Pharmacy Blog – Dr Vibore

In a study in 9 healthy subjects pharmacokinetics of a 50-mgdose of fosfomycin were not significantly altered by two 400 mgdoses of cimetidine, given both night before and 30 minutesbefore fosfomycin.(See reference number 1)

1. Bergan T,Mastropaolo G, Di Mario F, Naccarato R. Pharmacokinetics of fosfomycin and influence of cimetidine and metoclopramide on the bioavailability of fosfomycin trometamol.New Trends in Urinary Tract Infections (eds Neu and Williams) Int Symp Rome 1987, pp 157–

66. Published in 1988.

Pyrimethamine does not significantly affect pharmacokineticsof dapsone

Clinical evidence,mechanism, importance and management

A study in 7 healthy subjects given single doses of dapsone 100 mg, pyrimethamine 25mg or both drugs together found that peak plasma levels of dapsone fell by 17 % and half-life was unchanged, but apparent volume of distribution was significantly increased from 1.53 to

1.93 L/kg. The pharmacokinetics of pyrimethamine were not affected by dapsone (See reference number 1). In another study HIV-positive patients were given dapsone 200mg weekly (the maximum tolerated dose) either alone or with pyrimethamine 25mg weekly. In contrast to earlier study, there was a decrease in volume of distribution of dapsone when it was given with pyrimethamine, although dapsone levels were not significantly altered (See reference number 2). Furthermore, tolerability of one-weekly dapsone plus pyrimethamine was found to be similar to that of once-weekly dapsone alone (See reference number 2).

Ahmad RA,Rogers HJ. Pharmacokinetics and protein binding interactions of dapsone and pyrimethamine. Br J Clin Pharmacol (1980) 10, 519–24.

Falloon J,Lavelle J, Ogata-Arakaki D, Byrne A, Graziani A, Morgan A, Amantea MA, OwnbyK, Polis M, Davey RT, Kovacs JA, Lane HC, Masur H, MacGregor RR. Pharmacokinetics andsafety of weekly dapsone and dapsone plus pyrimethamine for prevention of pneumocystispneumonia. Antimicrob Agents Chemother (1994) 38, 1580–7.

Orange juice and an antacid (Mylanta) do not affect pharmacokinetics of cycloserine, but a high-fat meal delays its absorption.

Clinical evidence,mechanism, importance and management

A study in 12 healthy subjects found that bioavailability of a single 500mg dose of cycloserine was not affected by 15 mL of Mylanta (aluminium hydroxide 400 mg, magnesium hydroxide 400 mg, simeticone 40 mg per 5 mL). Mylanta was given 9 hrs before cycloserine, at same time as cycloserine, immediately after meals, and at bedtime on dosing day and following day (See reference number 1).

A study in 12 healthy subjects found that bioavailability of a single 500mg dose of cycloserine was not significantly affected by 240 mL of orange juice (See reference number 1). When cycloserine 500mg was given 15 minutes after start of a high-fat meal, which was completed within 30 minutes, AUC was not affected, but maximum serum levels were reduced by about 16 % and time to maximum levels was increased from 0.75 to

3.5 hours. It is possible that patients with relatively low plasma levels or patients receiving once rather than a twice daily dosage that delay in absorption could result in increased periods of subinhibitory levels (See reference number 1). However,there is no evidence to suggest that this is clinically significant.

1. Zhu M,Nix DE, Adam RD, Childs JM, Peloquin CA. Pharmacokinetics of cycloserine underfasting conditions and with high-fat meal, orange juice, and antacids. Pharmacotherapy (2001)21, 891–7.

The bioavailabilities of cefadroxil,cefalexin, cefixime, cefprozil,and cefradine are not affected by food. Cefaclor may be givenwithout regard to food but absorption of an extended-releasepreparation may be increased by food. The bioavailabilities ofcefetamet pivoxil and cefuroxime axetil may be increased by administration with food.

Clinical evidence,mechanism, importance and management

A study in 18 healthy subjects given a single 250mg capsule of cefaclor after an overnight fast or within 30 minutes of different meals found bioavailability was not significantly affected by food. The rate of absorption and maximum plasma levels were decreased: a low-fat vegetarian diet produced smallest decrease in maximum plasma levels (26%) and a high-fat non-vegetarian diet produced largest decrease (47%) compared with levels achieved after an overnight fast. None of diets significantly affected AUC0-∞ of cefaclor. Therapeutic efficacy (measured by time levels were above MIC50) was not significantly altered.(See reference number 1) In a further study,healthy subjects were given a single 500mg dose of cefaclor as an extended-release tablet. The rate of absorption was decreased by food but compared to fasting state, maximum levels were increased; by 52 % for rice-based diets, by 33 % for low-fat-vegetarian food, by 29 % for high-fat non-vegetarian food, by 12.5 % for high-fatvegetarian food,and by 7 % for low-fat non-vegetarian food. Compared with fasting state, all diets increased time above MIC90, with a significant increase of almost 42 % with low-fat vegetarian (wheat-based) food.(See reference number 2) The manufacturers of immediate-release cefaclor capsules state that total absorption is same whether drug is given with or without food,(See reference number 3) but for extended-release preparation since absorption is enhanced by administration with food, manufacturers recommend that this preparation should be taken with meals (See reference number 4).

The manufacturers of cefadroxil state that bioavailability of cefadroxil is unaffected by food so it may be taken either with meals or on an empty stomach (See reference number 5)

A study found that bioavailability of cefetamet pivoxil was up to 25 % higher when it was given 10 minutes after a standard breakfast rather than in fasting state (See reference number 7,8). However,in another study, healthy subjects were given oral cefetamet pivoxil hydrochloride 1 g (equivalent to 693mg of cefetamet free acid) either: 1 hour before food with 200 mL of water; with a standard breakfast and a cup of tea or coffee; or 1 hour after breakfast with 200 mL of water. The cefetamet maximum plasma levels were 5.5,

5.47. and 6.57 micrograms/mL, respectively, and AUCs were 38, 35.7,and 42.8 micrograms.hour/mL,respectively, suggesting that bioavailability of cefetamet pivoxil is lowest when taken with food. The time to reach maximum plasma levels was increased from 3.3 hrs when given before food to 4.3 hrs when given with food,and 4.1 hrs when given one hour after food (See reference number 9). It was thought possible that amount of fluid taken with cefetamet may have affected absorption, but a study in which cefetamet 1 g was given under fasting conditions with either 250 or 450 mL of water found that increasing fluid intake did not affect absorption. Further, absorption when taken with food, with or without 200 mL of water was similar. It was recommended that cefetamet pivoxil should be taken within an hour of a meal to improve absorption. The delay in absorption was not considered to be of significance,especially during multiple dose therapy (See reference number 9).

A study in healthy subjects given a single 400mg dose of cefixime, either in fasting state or immediately after a standard breakfast found that time to peak serum levels was increased from about 3.8 to 4.8 hrs when cefixime was given with food,probably because of delayed gastric emptying. Serum levels,AUC and 24 hour urinary recovery were similar for fasted and fed states (See reference number 10). Cefixime may be given without regard to meals (See reference number 10,11).

In a study in healthy subjects, cefpodoxime proxetil 400mg tablets were given with 180 mL of water after an overnight fast, or either 1 hour before, with, or 2 hrs after start of a high-fat meal. Dosing 1 hour before meal was similar to dosing in fasting state. However, when cefpodoxime was taken with, or 2 hrs after meal its peak plasma levels were increased by about 45 % and 46%, respectively, when compared with peak levels achieved in fasting state. The AUC was also increased,by 40%. The rate of cefpodoxime absorption was not greatly affected by food (See reference number 12). Studies with a 200mg dose of cefpodoxime have also found that food increases extent, but not rate, of cefpodoxime absorption (See reference number 13). However, extent of food effect appears to be greater with 400mg dose. This is possibly because bioavailability of 400mg tablets is less than that of 200mg tablets, so food may have a greater effect on higher strength preparation (See reference number 12). In another study by same authors AUC and urinary excretion of cefpodoxime proxetil 200mg given as a suspension were higher (11% and 14%, respectively) when taken with a high-fat meal rather than in fasting state. Maximum plasma levels were not affected by a high-fat meal but time to achieve maximum levels was prolonged (See reference number 14).

The manufacturers state that bioavailability of cefpodoxime proxetil 100mg tablets and suspension is increased by food (See reference number 15,16). The studies(See reference number 12-14)suggest increased bioavailability of tablets, but possibly not that of suspension, when given with food may be clinically significant.

A study in healthy subjects found that, although food caused slight changes in rate of absorption of a 1-g dose of cefprozil its pharmacokinetics (including total absorption) were not significantly affected (See reference number 17).

A study in healthy subjects given cefradine 500mg in fasting state or immediately after a meal found time to peak levels was increased from 0.8 hrs to 2 hrs by food. Peak serum levels of cefradine were reduced by 45 % when it was given after food. However, half-life and AUC were not affected.(See reference number 18)The manufacturers state that cefradine may be given without regard to meals (See reference number 19).

A study in healthy subjects given cefuroxime axetil 500mg intravenously or oral doses of 125mg to 1 g with or without food found that 36 % and 52 % of a 500mg oral dose was absorbed in fasting and fed states respectively (See reference number 20). In another study in healthy subjects,a single 1-g dose of cefuroxime axetil was given 2 hrs before or 35 minutes after a standard cooked breakfast. The bioavailability of cefuroxime was markedly enhanced by food (See reference number 21). The manufacturer notes that optimum absorption of cefuroxime axetil occurs when it is given after a meal (See reference number 22). This is probably because of delayed gastric emptying and transit which allowed more complete dissolution and absorption (See reference number 21).

Karim S,Ahmed T, Monif T, Saha N, Sharma PL. The effect of four different types of foodon the bioavailability of cefaclor. Eur J Drug Metab Pharmacokinet (2003), 28, 185–90.

Khan BAH,Ahmed T, Karim S, Monif T, Saha N. Comparative effect of different types offood on the bioavailability of cefaclor extended release tablet. Eur J Drug Metab Pharmacokinet (2004) 29, 125–32.

Distaclor (Cefaclor monohydrate). Flynn Pharma Ltd. UK Summary of product characteristics,November 2005.

Distaclor MR (Cefaclor monohydrate). Flynn Pharma Ltd. UK Summary of product characteristics,December 2006.

Baxan (Cefadroxil monohydrate) Bristol-Myers Pharmaceuticals,UK Summary of productcharacteristics, July 2005.

Keflex (Cefalexin monohydrate). Flynn Pharma Ltd. UK Summary of product characteristics,September 2005.

Blouin RA,Kneer J, Stoeckel K. Pharmacokinetics of intravenous cefetamet (Ro 15-8074)and oral cefetamet pivoxil (R0-8075) in young and elderly subjects. Antimicrob Agents Chemother (1989) 33, 291–6.

Koup JR,Dubach UC, Brandt R, Wyss R, Stoeckel K. Pharmacokinetics of cefetamet (Ro 158074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans. Antimicrob Agents Chemother (1988) 32, 573–9.

Tam YK,Kneer J, Dubach UC, Stoeckel K. Effects of timing of food and fluid volume oncefetamet pivoxil absorption in healthy normal volunteers. Antimicrob Agents Chemother (1990) 34, 1556–9.

Faulkner RD,Bohaychuk W, Haynes JD, Desjardins RE, Yacobi A, Silber BM. The pharmacokinetics of cefixime in the fasted and fed state. Eur J Clin Pharmacol (1988) 34, 525–8.

Suprax Tablets (Cefixime). Sanofi-Aventis. UK Summary of product characteristics,May2006.

Borin MT,Driver MR, Forbes KK. Effect of timing of food on absorption of cefpodoximeproxetil. J Clin Pharmacol (1995) 35, 505–9.

Hughes GS,Heald DL, Barker KB, Patel RK, Spillers CR, Watts KC, Batts DH, Euler AR.The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clin Pharmacol Ther (1989) 46, 674–85.

Borin MT,Forbes KK. Effect of food on absorption of cefpodoxime proxetil oral suspensionin adults. Antimicrob Agents Chemother (1995) 39, 273–5.

Orelox Tablets (Cefpodoxime proxetil). Sanofi-Aventis. UK Summary of product characteristics,April 2006.

Orelox Suspension (Cefpodoxime proxetil). Sanofi-Aventis. UK Summary of product characteristics,April 2006.

Shukla UA,Pittman KA, Barbhaiya RH. Pharmacokinetic interactions of cefprozil with food,propantheline, metoclopramide, and probenecid in healthy volunteers. J Clin Pharmacol (1992) 32, 725–31.

Mischler TW,Sugerman AA, Willard DA, Brannick LJ, Neiss ES. Influence of probenecidand food on the bioavailability of cephradine in normal male subjects. J Clin Pharmacol (1974) 14, 604–11.

Velosef (Cefradine). ER Squibb & Sons Ltd. UK Summary of product characteristics,June2005.

Finn A,Straughn A, Meyer M, Chubb J. Effect of dose and food on the bioavailability of cefuroxime axetil. Biopharm Drug Dispos (1987) 8, 519–26.

Sommers DK,Van Wyk M, Moncrieff J, Schoeman HS. Influence of food and reduced gastric acidity on the bioavailability of bacampicillin and cefuroxime axetil. Br J Clin Pharmacol (1984) 18, 535–9.

Zinnat Tablets (Cefuroxime axetil). GlaxoSmithKline UK. UK Summary of product characteristics,January 2007.

Verapamil appears to protect kidney from damage caused bygentamicin

Clinical evidence,mechanism, importance and management

In a comparative study,9 healthy subjects were given gentamicin alone (2 mg/kg loading dose, followed by doses every 8 hrs to achieve a peak concentration of 5.5 mg/L and a trough concentration of 0.5 mg/L), and 6 other subjects were given same dosage of gentamicin with sustained-release verapamil 180mg twice daily. The gentamicin AUCs of two groups were virtually same but 24-hour urinary excretion of alanine aminopeptidase (AAP) was modestly reduced, by 18%, in group given verapamil. The reduction in AAP excretion was particularly marked during first 6 days (See reference number 1). The significance of urinary AAP is that this enzyme is found primarily in brush border membranes of proximal renal tubules, and its excretion is an early and sensitive marker of renal damage. Thus it seems that verapamil may modestly protect kidneys from damage by gentamicin, but using a drug as potentially toxic as verapamil to provide this protection, when risks of renal toxicity can be minimised by carefully controlling gentamicin dosage, is unwarranted. Information about other aminoglycosides and other calcium-channel blockers seems to be lacking.

1. Kazierad DJ,Wojcik GJ, Nix DE, Goldfarb AL, Schentag JJ. The effect of verapamil on thenephrotoxic potential of gentamicin as measured by urinary enzyme excretion in healthy volunteers. J Clin Pharmacol (1995) 35, 196–201.

This section deals with interactions where effects of antibacterial are altered. In many cases antibacterial drugs interact by affecting other drugs, and these interactions are dealt with elsewhere in this publication. Some of macrolides and quinolones are potent enzyme inhibitors; macrolides exert their effects on cytochrome P450 isoenzyme CYP3A4, whereas many quinolones inhibit CYP1A2. Rifampicin (rifampin) is a potent non-specific enzyme inducer and therefore lowers levels of many drugs.

Many of interactions covered in this section concern absorption interactions, such as ability of tetracyclines and quinolones to chelate with divalent cations. More information on mechanism of these interactions can be found in Drug absorption interactions, .

Many monographs concern use of multiple antibacterials. One of great difficulties with these interactions is often poor correlation between in vitro and in vivo studies, so that it is difficult to get a thoroughly reliable indication of how antibacterial drugs will behave together in clinical practice. Two antibacterials may actually be less effective than one on its own, because, in theory, effects of a bactericidal drug, which requires actively dividing cells for it to be effective, may be reduced by a bacteriostatic drug. However,in practice this seems to be less important than might be supposed and there are relatively few well-authenticated clinical examples.

The antibacterials covered in this section are listed in table 1 below,(see below).

Amikacin,Astromicin, Dibekacin, Dihydrostreptomycin, Framycetin, Gentamicin, Isepamicin, Kanamycin, Micronomicin, Neomycin, Netilmicin, Paromomycin, Sisomicin, Streptomycin, Tobramycin

Aminosalicylic acid (PAS),Capreomycin, Clofazimine, Cycloserine, Dapsone, Ethambutol, Ethionamide, Isoniazid, Methaniazide, Protionamide, Pyrazinamide, Rifabutin, Rifampicin (Rifampin), Rifamycin, Rifapentine, Rifaximin

Biapenem,Ertapenem, Faropenem, Imipenem, Meropenem, Panipenem

Cefaclor,Cefadroxil, Cefalexin, Cefaloglycin, Cefaloridine, Cefalotin, Cefamandole, Cefapirin, Cefatrizine, Cefazolin, Cefbuperazone, Cefcapene, Cefdinir, Cefditoren, Cefepime, Cefetamet, Cefixime, Cefmenoxime, Cefmetazole, Cefminox, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpiramide, Cefpirome, Cefpodoxime, Cefprozil, Cefradine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Flomoxef, Latamoxef

Macrolides Azithromycin,Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Josamycin, Midecamycin, Rokitomycin,
Roxithromycin,Spiramycin, Telithromycin, Troleandomycin

Amoxicillin,Ampicillin, Azidocillin, Azlocillin, Bacampicillin, Benzylpenicillin (Penicillin G), Carbenicillin, Carindacillin, Ciclacillin, Clometocillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mecillinam, Meticillin, Mezlocillin, Nafcillin, Oxacillin, Phenethicillin, Phenoxymethylpenicillin (Penicillin V), Piperacillin, Pivampicillin, Pivmecillinam, Procaine benzylpenicillin (Procaine penicillin), Propicillin, Sulbenicillin, Temocillin, Ticarcillin

Bacitracin,Colistimethate sodium, Colistin, Polymyxin B, Teicoplanin, Vancomycin

Cinoxacin,Ciprofloxacin, Enoxacin, Fleroxacin, Flumequine, Gatifloxacin, Gemifloxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nadifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Oxolinic Acid, Pazufloxacin, Pefloxacin, Pipemidic Acid, Rosoxacin, Rufloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin, Trovafloxacin

Co-trimoxazole,Phthalylsulfathiazole, Sulfadiazine, Sulfadimidine (Sulfamethazine), Sulfafurazole (Sulfisoxazole), Sulfaguanidine, Sulfamerazine, Sulfamethizole, Sulfamethoxazole, Sulfametopyrazine, Sulfametrole

Chlortetracyline,Demeclocycline, Doxycycline, Lymecycline, Methacycline, Minocycline, Oxytetracycline, Rolitetracycline, Tetracycline, Tigecycline

Aztreonam,Carumonam, Chloramphenicol, Cilastatin, Clindamycin, Daptomycin, Fosfomycin, Fusidic acid, Lincomycin, Linezolid, Loracarbef, Methenamine, Metronidazole, Mupirocin, Nitrofurantoin, Novobiocin, Pristinamycin, Quinupristin/Dalfopristin, Spectinomycin, Trimethoprim, Vancomycin

Table 1 Antibacterials
Group	Drugs
Aminoglycosides	Amikacin, Astromicin, Dibekacin, Dihydrostreptomycin, Framycetin, Gentamicin, Isepamicin, Kanamycin, Micronomicin, Neomycin, Netilmicin, Paromomycin, Sisomicin, Streptomycin, Tobramycin
Antimycobacterials and related drugs	Aminosalicylic acid (PAS), Capreomycin, Clofazimine, Cycloserine, Dapsone, Ethambutol, Ethionamide, Isoniazid, Methaniazide, Protionamide, Pyrazinamide, Rifabutin, Rifampicin (Rifampin), Rifamycin, Rifapentine, Rifaximin
Carbapenems	Biapenem, Ertapenem, Faropenem, Imipenem, Meropenem, Panipenem
Cephalosporins	Cefaclor, Cefadroxil, Cefalexin, Cefaloglycin, Cefaloridine, Cefalotin, Cefamandole, Cefapirin, Cefatrizine, Cefazolin, Cefbuperazone, Cefcapene, Cefdinir, Cefditoren, Cefepime, Cefetamet, Cefixime, Cefmenoxime, Cefmetazole, Cefminox, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpiramide, Cefpirome, Cefpodoxime, Cefprozil, Cefradine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Flomoxef, Latamoxef

Metoclopramide slightly reduced absorption of quinidinefrom a sustained-release formulation in one study, but modestlyincreased quinidine levels in another.

A study of this interaction was prompted by case of a patient who was taking sustained-release quinidine (Quinidex) and whose arrhythmia became uncontrolled when metoclopramide was added. In a crossover study,9 healthy subjects were given either metoclopramide 10mg every 6 hrs for 24 hrs before, and 48 hrs after, a single 600- or 900mg oral dose of quinidine sulfate or quinidine alone. It was found that metoclopramide caused a mean 10 % decrease in AUC of quinidine, although two subjects had decreases of 22.5 and 28.1%,respectively. The elimination rate constant was unaffected.(See reference number 1)Another study in patients taking a sustained-release formulation of quinidine bisulfate 500mg every 12 hrs found that metoclopramide 10mg three times daily increased mean plasma levels measured 3.5 hrs after last dose of quinidine by almost 20%, from

to 1.9 micrograms/mL,and at 12 hrs by about 16%, from 2.4 to

Not understood. Metoclopramide alters both gastric emptying time and gastrointestinal motility, which can affect quinidine absorption.

Direct information seems to be limited to these studies using different quinidine preparations. The outcome of concurrent use is uncertain,but generally seems small.

Yuen GJ,Hansten PD, Collins J. Effect of metoclopramide on the absorption of an oral sustained-release quinidine product. Clin Pharm (1987) 6, 722–5.

Guckenbiehl W,Gilfrich HJ, Just H. Einfluß von Laxantien und Metoclopramid auf die Chin-din-Plasmakonzentration während Langzeittherapie bei Patienten mit Herzrhythmusstörugen.Med Welt (1976) 27, 1273–6.

Cimetidine 300mg four times daily for 7 days prolonged elimination half-life of a single 400mg dose of quinidine sulfate by 55%, from 5.8 to 9 hours,and decreased its clearance by 37 % in 6 healthy subjects. Peak plasma levels were raised by 21%. These changes were reflected in ECG changes, with 51 % and 28 % increases in mean areas under QT and QTc time curves, respectively, but these were not considered to be statistically significant (See reference number 1).

A later study in healthy subjects, prompted by observation of two patients who developed toxic quinidine levels when given cimetidine, found essentially same effects. The AUC and half-life of quinidine were increased by 14.5 and 22.6 % respectively, and clearance was decreased by 25 % by cimetidine 300mg four times daily (See reference number 2). A further study in 4 healthy subjects found that cimetidine 300mg four times daily for 5 days prolonged elimination half-life of quinidine by 54 % and decreased its total clearance by 36 % (See reference number 3,4). Cimetidine prolonged QT interval by 30 % more than effect of quinidine alone (See reference number 4). A case report describes marked increases in both quinidine and digitoxin concentrations in a woman also given cimetidine (See reference number 5). Similarly,quinidine levels increased by up to 50%, without causing any adverse effects, when a man taking quinidine was given cimetidine (See reference number 6).

It was originally suggested that cimetidine inhibits metabolism of quinidine by liver so that it is cleared more slowly (See reference number 2). However, further data suggest that cimetidine successfully competes with quinidine for its excretion by kidneys (See reference number 8).

The interaction between quinidine and cimetidine is established and of clinical importance. The incidence is unknown. Be alert for changes in response to quinidine if cimetidine is started or stopped. Ideally quinidine serum levels should be monitored and dosage reduced as necessary. Reductions of 25 % (oral) and 35 % (intravenous) have been suggested (See reference number 3). Those at greatest risk are likely to be patients with impaired renal function, patients with impaired liver function, elderly, and those with serum quinidine levels already at top end of therapeutic range (See reference number 2). The situation with ranitidine is uncertain.

Hardy BG,Zador IT, Golden L, Lalka D, Schentag JJ. Effect of cimetidine on the pharmacokinetics and pharmacodynamics of quinidine. Am J Cardiol (1983) 52, 172–5.

Kolb KW,Garnett WR, Small RE, Vetrovec GW, Kline BJ, Fox T. Effect of cimetidine on quinidine clearance. Ther Drug Monit (1984) 6, 306–12.

MacKichan JJ,Boudoulas H, Schaal SF. Effect of cimetidine on quinidine bioavailability. Biopharm Drug Dispos (1989) 10, 121–5.

Boudoulas H,MacKichan JJ, Schaal SF. Effect of cimetidine on the pharmacodynamics of quinidine. Med Sci Res (1988) 16, 713–14.

Polish LB,Branch RA, Fitzgerald GA. Digitoxin-quinidine interaction: potentiation during administration of cimetidine. South Med J (1981) 74, 633–4.

Farringer JA,McWay-Hess K, Clementi WA. Cimetidine–quinidine interaction. Clin Pharm (1984) 3, 81–3.

Iliopoulou A,Kontogiannis D, Tsoutsos D, Moulopoulos S. Quinidine-ranitidine adverse reaction. Eur Heart J (1986) 7, 360.

Hardy BG,Schentag JJ. Lack of effect of cimetidine on the metabolism of quinidine: effect onrenal clearance. Int J Clin Pharmacol Ther Toxicol (1988) 26, 388–91.

Co-phenotrope slightly reduced rate, but not extent, of absorption of a single dose of quinidine.

Clinical evidence,mechanism, importance and management

In one study,8 healthy subjects were given a single 300mg dose of quinidine sulfate alone and after taking two tablets of co-phenotrope (atropine sulfate 25 micrograms, diphenoxylate 2.5 mg; Lomotil) at midnight on evening before and another two tablets next morning an hour before quinidine (See reference number 1). It was found that maximum plasma quinidine levels were reduced by 21 % from 2.1 to 1.65 micrograms/mL by co-phenotrope, time to maximum level was prolonged from 0.89 to 1.21 hours,and there was a slight increase in elimination half-life from 5.7 to

6.8 hours. While these results were statistically significant, changes

were relatively small and it seems doubtful if they are clinically relevant, particularly as extent of absorption was unchanged. However it needs to be emphasised that because quinidine formulation used was an immediate-release preparation, these results may not necessarily apply to sustained-release preparations, and also may not apply if multiple doses of quinidine are used.

1. Ponzillo JJ,Scavone JM, Paone RP, Lewis GP, Rayment CM, Fitzsimmons WE. Effect ofdiphenoxylate with atropine sulfate on the bioavailability of quinidine sulfate in healthy subjects. Clin Pharm (1988) 7, 139–42.

A single study has shown that antiarrhythmic activity of quinidine can be opposed by amiloride

A study in 10 patients with inducible sustained ventricular tachycardia was carried out to see whether a beneficial interaction occurred between quinidine and amiloride. Patients were given oral quinidine until their trough serum levels reached 10 micromol/L, or maximum well-tolerated dose was reached. After electrophysiological studies,oral amiloride was added at a dosage of 5mg twice daily, increased up to 10mg twice daily (if serum potassium levels remained normal) for 3 days. The electrophysiological studies were then repeated. Unexpectedly, 7 of 10 patients demonstrated adverse responses while taking both drugs. Three developed sustained ventricular tachycardia and 3 others had somatic adverse effects (hypotension,nausea, diarrhoea), which prevented further studies being carried out. One patient had 12 episodes of sustained ventricular tachycardia while taking both drugs. Amiloride had no effect on quinidine levels (See reference number 1).

Not understood. The combination of quinidine and amiloride increased QRS interval, but did not prolong QT interval more than quinidine alone.

So far evidence seems to be limited to this single study but it suggests that amiloride can oppose antiarrhythmic activity of quinidine. The full clinical implications of this interaction are not yet known, but it would now clearly be prudent to consider monitoring to confirm that quinidine continues to be effective if amiloride is present.

1. Wang L,Sheldon RS, Mitchell B, Wyse DG, Gillis AM, Chiamvimonvat N, Duff HJ. Amiloride-quinidine interaction: adverse outcomes. Clin Pharmacol Ther (1994) 56, 659–67.