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).