Drug-related problems with special emphasis on drug : drug interactions

Abstract

The aim of this thesis was to address some aspects of drug related problems with special regard to drug-drug interactions.

In paper I we aimed to describe the scenario and frequency of drug-related problems (DRPs) in in-patients and to determine whether a pharmacotherapeutic advisory intervention aiming at reducing DRPs could affect rates of re-hospitalisation and / or death within 6 months. A total of 299 DRPs among 71% (106/150) of the patients were found, who had not previously been identified in the usual care. Thirty-five per cent (106/299) of DRPs in 39% (58/150) of the patients were judged to be of such importance that advice was given to the physician in charge. The proportion of re-hospitalisation and death in the intervention group was 49% (73/150) compared to 46% (69/150) in the control group (Risk ratio: 1.06, 95% confidence interval: 0.84 to 1.32, P=0.64). In conclusion, drug-related problems were common. The impact of drug-related problems on hard endpoints such as re-hospitalisation and death may however be overestimated. It is of importance to clarify if and in what way drug-related problems are preventable.

The purpose in paper II was to evaluate the clinical relevance of the Janus Web application in screening for potential drug-drug interactions. One hundred and fifty DDIs, regarding 58 different interaction pairs, were classified as significant. 126 interactions that were significant by definition did not result in advice. A look at the alerts which featured most frequently in such combinations illustrates the nature of this discrepancy. With the aim to develope a drug-drug interaction software with the goal of achieving and maintaining a general use on a routine basis, it is of great importance that the alerts are clinically relevant. Equally important may be to present the warnings in an adequate way to give the prescribing physician a balanced picture of the problem and thereby avoid "alert fatigue".

In paper III we evaluated if steady-state plasma levels of risperidone or the corresponding active moiety differed between patients exposed to 1 or several drugs defined as either substrates or inhibitors of the hepatic cytochrome P450 enzyme 2D6 (CYP2D6). The median concentration-to-dose (C/D) ratio of risperidone in patients with 0, 1 or >1 was 2.6, 8.5, and 17 nmol/L/mg, respectively (p<0.001). All of the medication lists in the 7 patients with >1 inhibitor of CYP2D6, included fluoxetine, paroxetine, thioridazine and/or levomepromazine, i.e. drugs known as potent inhibitors of CYP2D6. The active moiety (risperidone + 9-OH-risperidone), in patients with different numbers of concomitant CYP2D6 inhibitors was 17, 24 and 30 nmol/L/mg, respectively (p<0.01). We concluded that an increase in the number of concomitant inhibitors may be associated with a lower CYP2D6 activity, although the type of inhibitor is probably more important. Drug-dependent inhibition of CYP2D6 increases the active moiety of risperidone. An indication for risperidone TDM should consequently include concomitant medication with established CYP inhibitors.

In paper IV we used the Swedish prescribed drug register to determine whether doctors are taking potential drug-drug interactions (DDIs) for serotonin reuptake inhibitors into account in the prescribing decision. The use of CYP2D6-drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRI (paroxetine, fluoxetine) or SSRI that do not block CYP2D6 (citalopram, escitalopram, sertraline) was analysed, and related to the use of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Compared with patients who where dispensed citalopram/sertraline, patients dispensed fluoxetine/paroxetine faced a reduced risk of receiving metoprolol (adjusted odds ratio, 0.80; 95% CI, 0.76 to 0.85), donepezil (0.65; 0.49 to 0.86) and galantamine (0.58; 0.41 to 0.81). In contrast, the risk of receiving the prodrugs codeine (instead of propoxyphene) or tamoxifen (instead of anastrozole) was similar among patients on fluoxetine/paroxetine compared to citalopram /sertraline (adjusted odds ratios, 1.03; 95% CI, 0.94 to 1.12 and 1.29; 95% CI, 0.96 to 1.73 respectively). The results, suggest that drug-drug interactions (DDI) related to reduced bioactivation of pro-drugs may be more easily neglected in clinical practice, as compared to DDI that cause overt adverse drug reactions.