Protease inhibitors Fentanyl

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). 

ALFENTANIL, BUPRENORPHINE, FENTANYL, TRAMADOL PROTEASE INHIBITORS Possibly t adverse effects when buprenorphine is co administered with indinavir, ritonavir (with or without lopinavir) or saquinavir Inhibition of CYP3A4 (CYP2D6 in the case of tramadol) Halve the starting dose and titrate to effect. For single injection of fentanyl, monitor sedation and respiratoiy function closely. If continued use of fentanyl, i dose may be required. Concomitant use of ritonavir and transdermal fentanyl is not recommended... 

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. 

Opioids Fentanyl and related drugs + Protease inhibitors... 

Ritonavir markedly increases the levels of fentanyl, and markedly increases alfentanil-induced miosis. Other protease inhibitors such as nelfinavir may have a similar effect Care should also be taken if ritonavir is used with other protease inhibitors as a pharmacokinetic enhancer. 

Both fentanyl and alfentanii ate metabolised by the cytochrome P450 isoenzyme CYP3A4. Ritonavir, and other protease inhibitors, ate potent inhibitors of CYP3A4 and they therefore reduce the metabolism of these opioids, which results in increased levels and effects. 

Ritonavir is an inhibitor of HIV protease and a potent inhibitor of CYP3A4 and CYP2D6. The interaction between ritonavir and intravenous fentanyl has been investigated in 12 healthy volunteers in a double-blind, placebo-controUed, crossover study (84). The volunteers took ritonavir 600 mg on day 1, ritonavir 900 mg and intravenous fentanyl 5 pg/kg on day 2, and ritonavir 300 mg or placebo on day 3. Ritonavir reduced the clearance of fentanyl by 67% by inhibiting its metabolism. This could result in prolongation of fentanyl-induced respiratory depression in a patient with an aheady compromised cardiorespiratory system. 

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