Nitrates and newer antianginals Flashcards
Nitrates provide an exogenous source of vasodilator nitric oxide (NO•, usually given as NO), a very short-lived free radical, thereby inducing coronary vasodilation even when endogenous production of NO• is impaired by CAD. Thus nitrates act differently from the other classes of antianginals (see Fig. 2-2).
Nitrates provide an exogenous source of vasodilator nitric oxide (NO•, usually given as NO), a very short-lived free radical, thereby inducing coronary vasodilation even when endogenous production of NO• is impaired by CAD. Thus nitrates act differently from the other classes of antianginals (see Fig. 2-2).
Chronic use of nitrates produces ……, a significant clinical problem. The main focus of current clinical work remains on strategies to minimize or prevent the development of …….., with the major emphasis on the adverse role of excess NO• that produces harmful peroxynitrite. The thrust of basic work has shifted to endogenously produced NO• as a ubiquitous physiologic messenger. Although endogenously produced NO• has many functions (such as a role in vagal neurotransmission) quite different from the NO• derived from exogenous nitrates, there are important shared vasodilatory effects.
Chronic use of nitrates produces tolerance, a significant clinical problem. The main focus of current clinical work remains on strategies to minimize or prevent the development of tolerance, with the major emphasis on the adverse role of excess NO• that produces harmful peroxynitrite. The thrust of basic work has shifted to endogenously produced NO• as a ubiquitous physiologic messenger. Although endogenously produced NO• has many functions (such as a role in vagal neurotransmission) quite different from the NO• derived from exogenous nitrates, there are important shared vasodilatory effects.
Coronary and peripheral faso…… effects.
A distinction must be made between antianginal and coronary faso……..properties. Nitrates preferentially ……..large coronary arteries and arterioles greater than 100 mcm in diameter 6 to (1) redistribute blood flow along collateral channels and from epicardial to endocardial regions and (2) relieve coronary spasm and dynamic stenosis, especially at epicardial sites, including the coronary arterial constriction induced by exercise. Thereby exercise-induced myocardial ischemia is relieved. Thus nitrates are “effective” vasodilators for angina; dipyridamole and other vasodilators acting more distally in the arterial tree are not, but rather have the risk of diverting blood from the ischemic area—a “coronary steal” effect.
Coronary and peripheral vasodilatory effects.
A distinction must be made between antianginal and coronary vasodilator properties. Nitrates preferentially dilate large coronary arteries and arterioles greater than 100 mcm in diameter 6 to (1) redistribute blood flow along collateral channels and from epicardial to endocardial regions and (2) relieve coronary spasm and dynamic stenosis, especially at epicardial sites, including the coronary arterial constriction induced by exercise. Thereby exercise-induced myocardial ischemia is relieved. Thus nitrates are “effective” vasodilators for angina; dipyridamole and other vasodilators acting more distally in the arterial tree are not, but rather have the risk of diverting blood from the ischemic area—a “coronary steal” effect.
The additional peripheral hemodynamic effects of nitrates, originally observed by Lauder Brunton, cannot be ignored. Nitrates do reduce the ……., in addition to the ……… of the heart (Fig. 2-3). The arterial wave reflection from the periphery back to the aorta is altered in such a way that there is “true” …….. reduction, with the aortic systolic pressure falling even though the brachial artery pressure does not change.
The additional peripheral hemodynamic effects of nitrates, originally observed by Lauder Brunton, cannot be ignored. Nitrates do reduce the afterload, in addition to the preload of the heart (Fig. 2-3). The arterial wave reflection from the periphery back to the aorta is altered in such a way that there is “true” afterload reduction, with the aortic systolic pressure falling even though the brachial artery pressure does not change.
Reduced oxygen demand.
Nitrates increase the venous capacitance, causing …………… of blood in the peripheral veins and thereby a reduction in ……….. and in ventricular …………. There is less mechanical stress on the myocardial wall and the ………….. demand is reduced. Furthermore, a fall in the aortic …………… also reduces the oxygen demand.
Reduced oxygen demand.
Nitrates increase the venous capacitance, causing pooling of blood in the peripheral veins and thereby a reduction in venous return and in ventricular volume. There is less mechanical stress on the myocardial wall and the myocardial oxygen demand is reduced. Furthermore, a fall in the aortic systolic pressure also reduces the oxygen demand.
Endothelium and vascular mechanisms.
The fundamental mechanism of nitrate biological effect is the enzyme-mediated release of highly ……………… from the nitrate molecule (Fig. 2-4).
The fundamental mechanism of nitrate biological effect is the enzyme-mediated release of highly unstable NO• from the nitrate molecule (Fig. 2-4).
An intact vascular endothelium is required for the vasodilatory effects of some vascular active agents (thus acetylcholine physiologically vasodilates but constricts when the endothelium is damaged). Nitrates vasodilator ……………………. Prolonged nitrate therapy with formation of …………………… may, however, inhibit endothelial nitric oxide ……………………. (NOS), which is one of several postulated mechanisms of nitrate tolerance. Similarly, long-term use of long-acting nitrates may cause endothelial dysfunction mediated by ……………….. (see later, Fig. 2-5). Whether this problem extends to aggravation of preexisting endothelial dysfunction is uncertain. Thus nitrate tolerance and endothelial dysfunction have partially shared pathogenetic mechanisms.
An intact vascular endothelium is required for the vasodilatory effects of some vascular active agents (thus acetylcholine physiologically vasodilates but constricts when the endothelium is damaged). Nitrates vasodilate whether or not the endothelium is physically intact or functional. Prolonged nitrate therapy with formation of peroxynitrite may, however, inhibit endothelial nitric oxide synthase (NOS), which is one of several postulated mechanisms of nitrate tolerance. Similarly, long-term use of long-acting nitrates may cause endothelial dysfunction mediated by free radicals (see later, Fig. 2-5). Whether this problem extends to aggravation of preexisting endothelial dysfunction is uncertain. Thus nitrate tolerance and endothelial dysfunction have partially shared pathogenetic mechanisms.
Nitrates, after entering the vessel wall, are bioconverted to release NO•, which stimulates guanylate cyclase to produce ……….; see Fig. 2-4). In addition, NO• acts potentially via direct S-nitrosylation of a number of proteins, altering their physiologic properties via a posttranslational modification step. NO• may also be “scavenged” by the superoxide (O2–) radical, generating peroxynitrate (ONOO–), which in high concentrations contributes to nitrate toxicity (Fig. 2-5) and the induction of nitrate tolerance. Conversely, low concentrations enhance the vasodilator effects of NO•.
Nitrates, after entering the vessel wall, are bioconverted to release NO•, which stimulates guanylate cyclase to produce cyclic guanosine monophosphate (GMP; see Fig. 2-4). In addition, NO• acts potentially via direct S-nitrosylation of a number of proteins, altering their physiologic properties via a posttranslational modification step. NO• may also be “scavenged” by the superoxide (O2–) radical, generating peroxynitrate (ONOO–), which in high concentrations contributes to nitrate toxicity (Fig. 2-5) and the induction of nitrate tolerance. Conversely, low concentrations enhance the vasodilator effects of NO•.
Overall the best known mechanism linked to clinical practice is that ………….. in the vascular myocyte falls, and ……………. results (see Fig. 2-4). Sulfhydryl (SH) groups are required for such formation of NO• and the stimulation of guanylate cyclase. Nitroglycerin powerfully dilates when injected into an artery, an effect that is probably limited in humans by reflex adrenergic-mediated vasoconstriction.
Hence (1) nitrates are better …… than …….. dilators, and (2) there is an associated adrenergic reflex ………….. at can be attenuated by concurrent β-blockade.
Overall the best known mechanism linked to clinical practice is that calcium in the vascular myocyte falls, and vasodilation results (see Fig. 2-4). Sulfhydryl (SH) groups are required for such formation of NO• and the stimulation of guanylate cyclase. Nitroglycerin powerfully dilates when injected into an artery, an effect that is probably limited in humans by reflex adrenergic-mediated vasoconstriction. Hence (1) nitrates are better ………… than …………… dilators, and (2) there is an associated adrenergic reflex …………… that can be attenuated by concurrent β-blockade.
Effects of NO• on myocardial relaxation and contractile proteins.
NO• has a fundamental role as a modulator of myocardial …………….., mediated at least in part by cyclic GMP (see Fig. 2-4). This effect is independent of the restoration of coronary blood flow that in turn can reverse ischemic diastolic dysfunction. Furthermore, NO• improves ………….function in human heart muscle where it acts on the contractile proteins by increasing ……………… of the springlike cytoskeletal protein titin. In long-term therapy, NO• donors may limit or reverse left ventricular hypertrophy (LVH). These studies raise the possibility that organic nitrates may exert a role in the management of systemic hypertension, in which LVH is a marker and modulator of long-term cardiovascular risk. However, to date, there have been only sporadic clinical investigations.
Effects of NO• on myocardial relaxation and contractile proteins.
NO• has a fundamental role as a modulator of myocardial relaxation, mediated at least in part by cyclic GMP (see Fig. 2-4). This effect is independent of the restoration of coronary blood flow that in turn can reverse ischemic diastolic dysfunction. Furthermore, NO• improves diastolic function in human heart muscle where it acts on the contractile proteins by increasing troponin I phosphorylation of the springlike cytoskeletal protein titian. In long-term therapy, NO• donors may limit or reverse left ventricular hypertrophy (LVH). These studies raise the possibility that organic nitrates may exert a role in the management of systemic hypertension, in which LVH is a marker and modulator of long-term cardiovascular risk. However, to date, there have been only sporadic clinical investigations.
Antiaggregatory effects.
Organic nitrates mimic the effects of endogenous NO• in inhibiting and potentially reversing…………….. These effects are mediated primarily via the classical pathway of stimulation of activation of soluble guanylate cyclase (see Fig. 2-4).
Antiaggregatory effects.
Organic nitrates mimic the effects of endogenous NO• in inhibiting and potentially reversing platelet aggregation. These effects are mediated primarily via the classical pathway of stimulation of activation of soluble guanylate cyclase (see Fig. 2-4).
Pharmacokinetics of nitrates
Bioavailability and half-lives.
The various preparations differ so much that each needs to be considered separately. As a group, nitrates are absorbed from the ……….(3)
The various preparations differ so much that each needs to be considered separately. As a group, nitrates are absorbed from the mucous membranes, the skin, and the gastrointestinal (GI) tract.
The prototype agent, nitroglycerin, has pharmacokinetics that are not well understood. It rapidly disappears from the blood with a half-life of ……………, largely by extrahepatic mechanisms that convert the parent molecule to longer acting and active dinitrates.
The prototype agent, nitroglycerin, has pharmacokinetics that are not well understood. It rapidly disappears from the blood with a half-life of only a few minutes, largely by extrahepatic mechanisms that convert the parent molecule to longer acting and active dinitrates.
Isosorbide dinitrate, on the other hand, must first be converted in the liver to active mononitrates (see Fig. 2-4) that have half-lives of approximately ……………….. with ultimate renal excretion.
The mononitrates are completely bioavailable without any hepatic metabolism, with half-lives of ………… In reality, knowledge of pharmacokinetics is of limited interest because of the highly variable relationship between the plasma concentrations of the nitrates, the levels of their active metabolites, and the onset and duration of pharmacologic action that matter most to the clinician.
Isosorbide dinitrate, on the other hand, must first be converted in the liver to active mononitrates (see Fig. 2-4) that have half-lives of approximately 4 to 6 hours with ultimate renal excretion.
The mononitrates are completely bioavailable without any hepatic metabolism, with half-lives of 4-6 hours. In reality, knowledge of pharmacokinetics is of limited interest because of the highly variable relationship between the plasma concentrations of the nitrates, the levels of their active metabolites, and the onset and duration of pharmacologic action that matter most to the clinician.
Of the many nitrate preparations (Table 2-1), sublingual nitroglycerin remains the gold standard for acute anginal attacks. In practice, patients are often also given long-acting nitrates. “No matter which long-acting preparation is used, physicians should prescribe the drug in a manner to decrease the likelihood of ……………… This involves an on-off strategy of at least a 10-hour nitrate free interval each day.”
Of the many nitrate preparations (Table 2-1), sublingual nitroglycerin remains the gold standard for acute anginal attacks. In practice, patients are often also given long-acting nitrates. “No matter which long-acting preparation is used, physicians should prescribe the drug in a manner to decrease the likelihood of nitrate tolerance. This involves an on-off strategy of at least a 10-hour nitrate free interval each day.”
Nitrate interactions with other drugs
Many of the proposed interactions of nitrates are pharmacodynamic, involving potentiation of vasodilatory effects, as with the …………. However, the chief example of vasodilator interactions is with the selective phosphodiesterase-……………..inhibitors such as sildenafil as used for erectile dysfunction. PDE-5 inhibitors are increasingly used for the therapy of pulmonary hypertension (see Chapter 5) and their benefits in heart failure are being explored. As a group, these agents can cause serious …………. when combined with nitrates (see Fig. 2-5). Hence the package insert of each agent forbids co-administration to patients taking nitrates in any form either regularly or intermittently.
Many of the proposed interactions of nitrates are pharmacodynamic, involving potentiation of vasodilatory effects, as with the CCBs. However, the chief example of vasodilator interactions is with the selective phosphodiesterase-5 (PDE-5) inhibitors such as sildenafil as used for erectile dysfunction. PDE-5 inhibitors are increasingly used for the therapy of pulmonary hypertension (see Chapter 5) and their benefits in heart failure are being explored. As a group, these agents can cause serious hypotensive reactions when combined with nitrates (see Fig. 2-5). Hence the package insert of each agent forbids co-administration to patients taking nitrates in any form either regularly or intermittently.
For example, sildenafil decreases the blood pressure (BP) by approximately 8.4/5.5 mm Hg, and by much more in those taking nitrates. The exertion of sexual intercourse also stresses the cardiovascular system further. As a group, these drugs should also not be given with α-adrenergic blockers. In case of inadvertent PDE-5-nitrate combinations, administration of an α-adrenergic agonist or even of norepinephrine may be needed.
In clinical practice nitrates may be started 24 hours after sildenafil.
For example, sildenafil decreases the blood pressure (BP) by approximately 8.4/5.5 mm Hg, and by much more in those taking nitrates. The exertion of sexual intercourse also stresses the cardiovascular system further. As a group, these drugs should also not be given with α-adrenergic blockers. In case of inadvertent PDE-5-nitrate combinations, administration of an α-adrenergic agonist or even of norepinephrine may be needed.
In clinical practice nitrates may be started 24 hours after sildenafil.
Beneficial combination with …………..
There is a beneficial interaction between nitrates and …………. whereby the latter helps to lessen nitrate tolerance, probably acting through inhibition of free radical formation. This may explain why the combination of nitrates and hydralazine is effective in heart failure.
Beneficial combination with hydralazine.
There is a beneficial interaction between nitrates and hydralazine whereby the latter helps to lessen nitrate tolerance, probably acting through inhibition of free radical formation. This may explain why the combination of nitrates and hydralazine is effective in heart failure.
