Mechanism of Action

NTG enhances myocardial oxygen delivery and reduces myocardial oxygen demand. NTG is a smooth muscle relaxant that causes vasculature dilation. Nitrate-mediated vasodilation occurs with or without intact vascular endothelium.¹⁰ Nitrites, organic nitrites, nitroso compounds, and other nitrogen oxide–containing substances (e.g., nitroprusside) enter the smooth muscle cell and are converted to reactive nitric oxide (NO) or S-nitrosothiols, which stimulate guanylate cyclase metabolism to produce cyclic guanosine monophosphate (cGMP)^11–13 (Figure 10-1). A cGMP-dependent protein kinase is stimulated with resultant protein phosphorylation in the smooth muscle. This leads to a dephosphorylation of the myosin light chain and smooth muscle relaxation.^14,15 Vasodilation is also associated with a reduction of intracellular calcium.¹⁶ Sulfhydryl (SH) groups are required for formation of NO and the stimulation of guanylate cyclase. When excessive numbers of SH groups are metabolized by prolonged exposure to NTG, vascular tolerance occurs.¹⁷ The addition of N-acetylcysteine, an SH donor, reverses NTG tolerance.¹⁸ The mechanism by which NTG compounds are uniquely better venodilators, especially at lower serum concentrations, is unknown but may be related to increased uptake of NTG by veins compared with arteries.¹⁹

Figure 10-1 Mechanisms of the effects of nitrates in the generation of nitric oxide (NO•) and the stimulation of guanylate cyclase (+) and cyclic guanosine monophosphate (cGMP), which mediates vasodilation. Sulfhydryl (SH) groups are required for the formation of NO• and the stimulation of guanylate cyclase. Isosorbide dinitrate is metabolized by the liver, whereas this route of metabolism is bypassed by the mononitrates. GTP, guanosine triphosphate.

(Redrawn from Opie LH: Drugs for the heart, 4th ed. Philadelphia: WB Saunders, 1995, p 33.)

Physiologic Effects

Two important physiologic effects of NTG are systemic and regional venous dilation (Figure 10-2). Venodilation can markedly reduce venous pressure, venous return to the heart, and cardiac filling pressures. Prominent venodilation occurs at lower doses and does not increase further as the NTG dose increases.²⁰ Venodilation results primarily in pooling of blood in the splanchnic capacitance system.²¹ Mesenteric blood volume increases as ventricular size, ventricular pressures, and intrapericardial pressure decrease.²¹

Figure 10-2 Actions of organic nitrates on the major vascular beds and relation of vasodilation to the size of the administered dose. The venous capacitance system dilates maximally with very low doses of organic nitrates. Increasing the amount of drug does not cause appreciable additional venodilation. Arterial dilation and enhanced arterial conductance begin at low doses of nitrates, with further vasodilation as the dosage is increased. With high plasma concentrations of nitrates, the arteriolar resistance vessels dilate, resulting in decreases in systemic and regional vascular resistances.

(Modified from Abrams J: Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 110(part 2):216, 1985; and Abrams J: Nitrates. In Chatterjee K, Cheitlin MD, Karliner J, et al [eds]: Cardiology: An illustrated text/reference, vol 1. Philadelphia: JB Lippincott, 1991, pp 275–290.)

NTG increases the distensibility and conductance of large arteries without changing systemic vascular resistance (SVR) at low doses.²² Improved compliance of the large arteries does not necessarily imply afterload reduction. At greater doses, NTG dilates smaller arterioles and resistance vessels, reducing afterload and BP²³ (see Figure 10-2). Reductions in cardiac dimension and pressure reduce myocardial oxygen consumption (MVO₂) and improve myocardial ischemia²⁴ (Figure 10-3). NTG may preferentially reduce cardiac preload, while maintaining systemic perfusion pressure, an important hemodynamic effect in myocardial ischemia. However, in hypovolemic states, greater doses of NTG may markedly reduce systemic BP to dangerous levels. A reflex increase in HR may occur at arterial vasodilating doses.

Figure 10-3 Effect of sublingual nitroglycerin (NG) on the left ventricular (LV) diastolic pressure-dimension relation in a patient with chronic aortic regurgitation. Dimensions (from an echocardiogram) and pressure data points were obtained in early diastole (minimal pressure) and at end-diastole (peak of QRS). After the administration of nitroglycerin, the pressure-dimension curve is shifted to the left. Triangles represent control; squares represent post-NG.

(From Smith ER, Smiseth OA, Kingma I, et al: Mechanism of action of nitrates. Role of changes in venous capacitance and in the left ventricular diastolic pressure-volume relation. Am J Med 76:14, 1984. copyright 1984 with permission from Excerpta Medical Inc.)

NTG causes vasodilation of pulmonary arteries and veins and predictably decreases right atrial (RAP), pulmonary artery (PAP), and pulmonary capillary wedge pressures (PCWP).²³ Pulmonary artery hypertension may be reduced in various disease states and in congenital heart disease with NTG.^25,26 Renal arteries, cerebral arteries, and cutaneous vessels also dilate with NTG.²⁷ Blood flow to the kidney and brain may decrease if adequate renal and cerebral perfusion pressures are not maintained.

NTG has several important effects on the coronary circulation (Box 10-1). NTG is a potent epicardial coronary artery vasodilator in both normal and diseased vessels. Stenotic lesions dilate with NTG, reducing the resistance to coronary blood flow (CBF) and improving myocardial ischemia.^28,29 Smaller coronary arteries may dilate relatively more than larger coronary vessels; however, the degree of dilation may depend on the baseline tone of the vessel.³⁰ NTG effectively reverses or prevents coronary artery vasospasm.³¹

Total CBF may initially increase but eventually decreases with NTG despite coronary vasodilation³² (Figure 10-4). Autoregulatory mechanisms probably result in decreases in total flow as a result of reductions in wall tension and myocardial oxygen consumption.²³ However, regional myocardial blood flow may improve by vasodilation of intercoronary collateral vessels or reduction of subendocardial compressive forces³³ (Figure 10-5). Coronary arteriographic studies in humans demonstrate that coronary collateral vessels increase in size after NTG administration.³⁴ This effect may be especially important when epicardial vessels have subtotal or total occlusive disease.³⁵ Improvement in collateral flow also may be protective in situations in which coronary artery steal may occur with other potent coronary vasodilator agents. The improvement in blood flow to the subendocardium, the most vulnerable area to the development of ischemia, is secondary to both improvement in collateral flow and reductions in left ventricular end-diastolic pressure (LVEDP), which reduce subendocardial resistance to blood flow.³⁶ With the maintenance of an adequate CPP (e.g., with administration of phenylephrine), NTG can maximize subendocardial blood flow⁸ (see Figures 10-4 and 10-5). The ratio of endocardial to epicardial blood in transmural segments is enhanced with NTG.³⁶ Inhibition of platelet aggregation also occurs with NTG; however, the clinical significance of this action is unknown.³⁷

Figure 10-4 Mean blood flow (mL/min/g) ± standard error to four transmural layers of anterior nonischemic myocardium during occlusion of the circumflex coronary artery in animals. Data are reported during control conditions, during infusion of nitroglycerin (0.015 mg/kg/min) (A), during administration of phenylephrine to increase mean arterial pressure to 153 ± 6 mm Hg (B), and during simultaneous administration of nitroglycerin and phenylephrine (C). Nitroglycerin decreases blood flow, and phenylephrine generally increases blood flow in normal myocardium. The combination markedly augments flow. *P < 0.05 in comparison with control measurements. Light circles represent control; dark circles represent nitroglycerin; triangles represent phenylephrine; squares represent nitroglycerin + phenylephrine.

(From Bache RJ: Effect of nitroglycerin and arterial hypertension on myocardial blood flow following acute coronary artery occlusion in the dog. Circulation 57:557, 1978. copyright 1978 American Heart Association.)

Figure 10-5 Mean blood flow (mL/min/g) ± standard error to four transmural layers of the central ischemic zone during occlusion of the circumflex coronary artery in animals. Data are reported during control conditions, during infusion of nitroglycerin (0.015 mg/kg/min) (A), during administration of phenylephrine to increase mean arterial pressure to 153 ± 6 mm Hg (B), and during simultaneous administration of nitroglycerin and phenylephrine (C). Coronary blood flow to all layers of ischemic myocardium is enhanced with the combination. *P < 0.05 in comparison with control measurements. Light circles represent control; dark circles represent nitroglycerin; triangles represent phenylephrine; squares represent nitroglycerin + phenylephrine.

(From Bache RJ: Effect of nitroglycerin and arterial hypertension on myocardial blood flow following acute coronary artery occlusion in the dog. Circulation 57:557, 1978. copyright 1978 American Heart Association.)

Pharmacology

Organic nitrates are biotransformed by reduction hydrolysis catalyzed by the hepatic enzyme glutathione-organic nitrate reductase.¹⁵ The rate of hepatic denitrification is characteristic of each nitrate and is further dependent on hepatic blood flow or presence of hepatic disease.¹⁵ Common organic nitrates for clinical use are shown in Table 10-2.

Sublingual Nitroglycerin

Sublingual NTG (0.15- to 0.6-mg tablets) achieves blood levels adequate to cause hemodynamic changes within several minutes; physiologic effects last 30 to 45 minutes.³⁸ Sublingual bioavailability is approximately 80% and bypasses the high first-pass biodegradation in the liver (90%) by nitrate reductase to glycerol dinitrate and nitrite, which are excreted renally. Plasma half-life of sublingual NTG is 4 to 7 minutes. NTG spray has pharmacokinetics and pharmacodynamics equivalent to those of a 0.4-mg sublingual tablet; however, it has a longer shelf half-life compared with the tablets, which decompose in air and warm temperatures.³⁹ A tablet that adheres to the buccal area between the upper lip and teeth has rapid onset and has the advantage of longer half-life than sublingual tablets.⁴⁰ Although NTG is readily absorbed through the gastric mucosa, the high rate of liver metabolism makes oral administration highly unpredictable.

Nitroglycerin Ointment and Patches

NTG ointment (2%) is readily absorbed through the skin, with this method of administration providing longer-lasting effects.⁴¹ Adequate NTG blood levels are reached within 20 to 30 minutes, and duration of action is 4 to 6 hours.⁴¹ Ointment is administered in inches (15 mg/inch), but the surface area of application and not the amount administered determines the blood level achieved. NTG ointment is messy, requires application four times a day, and is most appropriate for nursing administration in special care units.⁴²

NTG patches contain either liquid NTG or NTG bonded to a polymer gel and slowly released to the skin through a semipermeable membrane.⁴³ The pharmacokinetics approach that of a consistent IV infusion.⁴³ Blood levels are reached within 20 to 30 minutes, and a steady state is reached within 2 hours. Blood levels may be maintained up to 24 hours and are largely determined by patch size. Patches or disks contain an NTG concentration per square centimeter, and dosages of 0.2 to 0.8 mg/hr usually are required for relief of myocardial ischemia. Although convenient for patients, tolerance may be a problem with these sustained-release preparations.⁴¹ Intermittent therapy is recommended to avoid tolerance.⁴⁴

Intravenous Nitroglycerin

NTG has been available since the early 1980s as an injectable drug with stable shelf half-life in a 400-μg/mL solution of D₅W (5% dextrose in water). Blood levels are achieved instantaneously, and arterial dilating doses with resulting hypotension may quickly occur. If the volume status of the patient is unknown, initial dosages of 5 to 10 μg/min are recommended. The dosage necessary for relieving myocardial ischemia may vary from patient to patient, but relief is usually achieved with 75 to 150 μg/min. In a clinical study of 20 patients with rest angina, a mean dosage of 72 μg/min reduced or abolished ischemic episodes in 85% of patients.⁴⁵ However, doses as high as 300 to 400 μg/min may be necessary for ischemic relief in some patients. Arterial dilation becomes clinically apparent at doses around 50 μg/min. Drug offset after discontinuation of an infusion is rapid (2 to 5 minutes). The dosage of NTG available is less when administered in plastic bags and polyvinylchloride tubing because of NTG absorption by the bag and tubing, although this is not a significant clinical problem because the drug is titrated to effect.⁴⁶

Adverse Effects

The metabolism of NTG by liver nitrate reductase produces a nitrite that oxidizes the ferrous iron of hemoglobin to the ferric form of methemoglobin. The ferric iron does not bind or release oxygen.⁴⁷ Methemoglobin is formed normally and is reduced by enzyme systems within the red blood cell.⁴⁸ Normally, methemoglobin levels do not exceed 1%, but may increase when direct oxidants are present in the serum (nitrates, sulfonamides, aniline dye derivates). Methemoglobinemia with levels up to 20% is not a clinical problem. Documented increases in methemoglobin blood levels occur with IV NTG, averaging 1.5% in one study of 50 patients receiving NTG for longer than 48 hours.⁴⁹ NTG dosages of 5 mg/kg/day orally should be avoided to prevent significant methemoglobinemia.⁵⁰ However, rare instances of smaller doses causing clinically significant problems have been reported.⁵¹ Nitrates are effective in producing methemoglobin to bind cyanide in sodium nitroprusside toxicity.

Several mechanisms of nitrate tolerance have been proposed, including a depletion of SH groups, neurohumoral activation, volume expansion, and/or downregulation of nitrate receptors.^52–57 Tolerance may occur with all forms of nitrate administration that maintain continuous blood levels of the drug.^17,58–61 Discontinuation of the drug after prolonged exposure may result in a rebound phenomenon, possibly resulting in coronary vasospasm and myocardial ischemia or infarction.⁶² Tolerance to NTG apparently does not occur in all patients.⁶³ If tolerance develops after prolonged exposure, physiologic responsiveness may be achieved with greater dosages of NTG, an important observation during NTG administration in cardiac surgery.⁶⁴ Intermittent dosing with a nitrate-free interval each day or night can maintain NTG responsiveness.^44,65

NTG interferes with platelet aggregation.⁶⁶ The ability of the platelet to adhere to damaged intima is reduced.⁶⁷ Primary and secondary wave aggregation of platelets is also attenuated.⁶⁸ Previously formed platelet plugs are disaggregated.⁶⁹ A clinical study of 10 patients with coronary artery disease (CAD) demonstrated that a mean dosage of NTG (1.19 μg/kg/min) inhibited platelet aggregation by 50%, with a return to baseline platelet aggregation 15 minutes after the infusion was discontinued⁷⁰ (Figure 10-6). NO production increases cGMP, which modulates intracellular platelet calcium and reduces platelet secretion of proaggregatory factors.⁷¹ The clinical significance of these actions remains unclear. As with other potent vasodilators, NTG may increase intrapulmonary shunting of blood and reduce arterial oxygen tension.

Figure 10-6 Typical examples of aggregation responses to (top) adenosine diphosphate (ADP) and to (bottom) thrombin before, during, and after infusion of nitroglycerin (NTG) in patients with coronary artery disease. The amplitude of the curve is calibrated in ohms using a dual-channel impedance aggregometer. Nitroglycerin inhibits platelet aggregation to both reagents, and the effect is rapidly reversible after discontinuation of the drug.

(Modified from Diodati J, Theroux P, Latour JG, et al: Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina pectoris and acute myocardial infarction. Am J Cardiol 66:683, 1990.)

NTG may induce resistance to the anticoagulant effects of heparin.⁷² During simultaneous infusions of NTG and heparin, an increase in the NTG infusion caused the activated partial thromboplastin time to decrease.⁷³ Becker et al⁷⁴ reported NTG-induced heparin resistance at NTG infusion rates greater than 350 μg/min. The authors suggested a qualitative problem with antithrombin III (AT III) because AT III levels did not decrease. Others have suggested that NTG interferes with AT III binding to heparin by N-desulfation of the heparin molecule at the AT III binding sites.⁷⁵ N-desulfation of heparin reduces its anticoagulant activity.⁷⁶

NTG is contraindicated in patients who have used sildenafil, vardenafil, or tadalafil, or in patients who are hypotensive. These drugs for erectile dysfunction inhibit the phosphodiesterase (PDE5) that degrades cGMP, and the cGMP mediates vascular smooth muscle relaxation by NO. NTG-mediated vasodilation is markedly enhanced and prolonged, resulting in cases of profound hypotension, myocardial infarction (MI), and death.⁷⁷ Small doses of NTG have been used, but the amount of time that must elapse after a patient’s last dose of one of these medications before regular doses of nitrates may be safely administered is unclear.^78–80

Summary

NTG remains a first-line agent for the treatment of myocardial ischemia. Special care must be taken in patients with signs of hypovolemia or hypotension because the vasodilating effects of the drug may worsen the clinical condition. Recent ACC/AHA Guidelines address the prophylactic intraoperative use of NTG and suggest that its usefulness in preventing myocardial ischemia and cardiac morbidity in high-risk patients undergoing noncardiac surgery is unclear.⁸¹

β Receptor

The β receptor was conceptualized by Ahlquist,⁹⁶ who divided various physiologic effects of catecholamine stimulation into α and β responses. The β receptor has been identified biochemically as a polypeptide chain of approximately 50,000 to 60,000 kDa.⁹⁷ The receptor’s structure is common to most receptor proteins that have been identified: seven transmembrane crossings with two extramembranous terminal ends⁹⁸ (Figure 10-11). All receptors that transduce a signal through G proteins share this basic structure.⁹⁹ There are three extracellular and intracellular loops connecting the intramembranous portion of the receptor.⁹⁸ Agonist-antagonist binding occurs at the intramembranous portion, whereas the intracellular loops modulate interaction with the G-protein complex.^100,101 The terminal intracellular end contains amino acid residues that undergo phosphorylation, which relates to desensitization and downregulation of the receptor.¹⁰²

Figure 10-11 Human β₂-adrenergic receptor (darkened area represents the cell membrane). Depicted are two sites of extracellular N-linked glycosylation (Asn5, 16), four cysteine residues that may participate in disulfide bonds (Cys106, 184, 190, 191), an intracellular cysteine residue (Cys341) that may serve as a site of attachment for a palmitate membrane anchor, as well as multiple threonine and serine residues located in C-III and the cytoplasmic carboxyl terminus, which are potential sites of phosphorylation by protein kinase A (PKA), protein kinase C (PKC), or β-adrenergic receptor kinase (βARK).

(Reproduced from Raymond JR, Hnatowich M, Lefkowitz RJ, Caron MG: Adrenergic receptors. Models for regulation of signal transduction processes. Hypertension 15:119, 1990. copyright 1990 American Heart Association.)

Receptor stimulation activates a G protein, which stimulates adenylyl cyclase. The G-protein complex is composed of both stimulatory (G_s) and inhibitory (G_i) intermediary proteins.⁹⁹ Adenylyl cyclase converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which phosphorylates a protein kinase and produces the appropriate cellular response. A typical cascade of this sequence leading to increases in myocardial contractility from β-receptor stimulation is illustrated in Figure 10-12.

Figure 10-12 The β-receptor, G protein, adenylyl cyclase system. With β-receptor stimulation, dynamic changes occur in the G_i and G_s regulatory proteins. Ultimately, G_s stimulates adenylyl cyclase (AC) to convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which is metabolized by phosphodiesterase enzyme (PDE). An inactive protein kinase (PK_i) is activated (PK_a) by cAMP, which opens an energy-dependent receptor-operated calcium channel allowing calcium entry into the cell. Calcium cycling occurs with calcium actively pumped out of the cell by Ca²⁺ adenosine triphosphatase (ATPase). This calcium cycling causes a release of calcium from the sarcoplasmic reticulum (SR), allowing calcium to bind to troponin C (T) with subsequent activation of the actin-myosin complex. AMP, adenosine monophosphate.

(Modified from Royster RL: Intraoperative administration of inotropes in cardiac surgery patients. J Cardiothorac Anesth 4:17, 1990.)

β-Receptor numbers in any tissue may decrease with chronic stimulation (downregulation) or increase with chronic blockade (upregulation). The process of desensitization of the adrenergic response in chronic stimulation (i.e., congestive heart failure [CHF]) may involve downregulation of the receptors but may involve either the G-protein complex or adenylyl cyclase. Desensitization may occur quickly, whereas downregulation with actual internalization of the receptor within the cell may take days to weeks.¹⁰³ Myocardial ischemia increases β-receptor density, although it remains controversial whether this upregulation results in greater adrenergic response.¹⁰⁴ Several studies have demonstrated that high-affinity β receptors in nonischemic tissue were shifted to a low-affinity state during ischemia.^105,106 Also, the levels of G_s and its activity are reduced during myocardial ischemia.¹⁰⁷ However, stimulation of these receptors with isoproterenol during ischemia does result in increases in cAMP production.^104,108

There are two types of β receptors with a multitude of responses¹⁰⁹ (Table 10-3). Both β₁– and β₂-receptor stimulation primarily involve cardiac function (Figure 10-13). Responses of isolated human atrial tissue demonstrated greater inotropic response to β₁– than to β₂-receptor stimulation.¹¹⁰ Endogenous norepinephrine produces inotropic responses in human atrial appendages and ventricular papillary muscle by β₁-receptor stimulation, whereas epinephrine produces its maximal inotropic effects on the atria by β₂-receptor stimulation and up to 50% of its maximal inotropic response in the ventricle by β₂-receptor stimulation.^111,112 Sinus node, atrioventricular (AV) node, the left and right bundle branches, and the Purkinje system contain higher densities of β₂ receptors.¹¹³ Clearly, both receptor subtypes have cardiac inotropic, chronotropic, and dromotropic properties.

TABLE 10-3 Physiologic Effects of β₁– and β₂-Receptor Stimulation