Kauistik omhandlende en patient i kombinationsbehandling med warfarin og cimetidin. Efter 5 ugers kombinationsbehandling indlægges patienten på hospitalet med smerter i hoften. PT måles til 38 sekunder mod normalt 17-19 sekunder.

Case-reports suggest that cimetidine 1-1,2 g/day may enhance the effect of anticoagulants, and now Dr Serlin and colleagues (Aug.18,p.317) have demonstrated this interaction in a planned study. We have seen a case which demonstrates the interaction of varying doses of cimetidine with warfarin.

Oral anticoagulants of the coumarin class are subject to both potentiating and inhibitory drug interactions, some of which are clinically significant. We report the case of a patient in whom th combined use of warfarin sodium and cimetidine led to excessive hypoprothrombinemia, resulting in soft-tissue and urinary tract hemorrage. Such an adverse effect of the recently marketed cimetidine has not been reported previously.

Kasuistik omhandlende en patient i kombinationsbehandling med warfarin og cimetidin. Efter få dages kombinationsbehandling stiger patientens PT fra 18 til 51 sekunder.Ved undersøgelse af abdomen se stor retroperitoneak hematom.

In 6 patients anticoagulated with warfarin, nicoumalone, or phenindione the addition of cimetidine prolonged the prothrombin-time (PT) by a mean of 12.6 s (range 5--23 s). In 7 volunteers taking daily subtherapeutic doses of warfarin the addition of cimetidine increased the PT from 19.4 to 22.9 s and the plasma-warfarin concentration from 0.96 to 1.76 microgram/ml. Cimetidine reduced the single-dose clearance of warfarin and antipyrine. The basis of the interaction between cimetidine and oral anticoagulants is probably inhibition of drug metabolism. Care should be exercised in concomitant therapy

The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem

Coumarin derivatives combine 3 unfavorable properties which make them prone to potentially life threatening drug-drug interactions: (i) high protein binding; (ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range. An entire list of drugs which are supposed to interact with coumarins (mostly with warfarin) comprises about 250 different compounds. Noteworthy are the interactions with cardiovascular or antilipidaemic drugs which are often coadministered with coumarins: amiodarone, propafenone and fibrates. Cardiovascular drugs which are obviously devoid or proven to be devoid of an interaction are angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers and cardiac glycosides. There are several other drugs which enhance the hypoprothrombinaemic response to coumarins by various mechanisms: inhibitors of the elimination of the eutomer S-(-)-warfarin (e.g. miconazole, phenylbutazone), combined with protein binding displacement (e.g., sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. cefazoline). Furthermore, bleeding complications may occur with drugs affecting platelet function [aspirin (acetylsalicylic acid) and several nonsteroidal anti- inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a drug first enhances the hypoprothrombinaemic response to a coumarin but has a sustained inducing effect on coumarin metabolism (e.g. phenytoin or sulfinpyrazone). The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected (e.g. on the basis of this review) to cause an interaction to patients on coumarin therapy. The onset of the adverse prothrombin time response might be from between 1 to 2 days up to 3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. With amiodarone, an adverse prothrombin time response might occur up to 2 months after initiating therapy. For heparins, only a drug interaction with aspirin or nitroglycerin seems clinically relevant due to the possibility of coadministration during acute cardiac events. Both drugs are shown to enhance the activated partial thromboplastin time response to heparin

Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species

Cimetidine potentiates the anticoagulant effect of warfarin sodium, but in one small study ranitidine hydrochloride did not. Furthermore, these drugs have not been compared in the same subjects. Eleven normal subjects received single oral doses of 1.5 mg/kg racemic warfarin sodium alone, with cimetidine (1,200 mg/day orally), or with ranitidine (300 mg/day orally), beginning three days before the warfarin and daily thereafter for the duration of hypoprothrombinemia. Blood samples were obtained daily for determination of prothrombin times and warfarin concentrations. Cimetidine augmented both the hypoprothrombinemia and the blood concentrations of warfarin, but ranitidine did not. Substituted imidazoles like cimetidine inhibit hepatic microsomal activity, which may cause reduced metabolic clearance of warfarin and augment its anticoagulant effect. Ranitidine, lacking these effects, may be safer for patients undergoing anticoagulation who require H2- receptor antagonists

Oxidative metabolism inhibition of a number of drugs by cimetidine has been attributed to its imidazole ring, a hypothesis that has been supported by reports that ranitidine does not affect drug metabolism despite being five times as potent as cimetidine as an H2-receptor antagonist. In five healthy subjects ranitidine at 150 mg twice daily induced a 27% fall in apparent oral warfarin clearance. In the same subjects cimetidine at 1 gm/day induced a 36% decrease in warfarin clearance. In two of the subjects the experiment was repeated after giving 750 mg ranitidine per day and in two other subjects after 200 mg cimetidine twice daily. In both instances there was a stepwise fall in warfarin clearance with increasing doses. The data indicate that interference with drug metabolism by H2-receptor antagonists is not confined to cimetidine but that on a molar basis ranitidine and cimetidine are roughly equivalent in inhibiting warfarin clearance and that the effects are related to dose

Et prospektivt studie udf°rt pÕ 27 patienter. Ved kombinationsbehandling med warfarin og cimetidin sÕs ikke-signifikante stigninger i PT hos patienterne.

1 In five volunteers taking daily subtherapeutic doses of warfarin the addition of ranitidine 200 mg twice daily for 14 days did not affect prothrombin time or plasma warfarin concentration. 2 Ranitidine had no effect on the single dose pharmacodynamics and pharmacokinetics of warfarin in the rat. 3 Ranitidine had no effect on pentobarbitone sleeping time in the rat whereas cimetidine significantly prolonged the sleeping time. 4 The interaction between cimetidine and oral anticoagulants is unrelated to histamine H2-receptor antagonism

In eight healthy male volunteers taking daily subtherapeutic doses of warfarin (mean daily dose = 4.0 mg), the addition of famotidine 40 mg once-a-day for seven days did not alter the prothrombin time profile, thrombotest coagulation time or total warfarin steady-state plasma concentration. Plasma peak concentration, time to peak concentration and area under curve for famotidine were not affected by the co- administration of warfarin. However the plasma half-life of famotidine was slightly, but statistically significantly longer (p less than 0.05) during maintenance treatment with warfarin (mean +/- s.e.m.: 2.58 +/- 0.14 h versus 2.96 +/- 0.16 h respectively)

Nizatidine is a new antagonist of H2 receptors. The nizatidine warfarin interaction was investigated in healthy volunteers during chronic warfarin (mean warfarin dose: 5 +/- 0.9 mg/d) and nizatidine (300 mg/d) administration. Nizatidine coadministration did not increase the prothrombin time, kaolin-cephalin clotting time, and did not modify the activity of clotting factors II, VII, IX, X. Nizatidine did not influence the steady-state plasma warfarin concentration

The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.

 

Kasuistik omhandlende en patient i kombinationsbehandling med warfarin og ranitidin. Efter en uges kombinationsbehandling ses stigninger i PT fra normalt 17,6 til 36,7 sekunder. Dosis af ranitidin reduceres, og patientens PT stabiliseres til at ligge pÕ mellem 19-20 sekunder.

The interaction between the histamine H-2 receptor antagonist, cimetidine, and warfarin sodium was prospectively studied in 14 patients who were previously anticoagulated for five years. The patients received warfarin and cimetidine concomitantly for a minimum of ten days. Seven of the patients experienced increases in plasma warfarin concentrations. This correspondingly resulted in abnormal prolongation of their prothrombin times. In these patients the elevation in the steady-state warfarin concentration demonstrates that coadministration of cimetidine significantly reduces the plasma clearance rate of warfarin. The serum and urine metabolite levels of warfarin were not qualitatively different in the absence in contrast to the presence of cimetidine. It is apparent that cimetidine can act as an inhibitory influence on the catabolic degradation of warfarin

The stereoselectivity of the pharmacokinetic interaction between warfarin and cimetidine was investigated in eight healthy volunteers. The warfarin enantiomers were given separately as single doses (15 mg) alone and during chronic administration of cimetidine (1 g day-1). Cimetidine did not interact with S warfarin but there was an interaction with the R enantiomer of warfarin. Cimetidine caused a significant increase in the mean plasma half-life of R warfarin (from 47.8 h to 57.8 h) and a significant decrease in its mean plasma clearance (from 2.3 to 1.7 ml h-1 kg-1) (P less than 0.02). Administration of a pharmacological dose of vitamin K1 together with the enantiomers of warfarin was necessary clinically and resulted in elevation of vitamin K1 2,3-epoxide concentrations, which were similar in each case

OBJECTIVE: The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers. METHODS: The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8-14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor- VII clotting activity. RESULTS: Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S- warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R- warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (+/-SD) of R-6- hydroxywarfarin (31.1+/-7.4 ml/h baseline; 18.5+/-4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9+/-1.3 ml/h baseline; 4.3+/-1.1 ml/h at end of cimetidine treatment; P < 0.01). CONCLUSION: Cimetidine stereoselectively affects the steady- state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients

Videnskabelig artikel omhandlende to prospektive studier udført på 13 raske forsøgspersoner. Ved kombinationsbehandling med warfarin og cimetidin så statistisk signifikante påvirkninger af R-warfarin`s kinetik.