PDF Nitrates and Nitrate Tolerance in Angina Pectoris

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Whether a specific drug is useful or harmful under heart failure and myocardial infarction depends on its speed of action: Fast acting substances such as glyceryl trinitrate and nitroprusside can be helpful for controlling blood pressure and consequently the amount of blood the heart has to pump, if the application is monitored continuously. Slow acting substances would hold the danger of ischaemia due to an uncontrollably low blood pressure and are therefore contraindicated.

Depending on the circumstances, even fast acting substances can be contraindicated — for example, glyceryl trinitrate in patients with obstructive heart failure. These drugs are also contraindicated in patients that have recently taken PDE5 inhibitors such as sildenafil Viagra. Most side effects are direct consequences of the vasodilation and the following low blood pressure. They include headache "nitrate headache" resulting from the widening of blood vessels in the brain, reflex tachycardia fast heart rate , flush , dizziness, nausea and vomiting.

Nicorandil Long-Acting Nitrates Vasodilator | ECR Journal

These effects usually subside after a few days if the treatment is continued. Occasionally, severe hypotension occurs shortly after beginning of treatment, possibly resulting in intensified angina symptoms or syncope , sometimes with bradycardia slow heart rate. A number of drugs add to the low blood pressure caused by nitrovasodilators: for example, other vasodilators, antihypertensive drugs , tricyclic antidepressantss , antipsychotics , general anaesthetics , as well as ethanol. Combination with PDE5 inhibitors, including sildenafil Viagra , is contraindicated because potentially life-threatening hypotension may occur.

Nitrates increase the bioavailability of dihydroergotamine DHE. High DHE levels may result in coronary spasms in patients with coronary disease. Nitrovasodilators are prodrugs that donate NO by various mechanisms. Nitrates undergo chemical reduction, likely mediated by enzymes. NO stimulates the soluble form of the enzyme guanylate cyclase in the smooth muscle cells of blood vessels.

Nitrate Therapy and Nitrate Tolerance

The most important effect in angina is the widening of veins , which increases their capacity to hold blood "venous pooling" and reduces the pressure of the blood returning to the heart the preload. Widening of the large arteries also reduces the pressure against which the heart has to pump, the afterload. Lower preload and afterload result in the heart needing less energy and thus less oxygen. Besides, NO donated by nitrovasodilators can reduce coronary spasms , increasing the heart's oxygen supply.

In combination with the increased cGMP production caused by nitrovasodilators, this leads to high concentrations of cGMP, extensive venous pooling, and potentially life-threatening hypotension. Nitrates exhibit development of tolerance, or more specifically tachyphylaxis , meaning that repeated application results in a fast decrease of effect, usually within 24 hours.

A pause of six to eight hours restores the original effectiveness. This phenomenon was originally thought to be a consequence of depletion of thiol —SH groups necessary for the reduction of nitrates. While this theory would fit the fact that molsidomine which is not reduced does not exhibit tachyphylaxis, it has meanwhile been refuted. Newer theories include increase of oxidative stress resulting in deactivation of NO to peroxynitrite , and liberation of the vasoconstrictors angiotensin II and endothelin as the blood vessels' reaction to NO-mediated vasodilation.

Nitrates mainly differ in speed and duration of their action. Nitrates vary in their potential to induce the development of tolerance. During long-lasting nitrate therapy, except pentaerythritol tetranitrate PETN , one can observe the development of reactive oxygen species ROS inside the muscular cell of a vessel wall, and these bind with nitric oxide NO. This leads to decreased NO activity, thus, nitrate tolerance.

Keywords: Stable angina pectoris, organic nitrates, nitrate tolerance, nitrate cross-tolerance. Affiliation: 2nd Dept.

NITRATES (PRE-REGISTRATION REVISION)

Abstract: Long-acting nitrates are effective antianginal drugs during initial treatment. Journal Name: Current Clinical Pharmacology. Volume 4 , Issue 2 , Barbara McGovern. The Lancet: Cardiovascular Disease The Lancet. Acute Pulmonary Embolism. Vascular Tumors and Developmental Malformations.

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