Drug Interactions PA_Ray_2025 HANDOUT PDF

Basics of Drug Interactions Gretchen Ray, PharmD, PhC, CDCES Associate Professor UNM College of Pharmacy Learning Objectives 1 2 3 4 Describe the Recognize Identify tools that Develop strategies types of drug...

Basics of Drug Interactions Gretchen Ray, PharmD, PhC, CDCES Associate Professor UNM College of Pharmacy Learning Objectives 1 2 3 4 Describe the Recognize Identify tools that Develop strategies types of drug substrates, can assist in to manage interactions inhibitors, and identifying and different types of inducers involved managing drug drug interactions in interactions interactions Drug interactions Can Cause Significant Harm 2015-2018 CDC Estimates Percent of persons using at least one prescription drug in the past 30 days: 48.6% Percent of persons using three or more prescription drugs in the past 30 days: 24.0% Percent of persons using five or more prescription drugs in the past 30 days: 12.8% https://www.cdc.gov/nchs/fastats/drug-use-therapeutic.htm Drug-drug interactions can affect either: A drug can be changed by the presence of another drug, herbal supplement, food, or beverage What the drug Pharmacodynamics does to the body OR What the body Pharmacokinetics does to the drug Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. Pharmacodynamic Interactions Interaction between either shared or competing mechanisms of drug action What the drug does to the body Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. SOME DRUGS WORK THROUGH AGONISM OR ANTAGONISM OF A RECEPTOR OR ENZYME Drug Type Effect Agonist Activation Antagonist Inhibition Example: Carvedilol is an alpha and beta blocker (antagonist) that lowers blood pressure and heart rate Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. PHARMACODYNAMIC INTERACTIONS OCCUR BETWEEN SHARED OR COMPETING MECHANISMS OF ACTION Opposing Additive mechanisms mechanisms i.e., multiple sedating medications/substances Examples of pharmacodynamic interactions Drug 1 Drug 2 Mechanism Result Warfarin (inhibits vitamin Vitamin K Competing mechanism Decreased effect of both K) drugs Warfarin (anticoagulant) Apixaban Shared mechanism Increased bleed risk (anticoagulant) ondansetron Haloperidol Additive risk; Both drugs Increased risk of QTc have side effect of QTc prolongation/Torsades prolongation de pointes NSAIDs ACE-I/ARBs Both drugs affect renal Risk of acute kidney filtration but in opposing injury manners Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Example PHARMACODYNAMIC interaction midodrine An alpha-1 agonist used for treatment of orthostatic hypotension terazosin An alpha-1 antagonist used for treatment of BPH Potential consequences? LexiDrug Pharmacodynamic Interactions Usually, cannot be managed by spacing out dose administration times Participating medications will be active for 3-4 times their half-life, after the last dose is given Avoidance of one Solution? medication or change to an alternative agent Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. Pharmacokinetic Interactions Pharmacokinetic Interactions Interactions where one or both drug’s pharmacokinetic parameters are altered by the presence of the other drug What the body does to the drug Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. Pharmacokinetic Interactions Pharmacokinetic interactions represent one drug’s interference with another drug’s ADME: Absorption How will it get into the body? Distribution Where will it go? Metabolism How is it broken down? Excretion/Elimination How is it cleared? Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al.  Pharmacokinetic Interaction Management Goal is to keep plasma drug concentrations of the affected drug relatively unchanged. Increased or decreased plasma drug concentrations can result from: Increases or Increases or decreases in OR decreases in bioavailability clearance  Absorption Interactions Increased absorption interactions can be influenced by: o pH effects § Example: levothyroxine absorption is decreased by antacids § Spacing dose administration may be a viable way of managing the interaction o Altered bacterial flora § Long term antibiotics may kill flora and affect absorption o Altered gastrointestinal tract motility § Some medications increase peristalsis and may decrease time of absorption Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al.  Patient Case #1 A 52-yo-woman presents to the primary care clinic with the following medication list: levothyroxine 100 micrograms daily Calcium carbonate 600 mg twice a day She is here for a follow-up and to review her thyroid labs. Despite consistently taking her levothyroxine, her TSH result is HIGH at 83 mIU/L.  Absorption Interactions These interactions often involve changes in solubility or chelation These can usually be managed through dose spacing You may hear recommendations such as: o “Give dose at least 1 - 2 hours apart” Drug Distribution Interactions Absorption How will it get into the body? Distribution Where will it go? Metabolism How is it broken down? Excretion/Elimination How is it cleared? Distribution interactions can occur with drugs that bind to protein Unbound molecules remain free and pharmacologically active à provide therapeutic effects Protein-bound molecules are pharmacologically inactive à do not have therapeutic effects Other drugs can compete for these binding sites and affect levels of protein-bound drugs Examples: o warfarin o Phenytoin Important Drug Interactions & Their Mechanisms, 13e. 2021. In: Katzung BG, et al. Drug Metabolism Interactions Absorption How will it get into the body? Distribution Where will it go? Metabolism How is it broken down? Excretion/Elimination How is it cleared? Metabolism Interactions AND THE CYP 450 ENZYMES Liver and intestines are the most common sites of these enzymes P450 enzymes can be inhibited (slowed) or induced (sped up) Medications often compete for same enzyme subgroup CYP-450 Enzymes CYP CYP Others 3A4 2D6 CYP CYP 2C9 1A2 Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. INTERACTIONS WITH DRUG TRANSPORTERS TYPICALLY ALTER BIOAVAILABILITY RATHER THAN SYSTEMIC CLEARANCE P-glycoprotein (P-gp) A drug transporter that determines the uptake and efflux of different medications Located throughout the body including the gastrointestinal tract P-gp inhibitors - increase concentration of P-gp substrates P-gp inducers - decrease concentration of P-gp substrates Organic Anion Transporting Polypeptides (OAT-P) Drug transporters that mediate hepatic uptake of medications as well as endogenous compounds Located predominately in the liver More than 11 OATPs have been identified Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. Inhibition results in increased drug concentrations Enzyme Inhibition Most common type and potentially the most serious drug metabolism Decreased metabolism of a drug interaction Increased bioavailability of a drug Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. Induction results in decreased drug concentrations Induction Increased drug metabolism Decreased drug bioavailability Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al.  Consider the time course of interactions CANNOT AVOID THIS INTERACTION WITH DOSE SPACING The onset of inhibition interactions is typically immediate Inhibition interactions persist until the causative drug is eliminated from the body. NOT when discontinued. In other words, until 3-4 half-lives after the last dose of the inhibitor is administered Induction vs Inhibition Interaction Timing Induction Inhibition Onset Slow (day to weeks) Fast (immediate) Frequency Less common Most common Decrease drug Increase drug metabolism metabolism Effect Decrease concentration Increase concentration Practice Case #2 A 40-yo-woman presents to the Family Practice Clinic with the following medication list: lisinopril 40 mg daily hydrochlorothiazide 25 mg daily simvastatin 20 mg daily She is here for an acute care visit due to a likely upper respiratory infection. You are thinking of prescribing Biaxin (clarithromycin) for her current infection.  Practice Case #2 A 40-yo-woman is here at our Family Practice Clinic for an acute care visit and is requesting a prescription for clarithromycin for a recurrent upper respiratory infection. When faced with an interaction, think of: How serious is the interaction? Is it serious enough to cause discomfort or Run an interaction checker danger? on Lexidrug We depend on our references for this information Clinical judgement and documentation are essential in these scenarios What do we need to know? What type of interaction is this? Which drug is the object of the interaction? Which drug causes the interaction? http://medicine.iupui.edu/clinpharm/ddis/clinical-table CYP-450 Interaction Table Substrate: medication that is being acted upon either inhibited or induced Inhibitor: slows down metabolism Inducer: speeds up metabolism Substrate: simvastatin Inhibitor: clarithromycin Pharmacist’s Letter Practice Case #2 Practice Case #2 Clarithromycin + simvastatin *Seek alternative Clarithromycin’s half-life is antibiotic or approximately 7 hours; thus statin that are interaction will persist for not discussed in about a day after the last the interaction dose of clarithromycin OR hold statin CASE #3 TIRZEPATIDE & ORAL CONTRACEPTIVES Practice Case #4 A 32-yo-woman presents to the Family Practice Clinic with the following medication list: sertraline 100 mg daily During your visit, she mentions starting St John’s Wort to further help her depression and anxiety. What do you tell her regarding this supplement? Practice Case #4 Strongly discourage use of this combination What if our patient is on a natural supplement that is not listed on LexiDrug?  Concerns with Natural Products Many areas of natural supplements are not well defined such as: Mechanism of action Disease interactions Drug interactions Adverse effects High risk patients include: Elderly Pregnancy or lactation Infants polypharmacy Natural Products Talking about supplement use Ask what OTC or herbal supplements they use Do not dismiss any therapy as a placebo Discuss therapy use with your patients at every visit  Practice Case A 55-yo-male presents to the Family Medicine Clinic looking for a natural product to help with his cholesterol. He is on the following medication: Simvastatin 20 mg daily He saw on the internet that red yeast rice can help lower his cholesterol more and wants your opinion on using this supplement. What do you tell the patient? LOOK OUT FOR FOOD-DRUG INTERACTIONS Green leafy vegetables à have high levels of Vitamin K can affect warfarin levels Salt substitutes have potassium (KCl) can cause hyperkalemia in patients on medicines that increase potassium (ACE inhibitors, spironolactone, ARBs) Grapefruit juice can increase concentrations of certain drugs Food can decrease or increase bioavailability of various drugs i.e. – levothyroxine absorption is inhibited by food  Grapefruit juice interactions inhibit gut wall enzymes and are irreversible Enzyme inhibition Enzymes and Grapefruit juice appears to last transporters most increases bioavailability approximately 72 hours affected are CYP 3A4, by irreversible inhibition after a single glass of CYP1A2, P-glycoprotein, of these enzymes and grapefruit juice and OAT-P transporters Dahan A, et al. Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance. Eur J Clin Nutr. 58, 1–9 (2004). Grapefruit Juice Interaction Common medications demonstrating this interaction: Calcium channel blockers Statins (except for pravastatin, rosuvastatin, and fluvastatin) Amiodarone Buspirone Cyclosporine Protease inhibitors Sertraline and trazodone Do NOT recommend dose spacing to manage grapefruit interactions. Important Drug Interactions & Their Mechanisms, 15e. 2021. In: Katzung BG, et al. Bauer LA. Pharmacotherapy: A Pathophysiologic Approach, 11e. 2020. In: DiPiro JT, et al. Summary points Pharmacodynamic: What the drug does to the body (Agonist vs Antagonist) Pharmacokinetics: What the body does to the drug (ADME) Bioavailability interactions: May be able to recommend dose spacing to manage interaction if not an induction or inhibition interaction Do not recommend dose-spacing to manage induction or inhibition interactions RECOMMENDED RESOURCES LexiDrug Natural Medicines Database Liverpool Drug Interaction Checker à for HIV or COVID medications Your team pharmacist Questions