How do medications interact to cause side effects?

Medications can “interact” in a variety of ways

Here are the most common types of drug-drug interactions (this is not a comprehensive list)

Displacement from transport proteins

Many medications travel in the bloodstream attached to proteins called “transport proteins.” Some medications/drugs might remove or “kick off” a medication from its transport protein.

Altering the activity of metabolic enzymes

Recall that enzymes are like “Pac-Man” that break down (or metabolize) drugs and medications. Some medications alter the activity of the enzymes that metabolize other medications and drugs. If an enzyme’s activity is increased, then the medication metabolized by that enzyme may be metabolized or broken down too quickly. This results in decreased blood levels of the medication which may decrease the medication’s effectiveness. If an enzyme’s activity is decreased, then the medication metabolized by that enzyme may be metabolized or broken down too slowly. This results in increased blood levels of the medication which might cause side effects and toxicity.

Competing for receptors

Some medications might compete with other medications at the same receptor. 

Altering the function of organs like the kidneys, intestines, and liver

Some medications can alter the body’s ability to eliminate drugs and medications. This can occur when one medication alters the functioning of the kidneys, intestines, and/or liver.

Below are the most common drug-drug interactions to be aware of when taking psychotropic medications (i.e., medications used to treat mental disorders)

Valproic acid (VPA, Depakote) + Lamotrigine (Lamictal)

  • Valproic acid (VPA) increases lamotrigine levels by decreasing lamotrigine metabolism
  • Increased lamotrigine levels increase the risk of developing a severe rash
  • Increased lamotrigine levels increase the risk of Steven-Johnson’s Syndrome (SJS/TEN)
  • When taking both valproic acid (Depakote) and lamotrigine (Lamictal), the general recommendation is to decrease the dose of lamotrigine by 50%

Carbamazepine (CBZ) is an inducer of CYP3A4

  • CBZ induces its own metabolism by increasing the activity of the CYP3A4 enzyme
  • CBZ also induces the metabolism of other medications that are metabolized by CYP3A4 such as oral contraceptives, clozapine, alprazolam, buspirone, and clonazepam

Lithium levels are INCREASED when combined with the following

  • Non-Steroid Anti-inflammatory Drugs (NSAIDs), except aspirin
  • Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)
  • Thiazide diuretics such as hydrochlorothiazide
  • Low sodium diets

Lithium levels are DECREASED when combined with the following

  • Caffeine
  • Theophylline
  • High sodium diets

Grapefruit Juice

  • Grapefruit juice is a potent inhibitor of CYP3A4 and P-glycoprotein (another protein that helps eliminate drugs)
  • Therefore, grapefruit juice increases blood levels of many medications metabolized by CYP3A4

Smoking Tobacco cigarettes

  • The hydrocarbons in the smoke of tobacco cigarettes, but not nicotine, increase the activity of CYP1A2 enzymes
  • Smoking cigarettes decreases blood levels of medications metabolized by CYP1A2 such as Olanzapine, Clozapine, and Caffeine

Tyramine + Monoamine Oxidase Inhibitors (MAOIs)

  • Tyramine (TIE-ruh-meen) is an amino acid that occurs naturally in the body and aids in regulating blood pressure. Elevated tyramine levels can lead to dangerously elevated blood pressures.
  • Tyramine is also found in certain foods such as banana peel, beer, fava beans, aged cheese, sauerkraut, sausage, soy sauce, and concentrated yeast extract.
  • An enzyme called monoamine oxidase (MAO) breaks down excess tyramine in the body. Monoamine oxidase inhibitors (MAOIs) are used to treat depression.
  • If taking a monoamine oxidase inhibitor, it is important to avoid certain foods high in tyramine.

Monoamine Oxidase Inhibitors (MAOIs)

  • Monoamine oxidase (MAO) is an enzyme that breaks down monoamines such as serotonin, dopamine and norepinephrine. Therefore, monoamine oxidase inhibitors (MAOIs), such as selegiline and phenelzine, are used to treat depression.
  • Combining MAOIs with Selective Serotonin Reuptake Inhibitors (SSRIs), Tricyclic Antidepressants (TCAs), Pseudoephedrine, and Stimulants increases the risk of serotonin toxicity and dangerously high blood pressures

Fluoxetine, Paroxetine, and Bupropion are potent inhibitors of CYP2D6 

  • Drugs like fluoxetine, paroxetine, and bupropion inhibit CYP2D6 enzymes and increase blood levels of other medications metabolized by CYP2D6.
  • Fluoxetine, paroxetine, and bupropion decrease the effectiveness of Tamoxifen and Codeine because Tamoxifen and Codeine require CYP2D6 activity to be effective. 

Antimicrobial-Psychotropic Drug Interactions

  • Antimalarials increase levels of phenothiazines such as chlorpromazine (Thorazine)
  • Azoles increase levels of alprazolam, midazolam, and buspirone
  • Clarithromycin and Erythromycin increase levels of alprazolam, midazolam, carbamazepine, clozapine, and buspirone
  • Quinolones increase levels of clozapine and benzodiazepines (but decreases the effects of benzodiazepines)
  • Isoniazid increases levels of haloperidol and carbamazepine. Isoniazid + disulfiram can cause problems with motor coordination (called ataxia)
  • Isoniazid and Linezolid are weak inhibitors of monoamine oxidase (MAO) and therefore increases the risk of serotonin syndrome and hypertensive emergencies if used with serotonergic drugs (like SSRIs, SNRIs, and TCAs)

Erythromycin, Clarithromycin, and Ketoconazole + Tricyclic Antidepressants or antipsychotics

  • Combining Erythromycin, Clarithromycin, or Ketoconazole with Tricyclic Antidepressants or antipsychotics increases the risk of QT prolongation and cardiac (ventricular) arrythmias

Drug-Drug Interaction Tables