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

<p>The aim of this thesis was to address some aspects of drug related problems with special regard to drug-drug interactions.</p><p>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.</p><p>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".</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>I. Mannheimer B, Ulfvarson J, Eklöf S, Bergqvist M, Andersén-Karlsson E, Pettersson H, von Bahr C (2006). Drug-related problems and pharmacotherapeutic advisory intervention at a medicine clinic. Eur J Clin Pharmacol. 62(12): 1075-81. <br><a href="https://pubmed.ncbi.nlm.nih.gov/17066294">https://pubmed.ncbi.nlm.nih.gov/17066294</a><br><br></p><p>II. Mannheimer B, Ulfvarson J, Eklöf S, Bergqvist M, von Bahr C (2008). A clinical evaluation of the Janus Web Application, a software screening tool for drug-drug interactions. Eur J Clin Pharmacol. 64(12): 1209-14. <br><a href="https://pubmed.ncbi.nlm.nih.gov/18695980">https://pubmed.ncbi.nlm.nih.gov/18695980</a><br><br></p><p>III. Mannheimer B, Bahr CV, Pettersson H, Eliasson E (2008). Impact of Multiple Inhibitors or Substrates of Cytochrome P450 2D6 on Plasma Risperidone Levels in Patients on Polypharmacy. Ther Drug Monit. 30(5): 565-69. <br><a href="https://pubmed.ncbi.nlm.nih.gov/18728628">https://pubmed.ncbi.nlm.nih.gov/18728628</a><br><br></p><p>IV. Mannheimer B, Wettermark B, Lundberg M, Pettersson H, Bahr CV, Eliasson E (2009). Important differences in adherence to drug label recommendations on metabolic interactions between commonly used drugs - a nationwide cross-sectional register study. [Submitted]</p>