Drug-Drug Interactions in Cocaine-users and their Clinical Implications.

Background: Drug-Drug Interactions (DDIs) represent a common problem in clinical practice during drug treatments. DDIs can both induce the development of adverse drug reactions or reduce the clinical efficacy of each drug.

Objectives: The main objective of this review was to analyze the pharmacokinetic and pharmacodynamic DDIs in cocaine consumers, focusing the interest on their clinical implications.

Methods: The PubMed, Embase and Cochrane library databases were searched for articles published until January 10, 2017. Secondary search included articles cited in reference lists identified by the primary search. Papers were deemed eligible if they included any form of words: "adverse drug reaction", "drug interactions", "poly-therapy", "cocaine", "systemic diseases".

Results: In this review, the nodal points treated concern: i) cocaine biochemical metabolism described for both, inactive benzoylecgonine and ecgonine methyl esters and norcocaine active metabolites. We provided evidences of concepts deriving from rat/mice experimental studies speculating a translation approach to human in order to treat cocaine overdose. ii) Drug-drug interactions, which come out from clinical evidences as the case of CYP450 family enzyme inhibitors or inductors modulating cocaine toxicity. Particularly, 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 induces increase in serotonin synaptic activity leading to the development of a serotoninergic syndrome when used with drugs that affect serotonin pathway. Genetic (i.e. glutathione peroxidase-1 deficiency) and epigenetic factors (i.e. microRNAs) may be involved in drug-drug interactions in cocaine-users are also being introduced.

Conclusion: DDIs represent an important potential complication in cocaine users in clinical setting. The knowledge of DDIs can also be used to select treatments for patients, thus optimizing clinical response and minimizing toxicity.