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Glyceryl trinitrate (pharmacology)
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Glyceryl trinitrate (GTN) is an alternate name for the chemical nitroglycerine, which 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."
as known from the time of its discovery in 1847 that the tasting or close handling of nitroglycerin could cause sudden intense headaches, which indicated some form of vasodilation effect.
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Encyclopedia
Glyceryl trinitrate (GTN) is an alternate name for the chemical nitroglycerine, which 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."
History
It was known from the time of its discovery in 1847 that the tasting or close handling of nitroglycerin could cause sudden intense headaches, which indicated some form of vasodilation effect. Following Doctor Thomas Brunton's discovery that amyl nitrite could be used to treat chest pain, Doctor William Murrell experimented with the use of nitroglycerin to alleviate angina pectoris and reduce blood pressure, and proved that the headaches occurred due to overdose. He began treating patients with small doses in 1878, and the substance was soon adopted into widespread use after he published his results in The Lancet in 1879. The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients who associated nitroglycerin with explosions.
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. cGMP then activates myosin light chain phosphatase.
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 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.
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.
Glyceryl trinitrate is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.
Advantages
Long acting Nitrates such as Glyceryl nitrates, Isosorbide dinitrates, Isosorbide mononitrates
can be more useful as they are generally more effective and stable in the short term.
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.
Dangers
- GTN patches should be removed before defibrillation, as they have the potential to cause burns. (This effect is not limited to GTN patches).
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