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.
Unfortunately for those of us trying to remember drug interactions, there are many subfamilies of CYP450 enzymes, including CYP 1A2, 2C19, 2D6, and 3A4. However, in terms of pediatric psychopharmacology, CYP 3A4 is the most clinically relevant enzyme system followed by 2D6 and 1A2, thus limiting the amount of memorization needed. Phase II metabolism continues the process of biotransformation, relying mainly on glucuronidation—which is rarely a factor in drug interactions in psychiatric practice.
There is some genetic variability in expression of CYP450 2D6 enzymes. Up to 10% of caucasians, 8% of Africans and 3% of east Asians are poor metabolizers at CYP450 2D6. Thus these patients would be expected to have higher blood levels and increased risk of side effects from drugs eliminated via CYP450 2D6 (Lanni C et al, Cell Mol Life Sci 2012: http://bit.ly/Yeu2A7). Since these genetic polymorphisms are often clinically insignificant, we do not routinely test patients for genetic polymorphism. However, for patients who do not respond to high doses of medications or who are prone to significant side effects at low doses of medications, testing may be reasonable.
While CYP450 enzymes are the most common cause of pharmacokinetic interactions, other pharmacokinetic drug interactions involving metabolism do exist. The most common one seen in pediatric psychopharmacology involves lamotrigine (lamictal). lamictal needs to be titrated slowly to avoid Steven Johnson’s syndrome. However, when given with divalproate, the lamotrigine dose should be halved. Conversely, when given with carbamazepine (Tegretol), phenobarbital, or phenytoin (Dilantin), the dose of lamictal should be doubled.
Excretion. In pediatrics, excretion drug interactions are less frequent as few drugs are renally eliminated and pediatric patients are less likely than adults to be on other medications that interfere with the kidney.
Lithium is the main exception. Unlike almost all other drugs in psychiatry, lithium is not metabolized by the liver. Instead, it is excreted unchanged by the kidneys. Because of this, various drugs that affect kidney function can severely affect lithium levels. Caffeine, from commonly ingested substances such as soda or energy drinks, speeds up kidney functioning and can lead to lower lithium levels. on the other hand, both ibuprofen (along with other NSAIDs) and ACE inhibitors can decrease lithium excretion and lead to toxicity.
Pharmacokinetics in Pediatrics
The pharmacokinetics of many medications have been studied in pediatric populations. Most studies find no clinically significant difference between pediatric and adult population pharmacokinetics (Vitiello B. Principles in using psychotropic medication in children and adolescents. In: Rey JM, ed. IACAPAP of Child Adolescent Mental Health. Geneva, Switzerland: International Association for Child and Adolescent Psychiatry and Allied Professions; 2012). However, in both populations there is large inter-individual variability. This, combined with pediatric patients’ increased sensitivity to side effects, supports the concept that psychotropics should always be started in small doses and titrated slowly in pediatric patients.
Practical Implications of Drug-Drug Interactions
To understand drug-drug interactions, you’ll need to refamiliarize yourself with some basic terms. Drugs are “substrates” of specific enzymes. An “inhibitor” is a drug that binds more tightly to an enzyme than the current resident. This “victim” drug then gets stuck in a game of metabolic musical chairs as it scurries around looking for a free enzyme system to break it down. Since this drug is not getting metabolized as quickly as it otherwise would, its serum levels become higher than expected.
“Induction” happens when the inciting drug stimulates the production of extra enzymes. With more enzymes around, the victim drug is broken down more rapidly, leading to lower levels. But since it takes a while for all this extra enzyme synthesis to occur, induction, unlike inhibition, does not happen immediately, but takes place over a one to three week period. Conversely, when an inducer is discontinued, the extra enzyme must “die off.” Thus induction can take a few weeks to fully reverse.
Now that you know the basics, how can you most efficiently apply them to your practice? Here are some tricks.
• Identify the 10 drugs that you most commonly prescribe, and memorize the major drug interactions for each one.
• Antidepressants, antipsychotics, antibiotics, antiretroviral, and older anticonvulsants have a high likelihood of significant drug interactions—so be particularly vigilant if your patient is taking any of these.
• Recognize the drugs with narrow therapeutic windows, ie, drugs for which the toxic dose is not much higher than the therapeutic dose. Commonly encountered narrow therapeutic window drugs in pediatric psychopharmacology include lithium, carbamazepine (Tegretol), and phenytoin (Dilantin).
• Recognize drugs that have serious side effects and outcomes if blood levels are significantly decreased or increased (eg, oral contraceptives, lamotrigine (Lamictal), clozapine, TCAs, warfarin).
• Drugs with long half-lives (eg, diazepam (Valium), aripiprazole (Abilify)) can be particularly troublesome when involved in drug interactions, because metabolic inhibitors can make them ultra long lasting.
• Be cautious with any new or rarely prescribed drugs, simply because neither you nor anybody else has had much experience with them, and unreported drug interactions can appear.
• The risk of drug interactions increase as the number of drugs increases. Setting a threshold to check for interactions is helpful (eg, any patient on three or more drugs).