Fentanyl metabolism

Labroo, R. B., Paine, M. F., Thummel, K. E., Kharasch, E. D., Fentanyl metabolism by human hepatic and intestinal cytochrome P4503A4. Implications for interindividual variability in disposition, efficacy and drug interactions, Drug Metab. Disp. 1997, 25, 1072-1080. 

Lee HR, et al Effect of histamine Hi-receptors on fentanyl metabolism. Pharmacology 1982 24 145. 

Feierman DE. The effect of paracetamol (acetaminophen) on fentanyl metabolism in vitro. Acta Anaesthesiol Scand(200G) 44, 560-3. 

The answer is c. (Hardman, pp 543—544. Katzang, p 2533) Fentanyl is a chemical relative of meperidine that is nearly 100 times more potent than morphine. The duration of action, usually between 30 and 60 min after parenteral administration, is shorter than that of meperidine. Fentanyl citrate is only available for parenteral administration intramuscularly and intravenously. Tran sbuc cal ( lollipop ) and transdermal patches avoid first-pass metabolism of fentanyl. 

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. 

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. 

Pharmacokinetic properties Fentanyl (Scholz et al., 1996) is a highly lipophilic compound and about 80% binds to plasma proteins. After parenteral administration it has a rapid onset and a short duration of action. The compound is rapidly transported into the CNS and lipid tissues. The short duration of action is due to redistribution rather than metabolic inactivation or excretion. It is released from tissue depots with a half-life of about 4 h and the terminal half-life is up to 7 h. The main metabolites, excreted in urine are 4-N-(N-propionylanilino)-piperidine and the N-hydroxypropionyl derivative. 

The transdermal system provides continuous systemic delivery of fentanyl for 72 h. The amount of drug released from the system per hour is proportional to the surface area. Following application of the patch to the skin, a depot of fentanyl concentrates in the upper skin layers. This is then available to the systemic circulation. There is an initial rise in blood fentanyl concentration after application followed by a leveling off that occurs 12 to 24 h later. Peak blood concentrations occur between 24 and 72 h after application. The skin does not appear to metabolize fentanyl when delivered transdermally. 

Drugs metabolized by CYP that interact with cimetidine include, but are not limited to, the following lidocaine, quinidine, midazolam, triazolam, nifedipine, verapamil, and fentanyl (4). In each instance, inhibition of CYP by cimetidine results in reduced metabolic clearance and increases in serum concentrations of the other drug, which can lead to the expected toxicity and adverse experiences characteristic of the other drug. 

Fentanyl competes for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22, 39) (SEDA-22, 41). 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

SSRIs OPIOIDS 1. Possible 1 analgesic effect of oxycodone and tramadol 2. T serotonin effects, including possible cases of serotonin syndrome, when opioids (oxycodone, pethidine, pentazocine, tramadol) are co-administered with SSRIs (fluoxetine and sertraline) 3. SSRIs may t codeine, fentanyl, methadone, pethidine and tramadol levels 1. Uncertain. Paroxetine inhibits CYP2D6, which is required to produce the active form of tramadol. 2. Uncertain 3. SSRIs inhibit CYP2D6-mediated metabolism of these opioids 1. Consider using an alternative opioid 2. Look for signs of T serotonin activity, particularly on initiating therapy 3. Watch for excessive narcotization... 

TCAs OPIOIDS 1. Risk of t respiratory depression and sedation 2. t levels of morphine 3. Case reports of seizures when tramadol was co-administered with TCAs 4. TCAs may t codeine, fentanyl, pethidine and tramadol levels 1. Additive effect 2. Uncertain likely t bioavailability of morphine 3. Unknown 4. TCAs inhibit CYP2D6-mediated metabolism of these opioids 1. Warn patients of this effect. Titrate doses carefully 2. Warn patients of this effect. Titrate doses carefully 3. Consider an alternative opioid 4. Watch for excessive narcotization... 

BARBITURATES ANALGESICS - OPIOIDS 1. Barbiturates t sedative effects of opioids 2.1 efficacy of fentanyl and methadone with phenobarbital and primidone 1. Additive sedative effect. 2. t hepatic metabolism of fentanyl and methadone 1. Monitor respiratory rate and conscious levels 2. Be aware that the dose of fentanyl and methadone may need to t... 

OPIOIDS ANTIEPILEPTICS 1. Barbiturates T sedative effects of opioids 2.1 efficacy of fentanyl and methadone with carbamazepine, phenobarbital, phenytoin or primidone 3. Carbamazepine l tramadol levels 4. Risk of pethidine toxicity 1. Additive sedative effect 2. t hepatic metabolism of fentanyl and methadone, and possibly an effect at the opioid receptor 3. Carbamazepine T metabolism of tramadol 4. Phenytoin induces metabolism of pethidine, which causes T level of a neurotoxic metabolite 1. Monitor respiratoiy rate and conscious levels 2. Be aware that the dose of fentanyl and methadone may need to be t 3. Watch for poor effect of tramadol. Consider using an alternative opioid 4. Co administer with caution the effect may be i by administering pethidine intravenously... 

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