Glyceryl trinitrate (pharmacology)

This article is about the chemical properties of nitroglycerin and its use medical and pharmacological applications. For as an explosive, see Nitroglycerin.

Glyceryl trinitrate (pharmacology)

Systematic (IUPAC) name
1,3-dinitrooxypropan-2-yl nitrate; [3-(nitrooxy)-2-[(nitrooxy)methyl]propyl] nitrate
Clinical data
AHFS/Drugs.com	nitroglycerin
MedlinePlus	a601086
Pregnancy cat.	C(US)
Legal status	Pharmacist Only (S3) (AU)
Routes	Sublingual, Transdermal, Oral, Intravenous
Pharmacokinetic data
Bioavailability	<1%
Metabolism	Hepatic (rapid)
Half-life	3 minutes
Identifiers
CAS number	55-63-0 Y
ATC code	C01DA02 D03AX07
PubChem	CID 4510
DrugBank	APRD00153
ChemSpider	4354 Y
UNII	G59M7S0WS3 Y
ChEBI	CHEBI:28787 Y
ChEMBL	CHEMBL454110 N
Chemical data
Formula	C3H5N3O9
Mol. mass	227.087 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C3H5N3O9/c7-4(8)13-1-3(15-6(11)12)2-14-5(9)10/h3H,1-2H2 Y Key:SNIOPGDIGTZGOP-UHFFFAOYSA-N Y
N(what is this?)  (verify)

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.

Three different forms of nitroglycerin: intravenous, sublingual spray, and the nitroglycerin patch.

Medical uses

Nitrogylcerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and coronary artery spasms due to cocaine.^[1]

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^[2]. 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^{[citation needed]}, 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.^{[citation needed]}

Glyceryl trinitrate is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.^[3]

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:

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^[4][5] 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.^[6]

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."^[7]

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 prodrug 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-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 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.

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.^[8]

Research

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."^[9][10]

Notes

1. ^ "Lisinopril". The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/lisinopril.html. Retrieved 3 April 2011. 
2. ^ medicines.org. "mknitro". http://www.medicines.org.au/files/mkpnitro.pdf. Retrieved 16 September 2011. 
3. ^ "Medicinenet info on Anal Fissures". Medicinenet.com. http://www.medicinenet.com/anal_fissure/page3.htm. Retrieved 2009-01-21. 
4. ^ http://www.resus.org.uk/pages/als.pdf
5. ^ http://www.ser.nl/nl/grenswaarden/~/media/Files/Internet/Grenswaarden/SCOEL/GSW524_SCOEL_Prov147Nitroglycerine.ashx
6. ^ Liddle, R.; Richmond, W. (1998). "Investigation into voltage breakdown in glyceryl trinitrate patches". Resuscitation 37 (3): 145–148. doi:10.1016/S0300-9572(98)00059-8. PMID 9715773. 
7. ^ http://mythbustersresults.com/episode73
8. ^ Sneader, Walter. Drug Discovery: A History, p433. John Wiley and Sons, 2005. ISBN 0-471-89980-1
9. ^ Futura Medical
10. ^ CNN Money

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. PMID 10779131.