User:Doc James/Nitro

Glyceryl trinitrate (GTN) is an alternative name for the chemical nitroglycerin, 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.

Indications
It is useful in reducing angina attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of nitric oxide, also called Endothelium-derived relaxing factor, before the structure of NO as the responsible agent was known. This led to the development of transdermal patches of glyceryl trinitrate, providing 24-hour release, becoming commercially available in the United States in the early 1980s. However the effectiveness of glyceryl trinitrate is limited by development of tolerance/tachyphylaxis within 2–3 weeks of sustained use. Continuous administration and absorption (such as provided by daily pills and especially skin patches) accelerate onset of tolerance and limit the usefulness of the agent. Thus glyceryl trinitrate works best when used only short term, pulse dosing. Glyceryl trinitrate is useful for AMI and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset, as a pulse dose. It may also be given as a sublingual or buccal dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack.

Because of this tolerance issue, inhibitors of enzymatic phosphodiesterase degradation of NO by the pharmaceutical company Pfizer were developed in a effort to reduce tolerance to glyceryl trinitrate. One inhibitor, sildenafil, though effective in increasing blood levels of nitric oxide, turned out not to be particularly effective for recurrent angina. However many test subjects, despite reporting the inhibitor was not particularly effective for reducing their frequency of angina, resisted giving the inhibitor pills back to the researchers. On recurring experience with different test groups and questioning of the members, it was discovered that test subjects had found the inhibitor had greatly reduced their impotence, thus Viagra came into being, a far larger and more profitable market than the developers of sildenafil anticipated.

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.

Also, tennis elbow sufferers have been known to be prescribed a 1/4 patch daily dose applied to the injury.

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 episode while having a tilt table test which will then give more accurate results.

Since the drug makes the blood vessels dilate slightly, it is also makes more blood accessible to the brain, which is a positive property for people suffering from hypersomnia. The extra blood flow causes the user to feel more alert for a short period of time, usually 15–20 minutes. This is desired because Ritalin usually takes the same amount of time to begin its effect, and this makes the user able to only take the drug when needed and not on a timetable basis.

Side effects
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:
 * 1) Impaired biotransformation of GTN to its active principle - 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, 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.

GTN must not be used together with vasodilators that combat erectile disfunction, such as Viagra, Cialis, or Levitra. The combination of the two can lead to severe hypotension, circulatory collapse and death.

Dangers
It is often recommended that GTN transdermal patches should be removed before defibrillation due to the risk of explosion, but careful investigations have concluded that reports of apparent GTN patch explosions during defibrillation are in fact due to voltage breakdown involving the metal mesh in some patches.

It has been questioned whether GTN patches do indeed combust or explode when exposed to the energy from a defibrillator. It has been proposed that this is in fact a myth. According to the MythBusters television show this is the case and GTN patches do not explode. The MythBusters concluded that:

"Using a homemade defibrillator, the build team attempted to see whether the electric shock it created was enough to cause the nitroglycerin in the patches to explode. However, the defibrillator failed to detonate the patches, as well as patches covered with pure nitroglycerin."

Mechanism of action
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 that 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 via a cGMP-dependent protein kinase.

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.