Nitrates - Pharmacology and Clinical Uses

Introduction:

Organic nitrates and nitrites have been used in the treatment of angina for well over 100 years. In 1857, inhalation of amyl nitrite, a volatile liquid and known vasodilator, was found to relieve anginal pain; however, the duration of action was brief and the dosage difficult to control. Organic nitrates were soon discovered to share many of the pharmacological properties of amyl nitrite, and by 1879 the sublingual administration of nitroglycerin was established for relief of acute anginal attacks. Research during the 1970s and 1980s established that nitrates and nitrites act via the formation of the reactive free radical, nitric oxide (NO). Thus, the term nitrovasodilator was coined to describe those nitrates, nitrites, and other compounds that are denitrated to release nitric oxide.

Endogenous Nitric Oxide:

Studies in isolated blood vessels demonstrated that acetylcholine acts upon endothelial cells to release a diffusible vasodilating substance whose chemical identity was unknown. The unidentified mediator was initially named "endothelium-derived relaxing factor (EDRF)" because of its inhibitory effect on vascular smooth muscle. Research by several laboratories noted striking similarities between the pharmacology of the nitrovasodilators and EDRF, thus leading to the proposal that EDRF is identical to NO. The release of NO from endothelial cells was subsequently confirmed and the importance of NO as a signaling molecule in the cardiovascular system, as well as other systems throughout the body, is now well established. In the cardiovascular system, endothelium-derived NO plays a key role in the local control of blood flow, regulation of blood pressure, and prevention of platelet aggregation and adhesion. Moreover, impaired NO signaling (e.g. decreased NO synthesis, release, or bioactivity) is associated with a number of common cardiovascular disorders (e.g. atherosclerosis, hypertension, diabetes, etc.). In 1998, the Nobel Prize was awarded to Furchgott, Ignarro, and Murad for their work on EDRF/NO-signaling in the cardiovascular system and elsewhere.

The interaction of agonists with endothelial cell receptors (R) leads to activation of nitric oxide synthase (NOS), resulting in the formation of nitric oxide (NO) from l-arginine. NO is also formed directly from exogenous nitrovasodilators, such as nitroglycerin (NTG), isosorbide dinitrate (ISDN), and isosorbide mononitrate (ISMN). NO activates the soluble form of guanylyl cyclase (GC), which catalyzes the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). Increased levels of cGMP cause relaxation of vascular smooth muscle. Phosphodiesterase (PDE) hydrolyzes cGMP to GMP.

Recent evidence suggests that NO may also activate, either directly or through cGMP-dependent mechanisms, potassium channels on the smooth muscle cell surface. The efflux of potassium ions hyperpolarizes the cell membrane, resulting in vascular smooth muscle relaxation.

Pharmacokinetics:

• Nitroglycerin, isosorbide dinitrate, and isosorbide 5- mononitrate, an active metabolite of isosorbide dinitrate, are the nitrovasodilators most commonly used in the clinical setting.
  
• All are lipid soluble and readily absorbed via several routes of administration.
  
• Most organic nitrates have very low oral bioavailability due to the presence of high-capacity nitrate reductase enzymes in the liver (exception is isosorbide mononitrate, has nearly 100 percent bioavailability following oral administration).
  
• Most denitrated metabolites are glucuronidated and excreted via the kidney.
• Nitroglycerin may be administered via several routes, including sublingual, buccal, oral, transdermal, and intravenous.
  
• Because of its rapid onset (1-3 minutes) and avoidance of first-pass hepatic metabolism, the sublingual route is preferred.
• Since nitroglycerin is moderately volatile and adsorbs to plastic, the sublingual tablets must be stored in tightly closed glass containers.
  
• The duration of action of sublingual nitroglycerin is relatively brief (~30 minutes).
  
• Nitroglycerin is readily absorbed across the skin and may be applied as either an ointment or transdermal patch.
  
• Intravenous nitroglycerin is used to rapidly attain therapeutic blood levels.
  
• The concentration can be quickly and safely titrated to the desired level, and the hemodynamic effects can be terminated rapidly by stopping the infusion.
  
• Isosorbide dinitrate and isosorbide mononitrate are primarily administered via the oral route.

Hemodynamic Effects:

• Myocardial Oxygen Demand: Nitroglycerin causes relaxation of vascular smooth muscle in both arteries and veins, although the effect on veins predominates at low doses. By dilating veins, nitroglycerin increases venous capacitance and decreases venous return to the heart - decreases preload (as described by the Laplace relationship). Arterial dilation by nitroglycerin decreases peripheral vascular resistance and leads to a reduction in afterload. Reduced preload and afterload result in decreased left ventricular wall tension, a major determinant of myocardial oxygen demand. Thus, the anti-ischemic effects of the nitrovasodilators are largely due to their ability to decrease myocardial work and oxygen consumption.
  
• Myocardial Oxygen supply: The nitrovasodilators have several effects on the coronary circulation, including dilation of large and intermediate-size coronary arteries, increased collateral flow, and redistribution of flow to ischemic regions of the heart. Accordingly, these beneficial effects are primarily responsible for the ability of nitrovasodilators to improve myocardial oxygen supply.

Clinical Use:

1. Nitrovasodilators are used in the treatment of most forms of angina. Patients with chronic, stable angina often have fixed atherosclerotic lesions that obstruct blood flow in the large coronary arteries. The beneficial effects of nitrovasodilators in stable angina are due primarily to their ability to decrease myocardial oxygen demand. By decreasing preload and afterload, nitrovasodilators reduce ventricular wall tension and myocardial oxygen consumption.
2. In patients with variant (Prinzmetal's) angina, the major underlying cause of angina is vasospasm of one or more coronary arteries. Intense vasoconstriction decreases coronary blood flow, thereby reducing myocardial oxygen supply.By dilating constricted coronary arteries and restoring coronary blood flow, nitrovasodilators increase myocardial oxygen supply and relieve variant angina.
3. Nitrovasodilators are also used in treating patients with unstable angina. The pathophysiology of this condition is often complex and may involve several underlying factors superimposed on one another, including rupture of atherosclerotic plaques and thrombus formation, constriction of coronary arteries, and increased myocardial oxygen demand. In these patients, the beneficial effects of the nitrovasodilators are likely due to both dilation of the coronary arteries and a reduction in myocardial oxygen consumption.
4. Nitrovasodilators are used for the immediate treatment of acute angina, as well as for long-term prevention. Because of its rapid onset of effect, sublingual nitroglycerin is the agent most frequently used to terminate an acute attack of angina. It may be used prophylactically when administered immediately prior to activities known to precipitate an anginal attack (e.g. physical exertion).
   
5. Intravenous nitroglycerin is also used to control acute angina.
   
6. Transdermal nitroglycerin and oral formulations of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate are widely used in long-term maintenance therapy of angina. Although sustained plasma drug levels can usually be attained with these products, their clinical efficacy may be limited by the development of tolerance.

Adverse Effects and Precautions:

The most frequently observed adverse effects of the nitrates are a direct result of the vasodilation produced by these drugs. Headache, due to dilation of cranial blood vessels, is common and may be severe. Symptoms of postural hypotension (e.g. dizziness) may also be encountered. Paradoxically, nitrates may increase myocardial oxygen demand in some patients by causing reflex tachycardia.

Concurrent use of nitrates and sildenafil may cause a sudden and dramatic drop in blood pressure, prompting the FDA to issue a warning about prescribing sildenafil to patients being treated with nitrovasodilators.

Although rarely used today as a therapeutic agent, amyl nitrite has gained popularity as a recreational drug. Inhalation of amyl nitrite, as well as isobutyl nitrite, purportedly enhances sexual pleasure and produces euphoria. Abuse of these products may cause severe cardiovascular toxicity.

Nitrate Tolerance:

Continuous or repeated exposure to high doses of organic nitrates rapidly leads to a reduction in the hemodynamic and antianginal effects of these drugs. This phenomenon, known as nitrate tolerance, may occur within 24-48 hours following exposure and represents a major limitation to the therapeutic use of organic nitrates. The cause of nitrate tolerance is unclear but it is likely to be multifactorial. Several mechanisms have been proposed including: (i) decreased activation or desensitization of the NO/cGMP signaling pathway (including reduced bioconversion of nitrates to NO); (ii) expansion of plasma volume; (iii) increased release and/or sensitivity to endogenous vasoconstrictors, such as endothelin, angiotensin II, and catecholamines; and (iv) increased production of superoxide anions, which destroy NO.

The most widely accepted method for preventing nitrate tolerance is to provide a period of low nitrate exposure during each day. For example, a common dosing strategy for transdermal nitroglycerin is to apply the patches for 12 hours and remove them for 12 hours each day.

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