Drug interactions are a common issue in psychopharmacology. The advent of drug interaction software has made it easier to keep track of drug interactions, but it is still important to have a sound understanding of the principles in order to apply the results of drug interaction software alerts to daily patient care.
This is true for several reasons:
1. software is overly inclusive, often listing interactions of dubious clinical significance
2. software does not analyze and apply specific patient symptoms in assessment of potential drug interactions, and
3. software does not apply specific patient risk factors in assessing the true risk from drug interactions.
In this article, we will review the basic science of drug interactions and give specific examples of how to assess drug interactions when treating pediatric patients with psychotropic medications. First let’s begin with a primer on the two large categories of drug interactions possible: pharmacodynamic and pharmacokinetic. Broadly speaking, pharmacodynamics can be thought of as what the drug does to the body, and pharmacokinetics as what the body does to the drug.
Pharmacodynamic interactions operate at the level of neurotransmitters and mechanisms of action. For example, clonazepam (Klonopin) makes people sleepy by stimulating GABA receptors. Quetiapine (seroquel) also makes people sleepy, probably by blocking histamine receptors. Combine the two, and patients become really sleepy.
Other times, pharmacodynamic interactions may cause two drugs to oppose one another. Antipsychotics work by blocking dopamine receptors. stimulants enhance dopamine release. So what happens when they are used together? Well, the answer depends on many different factors, such as tightness of drug-receptor binding and relative concentrations of the drugs at the site of action. So in some patients, the antipsychotics may, at least theoretically, be antagonized by the pro-dopamine effect of stimulants.
While we may not realize it, we account for pharmacodynamic interactions on a regular basis in clinical practices by doing things like lowering doses, choosing alternative medications, and increasing visit frequency. For example, risperidone (risperdal) and clonidine (Kapvey) can both cause orthostatic hypotension. So when adding risperdal to the regimen of a patient already treated with Kapvey for ADHD, psychiatrists will often start at lower risperdal doses and titrate more slowly to avoid orthostasis. Many psychiatrists consider these adjustments as simply the “art of prescribing,” not realizing just how skilled they are at understanding and managing pharmacodynamic interaction.
Pharmacokinetic interactions are hard to predict since they are unrelated to the pharmacologic action of drugs. The occurrence of the interaction depends on where and when two or more drugs come in contact during drug processing. Drugs can interact with one another at four different junctures:
1. absorption (that is, the process of getting the drug into the bloodstream)
2. distribution (ferrying drugs to different tissues once they’ve been absorbed)
3. metabolism (dismantling drugs into simpler components)
4. excretion (sending drugs into the sewage system)
Absorption. Drug-food, rather than drug-drug, interactions are most relevant during absorption. For example, ziprasidone (Geodon) absorption is halved when taken without food, which is why we instruct our patients to take this drug after a full meal (at least, we should be doing this!). Food also speeds absorption of both sertraline (Zoloft) and quetiapine, but only by 25% or so, usually not enough to be clinically relevant.
Distribution. Valproic acid (Depakote) is highly protein bound, and it is only the unbound portion (the “free fraction”) of the drug that has a therapeutic effect. Aspirin is also highly protein bound, so if your patient combines the two drugs, the aspirin will kick some of the valproic acid off its proteins, causing the free fraction of the drug to increase. Standard valproic acid levels do not account for the difference between free and bound fractions, so your patient’s serum level might appear normal, but the actual functioning valproic acid can be very high, potentially causing side effects. One way to account for this interaction is to order a free valproate level (with the normal therapeutic range being about 5 mcg/ml to 10 mcg/ml, much less than the total valproic acid therapeutic range of about 40 mcg/ml to 100 mcg/ml).
Liver metabolism. Most drug-drug interactions take place in the liver, where drugs are processed in order to render them water soluble, which allows the body to more easily excrete them, either in the urine or feces. There are two phases of liver metabolism. Phase I involves the famous cytochrome p-450 enzymes, or CYP450. These enzymes attack drugs in a variety of ways, such as “hydroxylation” (adding a hydroxyl group), “dealkylation” (taking away an alkyl group), and several others.