Contemporary Reviews in Cardiovascular Medicine

Nitrate Therapy
New Aspects Concerning Molecular Action and Tolerance
1. Thomas Mnzel, MD; 2. Andreas Daiber, PhD; 3. Tommaso Gori, MD, PhD + Author Affiliations 1. From II. Medizinische Klinik und Poliklinik, Kardiologie, Johannes Gutenberg Universitt, Mainz, Germany. 1. Correspondence to Thomas Mnzel, MD, II. Medizinische Klinik und Poliklinik, Kardiologie, Johannes Gutenberg Universitt, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail tmuenzel@uni-mainz.de

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Figure 1. Free radical biochemistry. The radical nitric oxide reacts with superoxide to form the highly reactive intermediate peroxynitrite. Superoxide is dismutated by superoxide dismutase (SOD), leading to the formation of hydrogen peroxide (H2O2) and molecular oxygen (O2).

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Figure 2. Antianginal effects of acutely administered glyceryl trinitrate (GTN).

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Figure 3. Effects of organic nitrates such as glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) on myocardial gene expression. Treatment with GTN significantly changed the expression of 532 genes; PETN treatment changed the expression of 1215 genes. Interestingly, only 68 genes were significantly changed by both compounds, raising doubt that a common vasoactive molecule, such as nitric oxide is released from both drugs. Adapted from Pautz et al.26

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Figure 4. Proposed mechanisms underlying bioactivation of organic nitrates. Left, Characterization of the bioactivation of high-potency nitrates such as nitroglycerin (glyceryl trinitrate [GTN]), pentaerythrityl tetranitrate (PETN), and pentaerythrityl trinitrate (PETriN) by mitochondrial aldehyde dehydrogenase (ALDH-2) when used at low, clinically relevant concentrations (<1 mol/L). The reductase activity converts the organic nitrates to nitrite and the denitrated metabolite (1,2-glyceryl dinitrate, PETriN, or its dinitrate, PEDN). In general, there are 3 proposed mechanisms including nitrogen oxide formed via a reduction of nitrite (NO2), nitric oxide, formed directly in response to interaction with the ALDH-2, and NO2, released from the mitochondria, may be reduced by the xanthine oxidase in the cytoplasm to form NO. Right, The bioactivation of low-potency nitrates such as isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN) but also GDN, PEDN, and their respective mononitrates GMN and PEMN by P450 enzyme(s) in the endoplasmic reticulum (ER), directly yielding nitric oxide. The latter mechanism also accounts for the highpotency nitrates when used at high concentrations (>1 mol/L). Cyt Ox indicates cytochrome c oxidase.

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Figure 5. Effects of in vivo glyceryl trinitrate (GTN) treatment in patients undergoing bypass surgery on tolerance of mammary artery and vena saphena magna. A and B, in vivo treatment will lead to a marked degree of tolerance in the mammary artery and in vena saphena magna veins (blue lines). The shift to the right was comparable when the mammary artery and the vena saphena were treated in vitro with the aldehyde dehydrogenase (ALDH-2) inhibitor benomyl (green line). C, In vivo and in vitro treatment with GTN and benomyl resulted in comparable inhibition of the activity of ALDH-2 in arteries and veins. D, Long-term treatment with GTN leads to a downregulation of the GTN-bioactivating enzyme ALDH-2. Adapted from Hink et al,32 with permission of the publisher. Copyright 2007, American College of Cardiology Foundation.

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Figure 6. Molecular mechanisms of nitrate tolerance. Within 1 day of continuous low-dose glyceryl trinitrate (GTN) therapy, neurohormonal counterregulation consisting of increased catecholamine and vasopressin plasma levels, increased intravascular volume, and activation of the renin-angiotensin-aldosterone system (RAAS) reduces therapeutic efficacy (pseudotolerance). After 3 days, endothelial and smooth muscle dysfunction develops (vascular tolerance and cross-tolerance) by different mechanisms: (1) increased endothelial and smooth muscle superoxide formation from NADPH oxidase activation by protein kinase C (PKC) and from the mitochondria; (2) direct inhibition of nitric oxide synthase (NOS) activation by PKC; (3) uncoupling of endothelial NOS caused by limited BH4 availability resulting from peroxynitrite (ONOO)-induced oxidation of BH4 and reduced expression of GTP-cyclohydrolase I (GTPCH-I); (4) vasoconstrictor supersensitivity caused by increased smooth muscle PKC activity; (5) impaired bioactivation of GTN caused by inhibition of aldehyde dehydrogenase (ALDH-2); (6) inhibition of smooth muscle soluble guanylate cyclase by superoxide and peroxynitrite; (7) increased inactivation of cGMP by phosphodiesterases (PDE); and (8) inhibition of prostacyclin synthase (PGI2-S) by peroxynitrite, leading to reduced PGI2 formation. For sake of clarity, toleranceinduced radical generation in endothelial mitochondria was omitted from the scheme.

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Figure 7. Organic nitrates cause endothelial dysfunction. Evidence for the development of endothelial dysfunction in response to nitroglycerin (glyceryl trinitrate [GTN]) in peripheral arterioles (A) and coronary arteries (B) and to isosorbide mononitrate (ISMN) peripheral arteries (C) was reported. Pentaerythrityl tetranitrate (PETN; D) caused no endothelial dysfunction in the brachial artery, whereas isosorbide dinitrate (ISDN) treatment did (E). Importantly, substances such as folic acid, which have been shown to cause recoupling of an uncoupled nitric oxide (NO) synthase, and the antioxidant vitamin C were able to improve endothelial dysfunction in patients treated with ISMN and GTN. The mechanisms underlying endothelial dysfunction in response to long-term ISDN therapy have not yet been established. FBF indicates forearm blood flow; C, control; LAD, left anterior descending artery; I/N, ratio of infused to noninfused arm; and Ach, acetylcholine. Adapted from Gori et al,4 Caramori et al,65 Thomas et al,66 Schnorbus et al,67 and Sekiya et al,68 with permission of the publisher. Copyright 1998, 2001, 2007, American College of Cardiology Foundation.

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Figure 8. Effects of manipulation of the activity and/or expression of the heme oxygenase-1 (HO-1) on the development of nitrate tolerance. Inhibition of HO-1 in pentaerythrityl tetranitrate (PETN)treated animals caused tolerance and increased mitochondrial superoxide production; induction of HO-1 prevented tolerance in glyceryl trinitrate (GTN)treated animals, mitochondrial vascular superoxide activity, and normalized the activity of the GTN-bioactivating enzyme aldehyde dehydrogenase (ALDH-2). Modified from Wenzel et al.84

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Figure 9. Effects of the mitochondria-targeted antioxidants (mito-quinone [MQ] and a glutathione ester [GSH]) on tolerance development (left) and superoxide production (right). MQ completely prevented tolerance in isolated organ chamber experiments as indicated by the normalization of the glyceryl trinitrate (GTN) dose-response relationship. In addition, the GTN-induced increase in production of reactive oxygen species (ROS) in cultured endothelial cells was completely prevented by MQ or GSH ester treatment and by depletion of mitochondrial proteins. CTR indicates control; p0, cells without mitochondria. Adapted from Esplugues et al,54 with permission of the publisher. Copyright 2006, Lippincott Williams & Wilkins.

Contemporary Reviews in Cardiovascular Medicine

Nitrate Therapy
New Aspects Concerning Molecular Action and Tolerance
1. Thomas Mnzel, MD; 2. Andreas Daiber, PhD; 3. Tommaso Gori, MD, PhD + Author Affiliations

1. From II. Medizinische Klinik und Poliklinik, Kardiologie, Johannes Gutenberg Universitt, Mainz, Germany. 1. Correspondence to Thomas Mnzel, MD, II. Medizinische Klinik und Poliklinik, Kardiologie, Johannes Gutenberg Universitt, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail tmuenzel@uni-mainz.de

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Figure 1. Free radical biochemistry. The radical nitric oxide reacts with superoxide to form the highly reactive intermediate peroxynitrite. Superoxide is dismutated by superoxide dismutase (SOD), leading to the formation of hydrogen peroxide (H2O2) and molecular oxygen (O2).

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Figure 2. Antianginal effects of acutely administered glyceryl trinitrate (GTN).

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Figure 3. Effects of organic nitrates such as glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) on myocardial gene expression. Treatment with GTN significantly changed the expression of 532 genes; PETN treatment changed the expression of 1215 genes. Interestingly, only 68 genes were significantly changed by both compounds, raising doubt that a common vasoactive molecule, such as nitric oxide is released from both drugs. Adapted from Pautz et al.26

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Figure 4. Proposed mechanisms underlying bioactivation of organic nitrates. Left, Characterization of the bioactivation of high-potency nitrates such as nitroglycerin (glyceryl trinitrate [GTN]), pentaerythrityl tetranitrate (PETN), and pentaerythrityl trinitrate (PETriN) by mitochondrial aldehyde dehydrogenase (ALDH-2) when used at low, clinically relevant concentrations (<1 mol/L). The reductase activity converts the organic nitrates to nitrite and the denitrated metabolite (1,2-glyceryl dinitrate, PETriN, or its dinitrate, PEDN). In general, there are 3 proposed mechanisms including nitrogen oxide formed via a reduction of nitrite (NO2), nitric oxide, formed directly in response to interaction with the ALDH-2, and NO2, released from the

mitochondria, may be reduced by the xanthine oxidase in the cytoplasm to form NO. Right, The bioactivation of low-potency nitrates such as isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN) but also GDN, PEDN, and their respective mononitrates GMN and PEMN by P450 enzyme(s) in the endoplasmic reticulum (ER), directly yielding nitric oxide. The latter mechanism also accounts for the highpotency nitrates when used at high concentrations (>1 mol/L). Cyt Ox indicates cytochrome c oxidase.

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Figure 5. Effects of in vivo glyceryl trinitrate (GTN) treatment in patients undergoing bypass surgery on tolerance of mammary artery and vena saphena magna. A and B, in vivo treatment will lead to a marked degree of tolerance in the mammary artery and in vena saphena magna veins (blue lines). The shift to the right was comparable when the mammary artery and the vena saphena were treated in vitro with the aldehyde dehydrogenase (ALDH-2) inhibitor benomyl (green line). C, In vivo and in vitro treatment with GTN and benomyl resulted in comparable inhibition of the activity of ALDH-2 in arteries and veins. D, Long-term treatment with GTN leads to a downregulation of the GTN-bioactivating enzyme ALDH-2. Adapted from Hink et al,32 with permission of the publisher. Copyright 2007, American College of Cardiology Foundation.

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Figure 6. Molecular mechanisms of nitrate tolerance. Within 1 day of continuous low-dose glyceryl trinitrate (GTN) therapy, neurohormonal counterregulation consisting of increased catecholamine and vasopressin plasma levels, increased intravascular volume, and activation of the renin-angiotensin-aldosterone system (RAAS) reduces therapeutic efficacy (pseudotolerance). After 3 days, endothelial and smooth muscle dysfunction develops (vascular tolerance and cross-tolerance) by different mechanisms: (1) increased endothelial and smooth muscle superoxide formation from NADPH oxidase activation by protein kinase C (PKC) and from the mitochondria; (2) direct inhibition of nitric oxide synthase (NOS) activation by PKC; (3) uncoupling of endothelial NOS caused by limited BH4 availability resulting from peroxynitrite (ONOO)-induced oxidation of BH4 and reduced expression of GTP-cyclohydrolase I (GTPCH-I); (4) vasoconstrictor supersensitivity caused by increased smooth muscle PKC activity; (5) impaired bioactivation of GTN caused by inhibition of aldehyde dehydrogenase (ALDH-2); (6) inhibition of smooth muscle soluble guanylate cyclase by superoxide and peroxynitrite; (7) increased inactivation of cGMP by phosphodiesterases (PDE); and (8) inhibition of prostacyclin synthase (PGI2-S) by peroxynitrite, leading to reduced PGI2 formation. For sake of clarity, toleranceinduced radical generation in endothelial mitochondria was omitted from the scheme.

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Figure 7. Organic nitrates cause endothelial dysfunction. Evidence for the development of endothelial dysfunction in response to nitroglycerin (glyceryl trinitrate [GTN]) in peripheral arterioles (A) and coronary arteries (B) and to isosorbide mononitrate (ISMN) peripheral arteries (C) was reported. Pentaerythrityl tetranitrate (PETN; D) caused no endothelial dysfunction in the brachial artery, whereas isosorbide dinitrate

(ISDN) treatment did (E). Importantly, substances such as folic acid, which have been shown to cause recoupling of an uncoupled nitric oxide (NO) synthase, and the antioxidant vitamin C were able to improve endothelial dysfunction in patients treated with ISMN and GTN. The mechanisms underlying endothelial dysfunction in response to long-term ISDN therapy have not yet been established. FBF indicates forearm blood flow; C, control; LAD, left anterior descending artery; I/N, ratio of infused to noninfused arm; and Ach, acetylcholine. Adapted from Gori et al,4 Caramori et al,65 Thomas et al,66 Schnorbus et al,67 and Sekiya et al,68 with permission of the publisher. Copyright 1998, 2001, 2007, American College of Cardiology Foundation.

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Figure 8. Effects of manipulation of the activity and/or expression of the heme oxygenase-1 (HO-1) on the development of nitrate tolerance. Inhibition of HO-1 in pentaerythrityl tetranitrate (PETN)treated animals caused tolerance and increased mitochondrial superoxide production; induction of HO-1 prevented tolerance in glyceryl trinitrate (GTN)treated animals, mitochondrial vascular superoxide activity, and normalized the activity of the GTN-bioactivating enzyme aldehyde dehydrogenase (ALDH-2). Modified from Wenzel et al.84

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Figure 9. Effects of the mitochondria-targeted antioxidants (mito-quinone [MQ] and a glutathione ester [GSH]) on tolerance development (left) and superoxide production (right). MQ completely prevented tolerance in isolated organ chamber experiments as indicated by the normalization of the glyceryl trinitrate (GTN) dose-response relationship. In addition, the GTN-induced increase in production of reactive oxygen species (ROS) in cultured endothelial cells was completely prevented by MQ or GSH ester treatment and by depletion of mitochondrial proteins. CTR indicates control; p0, cells without mitochondria. Adapted from Esplugues et al,54 with permission of the publisher. Copyright 2006, Lippincott Williams & Wilkins.

Contemporary Reviews in Cardiovascular Medicine

Nitrate Therapy
New Aspects Concerning Molecular Action and Tolerance
1. Thomas Mnzel, MD; 2. Andreas Daiber, PhD; 3. Tommaso Gori, MD, PhD + Author Affiliations 1. From II. Medizinische Klinik und Poliklinik, Kardiologie, Johannes Gutenberg Universitt, Mainz, Germany. 1. Correspondence to Thomas Mnzel, MD, II. Medizinische Klinik und Poliklinik, Kardiologie, Johannes Gutenberg Universitt, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail tmuenzel@uni-mainz.de

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Figure 1.

Free radical biochemistry. The radical nitric oxide reacts with superoxide to form the highly reactive intermediate peroxynitrite. Superoxide is dismutated by superoxide dismutase (SOD), leading to the formation of hydrogen peroxide (H2O2) and molecular oxygen (O2).

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Figure 2. Antianginal effects of acutely administered glyceryl trinitrate (GTN).

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Figure 3. Effects of organic nitrates such as glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) on myocardial gene expression. Treatment with GTN significantly changed the expression of 532 genes; PETN treatment changed the expression of 1215 genes. Interestingly, only 68 genes were significantly changed by both compounds, raising doubt that a common vasoactive molecule, such as nitric oxide is released from both drugs. Adapted from Pautz et al.26

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Figure 4. Proposed mechanisms underlying bioactivation of organic nitrates. Left, Characterization of the bioactivation of high-potency nitrates such as nitroglycerin (glyceryl trinitrate [GTN]), pentaerythrityl tetranitrate (PETN), and pentaerythrityl trinitrate (PETriN) by mitochondrial aldehyde dehydrogenase (ALDH-2) when used at low, clinically relevant concentrations (<1 mol/L). The reductase activity converts the organic nitrates to nitrite and the denitrated metabolite (1,2-glyceryl dinitrate, PETriN, or its dinitrate, PEDN). In general, there are 3 proposed mechanisms including nitrogen oxide formed via a reduction of nitrite (NO2), nitric oxide, formed directly in response to interaction with the ALDH-2, and NO2, released from the mitochondria, may be reduced by the xanthine oxidase in the cytoplasm to form NO. Right, The bioactivation of low-potency nitrates such as isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN) but also GDN, PEDN, and their respective mononitrates GMN and PEMN by P450 enzyme(s) in the endoplasmic reticulum (ER), directly yielding nitric oxide. The latter mechanism also accounts for the highpotency nitrates when used at high concentrations (>1 mol/L). Cyt Ox indicates cytochrome c oxidase.

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Figure 5. Effects of in vivo glyceryl trinitrate (GTN) treatment in patients undergoing bypass surgery on tolerance of mammary artery and vena saphena magna. A and B, in vivo treatment will lead to a marked degree of tolerance in the mammary artery and in vena saphena magna veins (blue lines). The shift to the right was comparable when the mammary artery and the vena saphena were treated in vitro with the aldehyde dehydrogenase (ALDH-2) inhibitor benomyl (green line). C, In vivo and in vitro treatment with GTN and benomyl resulted in comparable inhibition of the activity of ALDH-2 in arteries and veins. D, Long-term treatment with GTN leads to a downregulation of the GTN-bioactivating enzyme ALDH-2. Adapted from Hink et al,32 with permission of the publisher. Copyright 2007, American College of Cardiology Foundation.

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Figure 6. Molecular mechanisms of nitrate tolerance. Within 1 day of continuous low-dose glyceryl trinitrate (GTN) therapy, neurohormonal counterregulation consisting of increased catecholamine and vasopressin plasma levels, increased intravascular volume, and activation of the renin-angiotensin-aldosterone system (RAAS) reduces therapeutic efficacy (pseudotolerance). After 3 days, endothelial and smooth muscle dysfunction develops (vascular tolerance and cross-tolerance) by different mechanisms: (1) increased endothelial and smooth muscle superoxide formation from NADPH oxidase activation by protein kinase C (PKC) and from the mitochondria; (2) direct inhibition of nitric oxide synthase (NOS) activation by PKC; (3) uncoupling of endothelial NOS caused by limited BH4 availability resulting from peroxynitrite (ONOO)-induced oxidation of BH4 and reduced expression of GTP-cyclohydrolase I (GTPCH-I); (4) vasoconstrictor supersensitivity caused by increased smooth muscle PKC activity; (5) impaired bioactivation of GTN caused by inhibition of aldehyde dehydrogenase (ALDH-2); (6) inhibition of smooth muscle soluble guanylate cyclase by superoxide and peroxynitrite; (7) increased inactivation of cGMP by phosphodiesterases (PDE); and (8) inhibition of prostacyclin synthase (PGI2-S) by peroxynitrite, leading to reduced PGI2 formation. For sake of clarity, toleranceinduced radical generation in endothelial mitochondria was omitted from the scheme.

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Figure 7. Organic nitrates cause endothelial dysfunction. Evidence for the development of endothelial dysfunction in response to nitroglycerin (glyceryl trinitrate [GTN]) in peripheral arterioles (A) and coronary arteries (B) and to isosorbide mononitrate (ISMN) peripheral arteries (C) was reported. Pentaerythrityl tetranitrate (PETN; D) caused no endothelial dysfunction in the brachial artery, whereas isosorbide dinitrate (ISDN) treatment did (E). Importantly, substances such as folic acid, which have been shown to cause recoupling of an uncoupled nitric oxide (NO) synthase, and the antioxidant vitamin C were able to improve endothelial dysfunction in patients treated with ISMN and GTN. The mechanisms underlying endothelial dysfunction in response to long-term ISDN therapy have not yet been established. FBF indicates forearm blood flow; C, control; LAD, left anterior descending artery; I/N, ratio of infused to noninfused arm; and Ach, acetylcholine. Adapted from Gori et al,4 Caramori et al,65 Thomas et al,66 Schnorbus et al,67 and Sekiya et al,68 with permission of the publisher. Copyright 1998, 2001, 2007, American College of Cardiology Foundation.

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Figure 8. Effects of manipulation of the activity and/or expression of the heme oxygenase-1 (HO-1) on the development of nitrate tolerance. Inhibition of HO-1 in pentaerythrityl tetranitrate (PETN)treated animals caused tolerance and increased mitochondrial superoxide production; induction of HO-1 prevented tolerance in glyceryl trinitrate (GTN)treated animals, mitochondrial vascular superoxide activity, and normalized the activity of the GTN-bioactivating enzyme aldehyde dehydrogenase (ALDH-2). Modified from Wenzel et al.84

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Figure 9. Effects of the mitochondria-targeted antioxidants (mito-quinone [MQ] and a glutathione ester [GSH]) on tolerance development (left) and superoxide production (right). MQ completely prevented tolerance in isolated organ chamber experiments as indicated by the normalization of the glyceryl trinitrate (GTN) dose-response relationship. In addition, the GTN-induced increase in production of reactive oxygen species (ROS) in cultured endothelial cells was completely prevented by MQ or GSH ester treatment and by depletion of mitochondrial proteins. CTR indicates control; p0, cells without mitochondria. Adapted from Esplugues et al,54 with permission of the publisher. Copyright 2006, Lippincott Williams & Wilkins.

Nitrodilators
General Pharmacology
Nitric oxide (NO), a molecule produced by many cells in the body, and has several important actions (click here for details). In the cardiovascular system, NO is primarily produced by vascular endothelial cells. This endothelial-derived NO has several important functions including relaxing vascular smooth muscle (vasodilation), inhibiting platelet aggregation (anti-thrombotic), and inhibiting leukocyte-endothelial interactions (anti-inflammatory). These actions involve NO-stimulated formation of cGMP. Nitrodilators are drugs that mimic the actions of endogenous NO by releasing NO or forming NO within tissues. These drugs act directly on the vascular smooth muscle to cause relaxation and therefore serve as endothelial-independent vasodilators.

There are two basic types of nitrodilators: those that release NO spontaneously (e.g., sodium nitroprusside) and organic nitrates that require an enzymatic process to form NO. Organic nitrates do not directly release NO, however, their nitrate groups interact with enzymes and intracellular sulfhydryl groups that reduce the nitrate groups to NO or to S-nitrosothiol, which then is reduced to NO. Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation (click here for details). NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation. Tolerance to organic nitrates occurs with frequent dosing, which decreases their efficacy. The problem is partially circumvented by using the smallest effective dose of the compound coupled with infrequent or irregular dosing. The mechanism for tolerance is not fully understood, but it may involve depletion of tissue sulfhydryl groups, or scavenging of NO by superoxide anion and the subsequent production of peroxynitrite that may inhibit guanylyl cyclase.

Primary Cardiovascular Actions of Nitrodilators

Systemic vasculature

vasodilation (venous dilation > arterial dilation) decreased venous pressure decreased arterial pressure (small effect)

Cardiac

reduced preload and afterload (decreased wall stress) decreased oxygen demand

Coronary

prevents/reverses vasospasm vasodilation (primarily epicardial vessels) improves subendocardial perfusion

increased oxygen delivery

Although organic nitrates can dilate both arteries and veins, venous dilation predominates when these drugs are given at normal therapeutic doses. Venous dilation reduces venous pressure and decreases ventricular preload. This reduces ventricular wall stress and oxygen demand by the heart, thereby enhancing the oxygen supply/demand ratio. A reduction in preload (reduced diastolic wall stress) also helps to improve subendocardial blood flow, which is often compromised in coronary artery disease. Mild coronary dilation or reversal of coronary vasospasm will further enhance the oxygen supply/demand ratio and diminish the anginal pain. Coronary dilation occurs primarily in the large epicardial vessels, which diminishes the likelihood of coronary vascular steal. Systemic arterial dilation reduces afterload, which can enhance cardiac output while at the same time reducing ventricular wall stress and oxygen demand. At high concentrations, excessive systemic vasodilation may lead to hypotension and a baroreceptor reflex that produces tachycardia. When this occurs, the beneficial effects on the oxygen supply/demand ratio are partially offset. Furthermore, tachycardia, by reducing the duration of diastole, decreases the time available for coronary perfusion, most of which occurs during diastole (click here for more details).

Therapeutic Indications
The primary pharmacologic action of nitrodilators, arterial and venous dilation, make these compounds useful in the treatment of hypertension, heart failure, angina and myocardial infarction. Another beneficial action of nitrodilators is their ability to inhibit platelet aggregation.
Hypertension

Nitrodilators are not used to treat chronic primary or secondary hypertension; however, sodium nitroprusside and nitroglycerine are used to lower blood pressure in acute hypertensive emergencies that may result from a pheochromocytoma, renal artery stenosis, aortic dissection, etc. Nitrodilators may also be used during surgery to control arterial pressure within desired limits.
Heart failure

Nitrodilators are used in acute heart failure and in severe chronic heart failure. Arterial dilation reduces afterload on the failing ventricle and leads to an increase in stroke volume and ejection fraction. Furthermore, the venous dilation reduces venous pressure, which helps to reduce edema. Reducing both afterload and preload on the heart also helps to improve the mechanical efficiency of dilated hearts and to reduce wall stress and the oxygen demands placed on the failing heart.
Angina and myocardial infarction

Organic nitrates are used extensively to treat angina and myocardial infarction. They are useful in Printzmetal's variant angina because they improve coronary blood flow (i.e., increase oxygen supply) by reversing and inhibiting coronary vasospasm. They are important in other forms of angina because they reduce preload on the heart by producing venous dilation, which decreases myocardial oxygen demand. It is unclear if direct dilation of epicardial coronary arteries play a role in the antianginal effects of nitrodilators in chronic stable or unstable angina. These drugs also reduce systemic vascular resistance (depending on

dose) and arterial pressure, which further reduces myocardial oxygen demand. Taken together, these two actions dramatically improve the oxygen supply/demand ratio and thereby reduce anginal pain.

Specific Drugs
Several different nitrodilators are available for clinical use: (Go to www.rxlist.com for specific drug information)

isosorbide dinitrate isosorbide mononitrate nitroglycerin erythrityl tetranitrate pentaerythritol tetranitrate sodium nitroprusside

The nitrodilators listed above differ in the route of administration, onset of action, and duration of action. Nitroglycerin, which has been used since the 19th century, is commonly used in the treatment of angina because it is very fast acting (within 2 to 5 minutes) when administered sublingually. Its effects usually wear off within 30 minutes. Therefore, nitroglycerin is particularly useful for preventing or terminating an acute anginal attack. Longer-acting preparations of nitroglycerin (e.g., transdermal patches) have a longer onset of action (30 to 60 minutes), but are effective for 12 to 24 hours. Intravenous nitroglycerin is used in the hospital setting for unstable angina and acute heart failure. Isosorbide dinitrate and mononitrate, and tetranitrate compounds have a longer onset of action and duration of action than nitroglycerin. This makes these compounds more useful than short-acting nitroglycerin for the long-term prophylaxis and management of coronary artery disease. Oral bioavailability of many organic nitrates is low because of first-pass metabolism by the liver. Isosorbide mononitrate, which has nearly 100% bioavailability, is the exception. Therefore, oral administration of these compounds requires much higher doses than sublingual administration, which is not subject to first-pass hepatic metabolism. The metabolites of organic nitrates are biologically active and have a longer half-life than the parent compound. Therefore, the metabolites contribute significantly to the therapeutic activity of the compound. Sodium nitroprusside, unlike organic nitrates, dilates arterial resistance vessels more than venous vessels. Because of its rapid onset of action, it is used to treat severe hypertensive emergencies and severe heart failure. It is only available as an intravenous preparation, and because of its short half-life, continuous infusion is required.

Side Effects and Contraindications

The most common side effects of nitrodilators are headache (caused by cerebral vasodilation) and cutaneous flushing. Other side effects include postural hypotension and reflex tachycardia. Excessive hypotension and tachycardia can worsen the angina by increasing oxygen demand. Prolonged use of sodium nitroprusside carries the risk of thiocyanate toxicity because nitroprusside releases cyanide along with NO. The thiocyanate is formed in the liver from the reduction of cyanide by a sulfhydryl donor. There is clinical evidence that nitrodilators may interact adversely with cGMP-dependent phosphodiesterase inhibitors that are used to treat erectile dysfunction (e.g., sildenafil [Viagra]). The reason for this adverse reaction is that nitrodilators stimulate cGMP production and drugs like sildenafil inhibit cGMP degradation. When combined, these two drug classes greatly potentiate cGMP levels, which can lead to hypotension and impaired coronary perfusion. Revised 11/7/12

Cardiac Glycosides (Digitalis Compounds)

General Pharmacology
Cardiac glycosides represent a family of compounds that are derived from the foxglove plant (Digitalis purpurea). The therapeutic benefits of digitalis were first described by William Withering in 1785. Initially, digitalis was used to treat dropsy, which is an old term for edema. Subsequent investigations found that digitalis was most useful for edema that was caused by a weakened heart (i.e., heart failure).
Mechanisms of action

Digitalis compounds are potent inhibitors of cellular Na+/K+-ATPase. This ion transport system moves sodium ions out of the cell and brings potassium ions into the cell. This transport function is necessary for cell survival because sodium diffusion into the cell and potassium diffusion out of the cell down their concentration gradients would reduce their concentration differences (gradients) across the cell membrane over time. Loss of these ion gradients would lead to cellular depolarization and loss of the negative membrane potential that is required for normal cell function. The Na+/K+-ATPase also plays an active role in the membrane potential. this pump is electrogenic because it transports 3 sodium ions out of the cell for every 2 potassium ions that enter the cell. This can add several negative millivolts to the membrane potential depending on the activity of the pump.

Cardiac myocytes, as well as many other cells, have a Na+-Ca++ exchanger (not an active energy-requiring pump) that is essential for maintaining sodium and calcium homeostasis. The exact mechanism by which this exchanger works is unclear. It is known that calcium and sodium can move in either direction across the sarcolemma. Furthermore, three sodium ions are exchanged for each calcium, therefore an electrogenic potential is generated by this

exchanger. The direction of movement of these ions (either inward or outward) depends upon the membrane potential and the chemical gradient for the ions. We also know that an increase in intracellular sodium concentration competes for calcium through this exchange mechanism leading to an increase in intracellular calcium concentration. As intracellular sodium increases, the concentration gradient driving sodium into the cell across the exchanger is reduced, thereby reducing the activity of the exchanger, which decreases the movement of calcium out of the cell. Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a subsequent accumulation of intracellular calcium because of decreased exchange pump activity. By inhibiting the Na+/K+-ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na+-Ca++ exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy). Inhibition of the Na+/K+-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction. By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent activity to the heart. This parasympathomimetic action of digitalis reduces sinoatrial firing rate (decreases heart rate; negative chronotropy) and reduces conduction velocity of electrical impulses through the atrioventricular node (negative dromotropy).
Pharmacokinetics and toxicity

The long half-life of digitalis compounds necessitates special considerations when dosing. With a half-life of 40 hours, digoxin would require several days of constant dosing to reach steady-state, therapeutic plasma levels (digitoxin with a half-life of 160 hours, would require almost a month!). Therefore, when initiating treatment, a special dosing regimen involving "loading doses" is used to rapidly increase digoxin plasma levels. This process is termed "digitalization." For digoxin, the therapeutic plasma concentration range is 0.5 - 1.5 ng/ml. It is very important that therapeutic plasma levels are not exceeded because digitalis compounds have a relatively narrow therapeutic safety window. Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity, which is manifested as arrhythmias, some of which may be life-threatening. If toxicity occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels because of the long half-life. There is available for digoxin toxicity an immune Fab (Digibind) that can be used to rapidly reduce plasma digoxin levels. Potassium supplementation can also reverse the toxic effects of digoxin if the toxicity is related to hypokalemia (see below).
Drug Interactions

Many commonly used drugs interact with digitalis compounds. The Class IA antiarrhythmic, quinidine, competes with digoxin for binding sites and depresses renal clearance of digoxin. These effects increase digoxin levels and can produce toxicity. Similar interactions occur with calcium-channel blockers and nonsteroidal anti-inflammatory drugs. Other drugs that interact with digitalis compounds are amiodarone (Class III antiarrhythmic) and betablockers. Diuretics can indirectly interact with digoxin because of their potential for decreasing plasma potassium levels (i.e., producing hypokalemia). Because potassium competes with digoxin for binding sites on the Na+/K+-ATPase, hypokalemia results in increased digoxin binding and thereby enhances its therapeutic and toxic effects.

Hypercalcemia enhances digitalis-induced increases in intracellular calcium, which can lead to calcium overload and increased susceptibility to digitalis-induced arrhythmias. Hypomagnesemia also sensitizes the heart to digitalis-induced arrhythmias.

Therapeutic Uses Therapeutic Uses of Digitalis Compounds

Heart Failure

inotropy ejection fraction preload pulmonary congestion/edema

Arrhythmias

AV nodal conduction (parasympathomimetic effect) ventricular rate in atrial flutter and fibrillation

Heart failure

Digitalis compounds have historically been used in the treatment of chronic heart failure owing to their cardiotonic effect. Although newer and more efficacious treatments for heart failure are available, digitalis compounds are still widely used. Clinical studies in heart failure patients have shown that digoxin, when used in conjunction with diuretics and vasodilators, improves cardiac output and ejection fraction, and reduces filling pressures and pulmonary capillary wedge pressure (this reduces pulmonary congestion and edema); heart rate changes very little. These effects are to be expected for a drug that increases inotropy. Although the direct effect of digoxin on blood vessels is vasoconstriction, when given to patients in heart failure, the systemic vascular resistance falls. This most likely results from the improvement in cardiac output, which leads to withdrawal of compensatory vasoconstrictor mechanisms (e.g., sympathetic adrenergic activity and angiotensin II influences). Digitalis compounds have a small direct diuretic effect on the kidneys, which is beneficial in heart failure patients.
Atrial fibrillation and flutter

Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output. Furthermore, chronic ventricular tachycardia can lead to heart failure. Digitalis compounds, such as digoxin, are useful for reducing ventricular rate when it is being driven by a high atrial rate. The mechanism of this beneficial effect of digoxin is its ability to activate vagal efferent nerves to the heart (parasympathomimetic effect). Vagal activation can reduce the conduction of electrical impulses within the atrioventricular node to the point where some of the impulses will be

blocked. When this occurs, fewer impulses reach the ventricles and ventricular rate falls. Digoxin also increases the effective refractory period within the atrioventricular node.

Specific Drugs
Three different digitalis compounds (cardiac glycosides) are listed in the table below. The compound most commonly used in the U.S. is digoxin. Ouabain is used primarily as a research tool. (See www.rxlist.com for more details on digoxin).
ug Dr Di goxin Di gitoxin Ou abain Oral Availability* 75% >90% 0% Half-life (hours) 40 160 20 Elimi nation kidne ys liver kidne ys

* percent absorption

Side Effects, Contraindications and Warnings

The major side effect of digitalis compounds is cardiac arrhythmia, especially atrial tachycardias and atrioventricular block. Digitalis compounds are contraindicated in patients who are hypokalemic, or who have atrioventricular block or Wolff-Parkinson-White (WPW) syndrome. Impaired renal function leads to enhanced plasma levels of digoxin because digoxin is eliminated by the kidneys. Lean, elderly patients are more susceptible to digitalis toxicity because they often have reduced renal function, and their reduced muscle mass increases plasma digoxin levels at a given dose because muscle Na+/K+-ATPase acts as a large binding reservoir for digitalis. A 2012 analysis of the AFFIRM trial determined that digoxin significantly increased all-cause mortality in patients with atrial fibrillation. This calls into question the practice of using digoxin for lowering ventricular rate in patients with atrial fibrillation. Revised 12/3/12

hosphodiesterase Inhibitors
General Pharmacology of cAMP-Dependent Phosphodiesterase Inhibitors (PDE3)

Heart

Intracellular concentrations of cAMP play an important second messenger role in regulating cardiac muscle contraction. Activation of the sympathetic nervous system releases the neurotransmitter norepinephrine and increases circulating catecholamines (epinephrine and norepinephrine). These catecholamines bind primarily to beta1-adrenoceptors in the heart that are coupled to Gs-proteins. This activates adenylyl cyclase to form cAMP from ATP. Increased cAMP, through its coupling with other intracellular messengers, increases contractility (inotropy), heart rate (chronotropy) and conduction velocity (dromotropy). Cyclic-AMP is broken down by an enzyme called cAMP-dependent phosphodiesterase (PDE). The isoform of this enzyme that is targeted by currently used clinical drugs is the type 3 form (PDE3). Inhibition of this enzyme prevents cAMP breakdown and thereby increases its intracellular concentration. This increases cardiac inotropy, chronotropy and dromotropy. PDE3 inhibitors can be thought of as a backdoor approach to cardiac stimulation, whereas agonists go through the front door to produce the same cardiac effects.
Blood vessels

Cyclic-AMP also plays an important role in regulating the contraction of vascular smooth muscle. Beta2-adrenoceptor agonists such as epinephrine stimulate the Gs-protein and the formation of cAMP (click here for details). Unlike cardiac muscle, increased cAMP in smooth muscle causes relaxation. The reason for this is that cAMP normally inhibits myosin light chain kinase, the enzyme that is responsible for phosphorylating smooth muscle myosin and causing contraction. Like the heart, the cAMP is broken down by a cAMP-dependent PDE (PDE3).Therefore, inhibition of this enzyme increases intracellular cAMP, which further inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).

Cardiovascular Actions of cAMP-dependent PDE (type3) Inhibitors

Systemic Circulation

Vasodilation Increased organ perfusion Decreased systemic vascular resistance Decreased arterial pressure

Cardiopulmonary

Increased contractility and heart rate Increased stroke volume and ejection fraction Decreased ventricular preload
(secondary to increased output)

Decreased pulmonary capillary wedge pressure

Overall cardiovascular effects

The cardiac and vascular effects of cAMP-dependent PDE inhibitors cause cardiac stimulation, which increases cardiac output, and reduced systemic vascular resistance, which tends to lower arterial pressure. Because cardiac output increases and systemic vascular resistance decreases, the change in arterial pressure depends on the relative effects of the PDE inhibitor on the heart versus the vasculature. At normal therapeutic doses, PDE3 inhibitors such as milrinone have a greater vascular than cardiac effect so that arterial pressure is lowered in the presence of augmented cardiac output. Because of the dual cardiac and vascular effects of these compounds, they are sometimes referred to as "inodilators."
Other actions

PDE3 inhibitors also decrease platelet aggregation by increasing platelet cAMP. However, only cilostazol (see below) is used for this purpose in the treatment of intermittant claudication (ischemic leg pain associated with leg movement).

General Pharmacology of cGMP-Dependent Phosphodiesterase Inhibitors (PDE5)

There is a second isoenyme form of PDE in vascular smooth muscle that is a cGMPdependent phosphodiesterase. The type 5 isoform of this enzyme (PDE5) is found in the corpus cavernosum of the penis and in vascular smooth muscle. This enzyme is responsible for breaking down cGMP that forms in response to increased nitric oxide (NO). Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation (click here for details).

NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation. Therefore, inhibitors cGMP-dependent phosphodiesterase, by increasing intracellular cGMP, enhance smooth muscle relaxation and vasodilation, and cause penile erection.

Therapeutic Indications
The cardiostimulatory and vasodilatory actions of PDE3 inhibitors make them suitable for the treatment of heart failure. Arterial dilation reduces afterload on the failing ventricle and leads to an increase in stroke volume and ejection fraction, as well as increases organ perfusion. Reducing the afterload leads to a secondary decrease in preload on the heart that helps to improve the mechanical efficiency of dilated hearts and to reduce ventricular wall stress and the oxygen demands placed on the failing heart. The cardiostimulatory effects of these drugs increase inotropy, which further enhances stroke volume and ejection fraction. Tachycardia, however, also results, and this is not beneficial; therefore, doses are used that minimize the positive chronotropic actions of the drug. A baroreceptor reflex, which occurs in response to hypotension, may contribute to the tachycardia. Clinical trials have shown that long-term therapy with PDE3 inhibitors increases mortality in heart failure patients; therefore, these drugs are not used for long-term, chronic therapy. They are very useful, however, in treating acute, decompensated heart failure or temporary bouts of decompensated chronic failure. They are not used as a monotherapy. Instead, they are used in conjunction with other treatment modalities such as diuretics, ACE inhibitors, beta-blockers or digitalis. The somewhat selective vasodilatory actions of PDE5 inhibitors have made these compounds very useful in the treatment of male erectile dysfunction. The PDE5 inhibitor sildenafil is also approved for the treatment of pulmonary hypertension.

Specific Drugs
Several different PDE inhibitors are available for clinical use: (Go to www.rxlist.com for specific drug information)

PDE3 inhibitors o milrinone

o o

inamrinone (formerly amrinone) cilostazol

PDE5 inhibitors
o o

sildenafil tadalafil

The PDE3 inhibitors (except cilostazol) are used for treating acute, decompensated heart failure, whereas the PDE5 inhibitors are used for treating male erectile dysfunction and pulmonary hypertension. Note that the PDE3 inhibitors used in acute heart failure end in "one," whereas the PDE5 inhibitors end in "fil". Inhibition of platelet aggregation, along with vasodilation, is an important mechanism of action for cilostazol, which is used in the treatment of intermittant claudication in peripheral arterial disease. Cilostazol appears to have less cardiostimulatory effects than milrinone.

Side Effects and Contraindications

PDE3 inhibitors

Milrinone and inamrinone are not used in the treatment of chronic heart failure because clinical trials have shown that long-term use of these drugs worsen outcome. The most common and severe side effect of PDE3 inhibitors is ventricular arrhythmias in about 12% of patients, some of which may be life-threatening. Headaches and hypotension occur in about 3% of patients. These side effects are not uncommon for drugs that increase cAMP in cardiac and vascular tissues, other examples being -agonists.
PDE5 inhibitors

The most common side effects for PDE5 inhibitors include headache and cutaneous flushing, both of which are related to vascular dilation caused by increased vascular cGMP. There is clinical evidence that nitrodilators may interact adversely with PDE5 inhibitors. The reason for this adverse reaction is that nitrodilators stimulate cGMP production while PDE5 inhibitors inhibit cGMP degradation. When combined, these two drug classes greatly potentiate cGMP levels, which can lead to hypotension and impaired coronary perfusion. Revised 11/13/12

Beta-Adrenoceptor Antagonists (BetaBlockers)

General Pharmacology
Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors. This inhibits normal sympathetic effects that act through these receptors. Therefore, beta-blockers are sympatholytic drugs. Some beta-blockers, when they bind to the beta-adrenoceptor, partially activate the receptor while preventing norepinephrine from binding to the receptor. These partial agonists therefore provide some "background" of sympathetic activity while preventing normal and enhanced sympathetic activity. These particular beta-blockers (partial agonists) are said to possess intrinsic sympathomimetic activity (ISA). Some beta-blockers also possess what is referred to as membrane stabilizing activity (MSA). This effect is similar to the membrane stabilizing activity of sodium-channels blockers that represent Class I antiarrhythmics. The first generation of beta-blockers were non-selective, meaning that they blocked both beta-1 (1) and beta-1 (2) adrenoceptors. Second generation beta-blockers are more cardioselective in that they are relatively selective for 1 adrenoceptors. Note that this relative selectivity can be lost at higher drug doses. Finally, the third generation beta-blockers are drugs that also possess vasodilator actions through blockade of vascular alpha-adrenoceptors.

Heart

Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both 1 and 2 adrenoceptors, although the predominant receptor type in number and function is 1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood. Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from binding to the beta-adrenoceptor by competing for the binding site. Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cell. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate (chronotropy). PK-A also phosphorylates sites on the sarcoplasmic reticulum, which lead to enhanced release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate myosin light chains, which may contribute to the positive inotropic effect of beta-adrenoceptor stimulation. Because there is generally some level of sympathetic tone on the heart, beta-blockers are able to reduce sympathetic influences that normally stimulate chronotropy (heart rate), inotropy (contractility), dromotropy (electrical conduction) and lusitropy (relaxation). Therefore, betablockers cause decreases in heart rate, contractility, conduction velocity, and relaxation rate. These drugs have an even greater effect when there is elevated sympathetic activity.

Blood vessels

Vascular smooth muscle has 2-adrenoceptors that are normally activated by norepinephrine released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like

those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by 2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation). Compared to their effects in the heart, beta-blockers have relatively little vascular effect because 2-adrenoceptors have only a small modulatory role on basal vascular tone. Nevertheless, blockade of 2-adrenoceptors is associated with a small degree of vasoconstriction in many vascular beds. This occurs because beta-blockers remove a small 2-adrenoceptor vasodilator influence that is normally opposing the more dominant alphaadrenoceptor mediated vasoconstrictor influence.

Therapeutic Indications Beta-Blockers

Cardiac Effects

Decrease contractility (negative intropy) Decrease relaxation rate (negative lusitropy) Decrease heart rate (negative chronotropy) Decrease conduction velocity (negative dromotropy)

Vascular Effects

Smooth muscle contraction (mild vasoconstriction)

Beta-blockers are used for treating hypertension, angina, myocardial infarction, arrhythmias and heart failure.
Hypertension

Beta-blockers decrease arterial blood pressure by reducing cardiac output. Many forms of hypertension are associated with an increase in blood volume and cardiac output. Therefore, reducing cardiac output by beta-blockade can be an effective treatment for hypertension, especially when used in conjunction with a diuretic. Acute treatment with a beta-blocker is not very effective in reducing arterial pressure because of a compensatory increase in systemic vascular resistance. This may occur because of baroreceptor reflexes working in conjunction with the removal of 2 vasodilatory influences that normally offset, to a small degree, alpha-adrenergic mediated vascular tone. Chronic treatment with beta-blockers lowers arterial pressure more than acute treatment possibly because of reduced renin release

and effects of beta-blockade on central and peripheral nervous systems. Beta-blockers have an additional benefit as a treatment for hypertension in that they inhibit the release of renin by the kidneys (the release of which is partly regulated by 1-adrenoceptors in the kidney). Decreasing circulating plasma renin leads to a decrease in angiotensin II and aldosterone, which enhances renal loss of sodium and water and further diminishes arterial pressure. Hypertension in some patients is caused by emotional stress, which causes enhanced sympathetic activity. Beta-blockers can be very effective in these patients. Beta-blockers are used in the preoperative management of hypertension caused by a pheochromocytoma, which results in elevated circulating catecholamines. When used for this condition, the blood pressure is first controlled using an alpha-blocker such as phenoxybenzamine, and then a beta-blocker can be carefully administered to reduce the excessive cardiac stimulation by the catecholamines. It is important that a beta-blocker is administered only after adequate blockade of vascular alpha-adrenoceptors so that a hypertensive crisis does not occur as a result of unopposed alpha-adrenoceptor stimulation.
Angina and myocardial infarction

Theraputic Use of Beta-Blockers

Hypertension Angina Myocardial infarction Arrhythmias Heart failure

The antianginal effects of beta-blockers are attributed to their cardiodepressant and hypotensive actions. By reducing heart rate, contractility, and arterial pressure, beta-blockers reduce the work of the heart and the oxygen demand of the heart. Reducing oxygen demand improves the oxygen supply/demand ratio, which can relieve a patient of anginal pain that is caused by a reduction in the oxygen supply/demand ratio due to coronary artery disease. Furthermore, beta-blockers have been found to be very important in the treatment of myocardial infarction in that they have been shown to decrease mortality. Their benefit is derived not only from improving the oxygen supply/demand ratio and reducing arrhythmias, but also from their ability to inhibit subsequent cardiac remodeling.
Arrhythmias

The antiarrhythmic properties beta-blockers (Class II antiarrhythmic) are related to their ability to inhibit sympathetic influences on cardiac electrical activity. Sympathetic nerves increase sinoatrial node automaticity by increasing the pacemaker currents, which increases sinus rate. Sympathetic activation also increases conduction velocity (particularly at the atrioventricular node), and stimulates aberrant pacemaker activity (ectopic foci). These sympathetic influences are mediated primarily through 1-adrenoceptors. Therefore, betablockers can attenuate these sympathetic effects and thereby decrease sinus rate, decrease

conduction velocity (which can block reentry mechanisms), and inhibit aberrant pacemaker activity. Beta-blockers also affect non-pacemaker action potentials by increasing action potential duration and the effective refractory period. This effect can play a major role in blocking arrhythmias caused by reentry.
Heart failure

The majority of patients in heart failure have a form that is called systolic dysfunction, which means that the contractile function of the heart is depressed (loss of inotropy). Although it seems counterintuitive that cardioinhibitory drugs such as beta-blockers would be used in cases of systolic dysfunction, clinical studies have shown quite conclusively that some specific beta-blockers actually improve cardiac function and reduce mortality. Furthermore, they have been shown to reduce deleterious cardiac remodeling that occurs in chronic heart failure. Although the exact mechanism by which beta-blockers confer their benefit to heart failure patients is poorly understood, it may be related to blockade of excessive, chronic sympathetic influences on the heart, which are known to be harmful to the failing heart.

Different Classes of Beta-Blockers and Specific Drugs

Beta-blockers that are used clinically can be divided into two classes: 1) non-selective blockers (block both 1and 2 receptors), or 2) relatively selective 1 blockers ("cardioselective" beta-blockers). Some beta-blockers have additional mechanisms besides beta-blockade that contribute to their unique pharmacologic profile. The two classes of betablockers along with specific compounds are listed in the following table. Additional details for each drug may be found at www.rxlist.com. The clinical uses indicated in the table represent both on and off-label uses of beta-blockers. For example, a given beta-blocker may only be approved by the FDA for treatment of hypertension; however, physicians sometimes elect to prescribe the drug for angina because of the class-action benefit that beta-blockers have for angina.

Clinical Uses Cl ass/Dru g N onselectiv e 1/2 c arteolol c arvedil ol la betalol adololn p enbutol ol pi ndolol X X X X X X X X X X X X X ; long ISA acting; also used for glaucoma blocking activity ISA ; blocking activity lon g acting ISA ; MSA ISA H T N A ngi na A rrh y I M C H F Co mments

p ropran olol otalol s molol ti 1 selectiv e a cebutol ol a tenolol b etaxolo l bi soprolo l e smolol m etoprol ol n ebivolo l

X X

MS A; prototypi cal betablocker sev eral other significan t mechanis ms

pri marily used for glaucoma

X X X X X X X

X X X X

X X X X X X A

ISA

MS

ultr a short acting; intra or postopera tive HTN X X A MS

ativelyrel selective in most patients; vasodilati ng (NO release)

Abbreviations: HTN, hypertension; Arrhy, arrhythmias; MI, myocardial infarction; CHF, congestive heart failure; ISA, intrinsic sympathomimetic activity.

Side Effects and Contraindications

Cardiovascular side effects

Many of the side effects of beta-blockers are related to their cardiac mechanisms and include bradycardia, reduced exercise capacity, heart failure, hypotension, and atrioventicular (AV) nodal conduction block. Beta-blockers are therefore contraindicated in patients with sinus bradycardia and partial AV block. The side effects listed above result from excessive blockade of normal sympathetic influences on the heart. Considerable care needs to be exercised if a beta-blocker is given in conjunction with cardiac selective calcium-channel blockers (e.g., verapamil) because of their additive effects in producing electrical and mechanical depression. Although this may change with future clinical trials on safety and efficacy of beta-blockers in heart failure, at present only carvedilol and metoprolol have been approved by the FDA for this indication.
Other side effects

Bronchoconstriction can occur, especially when non-selective beta-blockers are administered to asthmatic patients. Therefore, non-selective beta-blockers are contraindicated in patients with asthma or chronic obstructive pulmonary disease. Bronchoconstriction occurs because

sympathetic nerves innervating the bronchioles normally activate 2-receptors that promote bronchodilation. Blockade of these receptors can lead to bronchoconstriction. Hypoglycemia can occur with beta-blockade because 2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glucose. Therefore, blocking 2-adrenoceptors lowers plasma glucose. 1blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia which serves as a warning sign for insulin-induced hypoglycemia may be masked. Therefore, beta-blockers are to be used cautiously in diabetics.