Alfentanil, metabolism

Yun CH, Wood M, Wood AJJ, et al. Identification of the pharmacogenetic determinants of alfentanil metabolism cytochrome P-4503A4. An explanation of the variable ehmination clearance. Anesthesiology 1992 77 467-474. 

Bartkowski P, Goldberg M, Larijani G, et al. Inhibition of alfentanil metabolism by erythromycin. Clin Pharmacol Ther 1989 46 99-102. 

Labroo, R.B., Thummel, K.E., Kunze, K.L., Podoll, T., Trager, W.F. and Kharasch, E.D. (1995) Catalytic role of cytochrome P4503A4 in multiple pathways of alfentanil metabolism. 

ED Kharasch, HF Hill, AC Eddy. Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism. Anesthesiology 75 520, 1991. 

Labroo RB, Thummel KE, Kunze KL, Podoll T, Trager WF, Kharasch ED. Catalytic role of cytochrome P4503A4 in multiple pa ways of alfentanil metabolism. Drug Metab Dispos (1995) 23, 490-6. 

Baitkow RR, Goldberg ME, Larijani GE and Boemer T. Inhibition of alfentanil metabolism by erythromyciiL CUnPhamuKol 7 r(1989) 46,99-102. 

Kharasch ED, Thummel KE. Human alfentanil metabolism by cytochrome P450 3A3/4. An ejqjlanation for the interindividual variability in alfentanil clearance Anes Analg (1993) 76,1033-9,... 

An example of N-dealkylation of an amine adjacent to a tertiary carbon can be found in the metabolism of synthetic opiod, alfentanil. The CYP3A4-catalyzed oxidation of the opiod alfentanil follows two major pathways (119) N-dealkylation to form no-ralfentanil and cleavage of the spiro center to generate N-phenylproprionamidc. Moreover,... 

Tertiary arylacetamides appear to undergo hydrolysis to a very limited extent only. Hydrolysis of the synthetic opioid fentanyl (4.117) to despropa-noylfentanyl (4.118) was a very minor pathway in humans [76], No metabolites resulting from amide hydrolysis were detected for the fentanil analogues alfentanil (4.119) and sufentanil (4.120) [77], for which oxidative N-dealkylation was the main metabolic pathway. 

The biotransformation of the phenylpiperidines is primarily by hepatic phase I metabolism, catalysed by cytochrome P-450 isoenzymes. The elimination of alfentanil is significantly slowed in patients treated with erythromycin, a P-450 inhibitor, with delayed recovery and prolonged postoperative respiratory depression (Bartkowski and McDonnell 1990). Apart from pethidine and phenoperidine, none of the phenylpiperidines has pharmacologically active metabolites. 

Pharmacokinetic properties Intravenous alfentanil (Hull, 1983) has a rapid onset and a short duration of action. It has a shorter elimination time (terminal half-life 1-2 h) than fentanyl. It is less lipid-soluble and the short duration of action is more dependent on metabolic inactivation than on redistribution. Alfentanil has a high (90%) plasma protein binding. Metabolic inactivation is effected by oxidative N- and O-demethylation. 

Krivoruk Y, Kinirons MT, Wood AJJ, et al. Metabolism of cytochrome P4503A substrates in vivo administered by the same route lack of correlation between alfentanil clearance and erythromycin breath test. Cbn Pharmacol Ther 1994 56 6084)14. 

Diltiazem caused a 43% mean increase in the half-life of midazolam in 30 patients who underwent coronary artery bypass grafting (57). Similar effects were observed with alfentanil. The proposed mechanism was diltiazem-induced inhibition of benzodiazepine metabolism by CYP3A. Patients taking diltiazem had delayed early postoperative recovery as a result. 

CALCIUM CHANNEL BLOCKERS OPIOIDS Diltiazem prolongs the action of alfentanil Diltiazem inhibits CYP3A4-mediated metabolism of alfentanil Watch for the prolonged action of alfentanil in patients taking calcium channel blockers case reports of delayed extubation in patients recovering from anaesthetics involving large doses of alfentanil in patients on diltiazem... 

OPIOIDS MACROLIDES Effects of alfentanil t by eiythromycin Erythromycin inhibits metabolism of alfentanil Be aware that the effects of alfentanil (especially when given as an infusion) may be prolonged by eiythromycin... 

OPIOIDS RIFAMPICIN 1 effect of alfentanil, codeine, methadone and morphine Rifampicin t hepatic metabolism of these opioids (alfentanil by CYP3A4, codeine by CYP2D6, morphine unknown). Rifampicin is also known to induce intestinal P-gp, which may 1 bioavailability of oral morphine Be aware that alfentanil, codeine, methadone and morphine doses may need to be t... 

OPIOIDS ANTIFUNGALS 1, Ketoconazole T effect of buprenorphine 2. Fluconazole and itraconazole T the effect of alfentanil 3. Fluconazole and possibly voriconazole T effect of methadone this is a recognized pharmacokinetic effect but of uncertain clinical significance 1. Ketoconazole 1 the CYP3A4-mediated metabolism of buprenorphine 2.1 clearance of alfentanil 3.1 hepatic metabolism 1. The dose of buprenorphine needs to be 1 (by up to 50%) 2. i dose of alfentanil 3. Watch for T effects of methadone... 

ALFENTANIL, FENTANYL, PETHIDINE, TRAMADOL CIMETIDINE Cimetidine may t fentanyl, pethidine and tramadol levels Cimetidine inhibits CYP2D6-medi-ated metabolism of these opioids. Ranitidine weakly inhibits CYP2D6 Watch for excessive narcotization... 

CANNABIS ANALGESICS - OPIOIDS -alfentanil, fentanyl, methadone, codeine, dextromethorphan Unpredictable changes in plasma concentration. Risk of toxicity or therapeutic failure, particularly of drugs with a narrow therapeutic index Induction or inhibition of CYP3A4-mediated metabolism by cannabis. It is not yet known whether the effects are dependent on the degree of cannabis consumption Be aware. Watch for signs of toxicity, especially when cannabis use abruptly changes... 

AMPHETAMINES ANALGESICS-OPIOIDS-alfentanil, fentanyl, propoxyphene t plasma concentrations of amphetamine, with risk of toxic effects Due to inhibition of CYP2D6-mediated metabolism of amphetamine Avoid concurrent use... 

The metabolism of alfentanil, a potent short-acting narcotic, is inhibited by macrolide antibiotics, resnlting in significant changes in half-life and clearance (86). 

The CYP3A4 isozyme is responsible for the metabolism of a large number of endogenous compounds as well as a wide range of drugs (50). Fentanyl, alfentanil, and sufentanil are substrates for CYP3A4, and therefore drugs that inhibit this enzyme, such as erythromycin, HIV protease inhibitors, or cimetidine. 

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