Which classes of drugs are used in the treatment of angina pectoris

Classification and Pharmacokinetics

Nitroglycerin (the active ingredient in dynamite) is the most important of the therapeutic nitrates and is available in forms that provide a range of durations of action from 10–20 min (sublingual for relief of acute attacks) to 8–10 h (transdermal for prophylaxis) (see the Drug Summary Table at the end of the chapter). Nitroglycerin (glyceryl trinitrate) is rapidly denitrated in the liver and in smooth muscle—first to the dinitrate (glyceryl dinitrate), which retains a significant vasodilating effect; and more slowly to the mononitrate, which is much less active. Because of the high enzyme activity in the liver, the first-pass effect for nitroglycerin is about 90%. The efficacy of oral (swallowed) nitroglycerin probably results from the high levels of glyceryl dinitrate in the blood. The effects of sublingual nitroglycerin are mainly the result of the unchanged drug because this route avoids the first-pass effect (see Chapters 1 and 3).

Other nitrates are similar to nitroglycerin in their pharmacokinetics and pharmacodynamics. Isosorbide dinitrate is another commonly used nitrate; it is available in sublingual and oral forms. Isosorbide dinitrate is rapidly denitrated in the liver and smooth muscle to isosorbide mononitrate, which is also active. Isosorbide mononitrate is available as a separate drug for oral use. Several other nitrates are available for oral use and, like the oral nitroglycerin preparation, have an intermediate duration of action (4–6 h). Amyl nitrite is a volatile and rapid-acting vasodilator that was used for angina by the inhalational route but is now rarely prescribed.

Mechanism of Action

Nitrates release nitric oxide (NO) within smooth muscle cells, probably through the action of the mitochondrial enzyme aldehyde dehydrogenase-2 (ALD2). NO stimulates guanylyl cyclase and causes an increase of the second messenger cGMP (cyclic guanosine monophosphate); the latter results in smooth muscle relaxation by dephosphorylation of myosin light-chain phosphate (Figure 12–3). Note that this mechanism is identical to that of nitroprusside (see Chapter 11).

Figure 12–3

Mechanisms of smooth muscle relaxation by calcium channel blockers and nitrates. Contraction results from phosphorylation of myosin light chains (MLC) by myosin light-chain kinase (MLCK). MLCK is activated by Ca2+, so calcium channel blockers reduce this step. Relaxation follows when the phosphorylated light chains are dephosphorylated, a process facilitated by cyclic guanosine monophosphate (cGMP). Nitrates and other sources of nitric oxide (NO) increase cGMP synthesis, and phosphodiesterase (PDE) inhibitors reduce cGMP metabolism. eNOS, endothelial nitric oxide synthase; GC, activated guanylyl cyclase; GTP, guanosine triphosphate. (Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 12–2.)

Organ System Effects

Cardiovascular

Smooth muscle relaxation by nitrates leads to an important degree of venodilation, which results in reduced cardiac size and cardiac output through reduced preload. Relaxation of arterial smooth muscle may increase flow through partially occluded epicardial coronary vessels. Reduced afterload, from arteriolar dilation of resistance vessels, may contribute to an increase in ejection and a further decrease in cardiac size. Some studies suggest that of the vascular beds, the veins are the most sensitive, arteries less so, and arterioles least sensitive. Venodilation leads to decreased diastolic heart size and fiber tension. Arteriolar dilation leads to reduced peripheral resistance and blood pressure. These changes contribute to an overall reduction in myocardial fiber tension, oxygen consumption, and the double product. Thus, the primary mechanism of therapeutic benefit in atherosclerotic angina is reduction of the oxygen requirement. A secondary mechanism—namely, an increase in coronary flow via collateral vessels in ischemic areas—has also been proposed. In vasospastic angina, a reversal of coronary spasm and increased flow can be demonstrated. Nitrates have no direct effects on cardiac muscle, but significant reflex tachycardia and increased force of contraction are common results when nitroglycerin reduces the blood pressure. These compensatory effects result from the baroreceptor mechanism shown in Figure 6–4.

Other Organs

Nitrates relax the smooth muscle of the bronchi, gastrointestinal tract, and genitourinary tract, but these effects are too small to be clinically useful. Intravenous nitroglycerin (sometimes used in unstable angina) reduces platelet aggregation. There are no clinically useful effects on other tissues.

Clinical Uses

As previously noted, nitroglycerin is available in several formulations (see Drug Summary Table). The standard form for treatment of acute anginal pain is the sublingual tablet or spray, which has a duration of action of 10–20 min. Sublingual isosorbide dinitrate is similar with a duration of 30 min. Oral (swallowed) normal-release formulations of nitroglycerin and isosorbide dinitrate have durations of action of 4–6 h. Sustained-release oral forms have a somewhat longer duration of action. Transdermal formulations (ointment or patch) can maintain blood levels for up to 24 h. Tolerance develops after 8–10 h, however, with rapidly diminishing effectiveness thereafter. It is therefore recommended that nitroglycerin patches be removed after 10–12 h to allow recovery of sensitivity to the drug.

Toxicity of Nitrates and Nitrites

The most common toxic effects of nitrates are the responses evoked by vasodilation. These include tachycardia (from the baroreceptor reflex), orthostatic hypotension (a direct extension of the venodilator effect), and throbbing headache from meningeal artery vasodilation.

Nitrates interact with sildenafil and similar drugs promoted for erectile dysfunction. These agents inhibit a phosphodiesterase isoform (PDE5) that metabolizes cGMP in smooth muscle (Figure 12–4). The increased cGMP in erectile smooth muscle relaxes it, allowing for greater inflow of blood and more effective and prolonged erection. This effect also occurs in vascular smooth muscle. As a result, the combination of nitrates (through increased production of cGMP) and a PDE5 inhibitor (through decreased breakdown of cGMP) causes a synergistic relaxation of vascular smooth muscle with potentially dangerous hypotension and inadequate perfusion of critical organs.

Figure 12–4

Mechanism of the interaction between nitrates and drugs used in erectile dysfunction. Because these drug groups increase cyclic guanosine monophosphate (cGMP) by complementary mechanisms, they can have a synergistic effect on blood pressure resulting in dangerous hypotension. GTP, guanosine triphosphate.

Nitrites are of significant toxicologic importance because they cause methemoglobinemia at high blood concentrations. This same effect has a potential antidotal action in cyanide poisoning (see later discussion). The nitrates do not cause methemoglobinemia. In the past, the nitrates were responsible for several occupational diseases in munitions factories in which workplace contamination by these volatile chemicals was severe. The most common of these diseases was "Monday disease," that is, the alternating development of tolerance (during the work week) and loss of tolerance (over the weekend) for the vasodilating action and its associated tachycardia and resulting in headache (from cranial vasodilation), tachycardia, and dizziness (from orthostatic hypotension) every Monday.

Nitrites in the Treatment of Cyanide Poisoning

Cyanide ion rapidly complexes with the iron in cytochrome oxidase, resulting in a block of oxidative metabolism and cell death. Fortunately, the iron in methemoglobin has a higher affinity for cyanide than does the iron in cytochrome oxidase. Nitrites convert the ferrous iron in hemoglobin to the ferric form, yielding methemoglobin. Therefore, cyanide poisoning can be treated by a 3-step procedure: (1) immediate exposure to amyl nitrite, followed by (2) intravenous administration of sodium nitrite, which rapidly increases the methemoglobin level to the degree necessary to remove a significant amount of cyanide from cytochrome oxidase. This is followed by (3) intravenous sodium thiosulfate, which converts cyanomethemoglobin resulting from step 2 to thiocyanate and methemoglobin. Thiocyanate is much less toxic than cyanide and is excreted by the kidney. (It should be noted that excessive methemoglobinemia is fatal because methemoglobin is a very poor oxygen carrier.) Recently, hydroxocobalamin, a form of vitamin B12, has become the preferred method of treating cyanide poisoning (see Chapter 58).

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