Nitroglycerin

Chapter 179 Nitroglycerin



Betsy R. Bond, DVM, DACVIM (Cardiology)



KEY POINTS



• The most common uses of nitrates in the critical care setting are transdermal nitroglycerin (NTG) and intravenous nitroprusside for acute congestive heart failure (CHF). Transdermal nitrates have a slower onset of activity and primarily affect the venous system. Nitroprusside is a potent arterial and venous dilator and should be used only when arterial blood pressure can be monitored.

• NTG is one of the most effective drugs to ameliorate pain in humans with angina pectoris. Although this use is not commonly needed in animals (as far as we know), nitrates have other beneficial effects that make them important therapy in CHF, especially acute CHF.

• NTG was first known as an explosive and retains that characteristic even today. Modulations of compounds prevent it from being dangerous in medical practice.

• Although patients develop tolerance rapidly to nitrates, this is not true of intravenous nitroprusside. However, nitroprusside can cause cyanide or thiocyanate toxicity, and its use should be limited to 48 hours of a constant rate infusion.

• If an animal cannot tolerate angiotensin-converting enzyme (ACE) inhibitors, the combination of oral NTG and hydralazine is as effective as enalapril in controlling clinical signs of CHF, although they do not have the benefit of the lowered mortality associated with ACE inhibitors.


INTRODUCTION


Nitroglycerin (NTG) is probably one of the most interesting drugs in the history of medicine because of its use as an explosive before its use as therapy for angina pectoris (chest pain) and as a vasodilator for congestive heart failure (CHF). Who in their right mind would have knowingly placed even a small amount of a known explosive on the tongue? Yet NTG has become the most universally prescribed and recognized treatments for angina pectoris,1 one of the most commonly diagnosed diseases in humans who live in developed nations.2



PHARMACOLOGY OF NITRATES


As a group, nitrates are absorbed from the skin, the mucous membranes, and the gastrointestinal tract.2 The common preparations include an oral tablet, a transdermal paste or patch, a sublingual spray or tablet, or a powder that is reconstituted and administered intravenously.2,3


NTG relaxes vascular smooth muscle primarily on the venous side and is therefore a preload reducer, although nitroprusside (the intravenous form) can also dilate arteries and is therefore used for severe hypertension or left-sided CHF.3 NTG is oxidized to nitric oxide (NO), a short-lived free radical that stimulates the production of cyclic guanosine monophosphate (cGMP). cGMP reduces cytosolic calcium by inhibiting flow into the cell while stimulating mitochondrial uptake, causing relaxation of smooth muscle cells.4



Tolerance


An important characteristic of NTG administration is tolerance, the loss of efficacy within a short time. Several hypotheses have been proposed to explain this.



Impaired Conversion of Nitrates to Nitric Oxide


The enzyme aldehyde dehydrogenase, which participates in the early steps of NO production, may function poorly. In support of this theory is the fact that nitroprusside, a spontaneous NO donor, is less subject to tolerance. This defect is also associated with the production of free radicals.2,4



Abnormalities in Signal Transduction


This mechanism works by either (1) decreasing the bioavailability of the second messenger cGMP or (2) impairing its effects.


Decreased bioavailability might be mediated by either decreased levels of guanylyl cyclase, the enzyme responsible for the formation of cGMP, or by increased activity of phosphodiesterase (PDE), the enzyme that breaks down cGMP. This latter mechanism explains why excessive lowering of blood pressure may occur when nitrates are combined with certain PDE inhibitors such as sildenafil.2


Finally, cGMP activity is impaired when the effects of cGMP-dependent protein kinase, which mediates vasorelaxation, are reduced.4



Free Radical Formation


There seem to be multiple sources for superoxide anion, which produces toxic peroxynitrite, which ultimately causes decreased formation of vasodilatory cGMP. This may the reason that vitamin C and hydralazine, acting as antioxidants, can lessen nitrate tolerance.2,4

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Nitroglycerin

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