Drug–Drug Interactions in Psychopharmacology

Overview

An understanding of drug–drug interactions is essential to the practice of psychopharmacology. As in other areas of medicine, polypharmacy has become an increasingly accepted approach in psychiatry for addressing difficult-to-treat disorders. Moreover, general medical co-morbidity is common among patients with psychiatric disorders, elevating the likelihood of complex medication regimens. Similarly, the widespread use of over-the-counter (OTC) supplements by patients receiving treatment for psychiatric disorders may invite additional risk of drug–drug interactions. When they occur, drug–drug interactions may manifest in myriad ways, from perplexing laboratory tests to symptoms that are difficult to distinguish from the underlying psychiatric and physical conditions under treatment. The comprehensive evaluation of patients with psychiatric disorders therefore requires a careful assessment of potential drug–drug interactions.

Drug–drug interactions refer to alterations in drug levels or drug effects (or both) attributed to the administration of two or more prescribed, illicit, or OTC agents in close temporal proximity. Although many drug–drug interactions involve drugs administered within minutes to hours of each other, some drugs may participate in interactions days or even weeks after their discontinuation because of prolonged elimination half-lives (e.g., fluoxetine) or due to their long-term impact on metabolic enzymes (e.g., carbamazepine). Some drug–drug interactions involving psychotropic medications are life-threatening, such as those involving the co-administration of monoamine oxidase inhibitors (MAOIs) and drugs with potent serotonergic (e.g., meperidine) or sympathomimetic (e.g., phenylpropanolamine) effects. These combinations are therefore absolutely contraindicated. However, most drug–drug interactions in psychopharmacology manifest in somewhat more subtle ways, often leading to poor medication tolerability and compliance due to adverse events (e.g., orthostatic hypotension, sedation, or irritability), diminished medication efficacy, or puzzling manifestations (such as altered mental status or unexpectedly high or low drug levels). Drug combinations that can produce these often less than catastrophic drug–drug interactions are usually not absolutely contraindicated. Some of these combinations may, indeed, be valuable in the treatment of some patients while wreaking havoc for other patients. The capacity to anticipate and to recognize both the major, but rare, and the more subtle, but common, potential drug–drug interactions allows the practitioner to minimize the impact of these interactions as an obstacle to patient safety and to therapeutic success. This is both an important goal and a considerable challenge in psychopharmacology.

While drug–drug interactions are ubiquitous, few studies have systematically assessed in vivo drug–drug interactions of most interest to psychiatrists. Fortunately, well-designed studies of drug–drug interactions are an increasingly integral part of drug development. Beyond these studies, however, the literature on drug–drug interactions remains a patchwork of case reports, post-marketing analyses, extrapolation from animal and in vitro studies, and extrapolation from what is known about other drugs with similar properties. While these studies often shed some light on the simplest case of a single drug (drug B) exerting an effect on another (drug A), they rarely consider the common clinical scenario in which multiple drugs with numerous potential interactions among them are co-administered. Under these circumstances, the range of possible, if not well-delineated, drug–drug interactions often seems overwhelming.

Fortunately, an increasing range of resources are available (including prescribing software packages and regularly updated websites, such as www.drug-interactions.com ) that allow for the prevention and detection of potential interactions. In addition, it is important to recall that numerous factors contribute to inter-individual variability in drug response. These factors include treatment adherence, age, gender, nutritional status, disease states, and genetic polymorphisms that may influence risk of adverse events and treatment resistance ( Figure 11-1 ). Drug–drug interactions are an additional factor that influence how patients react to drugs. The importance of these interactions depends heavily on the clinical context. In many cases, the practical impact of drug–drug interactions is likely to be very small compared with other factors that affect treatment response, drug levels, and toxicity. It is reasonable, therefore, to focus special attention on the contexts in which drug–drug interactions are most likely to be clinically problematic.

First, it is crucial to be familiar with the small number of drug–drug interactions in psychopharmacology that, though uncommon, are associated with potentially catastrophic consequences. These include drugs associated with ventricular arrhythmias, hypertensive crisis, serotonin syndrome, Stevens-Johnson syndrome, seizures, and severe bone marrow suppression. In addition, drug–drug interactions are important to consider when a patient's drugs include those with a low therapeutic index (e.g., lithium, digoxin, or warfarin) or a narrow therapeutic window (e.g., indinavir, nortriptyline, or cyclosporine) such that relatively small alterations in pharmacokinetic or pharmacodynamic behavior may jeopardize a patient's well-being. In addition, it is worthwhile to consider potential drug–drug interactions whenever evaluating a patient whose drug levels are unexpectedly variable or extreme, or a patient with a confusing clinical picture (such as clinical deterioration), or with unexpected side effects. Finally, drug–drug interactions are likely to be clinically salient for a patient who is medically frail or elderly, owing to altered pharmacokinetics and vulnerability to side effects, as well as for a patient heavily using alcohol, cigarettes, or illicit drugs, or being treated for a drug overdose.

Classification

Drug–drug interactions may be described as pharmacokinetic, pharmacodynamic, idiosyncratic, or mixed, depending on the presumed mechanism underlying the interaction ( Box 11-1 ). Pharmacokinetic interactions are those that involve a change in the plasma level or tissue distribution (or both) of one drug by virtue of co-administration of another drug. These interactions occur due to effects at one or more of the four pharmacokinetic processes by which drugs are acted on by the body: absorption, distribution, metabolism, and excretion. Because of the importance of these factors, particularly metabolism, in drug–drug interactions, a more detailed description of pharmacokinetic processes follows. An example of a pharmacokinetic drug–drug interaction is the inhibition of the metabolism of lamotrigine by valproic acid, thereby raising lamotrigine levels and increasing the risk of potentially serious adverse events, including hypersensitivity reactions (such as Stevens-Johnson syndrome). In contrast, pharmacodynamic interactions are those that involve a known pharmacological effect at biologically-active (receptor) sites. These interactions occur due to effects on the mechanisms through which the body is acted on by drugs and do not involve a change in drug levels. An example of a pharmacodynamic drug–drug interaction is the interference of the antiparkinsonian effects of a dopamine receptor agonist (such as pramipexole) by a dopamine receptor antagonist (such as risperidone). Mixed interactions are those that are believed to involve both pharmacological and pharmacodynamic effects. Symptoms of serotonin toxicity, such as agitation and confusion that have been observed in some individuals on the combination of paroxetine and dextromethorphan, for example, may reflect the shared pharmacodynamic effect of the two agents at serotonin receptor sites as well as the elevation of dextromethorphan levels due to inhibition of its cytochrome P450 metabolism by paroxetine. Finally, idiosyncratic interactions are those that occur sporadically in a small number of patients in ways that are not yet predicted by the known pharmacokinetic and pharmacodynamic properties of the drugs involved.

Pharmacokinetics

As described earlier, pharmacokinetic processes refer to absorption, distribution, metabolism, and excretion, factors that determine plasma levels and tissue concentrations of a drug. Pharmacokinetics refers to the mathematical analysis of these processes. Advances in analytic chemistry and computer methods of pharmacokinetic modeling and a growing understanding of the molecular pharmacology of the liver enzymes responsible for metabolism of most psychotropic medications have furnished increasingly sophisticated insights into the disposition and interaction of administered drugs. Although pharmacokinetics refers to only one of the two broad mechanisms by which drugs interact, pharmacokinetic interactions involve all classes of psychotropic and non-psychotropic medications. An overview of pharmacokinetic processes is a helpful prelude to a discussion of drug–drug interactions by psychotropic drug class.