C01DA02 - Glyceryl Trinitrate |
Not porphyrinogenic |
NP |
Rationale
The major metabolic pathway is non-CYP metabolism, CYP-mediated formation of nitric oxide from nitrate in humans is not of clinical significance. No evidence of capacity for CYP-induction. Clinical experience points to non-porphyrinogenicity, more than 12 patient reports of tolerance supports this.
Chemical description
Propane-1,2,3-triol trinitrate. M= 227.1
Therapeutic characteristics
Glyceryl trinitrate is a nitrovasodilator used in the management of angina pectoris, heart failure and myocardial infarction. Other indications include inducing hypotension and controlling hypertension during surgery. Tachycardia is a common side effect while nausea and vomiting are less common side effects.
Hepatic exposure
Insignificant.
Metabolism and pharmakokinetics
Glyceryl trinitrate is widely distributed with a large apparent volume of distribution. It is taken up by smooth muscle cells of blood vessels and the nitrate group is cleaved to inorganic nitrite and then to nitric oxide. This reaction requires the presence of cysteine or another thiol. Glyceryl trinitrate also undergoes hydrolysis in plasma and is rapidly metabolised in the liver by glutathione-organic nitrate reductase to dinitrates and mononitrates. The dinitrates are less potent vasodilators than glyceryl trinitrate; the mononitrates may have some vasodilator activity.
A high and variating plasma clearence 10-50 mL/min points to a high degree of extrahepatic metabolism. No clinical or experimental evidence of interactions with CYP-metabolism of other drugs.
Preclinical data
In animal studies continuous administration of organic nitrates decreased hepatic P450 content and simultaneously induced hemeoxygenase (Minamiyama). Rodent experiments suggest that the biotransformation of organic nitrates may take place by direct interaction with the heme moiety of cytochrome P450 and preferentially by isocénzymes that can be induced by phenobarbital.
Personal communication
S.Thunell 2004: 6 patient reports (tolerated). C Andersson 2004: 5 patient reports (tolerated). Peters 2004 : some patient reports (tolerated).
Published experience
Tolerated by two acute porphyria patients of unknown susceptibility (Kauppinen and Mustajoki).
IPNet drug reports
Uneventful use reported in 10 patients with acute porphyria.
References
- Scientific articles
- Bogaert 1994. Clinical pharmacokinetics of nitrates. PMID 7873466. PMID 7873466. #4383
- Kauppinen and Mustajoki. Prognosis of acute porphyria: Occurrence of acute attacks, precipitating factors,and assocciated diseases. Medicine 1992; 71, 1-13. #1218
- McDonald Benett 1990. Cytochrome P450 mediated biotransformation of organic nitrates. PMID 2128204. PMID 2128204. #4384
- Kepple A, Cernek PK. Amlodipine-induced acute intermittent porphyria exacerbation [3]. Annals of Pharmacotherapy 1997; 31(2):253. PMID 9034433. #1219
- Minamiyama Y et al. Continuous administration of organic nitrate decreases hepatic cytochrome P450. J Pharmacol Exp Ther 2004; 308(2): 729-35. PMID 14593088. PMID 14593088. #4385
- Roby HP, Harrison GA. Anaesthesia for coronary artery bypass in a patient with porphyria variegata. Anaesthesia & Intensive Care 1982; 10(3):276-278. #1221
- Shipton EA, Roelofse JA. Anaesthesia in a patient with variegate porphyria undergoing coronary bypass surgery. A case report. South African Medical Journal 1984; 65(2):53-54. #1222
- Sneyd JR, Kreimer-Birnbaum M, Lust MR, Heflin J. Use of sufentanil and atracurium anesthesia in a patient with acute porphyria undergoing coronary artery bypass surgery. Journal of Cardiothoracic & Vascular Anesthesia 1995; 9(1):75-78. #1223
- Drug reference publications
- Martindale 2009, #3271
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