Organic Nitrates

Organic Nitrates

These agents are prodrugs that are sources of nitric oxide (NO). NO activates the soluble isoform of guanylyl cyclase, thereby increasing intracellular levels of cyclic GMP. In turn, cyclic GMP promotes the dephosphorylation of the myosin light chain and the reduction of cystolic Ca²⁺ and leads to the relaxation of smooth muscle cells in a broad range of tissues. The NO-dependent relaxation of vascular smooth muscle leads to vasodilation; NO-mediated guanylyl cyclase activation inhibits platelet aggregation and relaxes smooth muscle in the bronchi and GI tract (Murad, 1996).

The broad biological response to nitrovasodilators reflects the existence of endogenous NO-modulated regulatory pathways. The endogenous synthesis of NO in humans is catalyzed by a family of NO synthases that oxidize the amino acid L-arginine to form NO, plus L-citrulline as a co-product. There are three distinct mammalian NO synthase isoforms termed nNOS, eNOS, and iNOS (see Chapter 3), and they are involved in processes as diverse as neurotransmission, vasomotion, and immunomodulation. In several vascular disease states, pathways of endogenous NO-dependent regulation appear to be deranged (reviewed in Dudzinski et al., 2006).

Mechanism of Action

Nitrites, organic nitrates, nitroso compounds, and a variety of other nitrogen oxide–containing substances (including nitroprusside; see later in the chapter) lead to the formation of the reactive gaseous free radical NO and related NO-containing compounds. Nitric oxide gas also may be administered by inhalation. The exact mechanism(s) of denitration of the organic nitrates to liberate NO remains an active area of investigation (Chen et al., 2002).

Phosphorylation of the myosin light chain regulates the maintenance of the contractile state in smooth muscle. NO can activate guanylyl cyclase, increase the cellular level of cyclic GMP, activate PKG, and modulate the activities of cyclic nucleotide phosphodiesterases (PDEs 2, 3, and 5) in a variety of cell types. In smooth muscle, the net result is reduced phosphorylation of myosin light chain, reduced Ca²⁺ concentration in the cytosol, and relaxation. One important consequence of the NO-mediated increase in intracellular cyclic GMP is the activation of PKG, which catalyzes the phosphorylation of various proteins in smooth muscle. Another important target of this kinase is the myosin light-chain phosphatase, which is activated on binding PKG and leads to dephosphorylation of the myosin light chain and thereby promotes vasorelaxation and smooth muscle relaxation in many other tissues.

The pharmacological and biochemical effects of the nitrovasodilators appear to be identical to those of an endothelium-derived relaxing factor now known to be NO. Although the soluble isoform of guanylyl cyclase remains the most extensively characterized molecular "receptor" for NO, it is increasingly clear that NO also forms specific adducts with thiol groups in proteins and with reduced glutathione to form nitrosothiol compounds with distinctive biological properties (Stamler et al., 2001). Mitochondrial aldehyde dehydrogenase has been shown to catalyze the reduction of nitroglycerin to yield bioactive NO metabolites (Chen et al., 2002), providing a potentially important clue to the biotransformation of organic nitrates in intact tissues. The regulation and pharmacology of eNOS have been reviewed (Dudzinski et al., 2006).

Absorption, Fate, and Excretion

More than a century after the first use of organic nitrates to treat angina pectoris, their biotransformation remains the subject of active investigation. Studies in the 1970s suggested that nitroglycerin is reductively hydrolyzed by hepatic glutathione–organic nitrate reductase. More recent studies have implicated a mitochondrial aldehyde dehydrogenase enzyme in the biotransformation of nitroglycerin (Chen et al., 2002). Other enzymatic and nonenzymatic pathways also may contribute to the biotransformation of nitrovasodilators. Despite uncertainties about the quantitative importance of the various pathways involved in nitrovasodilator metabolism, the pharmacokinetic properties of nitroglycerin and isosorbide dinitrate have been studied in some detail (Parker and Parker, 1998).

Nitroglycerin

In humans, peak concentrations of nitroglycerin are found in plasma within 4 minutes of sublingual administration; the drug has a t_1/2 of 1-3 minutes. The onset of action of nitroglycerin may be even more rapid if it is delivered as a sublingual spray rather than as a sublingual tablet. Glyceryl dinitrate metabolites, which have about one-tenth the vasodilator potency, appear to have half-lives of ~40 minutes.

Isosorbide Dinitrate

The major route of metabolism of isosorbide dinitrate in humans appears to be by enzymatic denitration followed by glucuronide conjugation. Sublingual administration produces maximal plasma concentrations of the drug by 6 minutes, and the fall in concentration is rapid (t_1/2 of ~45 minutes). The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have longer half-lives (3-6 hours) and are presumed to contribute to the therapeutic efficacy of the drug.

Isosorbide-5-Mononitrate

This agent is available in tablet form. It does not undergo significant first-pass metabolism and so has excellent bioavailability after oral administration. The mononitrate has a significantly longer t_1/2 than does isosorbide dinitrate and has been formulated as a plain tablet and as a sustained-release preparation; both have longer durations of action than the corresponding dosage forms of isosorbide dinitrate.

Interaction of Nitrates with PDE5 Inhibitors

Erectile dysfunction is a frequently encountered problem whose risk factors parallel those of coronary artery disease. Thus many men desiring therapy for erectile dysfunction already may be receiving (or may require, especially if they increase physical activity) anti-anginal therapy. The combination of sildenafil and other phosphodiesterase 5 (PDE5) inhibitors with organic nitrate vasodilators can cause extreme hypotension.

Cells in the corpus cavernosum produce NO during sexual arousal in response to nonadrenergic, noncholinergic neurotransmission (Burnett et al., 1992). NO stimulates the formation of cyclic GMP, which leads to relaxation of smooth muscle of the corpus cavernosum and penile arteries, engorgement of the corpus cavernosum, and erection. The accumulation of cyclic GMP can be enhanced by inhibition of the cyclic GMP–specific PDE5 family. Sildenafil (VIAGRA, REVATIO) and congeners inhibit PDE5 and have been demonstrated to improve erectile function in patients with erectile dysfunction. Not surprisingly, PDE5 inhibitors have assumed the status of widely used recreational drugs. Since the introduction of sildenafil, two additional PDE5 inhibitors have been developed for use in therapy of erectile dysfunction. Tadalafil (CIALIS, ADCIRCA) and vardenafil (LEVITRA) share similar therapeutic efficacy and side-effect profiles with sildenafil; tadalafil has a longer time to onset of action and a longer therapeutic t_1/2 than the other PDE5 inhibitors. Sildenafil has been the most thoroughly characterized of these compounds, but all three PDE5 inhibitors are contraindicated for patients taking organic nitrate vasodilators, and the PDE5 inhibitors should be used with caution in patients taking or adrenergic receptor antagonists (see Chapter 12).

The side effects of sildenafil and other PDE5 inhibitors are largely predictable on the basis of their effects on PDE5. Headache, flushing, and rhinitis may be observed, as well as dyspepsia owing to relaxation of the lower esophageal sphincter. Sildenafil and vardenafil also weakly inhibit PDE6, the enzyme involved in photoreceptor signal transduction (Chapters 3 and 64), and can produce visual disturbances, most notably changes in the perception of color hue or brightness. In addition to visual disturbances, sudden one-sided hearing loss has also been reported. Tadalafil inhibits PDE11, a widely distributed PDE isoform, but the clinical importance of this effect is not clear. The most important toxicity of all these PDE5 inhibitors is hemodynamic. When given alone to men with severe coronary artery disease, these drugs have modest effects on blood pressure, producing >10% fall in systolic, diastolic, and mean systemic pressures and in pulmonary artery systolic and mean pressures (Herrmann et al., 2000). However, sildenafil, tadalafil, and vardenafil all have a significant and potentially dangerous interaction with organic nitrates, the therapeutic actions of which are mediated via their conversion to NO with resulting increases in cyclic GMP. In the presence of a PDE5 inhibitor, nitrates cause profound increases in cyclic GMP and can produce dramatic reductions in blood pressure. Compared with controls, healthy male subjects pretreated with sildenafil or the other PDE5 inhibitors exhibit a much greater decrease in systolic blood pressure when treated with sublingual glyceryl trinitrate, and in many subjects a fall of more than 25 mm Hg was detected. This drug class toxicity is the basis for the warning that PDE5 inhibitors should not be prescribed to patients receiving any form of nitrate (Cheitlin et al., 1999) and dictates that patients should be questioned about the use of PDE5 inhibitors within 24 hours before nitrates are administered. A period of longer than 24 hours may be needed following administration of a PDE5 inhibitor for safe use of nitrates, especially with tadalafil because of its prolonged t_1/2. In the event that patients develop significant hypotension following combined administration of sildenafil and a nitrate, fluids and -adrenergic receptor agonists, if needed, should be used for support (Cheitlin et al., 1999). These same hemodynamic responses to PDE5 inhibition also may underlie the efficacy of sildenafil in the treatment of patients with primary pulmonary hypertension, in whom chronic treatment with the drug appears to result in enhanced exercise capacity associated with a decrease in pulmonary vascular resistance (Tsai and Kass, 2009). PDE5 inhibitors also are being studied in patients with congestive heart failure and cardiac hypertrophy (see Chapter 28).

Sildenafil, tadalafil, and vardenafil are metabolized via CYP3A4, and their toxicity may be enhanced in patients who receive other substrates of this enzyme, including macrolide and imidazole antibiotics, some statins, and antiretroviral agents (see individual chapters and Chapter 6). PDE5 inhibitors also may prolong cardiac repolarization by blocking the I_Kr. Although these interactions and effects are important clinically, the overall incidence and profile of adverse events observed with PDE5 inhibitors, when used without nitrates, are consistent with the expected background frequency of the same events in the treated population. In patients with coronary artery disease whose exercise capacity indicates that sexual activity is unlikely to precipitate angina and who are not currently taking nitrates, the use of PDE5 inhibitors can be considered. Such therapy needs to be individualized, and appropriate warnings must be given about the risk of toxicity if nitrates are taken subsequently for angina; this drug interaction may persist for approximately 24 hours for sildenafil and vardenafil and for considerably longer with tadalafil. Alternative nonnitrate anti-anginal therapy, such as adrenergic receptor antagonists, should be used during these time periods (Cheitlin et al., 1999).