L18 - Drug Interactions

Introduction to Drug Interactions

  • Drug interactions are a crucial aspect of clinical pharmacology.
  • Understanding these interactions is vital for:
    • Preventing adverse outcomes.
    • Optimizing therapeutic efficacy.
  • Types of interactions discussed:
    • Drug-drug interactions.
    • Drug-food interactions.
    • Drug interactions with complementary medicines.

Learning Objectives

  • Define drug-drug interactions and explain their clinical significance.
  • Differentiate between pharmacokinetic and pharmacodynamic drug interactions.
  • Describe the major mechanisms underlying drug-drug interactions, including:
    • Absorption.
    • Distribution.
    • Metabolism.
    • Excretion.
  • Identify common enzyme systems involved in drug-drug interactions, such as cytochrome P450 isoenzymes.
  • Discuss the management and prevention strategies for drug-drug interactions.

Preventing and Managing Drug-Drug Interactions

  • Identify potential drug-drug interactions before the patient takes the drugs.
  • If the patient must take interacting drugs:
    • Apply strategies to minimize adverse effects.
    • Minimize effects on therapeutic efficacy.

What is a Drug Interaction?

  • A drug interaction occurs when a drug interacts with:
    • Another drug.
    • Food or supplements.
    • Existing medical conditions.
  • Consequences:
    • Changes in therapeutic efficacy (increases or decreases).
    • Adverse effects.
  • Examples:
    • Warfarin and leafy greens (vitamin K): affects anticoagulation.
    • NSAIDs in patients with renal impairment: major clinical consequences.

Frequency of Drug-Drug Interactions

  • Difficult to determine the exact frequency.
  • Polypharmacy significantly increases the risk.
    • 2 drugs: ~5.6% risk.
    • 6 drugs: ~56% risk.

Challenges in Identifying Drug-Drug Interactions

  • Not always obvious.
  • Physiological and biochemical changes may be masked by:
    • Clinical signs and symptoms of the illness.
    • Other comorbidities.
  • Importance of awareness and reporting adverse effects.

Clinical Risk Factors for Drug-Drug Interactions

  • Polypharmacy.
  • Increasing age.
  • Drugs with narrow therapeutic range (e.g., digoxin, lithium, warfarin).
  • Dose of the drug.
  • Multiple prescribers.
  • Self-prescriptions.
  • Genetic polymorphisms (e.g., CYP450 enzymes).
  • Co-existing diseases.

Types of Drug-Drug Interactions

  • Pharmaceutical: Mixing drugs (e.g., in a syringe).
  • Pharmacodynamic.
  • Pharmacokinetic.

Pharmacodynamic Interactions

  • Definition: The effects of one drug are changed by the presence of another drug without alterations in drug kinetics.
  • Mechanism:
    • Competition at drug receptors.
    • Additive or synergistic interactions.
    • Antagonist interactions.

Pharmacokinetic Interactions

  • Definition: Changes in ADME (absorption, distribution, metabolism, elimination) of another drug.
  • Expressed as changes in kinetic parameters:
    • Peak serum concentration.
    • Area under the curve.
    • Half-life.
  • Most common: Metabolic interactions with cytochrome P450 isoenzymes.

Classification of Drug-Drug Interactions

  • Minor: No clinical action needed.
  • Moderate: Monitoring or adjustment required.
  • Major: Avoid combination if possibl; significant adverse effects, potentially fatal outcomes, or loss of therapeutic efficacy.

Direct vs. Indirect Pharmacodynamic Interactions

  • Direct: Additive effects at a common target or antagonism due to actions at different sites.
  • Indirect: The pharmacological effect of one drug alters the response to another drug, even though the two effects are not directly related.

Mechanisms of Pharmacodynamic Interactions

  • Additive effect: Two drugs with similar effects (e.g., benzodiazepines and opioids leading to respiratory depression).
  • Synergistic effect: Combined effect is greater than either drug alone (e.g., warfarin and aspirin increasing bleeding risk).
  • Antagonist effect: Drugs with opposing effects (e.g., NSAIDs decreasing the antihypertensive effect of ACE inhibitors).

Example of Direct Pharmacodynamic Interaction: Warfarin and Aspirin

  • Warfarin: Anticoagulant; inhibits vitamin K-mediated synthesis of clotting factors.
  • Aspirin: Irreversibly inhibits COX-1 in platelets, decreasing platelet aggregation by inhibiting the synthesis of thromboxane A2A_2.
  • Combined effect: Increased bleeding risk.
  • Management:
    • Use lowest effective doses of both drugs.
    • Monitor for bleeding.
    • Administer proton pump inhibitors for gastroprotection.
    • Continue monitoring INR.

Example of Indirect Pharmacodynamic Drug Interaction: Loop Diuretics and Digoxin

  • Loop diuretics: Can cause potassium loss leading to hypokalemia.
  • Digoxin: Inhibits the sodium-potassium ATPase pump in cardiac myocytes.
  • Interaction: Hypokalemia increases digoxin's binding to its target, raising the risk of toxicity.
  • Management:
    • Check serum potassium.
    • Consider potassium supplementation or potassium-sparing diuretic.
    • Educate patients about signs of digoxin toxicity.

Pharmacokinetic Drug Interactions

  • Alter drug levels through changes in absorption, distribution, metabolism, and excretion (ADME).
  • Major outcomes: Under-treatment or toxicity.
  • Focus on the diagram from here on in the lecture. So the oral drug is administered, whether there's any changes to absorption due to two drugs being administered at the same time, when the drug's in systemic circulation, how it's being distributed to the tissues, how it's being metabolised either to an active or inactive metabolite, and then when it's being excreted the drug itself or its metabolite in the urine, faeces or bile, how two drugs present at the same time or more in the cases of polypharmacy will cause a pharmacokinetic drug interaction that can cause changes to both therapeutic efficacy and also lead to potential toxicity.

Absorption-Related Drug Interactions

  • Mechanisms:
    • Altered gastric pH.
    • Chelation.
    • Changes in GI motility.
    • Modulation of drug transporters.
  • Clinical impact: Delayed or reduced drug onset.
  • Examples:
    • Changes in GI pH: Proton pump inhibitors (PPIs) raise the gastric pH and reduce the absorption of drugs that require an acidic environment where ketoconazole oral suspension cannot dissolve correctly. so its bioavailability decreases leading to therapeutic failure.
    • Chelation: Antacids with tetracyclines form insoluble complexes leading to a reduced antibiotic absorption, so you advise patients to space administration time so maybe take your tetracycline two hours before or else four hours after those antacids to avoid this drug drug interaction in particular.
    • Changes in GI motility: If we give metoclopramide that will accelerate gastric emptying and intestinal transit, which can increase cyclosporine absorption due to the more efficient delivery to the absorption sites.
    • P-glycoprotein Transporters: Rifampin induces P glycoprotein reducing absorption of digoxin by pushing it out of the enterocytes before it can release systemic circulation. This induction can also increase biliary excretion so it's critical to consider transporter mediated interactions especially in drugs with narrow therapeutic windows like digoxin.

Distribution-Related Drug Interactions

  • Mechanisms:

    • Displacement from protein-binding sites.
    • Modulation of drug transporter proteins.

  • Clinical impact: Increased free or active drug concentration (enhanced therapeutic effects or increased toxicity risk).

  • Example:

    • Warfarin is highly protein bound so when it's co administered for example with valproic acid, warfarin may be displaced from its binding site meaning there's more free warfarin in circulation increasing the risk of bleeding. This is complicated further as valproic acid also inhibits the CYP2C9 enzyme, an enzyme that metabolizes warfarin and compounding the interaction.

    • Co-administration of ketoconazole, which is a known P glycoprotein inhibitor, can increase, for example, ritonavir exposure in the central nervous system. This happens because inhibition of P glycoprotein reduces the efflux or removal of ritonavir from the central nervous system. And in turn, this can enhance the therapeutic or adverse CNS effects of certain drugs.

Metabolism-Related Drug Interactions

  • Often mediated by changes in enzyme activity, particularly in the liver (cytochrome P450 enzymes).

  • Mechanisms:

    • Enzyme induction:
      • Rimpopycin inducing CYP450 reducing oral contraceptives effectiveness.
      • Carbamenazine induces CYP3A4 that is the main enzyme responsible for metabolising simvastatin. This leads to reduced simvastatin levels potentially decreasing its lipid lowering effectiveness.
    • Enzyme inhibition: Erythromycin inhibits CYP3A4 increasing statin toxicity.
      • Amiodarone that inhibits several CYP450 enzymes including CYP2C9, CYP3A4 and CYP1A2, which are all involved in the metabolism of warfarin. Ultimately, this results in elevated warfarin levels and significantly increases the risk of bleeding.

  • Clinical impact: Altered drug levels (undertreatment or toxicity).

  • First-pass metabolism:

    • Verapamil increases hepatic blood flow, which can reduce first past metabolism of drugs, like dofetilide, which can lead to higher plasma concentrations and increase the risk of QT prolongation and potentially life threatening, arrhythmia.

  • Allopurinol is an inhibitor of the enzyme exanthine oxidase, which is used to treat gout and gouty arthritis. Azathioprine is a cancer treatment is converted to the active metabolite six mercaptopurine, which is metabolised by exanthine oxidase. However, if we've co administration of both of these drugs, it can lead to the accumulation of six mercaptopurine resulting in potentially life threatening bone marrow suppression.

  • Examples of CYP Mediated DDI

    • CYP3A4 inhibition: Caterconazole inhibits CYP3A4 that can increase the levels of midazolam, increasing sedation risk.
    • CYP2D6 inhibition: It's inhibited by FLUX18, that can increase the levels of codeine's active metabolites, causing reduced analgesia if both of those drugs are given together.
    • Amiodarone inhibits CYP2C9 that can increase warfarin levels and the bleeding risk.

Excretion-Related Drug Interactions

  • Primarily renal, but also includes umbilical and intestinal pathways.
  • Mechanisms:
    • Competition for renal tubular secretion.
    • Altered urine pH.
  • Clinical impact: Accumulation of drugs (toxicity).
  • Example: Methotrexate toxicity with NSAIDs.
  • Changes in urinary pH:
    • Antacids raise urinary pH, increasing excretion of aspirin.
  • Changes in active renal tubular excretion:
    • Aspirin competes with methotrexate, increasing the risk of methotrexate toxicity.
  • Enterohepatic shunt interference:
    • Some drugs undergo enterohepatic recirculation where they're secreted into the bile reabsorbed back into the intestine and recycled into the liver and interrupting this cycle can reduce overall drug exposure.

Examples of High-Risk Drug-Drug Combinations

  • Opioids and benzodiazepines: Respiratory depression and death.
    • Management: Avoid or use the lowest effective doses. Monitor sedation closely.
  • Warfarin and antibiotics: Increased INR and bleeding risk.
    • Management: Close INR monitoring and dose adjustment or give an alternative antibiotic to trimethoprim.
  • SSRIs and NSAIDs: Increased GI bleeding risk.
    • Management: Consider PPIs.
  • ACE inhibitors and potassium-sparing diuretics.
  • Lithium and diuretics.

Drug Interactions with Nutrients and Complementary Medicines

  • Occur when food components, vitamins, or minerals alter the absorption, metabolism, or effect of a drug (or vice versa).
  • Grapefruit inhibits CYP3A4.
  • St. John's wort can induce CYP enzymes and decrease the efficacy of oral contraceptives and SSRIs.

Grapefruit Juice Interactions

  • Inhibits intestinal CYP3A4 enzymes and P-glycoprotein transporters.
  • Effects can last up to 72 hours.
  • Advise patients to avoid grapefruit juice with high-risk medications.
  • Other fruits (Seville oranges and pomelos) have similar effects.

Other Food Interactions

  • Dairy products: May interact with tetracyclines and that can decrease their absorption through chelation.
  • Iron-rich foods: Decrease levodopa absorption.
  • Fiber rich foods
  • High fat meals
  • Alcohol

Resources for Detecting Drug-Drug Interactions

  • Australian Medicines Handbook (AMH).
  • MIMS drug interaction database.
  • AusDI drug interaction database.

Conclusion

  • Recognizing drug-drug interactions can prevent:
    • Therapeutic failure.
    • Adverse effects.
    • Toxicity.
  • Pharmacists and healthcare providers play a critical role.
  • Understanding the different types of drug-drug interactions and their mechanisms is key.

Summary

  • A drug-drug interaction occurs when the pharmacological or clinical response to a drug is altered by another drug.
  • Interactions can be pharmacokinetic or pharmacodynamic (direct or indirect).
  • Identifying drug-drug interactions is critical in pharmacy practice.
  • Pharmacokinetic drug interactions involve changes in ADME.