View source for Glyceryl trinitrate (pharmacology)

{{dablink|This article is about the pharmacological effects of glyceryl trinitrate.  For its chemical properties, see [[Nitroglycerin]]''.}}
{{drugbox
| IUPAC_name = 1,3-dinitrooxypropan-2-yl nitrate
| image = Nitroglycerin-2D-skeletal.png
| width = 150px
| image2 = Nitroglycerin-3D-vdW.png
| CAS_number = 55-63-0
| ATC_prefix = C01
| ATC_suffix = DA02
| ATC_supplemental = {{ATC|D03|AX07}}
| PubChem = 4510
| DrugBank = APRD00153
| C=3 | H=5 | N=3 | O=9
| molecular_weight = 227.087 g/mol
| bioavailability = <1%
| protein_bound = 
| metabolism = Hepatic (rapid)
| elimination_half-life = 3 minutes
| pregnancy_category = 
| pregnancy_US = C
| legal_status = 
| legal_AU = S3
| routes_of_administration = Sublingual, Transdermal, Oral, Intravenous
}}

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'''Glyceryl trinitrate''' (GTN) has been used to treat [[Angina pectoris|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."

==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-transferase]]s, [[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 [[Cyclic_guanosine_monophosphate|cGMP]] formation from guanosine triphosphate (GTP). Thus, NO increases the level of [[Cyclic_guanosine_monophosphate|cGMP]] within the cell.

==Uses==<!-- This section is linked from [[Nitroglycerin]] -->

It is more useful in preventing [[Angina pectoris|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 [[Myocardial_infarction|AMI]] and [[pulmonary edema]].
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.

It is used a cream that is applied in chronic anal fissure. As chronic fissure does to respond to dietary advice. A study was carried out by Queen Elizabeth Hospital, King's Lynn, UK.
<ref>[http://www.rcsed.ac.uk/journal/vol45_3/4530008.htm]</ref>

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."<ref>[http://www.futuramedical.co.uk/content/products/csd_500.asp Futura Medical]</ref><ref>[http://money.cnn.com/popups/2006/biz2/revolutions/8.html CNN Money]]</ref>

According to [[anecdotal evidence]], Nitroglycerin patches have also found [[glyceryl trinitrate (pharmacology)#Uses|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.{{Fact|date=May 2007}}

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 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: 
# Impaired biotransformation of GTN to its active pinciple NO (or a NO-related species)
# Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by GTN 
# Plasma volume expansion
# 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. The painful nature of these adverse effects has a marked negative impact on patient [[Compliance (medicine)|compliance]].

==References==
{{reflist}}
*{{cite journal
| author = Marsh N, Marsh A.
| title = A short history of nitroglycerine and nitric oxide in pharmacology and physiology
| journal = [[Clin Exp Pharmacol Physiol]]
| year = 2000
| volume = 27
| issue = 4
| pages = 313-9
| doi = 10.1046/j.1440-1681.2000.03240.x
}}
    
{{Antianginals (nitrates)}}
{{Preparations for treatment of wounds and ulcers}}
[[Category:Antianginals]]

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