My watch list
my.chemeurope.com  
Login  

Glyceryl trinitrate (pharmacology)



Glyceryl trinitrate (pharmacology)
Systematic (IUPAC) name
1,3-dinitrooxypropan-2-yl nitrate
Identifiers
CAS number 55-63-0
ATC code C01DA02 D03AX07
PubChem 4510
DrugBank APRD00153
Chemical data
Formula C3H5N3O9 
Mol. mass 227.087 g/mol
Pharmacokinetic data
Bioavailability <1%
Metabolism Hepatic (rapid)
Half life 3 minutes
Excretion  ?
Therapeutic considerations
Pregnancy cat.

C(US)

Legal status
Routes Sublingual, Transdermal, Oral, Intravenous

Glyceryl trinitrate (GTN) has been used to treat angina and heart failure since at least 1870. Despite this, the mechanism of nitric oxide (NO) generation from GTN and the metabolic consequences of this bioactivation are still not entirely understood. In medical circles it is often referred to as "Nitro."

Additional recommended knowledge

Contents

Denitration of glyceryl trinitrate

GTN is a prodrug which must first be denitrated to produce the active metabolite NO. Nitrates which undergo denitration within the body to produce NO are called nitrovasodilators and their denitration occurs via a variety of mechanisms. The mechanism by which nitrates produce NO is widely disputed. Some believe that nitrates produce NO by reacting with sulfhydryl groups, while others believe that enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of GTN bioactivation. In recent years a great deal of evidence has been produced which supports the belief that clinically relevant denitration of GTN to produce 1,2-glyceryl dinitrate (GDN) and NO is catalysed by mitochondrial aldehyde dehydrogenase (mtALDH). NO is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms; this activation results in cGMP formation from guanosine triphosphate (GTP). Thus, NO increases the level of cGMP within the cell.

Uses

It is more useful in preventing angina attacks than reversing them once they have commenced. Patches of glyceryl trinitrate with a long activity duration are commercially available. Glyceryl trinitrate is also indicated for AMI and pulmonary oedema. It may also be given as a sublingual dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack.

A recent medical development will include a small amount of nitroglycerin in the tip of a new Durex condom to stimulate erection during intercourse. "The CSD500 condom contains a chemical in its teat, called glyceryl trinitrate (GTN), which is absorbed by the skin and causes blood vessels to dilate."

According to anecdotal evidence, Nitroglycerin patches have also found use as treatment for the bite of the brown recluse spider, which has a vasoconstricting venom. However, research has suggested that nitroglycerin has negligible benefits and might even increase inflammation of the bite wound.

Advantages

Long acting Nitrates can be more useful as they are generally more effective and stable in the short term.[citation needed]

It is also used to help provoke a vasovagal syncopic attack while having a tilt table test which will then give more accurate results.

Disadvantages

After long term use for treating chronic conditions, tolerance may develop in a patient, reducing its effectiveness. Nitrate tolerance was first described soon after the introduction of GTN in cardiovascular therapy as the loss of symptomatic and hemodynamic effects of GTN and/or the need for higher dosages of the drug in order to achieve the same effects. The mechanisms of nitrate tolerance have been thoroughly investigated in the last 30 years and several hypotheses have been proposed. these include:

  1. Impaired biotransformation of GTN to its active pinciple NO (or a NO-related species)
  2. Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by GTN
  3. Plasma volume expansion
  4. The oxidative stress hypothesis (proposed by Munzel et al in 1995).

Recent evidence suggests that the latter hypothesis might represent a unifying hypothesis, and a GTN-induced inappropriate production of oxygen free radicals might induce a number of abnormalities which include the ones described above. Furthermore, studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients prognosis (Nakamura et al): these include endothelial and autonomic dysfunction (Gori et al). In the short run, glyceryl trinitrate can cause severe headaches, necessitating analgesic (very rarely up to morphine) administration for relief of pain as well as severe hypotension, and, in certain cases, bradycardia. This makes some physicians nervous and should prompt caution when starting nitrate administration.

Explosion risk of medical nitroglycerin

Medicinal nitroglycerin is chemically identical to the explosive, but it is safe because it is far more dilute than pure nitroglycerin, and is bound to other inert substances that disrupts its perfect oxygen balance. The urban legend about defibrillators causing medical nitroglycerin chest patches to explode is a myth, as has been demonstrated in the popular television show MythBusters (episode 73: Speed Cameras).

References

  • Marsh N, Marsh A. (2000). "A short history of nitroglycerine and nitric oxide in pharmacology and physiology". Clin Exp Pharmacol Physiol 27 (4): 313-9. doi:10.1046/j.1440-1681.2000.03240.x.


 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Glyceryl_trinitrate_(pharmacology)". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE