, the total dose administered by this route must be limited to avoid excessive effect; therefore, the total duration of effect is brief (15–30 minutes). When much longer duration of action is needed, oral preparations can be given that contain an amount of drug sufficient to result in sustained systemic blood levels of the parent drug plus active metabolites. Pentaerythritol tetranitrate (PETN) is another organic nitrate that is promoted for oral use as a “long-acting” nitrate (> 6 hours). Other routes of administration available for nitroglycerin include transdermal and buccal absorption from slow-release preparations (described below).
Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules packaged in a protective cloth covering. The ampule can be crushed with the fingers, resulting in rapid release of vapors inhalable through the cloth covering. The inhalation route provides very rapid absorption and, like the sublingual route, avoids the hepatic first-pass effect. Because of its unpleasant odor and extremely short duration of action, amyl nitrite is now obsolete for angina.
Once absorbed, the unchanged organic nitrate compounds have half-lives of only 2–8 minutes. The partially denitrated metabolites have much longer half-lives (up to 3 hours). Of the nitroglycerin metabolites (two dinitroglycerins and two mononitro forms), the 1,2-dinitro derivative has significant vasodilator efficacy and probably provides most of the therapeutic effect of orally administered nitroglycerin. The 5-mononitrate metabolite of isosorbide dinitrate is an active metabolite of the latter drug and is available for oral use as isosorbide mononitrate. It has a bioavailability of 100%.
Excretion, primarily in the form of glucuronide derivatives of the denitrated metabolites, is largely by way of the kidney.
A. Mechanism of Action in Smooth Muscle