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Glyceryl trinitrate (pharmacology)
Encyclopedia
Glyceryl trinitrate 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.
, acute myocardial infarction, severe hypertension
, and coronary artery spasms due to cocaine
.
It is useful in decreasing 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. 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.
Glyceryl trinitrate is also used in the treatment of anal fissure
s, though usually at a much lower concentration than that used for angina treatment.
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.
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."
However, MythBusters is a TV show and do not necessarily conduct true scientific experiments. The show is for entertainment purposes only.
which must first be denitrated to produce the active metabolite nitric oxide (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 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 cyclic guanosine triphosphate (cGTP). Thus, NO increases the level of cGMP
within the cell. cGMP then activates myosin light chain phosphatase via a cGMP-dependent protein kinase.
s, 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.
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."
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO) generation from GTN and the metabolic consequences of this bioactivation are still not entirely understood.
Medical uses
Nitrogylcerin is used for the treatment of anginaAngina
Angina pectoris, commonly known as angina, is chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries . Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries...
, acute myocardial infarction, severe hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, and coronary artery spasms due to cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
.
It is useful in decreasing angina attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of nitric oxide
NO
NO, N.O., No, or No. may refer to:* One of a pair of English words, yes and no, which signal confirmation or a negative response respectively.- Geographical locations :* Norway, ISO 3166-1 country code* Lake No, Sudan...
, also called Endothelium-derived relaxing factor
Endothelium-derived relaxing factor
Endothelium-derived relaxing factor is produced and released by the endothelium to promote smooth muscle relaxation. The best-characterized is nitric oxide . Some sources equate EDRF and nitric oxide....
, 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. However the effectiveness of glyceryl trinitrate is limited by development of tolerance/tachyphylaxis
Tachyphylaxis
Tachyphylaxis is a medical term describing a decrease in the response to a drug due to previous exposure to that drug. Increasing the dose of the drug may be able to restore the original response. In this context tachyphylaxis is a synonym for drug tolerance...
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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and pulmonary edema
Pulmonary edema
Pulmonary edema , or oedema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure...
, 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.
Glyceryl trinitrate is also used in the treatment of anal fissure
Anal fissure
An anal fissure is a break or tear in the skin of the anal canal. Anal fissures may be noticed by bright red anal bleeding on the toilet paper, sometimes in the toilet. If acute they may cause severe periodic pain after defecation but with chronic fissures pain intensity is often less...
s, though usually at a much lower concentration than that used for angina treatment.
Adverse 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:- Impaired biotransformation of GTN to its active principle - 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, severe hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, and, in certain cases, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
. 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
Compliance (medicine)
In medicine, compliance describes the degree to which a patient correctly follows medical advice...
.
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 breakdownBreakdown voltage
The breakdown voltage of an insulator is the minimum voltage that causes a portion of an insulator to become electrically conductive.The breakdown voltage of a diode is the minimum reverse voltage to make the diode conduct in reverse...
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
MythBusters
MythBusters is a science entertainment TV program created and produced by Beyond Television Productions for the Discovery Channel. The series is screened by numerous international broadcasters, including Discovery Channel Australia, Discovery Channel Latin America, Discovery Channel Canada, Quest...
television show this is the case and GTN patches do not explode. The MythBusters
MythBusters
MythBusters is a science entertainment TV program created and produced by Beyond Television Productions for the Discovery Channel. The series is screened by numerous international broadcasters, including Discovery Channel Australia, Discovery Channel Latin America, Discovery Channel Canada, Quest...
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."
However, MythBusters is a TV show and do not necessarily conduct true scientific experiments. The show is for entertainment purposes only.
Mechanism of action
GTN is a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
which must first be denitrated to produce the active metabolite nitric oxide (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
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
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 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
Aldehyde dehydrogenase
Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes.- Function :Aldehyde dehydrogenase is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized by the body’s muscle and heart...
(mtALDH). NO is a potent activator of guanylyl cyclase (GC) by heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
-dependent mechanisms; this activation results in cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
formation from cyclic guanosine triphosphate (cGTP). Thus, NO increases the level of cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
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 headacheHeadache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, which indicated some form of vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
effect. Following Doctor Thomas Brunton's discovery that amyl nitrite
Amyl nitrite
Amyl nitrite is the chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group...
could be used to treat chest pain, Doctor William Murrell experimented with the use of nitroglycerin to alleviate angina pectoris and reduce blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
, 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
The Lancet
The Lancet is a weekly peer-reviewed general medical journal. It is one of the world's best known, oldest, and most respected general medical journals...
in 1879. The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients who associated nitroglycerin with explosions.
Research
A recent medical development will include a small amount of nitroglycerin in the tip of a new DurexDurex
Durex is the trademarked name for a range of condoms that used to be made by British company SSL International. This company was sold to Reckitt Benckiser in July 2010....
condom
Condom
A condom is a barrier device most commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases . It is put on a man's erect penis and physically blocks ejaculated semen from entering the body of a sexual partner...
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."