NSAIDs; Diclofenac + Cephalosporins - Drug Interactions

Cefadroxil does not alter pharmacokinetics of diclofenac

Clinical evidence,mechanism, importance and management

A pharmacokinetic study in 8 patients who had undergone cholecystectomy and who had a T-drain in common bile duct, found that diclofenac 50mg every 12 hrs increased excretion of intravenous ceftriaxone 2 g in bile by about fourfold and roughly halved urinary excretion (See reference number 2). The clinical importance of this is uncertain,but probably small.

Animal studies have shown that diclofenac may alter pharmacokinetics of some cephalosporins (the AUCs of cefotiam and ceftriaxone were increased by diclofenac, although pharmacokinetics of cefmenoxime were not affected). The significance of these findings in humans is unknown and further studies are required before any valid conclusions can be drawn from this data (See reference number 3).

Schumacher A,Geissler HE, Mutschler E, Osterburg M. Untersuchungen potentieller Interaktionen von Diclofenac-Natrium (Voltaren) mit Antibiotika. Z Rheumatol (1983) 42, 25–7.

Merle-Melet M,Bresler L, Lokiec F, Dopff C, Boissel P, Dureux JB. Effects of diclofenac onceftriaxone pharmacokinetics in humans. Antimicrob Agents Chemother (1992) 36, 2331–3.

Joly V,Pangon B, Brion N, Vallois J-M, Carbon C. Enhancement of the therapeutic effect ofcephalosporins in experimental endocarditis by altering their pharmacokinetics with diclofenac. J Pharmacol Exp Ther (1988) 246, 695–700.

NSAIDs + Tricyclic antidepressants - Drug Interactions

The tricyclic antidepressants can delay absorption of phenylbutazone and oxyphenbutazone from gut, but their antirheumatic effects are probably not affected.

Clinical evidence,mechanism, importance and management

The absorption of a single 400mg dose of phenylbutazone in 4 depressed women was considerably delayed (time to maximum level, 4 to 10 hrs compared with 2 hours), but total amount absorbed (measured by urinary excretion of oxyphenbutazone) remained unchanged when they were pretreated with desipramine 75mg daily for 7 days (See reference number 1). In another 5 depressed women half-life of oxyphenbutazone was found to be unaltered by 75mg of desipramine or nortriptyline daily (See reference number 2). Animal studies have confirmed that absorption of phenylbutazone and oxyphenbutazone are delayed by tricyclic antidepressants, probably because their antimuscarinic effects reduce motility of gut,(See reference number 3,4) but there seems to be no direct clinical evidence that antirheumatic effects of either drug are reduced by this interaction. No particular precautions appear to be needed.

Consolo S,Morselli PL, Zaccala M, Garattini S. Delayed absorption of phenylbutazone causedby desmethylimipramine in humans. Eur J Pharmacol (1970) 10, 239–42.

Hammer W,Mårtens S, Sjöqvist F. A comparative study of the metabolism of desmethylimipramine, nortriptyline, and oxyphenylbutazone in man. Clin Pharmacol Ther (1969) 10, 44–9.

Consolo S. An interaction between desipramine and phenylbutazone. J Pharm Pharmacol (1968) 20,574–5.

Consolo S,Garattini S. Effect of desipramine on intestinal absorption of phenylbutazone andother drugs. Eur J Pharmacol (1969) 6, 322–6.

NSAIDs + Pesticides - Drug Interactions

Chronic exposure to lindane and other chlorinated pesticides canslightly increase rate of metabolism of phenazone (antipyrine)and phenylbutazone

Clinical evidence,mechanism, importance and management

A study in 26 men occupationally exposed to a mixture of insecticides, predominantly DDT, chlordane and lindane, found that half-life of phenazone 10 or 15 mg/kg was reduced from 13.1 hours,in a group of 33 unexposed subjects, to 7.7 hrs in exposed group (See reference number 1). The significance of this is unclear as changes in working practices have reduced occupational exposure to such chemicals.

The plasma half-life of phenylbutazone in a group of men who regularly used chlorinated insecticide sprays (mainly lindane) as part of their work, was found to be 20 % shorter (51 hours) than in a control group (64 hours), due, it is believed, to enzyme-inducing effects of pes-

ticides (See reference number 2). This modest increase in rate of metabolism is of doubtful direct clinical importance, but it illustrates changed metabolism that can occur in those exposed to environmental chemical agents.

Kolmodin B,Azarnoff DL, Sjöqvist F. Effect of environmental factors on drug metabolism:decreased plasma half-life of antipyrine in workers exposed to chlorinated hydrocarbon insecticides. Clin Pharmacol Ther (1969) 10, 638–42.

Kolmodin-Hedman B. Decreased plasma half-life of phenylbutazone in workers exposed tochlorinated pesticides. Eur J Clin Pharmacol (1973) 5,195–8.

NSAIDs or Aspirin + Proton pump inhibitors - Drug Interactions

The antiplatelet activity and pharmacokinetics of aspirin donot appear to be affected by omeprazole. There was no clinicallyrelevant pharmacokinetic interaction between omeprazole anddiclofenac,enteric-coated ketoprofen, naproxen or piroxicam, orbetween pantoprazole and diclofenac or naproxen, or betweenesomeprazole and naproxen or rofecoxib.

In a preliminary study in 11 healthy subjects, omeprazole 20mg daily for 2 days reduced serum levels of salicylic acid metabolite of aspirin at 30 and 90 minutes after a single 650mg dose of aspirin by 40 % and 52%, respectively (See reference number 1). However, another study in 14 healthy subjects given omeprazole 20 mg daily for 4 days with a final dose one hour before a single 125mg dose of aspirin found that omeprazole did not significantly affect plasma levels of either aspirin or salicylic acid. Omeprazole also did not affect antiplatelet effects of aspirin (See reference number 2). Similarly, omeprazole had no effect on bioavailability of aspirin (uncoated or entericcoated tablets) in another study, although it increased rate of absorption of aspirin from enteric-coated tablets (See reference number 3).

A single 105mg dose of diclofenac potassium suspension (Flogan) was given to 13 healthy subjects while fasting and after gastric acid secretion blockade with omeprazole. The pharmacokinetics of diclofenac were not changed to a clinically relevant extent by omeprazole (See reference number 4). Similarly, omeprazole 20mg daily given with diclofenac 50mg twice daily for one week had no effect on pharmacokinetics of either drug in 24 healthy subjects (See reference number 5).

Neither drug affected pharmacokinetics of other (See reference number 6)

There were no significant changes in pharmacokinetics of entericcoated ketoprofen, given with or without omeprazole, although a trend towards higher plasma concentrations with omeprazole was noted, indicating possibility of increased drug release in stomach in presence of an elevated pH (See reference number 7).

Naproxen 250mg twice daily given to healthy subjects with omeprazole 20 mg daily,(See reference number 5)pantoprazole 40mg daily,(See reference number 8) or esomeprazole 40mg daily(See reference number 9)for one week had no effect on pharmacokinetics of either naproxen or proton pump inhibitor

The pharmacokinetics of pantoprazole 40mg orally daily for 8 days was not altered to a clinically relevant extent by a single 5-mg/kg oral dose of phenazone given on day 8 of study. Pantoprazole did not affect pharmacokinetics of phenazone (See reference number 10)

Omeprazole 20 mg daily given to 24 healthy subjects with piroxicam 10mg daily for one week had no effect on pharmacokinetics of either drug (See reference number 5)

12.5 mg daily for one week had no effect on pharmacokinetics of either drug apart from a slight increase in maximum level and AUC of rofecoxib, which was not thought to be clinically relevant (See reference number 9).

Data from animal studies suggest that absorption and thus effects of aspirin and NSAIDs can be reduced by omeprazole and H2-receptor antagonists via a pH dependent mechanism (See reference number 11,12). However, note that clinical studies have not found H2-receptor antagonists to have any important effect on pharmacokinetics of aspirin or NSAIDs, see NSAIDs or Aspirin + H2-receptor antagonists interaction. It has been suggested that reducing gastric acidity with omeprazole results in earlier disruption of entericcoated tablets, and an increased absorption rate (See reference number 3).

The interaction between aspirin and omeprazole is not established. The balance of evidence suggests that omeprazole is unlikely to have an important effect on pharmacokinetics and efficacy of aspirin. However, because of uncertainty generated by animal and preliminary clinical data,(See reference number 1,11,12) it would be of benefit to confirm this in further studies (See reference number 2,13).

No clinically significant pharmacokinetic interactions have been identified between any of other NSAIDs and PPIs cited here, and no special precautions are needed during concurrent use. For mention that valdecoxib raises plasma levels of omeprazole see NSAIDs; Parecoxib + Miscellaneous interaction. Note that omeprazole and other proton pump inhibitors are widely used in management of gastrointestinal complications of aspirin and NSAIDs.

Anand BS,Sanduja SK, Lichtenberger LM. Effect of omeprazole on the bioavailability of aspirin: a randomized controlled study on healthy volunteers. Gastroenterology (1999) 116: A371.

Iñarrea P,Esteva F, Cornudella R, Lanas A. Omeprazole does not interfere with the antiplatelet effect of low-dose aspirin in man. Scand J Gastroenterol (2000) 35, 242–6.

Nefesoglu FZ,Ayanoglu-Dülger G, Ulusoy NB, Imeryüz N. Interaction of omeprazole withenteric-coated salicylate tablets. Int J Clin Pharmacol Ther (1998) 36, 549–53.

Poli A,Moreno RA, Ribeiro W, Dias HB, Moreno H, Muscara MN, De Nucci G. Influence of gastric acid secretion blockade and food intake on the bioavailability of a potassium diclofenac suspension in healthy male volunteers. Int J Clin Pharmacol Ther (1996) 34, 76–9.

Andersson T,Bredberg E, Lagerström P-O, Naesdal J, Wilson I. Lack of drug-drug interaction between three different non-steroidal anti-inflammatory drugs and omeprazole. Eur J Clin Pharmacol (1998) 54, 399–404.

Bliesath H,Huber R, Steinijans VW, Koch HJ, Wurst W, Mascher H. Lack of pharmacokinetic interaction between pantoprazole and diclofenac. Int J Clin Pharmacol Ther (1996) 34, 152–6.

Qureshi SA,Caillé G, Lacasse Y, McGilveray IJ. Pharmacokinetics of two enteric-coated ketoprofen products in humans with or without coadministration of omeprazole and comparisonwith dissolution findings. Pharm Res (1994) 11, 1669–72.

Schulz H-U,Hartmann M, Krupp S, Schuerer M, Huber R, Luehmann R, Bethke T, Wurst

W. Pantoprazole lacks interaction with the NSAID naproxen. Gastroenterology (2000) 118 (Suppl 2),A1304.

9. Hassan-Alin M,Naesdal J, Nilsson-Pieschl C, Långström G, Andersson T. Lack of pharmacokinetic interaction between esomeprazole and the nonsteroidal anti-inflammatory drugsnaproxen and rofecoxib in healthy subjects. Clin Drug Invest (2005) 25, 731–40.

De Mey C,Meineke I, Steinijans VW, Huber R, Hartmann M, Bliesath H, Wurst W. Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction. Int J Clin Pharmacol Ther (1994) 32, 98–106.

Lichtenberger LM,Ulloa C, Romero JJ, Vanous AL, Illich PA, Dial EJ. Nonsteroidal anti-inflammatory drug and phospholipid prodrugs: combination therapy with antisecretory agents in rats. Gastroenterology (1996) 111, 990–5.

Giraud M-N,Sanduja SK, Felder TB, Illich PA, Dial EJ, Lichtenberger LM. Effect of omeprazole on the bioavailability of unmodified and phospholipid-complexed aspirin in rats. Aliment Pharmacol Ther (1997) 11, 899–906.

Fernández-Fernández FJ. Might proton pump inhibitors prevent the antiplatelet effects oflow- or very low-dose aspirin? Arch Intern Med (2002) 162,2248.

NSAIDs + Ginkgo biloba - Drug Interactions

An isolated case describes fatal intracerebral bleeding in a patienttaking Ginkgo biloba with ibuprofen,and another case describesprolonged bleeding and subdural haematomas in another patients taking Ginkgo biloba with rofecoxib. Studies involving diclofenac and flurbiprofen showed that Ginkgo biloba had no effect on pharmacokinetics of these drugs.

A case of fatal intracerebral bleeding has been reported in a 71-year-old patient taking a Ginkgo biloba supplement (Gingium) 4 weeks after he started to take ibuprofen 600mg daily (See reference number 1). A 69-year-old man taking a Ginkgo biloba supplement and rofecoxib had a subdural haematoma after a head injury,then recurrent small spontaneous haematomas. He was subsequently found to have a prolonged bleeding time, which returned to normal one week after stopping Ginkgo biloba supplement and rofecoxib, and remained normal after restarting low-dose rofecoxib (See reference number 2).

A placebo-controlled study in 11 healthy subjects who were given Ginkgo biloba leaf (Ginkgold) 120mg twice daily for three doses, followed by a single 100mg dose of flurbiprofen, found that pharmacokinetics of flurbiprofen were unchanged (See reference number 3).

A study in 12 healthy subjects who were given diclofenac 50mg twice daily for 14 days, with Ginkgo biloba extract (Ginkgold) 120mg twice daily on days 8 to 15, found no alteration in AUC or oral clearance of diclofenac (See reference number 4).

The reason for bleeding is not known, but Ginkgo biloba extract contains ginkgolide B, which is a potent inhibitor of platelet-activating factor that is needed for arachidonate-independent platelet aggregation. On their own,Ginkgo biloba supplements have been associated with prolonged bleeding times,(See reference number 5,6) left and bilateral subdural haematomas,(See reference number 5,7) a right parietal haematoma,(See reference number 8) post-laparoscopic cholecystectomy bleeding,(See reference number 9) and sub-arachnoid haemorrhage (See reference number 6). Ibuprofen is an inhibitor of platelet aggregation,but selective inhibitors of COX-2 such as rofecoxib have no effect on platelets and would not be expected to potentiate any bleeding effect of Ginkgo biloba.

The pharmacokinetic study involving diclofenac was designed to identify whether Ginkgo biloba exerted an inhibitory effect on cytochrome P450 isoenzyme CYP2C9, which is involved in metabolism of diclofenac. Although an indication that such an effect may occur was noted in studies in vitro using S-warfarin, in vivo study did not confirm that this interaction would be seen clinically (See reference number 4).

The evidence from these reports is too slim to forbid patients to take NSAIDs and Ginkgo biloba concurrently,but some do recommend caution (See reference number 10). Medical professionals should be aware of possibility of increased bleeding tendency with Ginkgo biloba, and report any suspected cases (See reference number 8). Consider also Antiplatelet drugs + Herbal medicines interaction.

Meisel C,Johne A, Roots I. Fatal intracerebral mass bleeding associated with Ginkgo biloba and ibuprofen. Atherosclerosis (2003) 167, 367.

Hoffman T. Ginko,Vioxx and excessive bleeding – possible drug-herb interactions: case report. Hawaii Med J (2001) 60, 290.

Greenblatt DJ,von Moltke LL, Luo Y, Perloff ES, Horan KA, Bruce A, Reynolds RC, Harmatz JS, Avula B, Khan IA, Goldman P. Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate. J Clin Pharmacol (2006) 46, 214–21.

Mohutsky MA,Anderson GD, Miller JW, Elmer GW. Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther (2006) 13, 24–31.

Rowin J,Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology (1996) 46, 1775–6.

Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet (1998) 352,36.

Gilbert GJ. Ginkgo biloba. Neurology (1997) 48,1137.

Benjamin J,Muir T, Briggs K, Pentland B. A case of cerebral haemorrhage – can Ginkgo biloba be implicated? Postgrad Med J (2001) 77, 112–13.

Fessenden JM,Wittenborn W, Clarke L. Gingko biloba: a case report of herbal medicine andbleeding postoperatively from a laparoscopic cholecystectomy. Am Surg (2001) 67, 33–5.

Griffiths J,Jordan S, Pilon S. Natural health products and adverse reactions. Can Adverse React News (2004) 14, 2–3.

NSAIDs + Azoles - Drug Interactions

Fluconazole markedly raises celecoxib levels,whereas ketoconazole has no effect on celecoxib levels. Fluconazole and ketoconazole moderately increase levels of valdecoxib (the mainmetabolite of parecoxib). Ketoconazole moderately raises etoricoxib plasma levels,but this is unlikely to be of clinical relevance.Fluconazole has no clinically relevant effect on lumiracoxib pharmacokinetics.

The manufacturer notes that fluconazole 200mg daily increased AUC of a single 200mg dose of celecoxib by 130 % and increased maximum level by 60%. Conversely, ketoconazole had no effect on pharmacokinetics of celecoxib (See reference number 1).

The AUC of etoricoxib was increased by 43 % and maximum plasma levels was increased by 29 % (See reference number 2)

A placebo-controlled, crossover study in 13 healthy subjects(See reference number 3) found that fluconazole 400mg on day 1 and 200mg on days 2 to 4 had no clinically relevant effect on pharmacokinetics of a single 400mg dose of lumiracoxib given on day 4.

The manufacturer of parecoxib reports a study in which fluconazole increased plasma levels of valdecoxib (the main metabolite of parecoxib) by 19 % and raised its AUC by 62 % (See reference number 4). Ketoconazole had a similar, but more moderate effect on levels of valdecoxib (maximum plasma levels increased by 24%, AUC increased by 38%) (See reference number 4).

Fluconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP2C9 and ketoconazole inhibits CYP3A4. Celecoxib is extensively metabolised by CYP2C9,and therefore shows marked rises in plasma levels when given with fluconazole but not ketoconazole. Etoricoxib is partially metabolised by CYP3A4,therefore shows moderate rises in plasma levels with ketoconazole. Valdecoxib is metabolised by both CYP2C9 and CYP3A4,therefore was modestly affected by both fluconazole and ketoconazole. Parecoxib is a valdecoxib prodrug,and interacts similarly. From study with lumiracoxib it appears that its pharmacokinetics are unlikely to be affected by inhibitors of CYP2C9, because, even though lumiracoxib is largely metabolised by CYP2C9, other pathways are also important (e.g. glucuronidation) (See reference number 3).

These pharmacokinetic interactions are established,although their effect in clinical practice has not been assessed. The marked rise in celecoxib levels with fluconazole could be important, and UK manufacturer recommends that dose of celecoxib should be halved in patients receiving fluconazole,(See reference number 1) whereas US manufacturer suggests starting with lowest recommended dose (See reference number 5). The rise in valdecoxib levels with fluconazole is less marked, nevertheless manufacturer recommends that for parecoxib dosage should be reduced (but they do not suggest by how much) (See reference number 4). No dosage adjustments are thought to be necessary if etoricoxib or parecoxib are given with ketoconazole,and if lumiracoxib is given with fluconazole.

Celebrex (Celecoxib). Pharmacia Ltd. UK Summary of product characteristics,February 2007.

Agrawal NGB,Matthews CZ, Mazenko RS, Woolf EJ, Porras AG, Chen X, Miller JL,Michiels N, Wehling M, Schultz A, Gottlieb AB, Kraft WK, Greenberg HE, Waldman SA,Curtis SP, Gottesdiener KM. The effects of modifying in vivo cytochrome P450 3A (CYP3A)activity on etoricoxib pharmacokinetics and of etoricoxib administration on CYP3A activity.J Clin Pharmacol (2004) 44, 1125–31.

Scott G,Yih L, Yeh C-M, Milosavljev S, Laurent A, Rordorf C. Lumiracoxib: pharmacokinetic and pharmacodynamic profile when coadministered with fluconazole in healthy subjects. J Clin Pharmacol (2004) 44, 193–9.

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

Celebrex (Celecoxib). Pfizer Inc. US Prescribing information,February 2007.

Aspirin + Levamisole - Drug Interactions

The salicylate levels of a patient taking aspirin rose when levamisole was given,but this effect was not confirmed in a subsequentcontrolled study.

Clinical evidence,mechanism, importance and management

A preliminary report of a patient who had an increase in salicylate levels when levamisole was given with aspirin(See reference number 1) prompted a study in 9 healthy subjects of this possible interaction. Sustained-release aspirin 3.9 g daily in two divided doses was given over a period of 3 weeks,with levamisole 50mg three times a day for a week, each subject acting as his own control. No significant changes in plasma salicylate levels were found (See reference number 2).

Laidlaw D’A. Rheumatoid arthritis improved by treatment with levamisole and L-histidine.Med J Aust (1976) 2,382–5.

Rumble RH,Brooks PM, Roberts MS. Interaction between levamisole and aspirin in man. Br J Clin Pharmacol (1979) 7, 631–3.

Aspirin + Dapsone - Drug Interactions

Dapsone does not significantly affect pharmacokinetics of aspirin

Clinical evidence,mechanism, importance and management

A comparison of pharmacokinetics of aspirin in 8 healthy subjects and 8 patients with uncomplicated lepromatous leprosy found that pharmacokinetics of a single 600mg dose of aspirin was not affected by either leprosy, or by treatment with dapsone 100mg daily for 8 days (See reference number 1). No special precautions would seem likely to be needed on concurrent use.

1. Garg SK,Kumar B, Shukla VK, Bakaya V, Lal R, Kaur S. Pharmacokinetics of aspirin andchloramphenicol in normal and leprotic patients before and after dapsone therapy. Int J Clin Pharmacol Ther Toxicol (1988) 26, 204–5.

Aspirin or other Salicylates + Carbonic anhydrase inhibitors - Drug Interactions

A severe and even life-threatening toxic reaction can occur in patients taking high-dose salicylates if they are given carbonic anhydrase inhibitors (acetazolamide,diclofenamide).

An 8-year-old boy with chronic juvenile arthritis, taking prednisolone, indometacin and aloxiprin, was admitted to hospital with drowsiness, vomiting and hyperventilation (diagnosed as metabolic acidosis) within a month of aloxiprin dosage being increased from 3 to 3.6 g daily and starting to take diclofenamide 25mg three times daily for glaucoma (See reference number 1).

Other cases of toxicity (metabolic acidosis) have included a 22-year-old woman taking salsalate with acetazolamide 250 mg four times daily,(See reference number 1)and 2 elderly women taking large doses of aspirin with acetazolamide or diclofenamide (See reference number 2). A 50-year-old woman taking acetazolamide for glaucoma was admitted to hospital with confusion and cerebellar ataxia,associated with hyperchloraemic acidosis, 14 days after starting to take aspirin for acute pericarditis (See reference number 3). A man taking diclofenamide developed salicylate poisoning within 10 days of starting to take aspirin 3.9 g daily (See reference number 4). Coma developed in an 85-year-old woman taking aspirin 3.9 g daily when her dosage of acetazolamide was increased from 500mg to 1 g daily,(See reference number 5,6) and toxicity was seen in a very elderly man given both drugs: levels of unbound acetazolamide were found to be unusually high (See reference number 6). An elderly man became confused,lethargic, incontinent and anorexic while taking acetazolamide and salsalate. He needed intravenous hydration (See reference number 7).

Not fully established. One idea is that these carbonic anhydrase inhibitors (acetazolamide, diclofenamide) affect plasma pH, so that more of salicylate exists in un-ionised (lipid-soluble) form, which can enter CNS and other tissues more easily, leading to salicylate toxicity (See reference number 2). However, carbonic anhydrase inhibitors also make urine more alkaline, which increases loss of salicylate(See reference number 8) (see also Aspirin or other Salicylates + Antacids interaction). Animal studies confirm that carbonic anhydrase inhibitors increase lethal toxicity of aspirin (See reference number 4). An alternative suggestion is that because salicylate inhibits plasma protein binding of acetazolamide and its excretion by kidney, acetazolamide toxicity, which mimics salicylate toxicity, may occur (See reference number 6).

Although there are few clinical reports on record, interaction between carbonic anhydrase inhibitors and salicylates is established, well confirmed by animal studies, and potentially serious. One study recommended that carbonic anhydrase inhibitors should probably be avoided in those receiving high-dose salicylate treatment (See reference number 6). If they are used, patient should be well monitored for any evidence of toxicity (confusion, lethargy, hyperventilation, tinnitus) because interaction may develop slowly and insidiously (See reference number 2). In this context NSAIDs may be a safer alternative. Naproxen proved to be a satisfactory substitute in one case (See reference number 1). The authors of one study suggest that methazolamide may possibly be a safer alternative to acetazolamide because it is minimally bound to plasma proteins. They also suggest paracetamol (acetaminophen) as an alternative to salicylate in patients taking acetazolamide (See reference number 6). The reports cited here concern carbonic anhydrase inhibitors given orally,not as eye drops. It is not known whether latter interact similarly, but there appear to be no reports.

Cowan RA,Hartnell GG, Lowdell CP, McLean Baird I, Leak AM. Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function. BMJ (1984) 289, 347–8.

Anderson CJ,Kaufman PL, Sturm RJ. Toxicity of combined therapy with carbonic anhydraseinhibitors and aspirin. Am J Ophthalmol (1978) 86, 516–19.

Hazouard E,Grimbert M, Jonville-Berra A-P, De Toffol M-C, Legras A. Salicylisme et glaucome: augmentation réciproque de la toxicité de l’acétazolamide et de l’acide acétyl salicylique. J Fr Ophtalmol (1999) 22, 73–5.

Hurwitz GA,Wingfield W, Cowart TD, Jollow DJ. Toxic interaction between salicylates anda carbonic anhydrase inhibitor: the role of cerebral edema. Vet Hum Toxicol (1980) 22 (Suppl), 42–4.

Chapron DJ,Brandt JL, Sweeny KR, Olesen-Zammett L. Interaction between acetazolamideand aspirin — a possible unrecognized cause of drug-induced coma. J Am Geriatr Soc (1984) 32, S18.

Sweeney KR,Chapron DJ, Brandt JL, Gomolin IH, Feig PU, Kramer PA. Toxic interaction between acetazolamide and salicylate: case reports and a pharmacokinetic explanation. Clin Pharmacol Ther (1986) 40, 518–24.

Rousseau P,Fuentevilla-Clifton A. Acetazolamide and salicylate interaction in the elderly: a case report. J Am Geriatr Soc (1993) 41, 868–9.

Macpherson CR,Milne MD, Evans BM. The excretion of salicylate. Br J Pharmacol (1955) 10, 484–9.

Analgesics and NSAIDs - Drug Interactions

The drugs dealt with in this section include aspirin and other salicylates, NSAIDs, opioid analgesics, and miscellaneous analgesics, such as nefopam and paracetamol. table 1 below, contains a listing, with a further classification of NSAIDs.

Aspirin and NSAIDs generally undergo few clinically significant pharmacokinetic interactions. The majority are highly protein bound, and have potential to interact with other drugs via this mechanism. However,with a few exceptions, most of these interactions are not clinically important (see Protein-binding interactions, ).

Of newer NSAIDs, celecoxib is metabolised by cytochrome P450 isoenzyme CYP2C9, and inhibits CYP2D6. Rofecoxib,now withdrawn, inhibits CYP1A2, see Tizanidine + CYP1A2 inhibitors interaction. Nevertheless, most of important interactions with NSAIDs and aspirin are pharmacodynamic. Aspirin and all non-selective NSAIDs inhibit platelet aggregation, and so can increase risk of bleeding and interact with other drugs that have this effect. NSAIDs that are highly selective for cyclooxygenase-2 (COX-2) do not inhibit platelet aggregation.

Aspirin and all NSAIDs (including COX-2 selective NSAIDs) affect synthesis of renal prostaglandins, and so can cause salt and water retention. This can increase blood pressure and affect antihypertensive therapy.

Aspirin and non-selective NSAIDs inhibit mechanisms that protect gastrointestinal mucosa and so cause gastrointestinal toxicity

Morphine is metabolised by glucuronidation by UDP-glucuronyltransferases,mainly to one active and one inactive metabolite. The glucuronidation of morphine can be induced or inhibited by various drugs. Morphine is not significantly affected by cytochrome P450 isoenzymes. The semi-synthetic morphine analogues,hydromorphone and oxymorphone, are metabolised similarly.

Codeine,dihydrocodeine, and hydrocodone are thought to be pro-drugs, and require metabolic activation, possibly by CYP2D6 or UGT enzymes. Inhibitors of these enzymes may therefore reduce their efficacy. Oxycodone is also metabolised by CYP2D6 and CYP3A4.

Pethidine is metabolised via several cytochrome P450 isoenzymes. If metabolism of pethidine is increased it can lead to increased production of toxic metabolite, norpethidine, and increased CNS adverse effects.

Methadone is principally metabolised by CYP3A4 and CYP2D6,although CYP2C8 may also play a role. Buprenorphine is metabolised by CYP3A4.

Alfentanil is extensively metabolised by CYP3A4,and has been used as a probe drug for assessing CYP3A4 activity. Fentanyl and sufentanil are also metabolised,but because they are high hepatic-extraction drugs (see Changes in first-pass metabolism, ) they are less affected by inhibitors or inducers of CYP3A4, although in some instances this may still lead to clinically significant effects.

Paracetamol is not absorbed from stomach, and rate of absorption is well correlated with gastric emptying rate. Paracetamol has therefore been used as a marker drug in studies of gastric emptying. Paracetamol is primarily metabolised by liver to a variety of metabolites, principally glucuronide and sulfate conjugates. Hepatotoxicity of paracetamol is thought to be due to a minor metabolite,N-acetyl-p-benzoquinone imine (NAPQI), which is inactivated with glutathione and excreted as mercapturate and cysteine conjugates. When liver stores of glutathione are depleted, and rate of production of NAPQI exceeds rate of production of glutathione, excess NAPQI attaches to liver proteins and causes liver damage. CYP2E1 may be involved in formation of this hepatotoxic metabolite.

Brouwers JRBJ,de Smet PAGM. Pharmacokinetic-pharmacodynamic drug interactions withnonsteroidal anti-inflammatory drugs. Clin Pharmacokinet (1994) 27, 462–5.

Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol (2002) 40,3–20.

Armstrong AC,Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and theirderivatives: theory and clinical reality, Part I. Psychosomatics (2003) 44, 167–71.

Armstrong AC,Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and theirderivatives: theory and clinical reality, Part II. Psychosomatics (2003) 44, 515–20.

Aloxiprin,Aspirin, Benorilate, Choline salicylate, Diflunisal, Ethenzamide, Lysine aspirin, Magnesium salicylate, Salsalate, Sodium salicylate

Floctafenine,Flufenamic acid, Meclofenamic acid, Mefenamic acid, Tolfenamic acid

Acemetacin,Indometacin, Sulindac

Lornoxicam,Meloxicam, Piroxicam, Tenoxicam


Dexketoprofen,Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Oxaprozin, Tiaprofenic acid

Azapropazone,Feprazone, Kebuzone, Metamizole sodium (Dipyrone), Oxyphenbutazone, Phenylbutazone

Celecoxib,Etodolac, Etoricoxib, Meloxicam (see under Oxicams), Nimesulide, Parecoxib, Rofecoxib, Valdecoxib

Benzydamine hydrochloride,Felbinac, Ketorolac, Nabumetone, Phenazone (Antipyrine), Tolmetin

Alfentanil,Fentanyl, Remifentanil, Sufentanil

Codeine,Dextropropoxyphene (Propoxyphene), Dihydrocodeine

Buprenorphine (also used for opioid dependence),Butorphanol, Meptazinol, Nalbuphine, Pentazocine

Dextromoramide,Diamorphine (Heroin), Dipipanone, Hydrocodone, Hydromorphone, Methadone (also used for opioid dependence), Morphine, Oxycodone, Oxymorphone, Papaveretum, Pethidine (Meperidine), Tramadol

Nefopam,Paracetamol (Acetaminophen)

Table 1 Analgesics and NSAIDs
Group Drugs
Aspirin and oral salicylates Aloxiprin, Aspirin, Benorilate, Choline salicylate, Diflunisal, Ethenzamide, Lysine aspirin, Magnesium salicylate, Salsalate, Sodium salicylate
Fenamates Floctafenine, Flufenamic acid, Meclofenamic acid, Mefenamic acid, Tolfenamic acid
Indole- and indene-acetic acids Acemetacin, Indometacin, Sulindac
Oxicams Lornoxicam, Meloxicam, Piroxicam, Tenoxicam
Phenylacetic acid derivatives Alclofenac, Diclofenac
Propionic acid derivatives Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Oxaprozin, Tiaprofenic acid
Pyrazolone derivatives Azapropazone, Feprazone, Kebuzone, Metamizole sodium (Dipyrone), Oxyphenbutazone, Phenylbutazone
Selective inhibitors of cyclo-oxygenase-2 (Coxibs) Celecoxib, Etodolac, Etoricoxib, Meloxicam (see under Oxicams), Nimesulide, Parecoxib, Rofecoxib, Valdecoxib
Other Benzydamine hydrochloride, Felbinac, Ketorolac, Nabumetone, Phenazone (Antipyrine), Tolmetin
Opioid and related analgesics
Anaesthetic adjuncts Alfentanil, Fentanyl, Remifentanil, Sufentanil
Mild to moderate pain Codeine, Dextropropoxyphene (Propoxyphene), Dihydrocodeine
Moderate to severe pain:
Partial agonists and agonists/antagonists Buprenorphine (also used for opioid dependence), Butorphanol, Meptazinol, Nalbuphine, Pentazocine
Pure agonists Dextromoramide, Diamorphine (Heroin), Dipipanone, Hydrocodone, Hydromorphone, Methadone (also used for opioid dependence), Morphine, Oxycodone, Oxymorphone, Papaveretum, Pethidine (Meperidine), Tramadol
Miscellaneous Nefopam, Paracetamol (Acetaminophen)