Potentially hazardous drug interactions with psychotropics

Abstract

Of the many interactions with psychotropic drugs, a minority are potentially hazardous. Most interactions are pharmacodynamic, resulting from augmented or antagonistic actions at a receptor or from different mechanisms in the same tissue. Most important pharmacokinetic interactions are due to effects on metabolism or renal excretion. The major enzymes involved in metabolism belong to the cytochrome P450 (CYP) system. Genetic variation in the CYP system produces people who are 'poor', 'extensive' or 'ultra-rapid' drug metabolisers. Hazardous interactions more often result from enzyme inhibition, but the probability of interaction depends on the initial level of enzyme activity and the availability of alternative metabolic routes for elimination of the drug. There is currently interest in interactions involving uridine diphosphate glucuronosyltransferases and the P-glycoprotein cell transport system, but their importance for psychotropics has yet to be defined. The most serious interactions with psychotropics result in profound sedation, central nervous system toxicity, large changes in blood pressure, ventricular arrhythmias, an increased risk of dangerous side-effects or a decreased therapeutic effect of one of the interacting drugs.

Lysosomal Sequestration (Trapping) of Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells)

“…The potential for DDIs involving lysosomes is a topic of speculation (Daniel and Wojcikowski, 1999;Chadwick et al, 2005;Funk and Krise, 2012;Logan et al, 2012). Although coadministration-related subtle changes in organ distribution may occur, there are no known clinical examples of lysosomal-related DDI in which changes in drug (1) the substrate and inhibitor were added simultaneously (coincubation), (2) the inhibitor was added 5 minutes before substrate but was not removed (preincubation and coincubation), and (3) the inhibitor was added 5 minutes before the substrate, but the cells were washed before adding the substrate (preincubation), as described in Materials and Methods.…”

“…Competition for lysosomal trapping has been the subject of some speculation as a potential mechanism of drug-drug interactions (DDIs) (Daniel and Wojcikowski, 1999;Chadwick et al, 2005;Funk and Krise, 2012;Logan et al, 2012). Because many central nervous system and cardiovascular drugs are lysosomotropics (drugs that undergo lysosomal sequestration), there is the possibility that concomitant administration of lysosomotropics could lead to elevated drug exposure levels as competition for lysosomal sequestration increases or lysosomal pH is elevated by amine accumulation Vestal et al, 1980;Logan et al, 2012).…”

Risk of Hip Fracture in Older People Using Selective Serotonin Reuptake Inhibitors and Other Psychoactive Medicines Concurrently: A Matched Case–Control Study in Australia

“…In a cross-sectional study, half of all older Australians admitted to hospital for hip fracture used at least two medicines associated with falls or hip fracture during the 6 weeks before hospital admission [2]. The concurrent use of multiple psychoactive medicines could increase a patient’s risk owing to the potential for pharmacodynamic or pharmacokinetic interactions between the medicines [3]. For example, an antidepressant can add to the sedative effect of a benzodiazepine [4].…”

Advances of Molecular Clinical Pharmacology in Gastroenterology and Hepatology

“…73 CYP2D6 Table 8 presents examples of drugs that inhibit CYP450 enzymes. 34 It must be emphasized that CYP activity can be inhibited by many drugs at clinically relevant concentrations, and data about potential drug-drug interactions and concentration-dependent adverse drug reactions must be available to physicians. Important examples are cimetidine, which inhibits several different CYPs, and the HIV-protease inhibitors that inhibit CYP3A4.…”

“…32 Like CYP enzymes, P-glycoprotein can be induced and inhibited by other drugs, which creates the potential for drug interactions (Table 4). 33,34 The study of 247 individuals enabled identification of 110 different MDR1 haplotypes. 35 In predicting MDR1 phenotype, results of digoxin pharmacokinetic studies evaluated on the basis of steady-state drug plasma concentration have shown that haplotype analysis was more accurate than single nucleotide polymorphism (SNP) estimation.…”