Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Oral sustained-release (generic, Calan SR, Verelan): 120, 180, 240 mg tablets; 100, 120, 180, 200, 240, 300 mg capsules

Parenteral: 2.5 mg/mL for injection

Angiotensin-Converting Enzyme Inhibitors

Benazepril(Lotensin)

Oral: 5, 10, 20, 40, mg tablets

Captopril (generic, Capoten)

Oral: 12.5, 25, 50, 100 mg tablets

Enalapril(Vasotec)

Oral: 2.5, 5, 10, 20 mg tablets

Parenteral (Enalaprilat): 1.25 mg/mL for injection

Fosinopril(Monopril)

Oral: 10, 20, 40 mg tablets

Lisinopril(Prinivil, Zestril)

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Moexipril(Univasc)

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Perindopril (Aceon)

Oral: 2, 4, 8 mg tablets

Quinapril(Accupril)

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Ramipril (Altace)

Oral: 1.25, 2.5, 5, 10 mg capsules

Trandolapril(Mavik)

Oral: 1, 2, 4 mg tablets

Angiotensin Receptor Blockers

Candesartan (Atacand)

Oral: 4, 8, 16, 32 mg tablets

Eprosartan(Teveten)

Oral: 400, 600 mg tablets

Irbesartan (Avapro)

Oral; 75, 150, 300 mg tablets

Losartan (Cozaar)

Oral: 25, 50, 100 mg tablets

Olmisartan (Benicar)

Oral: 5, 20, 40 mg tablets

Telmisartan(Micardis)

Oral: 20, 40, 80 mg tablets

Valsartan (Diovan)

Oral: 40, 80, 160, 320 mg tablet

Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents >

Chapter 12. Vasodilators & the Treatment of Angina Pectoris

Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris >

Vasodilators & the Treatment of Angina Pectoris

Angina pectoris is the most common condition involving tissue ischemia in which vasodilator drugs are used. Angina (pain) is caused by the accumulation of metabolites in striated muscle; angina pectoris is the severe chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by the heart. The organic nitrates, eg, nitroglycerin, are the mainstay of therapy for the immediate relief of angina. Another group of vasodilators, the calcium channel blockers, is also important, especially for prophylaxis, and the -blockers, which are not vasodilators, are also useful in prophylaxis. A new group of drugs (fatty acid oxidation inhibitors) that are not vasodilators but alter myocardial metabolism are under intense investigation.

Ischemic heart disease is the most common serious health problem in many Western societies. By far the most frequent cause of angina is atheromatous obstruction of the large coronary vessels (atherosclerotic angina, classic angina). However, transient spasm of localized portions of these vessels, which is usually associated with underlying atheromas, can also cause significant myocardial ischemia and pain (angiospastic or variant angina).

The primary cause of angina pectoris is an imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels. In classic angina, the imbalance occurs when the myocardial oxygen requirement increases, as during exercise, and coronary blood flow does not increase proportionately. The resulting ischemia usually leads to pain. Classic angina is therefore "angina of effort." (In some individuals, the ischemia is not always accompanied by pain, resulting in "silent" or "ambulatory" ischemia.) In variant angina, oxygen delivery decreases as a result of reversible coronary vasospasm. Variant angina is also called vasospastic or Prinzmetal's angina.

In theory, the imbalance between oxygen delivery and myocardial oxygen demand can be corrected by decreasing oxygen demand or by increasing delivery (by increasing coronary flow). Oxygen demand can be reduced by decreasing cardiac work or, according to recent studies, by shifting myocardial metabolism to substrates that require less oxygen per unit of ATP produced. In effort angina, acute reduction of demand has traditionally been achieved by means of organic nitrates— potent vasodilators—and several other classes of drugs, which decrease cardiac work. Increased delivery via increased coronary flow is difficult to achieve rapidly by pharmacologic means when flow is limited by fixed atheromatous plaques. In this situation, invasive measures (coronary bypass grafts or angioplasty) may be needed if reduction of oxygen demand does not control symptoms. In variant angina, on the other hand, spasm of coronary vessels can be reversed by nitrates or calcium channel blockers. It should be emphasized that not all vasodilators are effective in angina and, conversely, that some agents useful in angina (eg, propranolol) are not vasodilators. Lipid-lowering drugs, especially the "statins," have become extremely important in the long-term treatment of atherosclerotic disease (see Chapter 35: Agents Used in Hyperlipidemia).

Unstable angina, an acute coronary syndrome, is said to be present when there are episodes of angina at rest and when there is a change in the character, frequency, and duration of chest pain as well as precipitating factors in patients with previously stable angina. Unstable angina is caused by episodes of increased epicardial coronary artery tone or small platelet clots occurring in the vicinity of an atherosclerotic plaque. In most cases, formation of labile nonocclusive thrombi at the site of a fissured or ulcerated plaque is the mechanism for reduction in flow. The course and the prognosis of unstable angina are variable, but this subset of acute coronary syndrome is associated with a high risk of myocardial infarction and death.

Pathophysiology of Angina

Determinants of Myocardial Oxygen Demand

The major and minor determinants of myocardial oxygen requirement are set forth in Table 12–1. Unlike skeletal muscle, human cardiac muscle cannot develop an appreciable oxygen debt during stress and repay it later. As a consequence of its continuous activity, the heart's oxygen needs are relatively high, and it extracts approximately 75% of the available oxygen even under conditions of no stress. The myocardial oxygen requirement increases when there is an increase in heart rate, contractility, arterial pressure, or ventricular volume. These hemodynamic alterations frequently occur during physical exercise and sympathetic discharge, which often precipitate angina in patients with obstructive coronary artery disease. The relative contributions of basal metabolism and activation of contraction to the overall myocardial oxygen consumption appear to be small, but

under pathologic conditions these apparently minor determinants of myocardial oxygen consumption may become relevant.

Table 12–1. Determinants of Myocardial Oxygen Consumption.

Major

Wall stress

Intraventricular pressure

Ventricular radius (volume)

Wall thickness

Heart rate

Contractility

Minor

Activation energy

Resting metabolism

The heart favors fatty acids as a substrate for energy production. However, oxidation of fatty acids requires more oxygen per unit of ATP generated than oxidation of carbohydrates. Therefore, drugs that shift myocardial metabolism toward greater use of glucose (fatty acid oxidation inhibitors) have the potential of reducing the oxygen demand without altering hemodynamics. Experimental models suggest that ranolazine and trimetazidine may have this effect. Preliminary clinical trials have shown favorable results.

Determinants of Coronary Blood Flow & Myocardial Oxygen Supply

Increased myocardial demands for oxygen in the normal heart are met by augmenting coronary blood flow. Coronary blood flow is directly related to the perfusion pressure (aortic diastolic pressure) and the duration of diastole. Because coronary flow drops to negligible values during systole, the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia. Coronary blood flow is inversely proportional to coronary vascular bed resistance. Resistance is determined mainly by intrinsic factors, including metabolic products and autonomic activity; and by various pharmacologic agents. Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance.

Determinants of Vascular Tone

Arteriolar and venous tone (smooth muscle tension) both play a role in determining myocardial wall stress (Table 12–1). Arteriolar tone directly controls peripheral vascular resistance and thus arterial blood pressure. In systole, intraventricular pressure must exceed aortic pressure to eject blood; arterial blood pressure thus determines the systolic wall stress in an important way. Venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered in the venous system versus the amount returned to the heart. Venous tone thereby determines the diastolic wall stress.

The regulation of smooth muscle contraction and relaxation is shown schematically in Figure 12–1.

As shown in Figures 12–1 and 12–2, drugs may relax vascular smooth muscle in several ways:

Figure 12–1.

Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell (not shown).

Figure 12–1. Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell (not shown).

1.Increasing cGMP—As indicated in Figure 12–2, cGMP facilitates the dephosphorylation of myosin light chains, preventing the interaction of myosin with actin. Nitric oxide is an effective activator of soluble guanylyl cyclase and acts mainly through this mechanism. Important molecular donors of nitric oxide include nitroprusside (see Chapter 11: Antihypertensive Agents) and the organic nitrates used in angina.

2.Decreasing intracellular Ca2+—Calcium channel blockers predictably cause vasodilation because they reduce intracellular Ca2+, a major modulator of the activation of myosin light chain kinase. (Beta blockers and calcium channel blockers reduce Ca2+influx in cardiac muscle,

thereby reducing rate, contractility, and oxygen requirement unless reversed by compensatory responses.)

3.Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane—The membrane potential of excitable cells is stabilized near the resting potential by increasing

potassium permeability. Potassium channel openers, such as minoxidil sulfate, (see Chapter 11: Antihypertensive Agents) increase the permeability of K+ channels, probably ATP-dependent K+ channels. Certain newer agents under investigation for use in angina (eg, nicorandil) may act, in part, by this mechanism.

4.Increasing cAMP in the vascular cells—As shown in Figure 12–1, an increase in cAMP increases the rate of inactivation of myosin light chain kinase, the enzyme responsible for triggering the interaction of actin with myosin in these cells. This appears to be the mechanism of vasodilation caused by 2-agonists, drugs that are not used in angina.

Figure 12–2.

Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in smooth muscle cells. (MLCK*, activated myosin light chain kinase [see Figure 12–1]; guanylyl cyclase*, activated guanylyl cyclase; ?, unknown intermediate steps. Steps leading to relaxation are shown with heavy arrows.)

Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris >

Basic Pharmacology of Drugs Used to Treat Angina

Drug Action in Angina

All three of the drug groups currently approved for use in angina (organic nitrates, calcium channel blockers, and -blockers) decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate, ventricular volume, blood pressure, and contractility). In some

patients, a redistribution of coronary flow may increase oxygen delivery to ischemic tissue. In variant angina, the nitrates and the calcium channel blockers may also increase myocardial oxygen delivery by reversing coronary arterial spasm.

Nitrates & Nitrites

Chemistry

These agents are simple nitric and nitrous acid esters of polyalcohols. Nitroglycerin may be considered the prototype of the group. Although it is used in the manufacture of dynamite, the formulations of nitroglycerin 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. It is not sensitive to light.

All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates.

Pharmacokinetics

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 very low (typically < 10–20%). The sublingual route, which avoids the first-pass effect, is therefore preferred for achieving a therapeutic blood level rapidly. Nitroglycerin and isosorbide dinitrate are both absorbed efficiently by this 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. Other routes of administration available for nitroglycerin include transdermal and buccal absorption from slowrelease preparations; these are 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 inhalable vapors 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 short duration of action, amyl nitrite is now obsolete for angina.

Once absorbed, the unchanged 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 dinitro derivatives have significant vasodilator

efficacy; they probably provide 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 clinical 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.

Pharmacodynamics

Mechanism of Action in Smooth Muscle

Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite ion is released, which is then converted to nitric oxide (see Chapter 19: Nitric Oxide, Donors, & Inhibitors). A different unknown enzymatic reaction releases nitric oxide directly from the parent drug molecule. As shown in Figure 12–2, nitric oxide (or an S-nitrosothiol derivative) causes activation of guanylyl cyclase and an increase in cGMP, which are the first steps toward smooth muscle relaxation. The production of prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarization may also be involved. There is no evidence that autonomic receptors are involved in the primary nitrate response (although autonomic reflex responses are evoked when hypotensive doses are given).

As described below, tolerance is an important consideration in the use of nitrates. While tolerance may be caused in part by a decrease in tissue sulfhydryl groups, it can be only partially prevented or reversed with a sulfhydryl-regenerating agent. The site of this cellular tolerance may be in the unknown reaction responsible for the release of nitric oxide from the nitrate, since other agents, eg, acetylcholine, that cause vasodilation via release of nitric oxide from endogenous substrates do not show cross tolerance with the nitrates.

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.

Organ System Effects

Nitroglycerin relaxes all types of smooth muscle irrespective of the cause of the preexisting muscle tone (Figure 12–3). It has practically no direct effect on cardiac or skeletal muscle.

Figure 12–3.

Effects of vasodilators on contractions of human vein segments studied in vitro. Panel A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE) and potassium (K+). Panel B shows the relaxation induced by nitroglycerin (NTG), 4 mol/L. The relaxation is prompt. Panel C shows the relaxation induced by verapamil, 2.2 mol/L. The relaxation is slower but more sustained. (Modified and reproduced, with permission, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins. Acta Pharmacol Toxicol 1978;42:14.)

Vascular Smooth Muscle

All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin. Veins respond at the lowest concentrations, arteries at slightly higher ones. Arterioles and precapillary sphincters are dilated less than the large arteries and the veins, partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide (see The Coronary Steal Phenomenon). The primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload. Pulmonary vascular pressures and heart size are significantly reduced. In the absence of heart failure, cardiac output is reduced. Because venous capacitance is increased, orthostatic hypotension may be marked and syncope can result. Dilation of some large arteries (including the aorta) may be significant because of their large increase in compliance. Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are frequent effects of nitroglycerin and amyl nitrite. In heart failure, preload is often abnormally high; the nitrates and other vasodilators, by reducing preload, may have a beneficial effect on cardiac output in this condition (see Chapter 13: Drugs Used in Heart Failure).

The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decreased arterial pressure (see Figure 6–7); this consistently results in tachycardia and increased cardiac contractility. Retention of salt and water may also be significant, especially with intermediateand long-acting nitrates. These compensatory responses contribute to the development of tolerance.

In normal subjects without coronary disease, nitroglycerin can induce a significant, if transient, increase in total coronary blood flow. In contrast, there is no evidence that total coronary flow is increased in patients with angina due to atherosclerotic obstructive coronary artery disease.

However, some studies suggest that redistribution of coronary flow from normal to ischemic regions may play a role in nitroglycerin's therapeutic effect. Nitroglycerin also exerts a weak negative inotropic effect via nitric oxide.

Other Smooth Muscle Organs

Relaxation of smooth muscle of the bronchi, gastrointestinal tract (including biliary system), and genitourinary tract has been demonstrated experimentally. Because of their brief duration, these actions of the nitrates are rarely of any clinical value. During recent years, the use of amyl nitrite and isobutyl nitrite by inhalation as purported recreational (sex-enhancing) drugs has become popular with some segments of the population. Nitrites release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase. The resulting increase in cGMP causes dephosphorylation of myosin light chains and relaxation (Figure 12–2), which enhances erection. Drugs used in the treatment of erectile dysfunction are discussed in the section, Drugs Used in the Treatment of Erectile Dysfunction.

Action on Platelets

Nitric oxide released from nitroglycerin stimulates guanylyl cyclase in platelets as in smooth muscle. The increase in cGMP that results is responsible for a decrease in platelet aggregation. Unfortunately, recent prospective trials have established no survival benefit when nitroglycerin is used in acute myocardial infarction.

Other Effects

Nitrite ion reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains ferric iron). Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death. Fortunately, the plasma level of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults. However, sodium nitrite is used as a curing agent for meats. In nursing infants, the intestinal flora is capable of converting significant amounts of inorganic nitrate, eg, from well water, to nitrite ion. Thus, inadvertent exposure to large amounts of nitrite ion can occur and may produce serious toxicity.

One therapeutic application of this otherwise toxic effect of nitrite has been discovered. Cyanide poisoning results from complexing of cytochrome iron by the CN- ion. Methemoglobin iron has a very high affinity for CN-; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure will regenerate active cytochrome. The cyanmethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3); this results in formation of thiocyanate ion (SCN-), a less toxic ion that is readily excreted. Methemoglobinemia, if excessive, can be treated by giving methylene blue intravenously.

Toxicity & Tolerance

Acute Adverse Effects

The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache. Glaucoma, once thought to be a