Nitrovasodilators: Pharmacology and use in the treatment of myocardial ischemia

American Journal of Pharmaceutical Education, Summer 2002 by O'Rourke, Stephen T

PROLOGUE

Cardiovascular pharmacology is taught during the second year of the PharmD curriculum at North Dakota State University. The course draws heavily on material learned in previous coursework, including biochemistry, pathophysiology, and autonomic pharmacology. This paper summarizes the general approach and content used in teaching the pharmacology of nitroglycerin and related drugs used in the treatment of angina. Relevant aspects of cardiovascular physiology and the pathogenesis of myocardial ischemia are reviewed in depth prior to presenting this material.

INTRODUCTION

Ischemic heart disease is the most common cause of death and disability in the United States. The first clinical sign of myocardial ischemia is usually angina pectoris, a term used to describe the strangling chest pain experienced by many patients with ischemic heart disease. Myocardial ischemia, or lack of oxygen, is caused by an imbalance between oxygen supply and oxygen demand in the heart. This imbalance is usually due to an inability to increase coronary blood flow in response to increased myocardial oxygen requirements. The inability to increase coronary blood flow is often related to atherosclerosis of the large coronary arteries, which leads to a progressive narrowing of the blood vessel lumen and a reduction in coronary blood flow. Reduced coronary blood flow may also be caused by either focal or generalized vasospasm (i.e. intense vasoconstriction) of the major coronary arteries. Antianginal drugs may effectively relieve or prevent acute ischemic episodes by increasing myocardial oxygen supply, decreasing myocardial oxygen demand, or both.

ORGANIC NITRATES

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 pharmacologic properties of amyl nitrite, and by 1879 the sublingual administration of nitroglycerin was established for relief of acute anginal attacks. Although the vasodepressant effect of these drugs was deemed necessary for their usefulness in treating angina, the molecular mechanism of action remained a mystery for nearly a century. Research during the 1970s and 1980s established that nitrates and nitrites act via the formation of the reactive free radical, nitric oxide (NO)(1). Thus, the term nitrovasodilator was coined to describe those nitrates, nitrites, and other compounds that are denitrated to release nitric oxide. Nitroglycerin is the best studied member of this class of drugs and is considered the prototype.

ENDOGENOUS NITRIC OXIDE

In parallel with work on the mechanism of action of nitroglycerin and related compounds, the obligatory role of the vascular endothelium in the vasodilator response to acetylcholine was first reported(2). The endothelium comprises the innermost layer of cells within the blood vessel wall. As such, it lies in intimate contact with circulating blood and with smooth muscle cells in the medial layer of the vascular wall. 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. Soon thereafter it was recognized that many other neurotransmitters, hormones, and autacoids require the presence of endothelial cells to produce vasodilation. 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.

CELLULAR MECHANISMS OF ACTION

In endothelial cells, NO is formed from 1-arginine by the calcium-calmodulin dependent enzyme, nitric oxide synthase, and it rapidly diffuses to the underlying smooth muscle (Figure 1). Vasodilators that require the presence of endothelial cells to generate NO and produce vasodilation (e.g. acetylcholine) are termed endothelium-dependent vasodilators. Exogenous nitrovasodilators, such as nitroglycerin, form NO directly via denitration by either enzymatic or nonenzymatic mechanisms in a manner that does not require endothelial cells; such substances are termed endothelium-independent vasodilators. Once formed, NO activates guanylyl cyclase, an enzyme that catalyzes the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP)(3). Increased levels of cGMP lead to the activation of cGMP-dependent kinases, phosphorylation of several proteins, and relaxation of vascular smooth muscle. Cyclic GMP is hydrolyzed to its inactive form by phosphodiesterase enzymes. Recent evidence suggests that NO may also activate, either directly or through cGMP-dependent mechanisms, potassium channels on the smooth muscle cell surface(4,5). The efflux of potassium ions hyperpolarizes the cell membrane, resulting in vascular smooth muscle relaxation.