Drug-Drug Interactions in cocaine-users and their clinical implications

Drug-drug interactions (DDIs) are a common problem in clinical practice during drug treatments. DDIs can induce development of adverse drug reactions or reduce clinical efficacy of the drugs. In this review, using PubMed, Embase and Cochrane library we searched articles published until January 10, 2017, and described both pharmacokinetic and pharmacodynamic DDIs in cocaine consumers, focusing the interest on their clinical implications. In this review, the nodal points treated focused on: i) cocaine biochemical metabolism described for both, inactive benzoylecgonine and ecgonine methyl esters and norcocaine active metabolites. We evidenced proof of concepts deriving from rat/mice experimental studies speculating a translational approach to human in order to treat cocaine overdose. ii) Drug-drug interactions that come from clinical evidences as the case of CYP450 family enzyme inhibitors or inductors that can modulate cocaine toxicity. We highlighted the lack of knowledge concerning cocaine and CYP3A4 inhibitors (such as ketoconazole, nefazodone, erythromycin, and clarithromycin). We recorded the worst association of cocaine and beta-blockers by direct and indirect action, particularly at postsynaptic levels on dopamine and norepinephrine reuptake, sympathetic activation and increase of heart rate, blood pressure and cardiovascular toxicity. Cocaine also increased serotonin synaptic activity leading to developing serotoninergic syndrome when used with drugs that affect serotonin pathway. Genetic (i.e glutathione peroxidase-1 deficiency) and epigenetic factors (i.e microRNAs) that may be involved in drug-drug interactions in cocaine-users are also introduced.