Drug-drug Interactions (intro)
PHARMACODYNAMICS VS PHARMACOKINETICS
Drug-drug interactions fall into two main categories: pharmacokinetic and pharmacodynamic.
Pharmacodynamics is what a drug does to the body. Pharmacodynamic interactions are based on the drugs’ mechanisms of action and do not involve alteration in blood levels of either interacting drug.
Pharmacokinetics is what the body does to a drug. Kinetic derives from the Greek verb kinein, "to move”. In this case we’re talking movement into and out of the body, for instance absorbing the chemical from the gut and processing it for excretion in urine or feces. Pharmacokinetic (PK) interactions are generally manifested by alteration of blood levels of one of the interacting drugs.
For simplicity’s sake, let’s drop the pharmaco- prefix and refer to these concepts as kinetic interactions and dynamic interactions.
Dynamic interactions are intuitive if you understand how the interacting drugs work. Although dynamic interactions are understandable without silly pictures, here are a couple anyhow.
Dynamic interactions can be additive/synergistic, with enhanced effects brought about by combining medications with similar or complementary effects.
Other dynamic interactions are antagonistic, for instance combining a dopaminergic such as pramipexole (for restless legs) with an antidopaminergic like haloperidol (antipsychotic). Here’s another example:
Kinetics involves the rate at which a drug gets into or out of the body or brain.
Drug-drug Interactions involving absorption are generally straightforward. For instance, anticholinergics slow gut motility and delay gastrointestinal absorption of other medications.
Kinetic interactions involving rate of elimination from the body are challenging to learn and daunting to memorize. It is important to consider these interactions to avoid underdosing or overdosing certain medications. This book tackles these tricky elimination interactions by illustrating:
❖ Phase I metabolism involving the six most important cytochrome P450
❖ Phase II metabolism involving UGT enzymes, as applicable to
❖ Renal clearance of lithium
A mysterious type of kinetic interaction involves drugs getting across the blood-brain barrier, as is necessary for a psychiatric medication to take effect. If such an interaction is occurring, the effect will not be detectable in serum drug levels. This will be discussed in the context of P-glycoprotein.
CYTOCHROME P450 ENZYMES
In the liver, kinetic interactions predominantly involve CYtochrome P450 enzymes, CYP enzymes for short, which can be pronounced “sip”. Instead of concerning yourself with the origin of P450 nomenclature, take a moment to contemplate this picture of Ken (kinetic) taking a “sip” (CYP).
CYP enzymes, which reside primarily in the liver, make chemicals less lipid-soluble so they can be more easily excreted in urine or bile. Of over 50 CYP enzymes, six play a major role in the biotransformation of medications: 1A2, 2B6, 2C9, 2C19, 2D6 and 3A4. Our visual mnemonics will be built on the following phraseology:
The three most important CYPs are 1A2, 2D6 and 3A4. For psychiatrists, 2C19 can be important, while 2B6 and 2C9 are rarely significant.
A drug that is biotransformed by a particular enzyme is referred to as a substrate of that enzyme. When the substrate is biotransformed (metabolized) it is then referred to as a metabolite.
Each CYP enzyme can metabolize several substrates and most substrates can be metabolized by several CYP enzymes. Substrates are the “victims” of the interactions described in this chapter. Throughout this book we use the following visuals for CYP substrates:
“Aggressor” medications affect how long victim substrates linger in the blood, and the relative serum concentration of parent drug (substrate) to metabolite. For a given enzyme, interfering medications (aggressors) are either inDucers or inHibitors. InDucers stimulate (inDuce) production of metabolic enzymes. InHibitors interfere with an enzyme’s ability to metabolize other medications.
InHibition of an enzyme occurs when one drug (the inHibitor) binds more tightly to the enzyme than the victim substrate binds. The inHibitor itself may be metabolized by the enzyme, or act as a non-competitive inhibitor. When an inhibitor is bound to an enzyme, the victim substrate must find another enzyme to metabolize it, or hope that it can eventually be excreted unchanged. Strong inhibitors may cause the victim substrate to linger longer, prolonging the victim’s half-life and elevating its concentration in the blood. For victim substrates that cross the blood brain barrier (as is necessary to be psychoactive), inhibition leads to increased drug concentration in the central nervous system.
Why is H being emphasized? Well, when an inHibitor is added to an individual’s medication regimen, levels of victim drugs can escalate (H for High). InHibition takes effect quickly, within Hours (H for Hurried), although the effect may not be clinically evident for 2 to 4 days, until the victim substrate accumulates.
Some (but not all) substrates are also competitive inHibitors of the same CYP enzyme.
InHibitors of CYP enzymes will be represented by:
The magnitude to which an inHibitor increases the serum concentration of a specific substrate depends on the number of alternative pathways available to metabolize the substrate. If the drug is a substrate of, e.g., 1A2, 2D6 and 3A4, then inhibiting one of the three pathways should be of no consequence. Such substrates may be described as multi-CYP.
For a substrate metabolized by a single pathway, the effect of inhibition (and induction) will be dramatic. An example is lurasidone (Latuda), which is contraindicated with strong 3A4 inhibitors or inducers.
Some inhibitors are stronger than others. In general, expect blood levels of susceptible substrates to increase in the ballpark of:
mild inhibitor ~ 25% - 50% increase
moderate inhibitor ~ 50% - 100% increase
strong inhibitor > 100% increase
Expect these numbers to vary widely between substrates and individuals, often unpredictably. Note that magnitude of inhibition tends to be dose-related over the dosage range of the inhibitor.
The opposite of inHibition is inDuction. InDuction occurs when an inDucer stimulates the liver to produce extra enzymes, leading to enhanced metabolism and quicker clearance of victim drugs.
The D is for Down, i.e., Decreased serum concentrations of victim substrates. Unlike inHibition (H for Hurried), inDuction is Delayed, not taking full effect for 2 to 4 weeks while we…wait for the liver to ramp up enzyme production.
InDucers will be depicted by:
More often than not, an inducer is itself a substrate of the enzyme. For example, carbamazepine (Tegretol) is represented as both an anvil and a fish.
The “shredders” are four strong inDucers of several CYPs, which cause countless chemicals to be quickly expelled from the body:
carbamazepine (Tegretol) - antiepileptic
phenobarbital (Luminal) - barbiturate
phenytoin (Dilantin) - antiepileptic
rifampin (Rifadin) - antimicrobial
Dr. Jonathan Heldt refers to the shredders as “Carb & Barb”
in his book Memorable Psychopharmacology.
St John’s Wort (herbal antidepressant) also inDuces several CYPs, but does so with less potency than the four shredders.
Can shredding be problematic even if the patient is not taking a victim medication? Consider this:
For an example of reversal of inHibition, consider a patient taking alprazolam (Xanax, 3A4 substrate) who suddenly stops fluvoxamine (Luvox, 3A4 inHibitor). In absence of the inhibitor, alprazolam levels drop (from double) to normal. Since fluvoxamine has a short elimination half-life of 15 hours, it should be out of the body at 75 hours (15 hr x 5). So, you would expect the patient on Xanax to become more anxious 3 days after stopping Luvox. It may be difficult to discern whether the patient’s emerging distress is due to serotonin withdrawal or decreased alprazolam levels.
An example of reversal of inDuction involves tobacco, which is a 1A2 inDucer. A patient taking clozapine (1A2 substrate) stops smoking, reversing inDuction and causing clozapine levels to potentially double over the first week (which is faster than occurs with other inducers). The individual may become obtunded, hypotensive, or even have a seizure. To avoid this, the recommendation is to decrease clozapine dose by 10% daily over the first four days upon smoking cessation, and to check clozapine blood levels before and after the dose adjustment. Note that nicotine products (gum, patches, e-cigs) do not induce 1A2.
Although reversal of inHibition is typically faster than reversal of induction, this does not apply to inhibitors with extremely long half-lives. For instance, fluoxetine (Prozac) has a long elimination half-life of about 7 days, keeping itself around for about 35 days (7 days x 5). Consider a patient with schizophrenia on aripiprazole (Abilify, 2D6 substrate) who stops Prozac (2D6 inHibitor). The patient is doing well at one month, but becomes paranoid two months out. Unless the prescriber anticipated this possibility, no one will realize what happened.
REVERSAL OF INHIBITION/INDUCTION
All things being equal, it is best to avoid prescribing strong inducers or inhibitors. Even if there is no problematic interaction at the time, having a strong inhibitor or inducer on board may complicate future medication management.
Consider an individual on an established medication regimen who stops taking an inducer or inhibitor. The serum concentration of victim substrate(s) will change due to the reversal of induction/inhibition.
After an inDucer is withdrawn, the concentration of a victim substrate will increase gradually (D for Delayed) over a few weeks because the extra CYP enzymes are degraded without being replenished.
When an inHibitor is stopped, levels of a victim substrate will decrease as soon as the aggressor exits the body. “Hurriedly” does not mean immediately, because it takes about five half-lives for the inhibitor to be completely cleared.
For a patient on several psychotropic medications, reversal of inhibition or induction can really throw things out of whack.
For a few medications, the parent drug has low therapeutic activity until it is biotransformed by a CYP enzyme. In such cases, the substrate is called a prodrug, and the biotransformation process can be referred to as bioactivation.
For most medications (active parent drug to inactive metabolite) inDuction decreases (D for Down) effect of the drug and inHibition (H for High) amplifies the therapeutic effect and/or side effects.
With prodrugs, the opposite effect is observed clinically. Induction increases and inhibition decreases the medication’s effect(s).
Don’t let prodrugs confuse you. InHibitors increase and InDucers decrease the levels of substrate regardless of whether the parent drug is pharmacologically active.
Phase I metabolism typically involves biotransformation of an active drug to an inactive (or less active) chemical.
PHASE II METABOLISM
Phase II reactions typically involve conjugation of a substrate with glucuronic acid. This makes the drug water-soluble and prepped for renal excretion.
The responsible enzyme is UDP-glucuronosyltransferase, abbreviated UGT, as in “U Got Tagged” with glucuronic acid.
Medications metabolized primarily by Phase II are relatively immune to drug interactions. Examples of clinically relevant Phase II interactions are those involving lamotrigine (Lamictal) as a substrate.
A few medications are excreted in urine without being metabolised. Such drugs are not subject to Phase I or II interactions, but may be victims of kinetic interactions. Renal “aggressors” act by slowing or hastening the rate of excretion of the victim drug in urine.
The aggressor in a renal interaction is not referred to as an inducer or inhibitor, because no enzyme is involved. Nor is the victim called a substrate, because it is not being biotransformed.
Lithium, excreted unchanged in urine, is subject to victimization by medications that slow lithium's renal clearance, such as NSAIDs and thiazide diuretics.
CYP GENETIC PROFILES
Genetic polymorphisms can influence an individual’s medication kinetics, which is most relevant for 2D6 and 2C19. Let’s talk about 2D6, arguably the most consequential example.
Most individuals are genetically equipped with 2D6 genes that produce normal 2D6 enzymes that metabolize 2D6 substrates at the usual rate. These normal individuals are said to have a 2D6 extensive metabolizer (EM) genotype, resulting in a 2D6 EM phenotype.
About 5% of the population have extra copies of 2D6 genes, resulting in an ultrarapid metabolizer (UM) phenotype. These individuals clear 2D6 substrates quickly.
About 10% of individuals have defective 2D6 enzymes resulting in a 2D6 poor metabolizer (PM) phenotype. This condition may be found on a diagnosis list as “Cytochrome P450 2D6 enzyme deficiency”.
In summary, genetic testing of CYP polymorphisms will interpret the individual’s metabolizer profile for a given enzyme as either:
Extensive metabolizer (EM) - normal
Ultrarapid metabolizer (UM) - fast clearance of substrates
Poor metabolizer (PM) - slow clearance of substrates
A genetic test result of intermediate metabolizer (IM) means that enzyme activity is likely to be a bit lower than that of an EM, i.e., an intermediate between EM and PM. Generally, IM individuals can be clinically managed normally, like an EM individual.
Standalone 2D6 genotyping costs at least $200. GeneSight or Genecept panels cost about $4,000 and report the six relevant CYPs and two UGT enzymes (UGT1A4 and UGT2B15). 23andMe ($199) reports 1A2, 2C9, and 2C19, among 100s of other genes. 23andMe does not report the most relevant CYP genotype, 2D6, because the genetics of 2D6 metabolism is more complicated.
Genotyping may be useful when choosing which medication to prescribe an individual patient. With GeneSight, about 1 in 5 patients have a genetic variation relevant to their treatment. For an individual already established on a medication, serum drug levels may be more useful than genotyping. There are situations when knowing the actual blood levels of clozapine, risperidone, olanzapine, aripiprazole, haloperidol, lamotrigine, etc. are clinically relevant. Unfortunately, these tests usually must be sent to an outside lab, and it may take a week to see the results. Levels of lithium, carbamazepine, phenytoin, and valproic acid are usually reported the same day.
P-glycoprotein (P-gp) is a gatekeeper at the gut lumen and the blood-brain barrier. P-gp pumps P-gp substrates out of the brain—“Pumpers gonna pump”.
P-glycoprotein (P-gp) is a gatekeeper at the gut lumen and the blood-brain barrier. P-gp pumps P-gp substrates out of the brain—“Pumpers gonna pump”.
An example of a relevant P-gp interaction involves the OTC opioid antidiarrheal loperamide (Imodium). Loperamide does not cause central opioid effects under normal circumstances. If the individual takes a potent P-gp inhibitor, megadose loperamide can stay in the brain long enough to cause euphoria. The P-gp inhibitor typically used the achieve this recreational effect is omeprazole (Prilosec).