Pharmacy Blog – Dr Vibore

Probenecid reduces clearance of paracetamol

Clinical evidence,mechanism, importance and management

A metabolic study in 10 healthy subjects found that clearance of paracetamol 1.5 g was almost halved (from 6.23 to 3.42 mL/minute per kg) when it was taken 1 hour after a 1-g dose of probenecid. The amount of unchanged paracetamol in urine stayed same, but glucuronide metabolite fell sharply (See reference number 1). Another study in 11 subjects also found that probenecid 500mg every 6 hrs almost halved (from 329 to 178 mL/minute) clearance of a 650mg intravenous dose of paracetamol. The urinary excretion of glucuronide metabolite was decreased by 68 % and excretion of sulfate metabolite increased by 49 % (See reference number 2). These studies suggest that probenecid inhibits paracetamol glucuronidation,possibly by inhibiting glucuronyltransferase. See also paracetamol,. The practical consequences of this interaction are uncertain but there seem to be no adverse reports.

Kamali F. The effect of probenecid on paracetamol metabolism and pharmacokinetics. Eur J Clin Pharmacol (1993) 45,551–3.

Abernethy DR,Greenblatt DJ, Ameer B, Shader RI. Probenecid impairment of acetaminophenand lorazepam clearance: direct inhibition of ether glucuronide formation. J Pharmacol Exp Ther (1985) 234, 345–9.

Caffeine has been variously reported to increase, decrease, andhave no effect on absorption of paracetamol.

Clinical evidence,mechanism, importance and management

Caffeine citrate 120mg increased AUC of a single 500mg dose of paracetamol in 10 healthy subjects by 29%, increased maximum plasma levels by 15 % and decreased total body clearance by 32%. The decrease in time to maximum level and increase in absorption rate did not reach statistical significance (See reference number 1). However, in another study, although caffeine slightly increased rate of absorption of paracetamol, it had no effect on extent of absorption (See reference number 2). Moreover,a third study states that caffeine decreased plasma paracetamol levels and AUC and increased paracetamol elimination in healthy men (See reference number 3). Caffeine is commonly included in paracetamol preparations as an analgesic adjuvant. Its potential benefit and mechanisms behind its possible effects remain unclear.

Iqbal N,Ahmad B, Janbaz KH, Gilani A-UH, Niazi SK. The effect of caffeine on the pharmacokinetics of acetaminophen in man. Biopharm Drug Dispos (1995) 16, 481–7.

Tukker JJ,Sitsen JMA, Gusdorf CF. Bioavailability of paracetamol after oral administration tohealthy volunteers. Influence of caffeine on rate and extent of absorption. Pharm Weekbl (Sci) (1986) 8, 239–43.

Raińska-Giezek T. Influence of caffeine on toxicity and pharmacokinetics of paracetamol [Article in Polish]. Ann Acad Med Stetin (1995) 41,69–85.

1. Saari TI,Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT. Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life. Clin Pharmacol Ther (2006) 80, 502–8.

Ritonavir decreases pethidine (meperidine) and increases norpethidine levels,which may possibly increase toxicity on long-termuse. Similarly,ritonavir and other protease inhibitors increasebuprenorphine levels. Ritonavir may increase metabolism ofmorphine, and decrease metabolism of dextropropoxyphene(CYP3A4 substrate) and tramadol or other CYP2D6 substrates(such as codeine).

One report describes 3 HIV-positive patients who experienced increased buprenorphine adverse effects (e.g. daytime sleepiness,dizziness, and reduced mental function) within about 2 days of starting to take atazanavir boosted by low-dose ritonavir. When dose of buprenorphine was reduced there was a reduction in sedative symptoms within a week (See reference number 1).

In a study in opioid-dependent patients treated with sublingual buprenorphine and naloxone, patients were given an antiretroviral (nelfinavir, lopinavir/ritonavir, or ritonavir) for 5 to 15 days to investigate effect of these drugs on QT interval. Buprenorphine/naloxone alone did not significantly alter QT interval, but when combined with an antiretroviral there was a statistically, but probably not clinically, significant increase in QT interval. The greatest increase in QTc interval was seen in patients receiving buprenorphine/naloxone with ritonavir 100mg twice daily (low booster dose) (See reference number 2).

Ritonavir 500mg twice daily for 10 days decreased AUC of a single 50mg dose of oral pethidine by 62 % and increased AUC of norpethidine by 47 % in 8 healthy subjects (See reference number 3,4). Norpethidine is pharmacologically active, and is possibly less effective an analgesic than parent compound, and more likely to cause CNS effects such as seizures.

In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4 and to a lesser extent CYP2D6, and may also induce glucuronidation (See reference number 4). An in vitro study suggested that buprenorphine metabolism may be inhibited by ritonavir and to a lesser extent by indinavir and saquinavir,(See reference number 5) which would be expected to lead to increased buprenorphine levels. Other opioids metabolised by CYP3A4 include dextropropoxyphene (propoxyphene),fentanyl and related drugs, (below), and methadone, . Substrates of CYP2D6 include codeine,dihydrocodeine, oxycodone, and tramadol. Morphine undergoes glucuronidation, and morphine metabolite M6G [morphine6 beta-glucuronide] is believed to contribute to analgesic effects of morphine. Buprenorphine,and to some extent, codeine also undergo glucuronidation (See reference number 6).

Most of these interactions remain theoretical, but they are consistent with way protease inhibitors and opioids interact with other drugs. The consequences of inhibition of CYP2D6 are most pronounced for codeine, and CYP2D6 inhibition will lead to decreased levels of morphine metabolite of codeine and therefore, perhaps contrary to expectation, a reduced effect. The levels of other CYP2D6 substrates dihydrocodeine,oxycodone, and tramadol would be expected to be raised, and dose reductions may be necessary. This has been suggested for tramadol (See reference number 7). It would seem prudent to monitor for adverse effects such as sedation. However,note that low-dose ritonavir (i.e. the dose used as a pharmacokinetic enhancer with other protease inhibitors) has a less potent effect on CYP2D6 and dose reductions of drugs metabolised by CYP2D6 would not generally be required if this dose of ritonavir is given concurrently (See reference number 8).

Ritonavir is a potent inhibitor of CYP3A4 and therefore UK manufacturer of ritonavir contraindicates its use with dextropropoxyphene as extremely raised dextropropoxyphene levels may occur, which would increase risk of serious respiratory depression or other serious adverse events (See reference number 4). However, US manufacturer only suggests that a dose decrease may be needed (See reference number 7).

The outcome of taking ritonavir with morphine is less clear,but it is expected that its levels will be decreased (See reference number 4,9). It would seem prudent to monitor closely to ensure morphine is effective in patients taking ritonavir. More study is needed.

It has been suggested that starting dose of buprenorphine should be halved in patients taking CYP3A4 inhibitors, such as protease inhibitors, when it is used for opioid dependence (See reference number 10). However, it has also been suggested that, since magnitude of an inhibitory effect is unknown, such drug combinations should be avoided when buprenorphine is used parenterally or sublingually as a strong analgesic (See reference number 11,12).

The manufacturers of pethidine oral preparations and injection contraindicate or advise against its use with ritonavir because of risk of norpethidine toxicity (See reference number 13,14). Long-term use of pethidine with other protease inhibitors e.g. tipranavir,which are given with low-dose ritonavir is also not recommended (See reference number 15,16).

Bruce RD,Altice FL. Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS (2006) 20, 783–4.

Baker JR,Best AM, Pade PA, McCance-Katz EF. Effect of buprenorphine and antiretroviralagents on the QT interval in opioid-dependent patients. Ann Pharmacother (2006) 40, 392–6.

Piscitelli SC,Kress DR, Bertz RJ, Pau A, Davey R. The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine. Pharmacotherapy (2000) 20, 549–53.

Norvir (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May2007.

Iribarne C,Berthou F, Carlhant D, Dreano Y, Picart D, Lohezic F, Riche C. Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug Me-tab Dispos (1998) 26, 257–60.

Lötsch J,Skarke C, Tegeder I, Geisslinger G. Drug interactions with patient-controlled analgesia. Clin Pharmacokinet (2002) 41, 31–57.

Norvir (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.

Aarnoutse RE,Kleinnijenhuis J, Koopmans PP, Touw DJ, Wieling J, Hekster YA, BurgerDM. Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther (2005) 78, 664–74.

Abbott Laboratories Ltd (UK). Personal communication,March 1998.

Subutex (Buprenorphine hydrochloride). Schering-Plough Ltd. UK Summary of productcharacteristics,January 2006.

Temgesic Injection (Buprenorphine hydrochloride). Schering-Plough Ltd. UK Summary ofproduct characteristics,April 2004.

Temgesic Sublingual Tablets (Buprenorphine hydrochloride). Schering-Plough Ltd. UKSummary of product characteristics,April 2004.

Pethidine Injection (Pethidine hydrochloride). Wockhardt UK Ltd. UK Summary of productcharacteristics,March 2005.

Demerol (Meperidine hydrochloride). Sanofi-Aventis US LLC. US Prescribing information,July 2007.

Aptivus (Tipranavir). Boehringer Ingelheim Ltd. UK Summary of product characteristics,March 2007.

Aptivus (Tipranavir). Boehringer Ingelheim. US Prescribing information,February 2007.

Zidovudine had no effect on methadone levels in one study,butthere is one report of a patient requiring a modest increase inmethadone dose after starting zidovudine. Similarly case reportsdescribe patients requiring a modest increase in methadone doseafter starting abacavir. Methadone can increase zidovudine serum levels, and reduce levels of abacavir, stavudine, and didanosine from tablet formulation, but not enteric-coated capsule preparation. Tenofovir,and a single dose of zidovudine/lamivudine had no effect on methadone pharmacokinetics.

Eleven patients given methadone with abacavir had a 23 % increase in rate of methadone clearance but no change in half-life or renal clearance. In addition, there was a delay, and a 34 % decrease in peak concentration of abacavir, but no change in abacavir clearance or half-life (See reference number 1). Of 3 patients taking methadone who started taking abacavir,lamivudine and zidovudine, 2 required methadone dosage increases (31% and 46%, respectively). The abacavir was thought to be responsible for this effect (See reference number 2). A patient receiving methadone experienced torsades de pointes when receiving abacavir,lamivudine and zidovudine (See reference number 3).

A study in 17 subjects taking methadone found that AUC and maximum levels of didanosine tablets were 57 % and 66 % lower, respectively, when compared with 10 control subjects. Trough levels of methadone did not differ from historical controls,suggesting that didanosine had no effect on methadone pharmacokinetics (See reference number 4). A later study found that there was no reduction in AUC of didanosine given as enteric-coated capsules (See reference number 5).

A study in 17 subjects taking methadone found that AUC and maximum levels of stavudine were 23 % and 44 % lower, respectively, when compared with 10 control subjects. Trough levels of methadone did not differ from historical controls suggesting that stavudine had no effect on methadone pharmacokinetics (See reference number 4).

In a study in 13 healthy subjects receiving methadone, tenofovir 300mg daily for 2 weeks did not alter pharmacokinetics of methadone, and no symptoms of opioid toxicity or opioid withdrawal were detected (See reference number 6).

Buprenorphine. In one study, there was no difference in pharmacokinetics of oral zidovudine between patients receiving buprenorphine and control subjects (See reference number 7). Buprenorphine is not expected to cause zidovudine toxicity.

Methadone effects reduced or unaffected. A drug abuser with AIDS needed an increase in his levomethadone (R-methadone) dosage from 40 to 60mg daily,within a month of starting to take zidovudine 1 g daily (See reference number 8).

In contrast, a study found no evidence of any change in pharmacokinetics of methadone in HIV-positive patients taking methadone 14 days after they started zidovudine 200mg every 4 hours. No methadone withdrawal symptoms occurred (See reference number 9). Another study in 16 patients taking methadone found that a single-dose of a fixed combination of zidovudine 300mg with lamivudine 150mg (Combivir) had no effect on pharmacokinetics of methadone, and there was no evidence of withdrawal or toxicity (See reference number 10).

3. Zidovudine effects increased. In one study mean AUC of zidovudine was increased by 43 % by methadone, and in 4 of 9 patients it was doubled (See reference number 9). In another study, 8 HIV-positive patients starting methadone found a 29 % increase in AUC of oral zidovudine and a 41 % increase in AUC of intravenous zidovudine. Three of 8 patients stopped zidovudine because of adverse effects or haematologic toxicity (See reference number 11). Decreased zidovudine clearance in patients taking methadone is described in another report (See reference number 12).

Uncertain. It appears that methadone reduces bioavailability of didanosine, and to a lesser extent, stavudine, possibly because it delays gastric emptying. Thus, enteric-coated didanosine preparation appears not to be affected (See reference number 4,5). Conversely, methadone apparently reduces glucuronidation of zidovudine by liver, resulting in an increase in its serum levels (See reference number 13). Methadone may also reduce renal clearance of zidovudine (See reference number 11).

The increase in zidovudine levels with methadone is established, although clinical relevance is uncertain. Be alert for any increase in zidovudine adverse effects. The balance of evidence suggests that zidovudine is unlikely to reduce methadone levels, and one case reported remains unexplained, although note that some of adverse effects of zidovudine may be mistaken for opioid withdrawal effects.

The reduction in didanosine levels with methadone may be clinically relevant, and authors suggest increasing dose of tablet formulation. Monitor virological response. The enteric-coated didanosine preparation is not affected and it may therefore be worth considering using this preparation instead.

The reduction in stavudine levels and changes in abacavir peak levels with methadone are probably not clinically relevant, but again, further data are required. The reports with abacavir suggest that it would be prudent to monitor methadone dose requirements when this drug is started. Tenofovir does not appear to affect methadone levels.

Sellers E,Lam R, McDowell J, Corrigan B, Hedayetullah N, Somer G, Kirby L, Kersey K,Yuen G. The pharmacokinetics of abacavir and methadone following coadministration:CNAA1012. Intersci Conf Antimicrob Agents Chemother (1999) 39, 663.

Pardo López MA,Cuadrado Pastor JM, Pérez Hervás MP, Fernández Villalba E. Síndromede abstinencia a opiáceos tras la administración de zidovudina + lamivudina + abacavir enpacientes infectados por el virus de la inmunodeficiencia humana en tratamiento con metadona. Rev Clin Esp (2003) 203, 407–8.

Anon. Torsades de pointes with methadone. Prescrire Int (2005) 14,61–2.

Rainey PM,Friedland G, McCance-Katz EF, Andrews L, Mitchell SM, Charles C, Jatlow P.Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr (2000) 24, 241–8.

Friedland G,Rainey P, Jatlow P, Andrews L, Damle B, McCance-Katz E. Pharmacokineticsof didanosine from encapsulated enteric coated bead formulation vs chewable tablet formulation in patients on chronic methadone therapy. XIV International AIDS Conference, Barcelona, 2002. Abstract TuPeB4548.

Smith PF,Kearney BP, Liaw S, Cloen D, Bullock JM, Haas CE, Yale K, Booker BM, Berenson CS, Coakley DF, Flaherty JF. Effect of tenofovir disoproxil fumarate on the pharmacokinetics and pharmacodynamics of total, R-, and S-methdone. Pharmacotherapy (2004) 24, 970–77.

McCance-Katz EF,Rainey PM, Friedland G, Kosten TR, Jatlow P. Effect of opioid dependence pharmacotherapies on zidovudine disposition. Am J Addict (2001) 10, 296–307.

Brockmeyer NH,Mertins L, Goos M. Pharmacokinetic interaction of antimicrobial agentswith levomethadon in drug-addicted AIDS patients. Klin Wochenschr (1991) 69, 16–18.

Schwartz EL,Brechbühl A-B, Kahl P, Miller MA, Selwyn PA, Friedland GH. Pharmacokinetic interactions of zidovudine and methadone in intravenous drug-using patients with HIVinfection. J Acquir Immune Defic Syndr (1992) 5, 619–26.

Rainey PM,Friedland GH, Snidow JW, McCance-Katz EF, Mitchell SM, Andrews L, LaneB, Jatlow P. The pharmacokinetics of methadone following co-administration with a lamivudine/zidovudine combination tablet in opiate-dependent subjects. Am J Addict (2002) 11, 66–

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McCance-Katz EF,Rainey PM, Jatlow P, Friedland G. Methadone effects on zidovudine disposition (AIDS clinical trials group 262). J Acquir Immune Defic Syndr Hum Retrovirol (1998) 18, 435–43.

Burger DM,Meenhorst PL, ten Napel CHH, Mulder JW, Neef C, Koks CHW, Bult A, Beijnen JH. Pharmacokinetic variability of zidovudine in HIV-infected individuals: subgroupanalysis and drug interactions. AIDS (1994) 8, 1683–9.

Cretton-Scott E,de Sousa G, Nicolas F, Rahmani R, Sommadossi J-P. Methadone and its metabolite N-demethyl methadone, inhibit AZT glucuronidation in vitro. Clin Pharmacol Ther (1996) 59, 168.

In general concurrent use of opioids and benzodiazepines results in both beneficial analgesic effects, and enhanced sedationand respiratory depression; however, in some cases benzodiazepines have antagonised respiratory depressant effects ofopioids, and, rarely, have antagonised their analgesic effects.

Clinical evidence,mechanism, importance and management

In one study, low-dose midazolam (given to achieve levels of 50 nanograms/mL) reduced dose of morphine required for postoperative analgesia in first 12 hrs (See reference number 1). However,in another study postoperative pain scores were higher in patients premedicated with oral diazepam 10 mg than with placebo, although morphine consumption did not differ (See reference number 2). Similarly, in another study, benzodiazepine antagonist flumazenil enhanced morphine analgesia in patients who had been premedicated with diazepam (See reference number 3). It is suggested that benzodiazepines antagonise analgesic effect of opioids via their effect on supraspinal GABA receptors. Why this has been shown in some studies,but not others, is unclear. Benzodiazepines and opioids are commonly used in surgical anaesthesia, and relevance of these findings to clinical practice is uncertain.

Sudden deaths in patients who abuse opioids are frequently associated with ingestion of other CNS depressants,particularly benzodiazepines.

Cases have been reported with buprenorphine,oxycodone,and tramadol(See reference number 7)taken with various benzodiazepines. It has not been established exactly why this occurs,but both pharmacodynamic and pharmacokinetic mechanisms are possible. The deleterious interaction of benzodiazepines and opioids on respiration is possibly due to central effects and/or additive actions on different neuromuscular components of respiration (See reference number 8). For buprenorphine,it is considered most likely that excessive CNS depression is solely due to combined pharmacological effects, and not to any pharmacokinetic interaction.(See reference number 9-11) See also Pharmacokinetics,below.

Intramuscular pethidine 100mg and intramuscular morphine 10mg delayed absorption of oral diazepam 10 mg. Diazepam levels were found to be lower and peak levels were not reached in 90-minute study period, when compared with peak level at 60 minutes in control group (See reference number 12). The underlying mechanism is that opioid analgesics delay gastric emptying so that rate of absorption of diazepam is reduced. The maximal effect of diazepam would be expected to be delayed in patients receiving these opioids.

Another study in healthy subjects found that dextropropoxyphene 65 mg every 6 hrs prolonged alprazolam half-life from 11

18.3 hours, and decreased clearance from 1.3 to 0.8 mL/minute per kg. The pharmacokinetics of single doses of diazepam and lorazepam were not significantly affected (See reference number 13). It would seem that dextropropoxyphene inhibits metabolism (hydroxylation) of alprazolam by liver, thereby reducing its loss from body, but has little or no effect on N-demethylation or glucuronidation of other two benzodiazepines. The clinical importance of this is uncertain, but inference to be drawn is that CNS depressant effects of alprazolam will be increased, over and above simple additive CNS depressant effects likely when other benzodiazepines and dextropropoxyphene are taken together. More study is needed.

Extended-release oxymorphone did not affect metabolism of midazolam in healthy subjects (See reference number 14). An in vitro study found that buprenorphine metabolism to norbuprenorphine was only weakly or negligibly inhibited by benzodiazepines,but midazolam had some modest effects and it was suggested that it may possibly cause some clinically relevant inhibition of buprenorphine metabolism (See reference number 15).

A 14-year-old boy with staphylococcal pneumonia secondary to influenza developed adult respiratory distress syndrome. It was decided to suppress his voluntary breathing with opioids and use assisted ventilation and he was therefore given phenoperidine and diazepam for 11 days,and later diamorphine with lorazepam. Despite receiving diamorphine 19.2mg in 24 hrs his respiratory drive was not suppressed. On day 17,despite serum morphine and lorazepam levels of 320 and 5.3 micrograms/mL,respectively, he remained conscious and his pupils were not constricted (See reference number 16). Later animal studies confirmed that lorazepam opposed respiratory depressant effects of morphine (See reference number 16).

In contrast, intravenous diazepam 150 micrograms/kg did not alter respiratory depressant effect of intravenous pethidine 1.5 mg/kg in a study in healthy subjects(See reference number 17) or in patients with chronic obstructive pulmonary disease (See reference number 18). Moreover, in setting of overdose (see (b) above), benzodiazepines might increase respiratory depressant effects of opioids.

The sedative effects of midazolam and morphine were additive in a study in patients given these drugs intravenously prior to surgery (See reference number 19). A prospective study of 80 patients undergoing elective endoscopy found that deep sedation occurred frequently (68% of patients) with pethidine and midazolam used with intent of moderate sedation (See reference number 20). Another study found that single oral doses of diazepam 10 or 20mg given to 8 buprenorphine-maintained patients increased subjective effects such as sedation and strength of drug effects,and also caused a deterioration in performance measures such as cancellation time, compared with placebo (See reference number 21).

Gilliland HE,Prasad BK, Mirakhur RK, Fee JPH. An investigation of the potential morphinesparing effect of midazolam. Anaesthesia (1996) 51, 808–11.

Caumo W,Hidalgo MPL, Schmidt AP, Iwamoto CW, Adamatti LC, Bergmann J, FerreiraMBC. Effect of pre-operative anxiolysis on postoperative pain response in patients undergoing total abdominal hysterectomy. Anaesthesia (2002) 57, 740–6.

Gear RW,Miaskowski C, Heller PH, Paul SM, Gordon NC, Levine JD. Benzodiazepine mediated antagonism of opioid analgesia. Pain (1997) 71, 25–9.

Reynaud M,Petit G, Potard D, Courty P. Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Addiction (1998) 93, 1385–92.

Kintz P. A new series of 13 buprenorphine-related deaths. Clin Biochem (2002) 35,513–16.

Burrows DL,Hagardorn AN, Harlan GC, Wallen EDB, Ferslew KE. A fatal drug interactionbetween oxycodone and clonazepam. J Forensic Sci (2003) 48, 683–6.

Clarot F,Goullé JP, Vaz E, Proust B. Fatal overdoses of tramadol: is benzodiazepine a riskfactor of lethality? Forensic Sci Int (2003) 134, 57–61.

Megarbane B,Gueye P, Baud F. Interactions entre benzodiazépines et produits opioïdes. Ann Med Interne (Paris) (2003) 154 (Spec No 2) S64–S72.

Ibrahim RB,Wilson JG, Thorsby ME, Edwards DJ. Effect of buprenorphine on CYP3A activity in rat and human liver microsomes. Life Sci (2000) 66, 1293–8.

Kilicarslan T,Sellers EM. Lack of interaction of buprenorphine with flunitrazepam metabolism. Am J Psychiatry (2000) 157, 1164–6.

Elkader A,Sproule B. Buprenorphine: clinical pharmacokinetics in the treatment of opioiddependence. Clin Pharmacokinet (2005) 44, 661–80.

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Abernethy DR,Greenblatt DJ, Morse DS, Shader RI. Interaction of propoxyphene with diazepam, alprazolam and lorazepam. Br J Clin Pharmacol (1985) 19, 51–7.

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Chang Y,Moody DE. Effect of benzodiazepines on the metabolism of buprenorphine in human liver microsomes. Eur J Clin Pharmacol (2005) 60, 875–81.

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Tverskoy M,Fleyshman G, Ezry J, Bradley EL, Kissin I. Midazolam-morphine sedative interaction in patients. Anesth Analg (1989) 68, 282–5.

Patel S,Vargo JJ, Khandwala F, Lopez R, Trolli P, Dumot JA, Conwell DL, Zuccaro G. Deepsedation occurs frequently during elective endoscopy with meperidine and midazolam. Am J Gastroenterol (2005) 100, 2689–95.

Lintzeris N,Mitchell TB, Bond A, Nestor L, Strang J. Interactions on mixing diazepam withmethadone or buprenorphine in maintenance patients. J Clin Psychopharmacol (2006) 26, 274–83.

Diltiazem prolonged effects of alfentanil in one study

Clinical evidence,mechanism, importance and management

A 24 % increase in AUC of alfentanil and a 50 % increase in its half-life were seen in 15 patients anaesthetised with midazolam and alfentanil (induced with 50 micrograms/kg, then maintained with 1 microgram/kg per minute) when they were given diltiazem 60mg orally 2 hrs before induction, then an infusion for 23 hrs starting at induction. Tracheal extubation was performed on average 2.5 hrs later in patients receiving diltiazem than in a placebo group (See reference number 3). Diltiazem is an inhibitor of cytochrome P450 isoenzyme CYP3A4, which is responsible for metabolism of alfentanil (See reference number 3). Caution is required as there could be an increased risk of prolonged or delayed respiratory depression. The manufacturer says that concurrent use of diltiazem and alfentanil requires special patient care and observation; it may be necessary to lower dose of alfentanil (See reference number 4).

A double-blind, placebo-controlled study in 26 patients undergoing surgery found that 2 doses of slow-release nifedipine 20mg given on day preceding surgery and a further dose given 60 to 90 minutes before surgery increased analgesic effect of morphine (See reference number 5). A study in animals found that verapamil potentiated morphine analgesia (See reference number 6). A further study in animals found that diltiazem, nimodipine and verapamil, given before morphine, potentiated analgesic effect of morphine and markedly increased morphine serum levels (See reference number 7).

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As parecoxib is rapidly metabolised to valdecoxib, interactions are usually considered to be due to effects of valdecoxib.The manufacturer of parecoxib cautions concurrent use withcarbamazepine, dexamethasone and rifampicin as their effects onparecoxib have not been studied. Valdecoxib increases levelsof dextromethorphan and omeprazole. Because of these interactions,caution is advised with drugs that are metabolised by thesame isoenzymes, namely flecainide, metoprolol, propafenone,omeprazole, diazepam, imipramine and phenytoin. No interaction appears to occur between parecoxib and midazolam.

Clinical evidence,mechanism, importance and management

Parecoxib is a parenteral drug that is rapidly metabolised in liver to active COX-2 inhibitor valdecoxib. Valdecoxib is predominantly metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP2C9. The interactions therefore are usually considered to be due to effects of valdecoxib

The manufacturers have done several interaction studies to find out whether parecoxib or valdecoxib can inhibit or induce cytochrome P450 isoenzymes CYP2C9, CYP2D6, CYP2C19, and CYP3A4 and thereby determine their potential to interact with drugs metabolised by these isoenzymes.

CYP2C19. The manufacturers say that AUC of omeprazole 40mg was increased by 46 % by valdecoxib 40mg twice daily for a week. This indicates that valdecoxib is an inhibitor of CYP2C19 and although manufacturers consider it to be a weak inhibitor(See reference number 1)they suggest that caution should be observed with drugs that have a narrow therapeutic margin and are known to be metabolised by CYP2C19. They list diazepam,imipramine and phenytoin (See reference number 2). The implication is that serum levels of these drugs and their effects may possibly be increased by use of parecoxib.

CYP2D6. The manufacturers say that treatment with 40mg of valdecoxib twice daily for a week caused a threefold increase in serum levels of dextromethorphan. This indicates that valdecoxib is an inhibitor of CYP2D6, and therefore manufacturers(See reference number 1) suggest that caution should be observed with drugs that have a narrow therapeutic margin and are known to be predominantly metabolised by CYP2D6. They list flecainide, metoprolol and propafenone (See reference number 2). The implication is that serum levels of these

drugs and their effects may possibly be increased by use of parecoxib, but so far there appears to be no direct clinical reports of any problems with concurrent use.

A study in 12 healthy adults found no significant changes in pharmacokinetics of midazolam 70 micrograms/kg given an hour after a 40mg dose of intravenous parecoxib (See reference number 3). This suggests that parecoxib and valdecoxib are unlikely to inhibit or induce activity of CYP3A4

Enzyme inducers. The effects of enzyme inducers carbamazepine, dexamethasone, phenytoin and rifampicin have not been studied with parecoxib. Nevertheless, manufacturer of parecoxib warns that they may increase metabolism of valdecoxib (See reference number 2).

Pharmacia Ltd. Personal communication,May 2002.

Dynastat Injection (Parecoxib sodium). Pfizer Ltd. UK Summary of product characteristics,April 2007.

Ibrahim A,Karim A, Feldman J, Kharasch E. The influence of parecoxib, a parenteral cyclooxygenase-2 specific inhibitor, on the pharmacokinetics and clinical effects of midazolam. Anesth Analg (2002) 95, 667–73.

Some very limited evidence suggests that response to immunisation with live vaccines may be more severe than usual in thepresence of indometacin

Clinical evidence,mechanism, importance and management

A man with ankylosing spondylitis taking indometacin 25mg three times daily had a strong primary-type reaction 12 days after smallpox vaccination. He experienced 3 days of severe malaise,headache and nausea, as well as enlarged lymph nodes. The scab that formed was unusually large (3 cm in diameter) but he suffered no long term ill-effects (See reference number 1). The suggestion was that indometacin alters response of body to viral infections, whether originating from vaccines or not (See reference number 1). This suggestion is supported by case of a child taking indometacin who developed haemorrhagic chickenpox during a ward outbreak of disease (See reference number 2). These appear to be isolated reports,and of little general importance. Note that NSAIDs such as indometacin may mask some of signs and symptoms of infection.

Maddocks AC. Indomethacin and vaccination. Lancet (1973) ii,210–11.

Rodriguez RS,Barbabosa E. Hemorrhagic chickenpox after indomethacin. N Engl J Med (1971) 285, 690.

Moclobemide did not alter pharmacokinetics of ibuprofen, oribuprofen-induced faecal blood loss in one study. Ibuprofen doesnot affect pharmacokinetics of moclobemide.

Clinical evidence,mechanism, importance and management

A study in 24 healthy subjects found that moclobemide 150mg three times daily for 7 days had no effect on steady-state pharmacokinetics of ibuprofen 600mg three times daily, and amount of ibuprofen-induced faecal blood loss was unaffected (See reference number 1). Ibuprofen did not affect pharmacokinetics of moclobemide. No special precautions appear to be required during concurrent use.

1. Güntert TW,Schmitt M, Dingemanse J, Jonkman JHG. Influence of moclobemide on ibuprofen-induced faecal blood loss. Psychopharmacology (Berl) (1992) 106, S40–S42.