12.1 Mechanisms of drug interactions

Drug interactions can significantly impact medication effectiveness and safety. These interactions occur when one substance affects another's action in the body, potentially altering its therapeutic effects or causing harm.

Understanding the mechanisms behind drug interactions is crucial for healthcare providers. This knowledge helps prevent adverse effects, optimize treatment outcomes, and ensure patient safety when prescribing multiple medications or addressing complex medical conditions.

Drug Interactions: Types and Mechanisms

Classification of Drug Interactions

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• Drug interactions alter the effects of one drug due to the presence of another drug, food, or herb in the body
• Pharmacokinetic interactions affect absorption, distribution, metabolism, or excretion (ADME) of a drug, changing its concentration in the body
• Pharmacodynamic interactions occur when drugs with similar or opposing effects are administered together, resulting in additive (1+1=2), synergistic (1+1>2), or antagonistic (1+1<2) effects
• Drug-drug interactions involve two or more medications interacting with each other, potentially altering their effectiveness or safety profiles (warfarin and aspirin)
• Drug-food interactions occur when certain foods affect the absorption, metabolism, or effectiveness of a medication (grapefruit juice and statins)
• Drug-herb interactions involve herbal supplements or remedies interfering with the action or metabolism of prescription or over-the-counter medications (St. John's Wort and oral contraceptives)

Mechanisms of Pharmacokinetic Interactions

• Absorption interactions in the gastrointestinal tract affect the rate or extent of drug absorption
  • pH alterations change drug ionization and absorption (antacids reducing tetracycline absorption)
  • Chelation forms insoluble complexes, reducing drug absorption (calcium in dairy products binding to tetracycline)
  • Changes in gastric emptying or intestinal motility affect drug absorption rate (metoclopramide accelerating gastric emptying)
• Distribution interactions involve competition for plasma protein binding sites or alterations in tissue penetration
  • Displacement of a drug from plasma proteins increases its free concentration and potential for toxicity (warfarin displaced by NSAIDs)
  • Changes in blood flow or membrane permeability affect drug distribution to tissues (beta-blockers reducing blood flow to certain organs)
• Metabolism interactions primarily occur in the liver through induction or inhibition of cytochrome P450 enzymes
  • Enzyme induction increases drug metabolism, potentially reducing its effectiveness (rifampicin inducing CYP3A4)
  • Enzyme inhibition decreases drug metabolism, potentially leading to increased drug concentrations and toxicity (ketoconazole inhibiting CYP3A4)
• Excretion interactions affect renal clearance through changes in urine pH, competition for active tubular secretion, or alterations in renal blood flow
  • Urine pH changes affect ionization and reabsorption of drugs (alkalinization increasing excretion of acidic drugs)
  • Competition for active tubular secretion alters drug elimination (probenecid reducing penicillin excretion)
• Transporter-mediated interactions affect drug movement across cellular membranes at various stages of ADME (P-glycoprotein inhibition increasing drug absorption)

Drug Interactions: Absorption, Distribution, Metabolism, and Excretion

Absorption Interactions

• Gastrointestinal pH alterations affect drug ionization and absorption
  • Antacids increase stomach pH, reducing absorption of weakly acidic drugs (ketoconazole)
  • Proton pump inhibitors decrease absorption of drugs requiring acidic environment (atazanavir)
• Chelation forms insoluble complexes, reducing drug absorption
  • Calcium in dairy products binds to tetracycline antibiotics, decreasing their absorption
  • Iron supplements form complexes with fluoroquinolones, reducing their bioavailability
• Changes in gastric emptying or intestinal motility affect drug absorption rate
  • Metoclopramide accelerates gastric emptying, potentially increasing absorption of some drugs
  • Opioids slow gastrointestinal motility, delaying absorption of other medications

Distribution Interactions

• Competition for plasma protein binding sites affects free drug concentrations
  • Warfarin displaced from albumin by NSAIDs, increasing its anticoagulant effect
  • Phenytoin displaced by valproic acid, potentially leading to toxicity
• Alterations in tissue penetration change drug distribution
  • Beta-blockers reduce blood flow to certain organs, affecting drug distribution
  • P-glycoprotein inhibitors increase brain penetration of certain drugs (digoxin)

Metabolism Interactions

• Cytochrome P450 enzyme induction increases drug metabolism
  • Rifampicin induces CYP3A4, reducing the effectiveness of oral contraceptives
  • Carbamazepine induces CYP3A4, decreasing levels of calcium channel blockers
• Cytochrome P450 enzyme inhibition decreases drug metabolism
  • Ketoconazole inhibits CYP3A4, increasing levels of statins and risk of myopathy
  • Fluoxetine inhibits CYP2D6, potentially increasing levels of tricyclic antidepressants

Excretion Interactions

• Urine pH changes affect ionization and reabsorption of drugs
  • Alkalinization of urine increases excretion of acidic drugs (aspirin)
  • Acidification of urine increases excretion of basic drugs (amphetamines)
• Competition for active tubular secretion alters drug elimination
  • Probenecid reduces penicillin excretion, prolonging its therapeutic effect
  • NSAIDs compete with methotrexate for renal tubular secretion, increasing toxicity risk
• Alterations in renal blood flow affect drug clearance
  • NSAIDs reduce renal blood flow, potentially decreasing clearance of other drugs
  • ACE inhibitors alter renal hemodynamics, affecting clearance of renally excreted drugs

Common Drug Interactions and Consequences

Drug-Drug Interactions

• Warfarin and NSAIDs increase risk of bleeding due to pharmacodynamic and pharmacokinetic interactions
  • NSAIDs displace warfarin from protein binding sites and increase gastrointestinal bleeding risk
• Statins and CYP3A4 inhibitors (erythromycin, ketoconazole) increase statin concentrations and risk of myopathy
• Monoamine oxidase inhibitors (MAOIs) and serotonergic drugs (SSRIs, triptans) risk serotonin syndrome
• ACE inhibitors and potassium-sparing diuretics increase risk of hyperkalemia due to additive effects on potassium retention
• Digoxin and amiodarone increase digoxin levels due to P-glycoprotein inhibition, risking toxicity

Drug-Food Interactions

• Statins and grapefruit juice increase statin concentrations and risk of myopathy due to CYP3A4 enzyme inhibition
• Monoamine oxidase inhibitors (MAOIs) and tyramine-rich foods (aged cheeses, cured meats) risk hypertensive crisis due to tyramine accumulation
• Tetracycline antibiotics and dairy products reduce antibiotic absorption due to chelation with calcium
• Warfarin and vitamin K-rich foods (leafy greens) decrease anticoagulant effect due to antagonism
• Levodopa and high-protein meals decrease drug absorption and effectiveness in Parkinson's disease treatment

Drug-Herb Interactions

• St. John's Wort and oral contraceptives reduce contraceptive efficacy due to induction of CYP3A4 enzymes
• Ginkgo biloba and anticoagulants (warfarin, aspirin) increase bleeding risk due to antiplatelet effects
• Garlic supplements and HIV protease inhibitors potentially reduce antiretroviral efficacy due to CYP3A4 induction
• Echinacea and immunosuppressants may reduce immunosuppressive effects, risking transplant rejection
• Ginseng and antidiabetic medications may cause hypoglycemia due to additive glucose-lowering effects

Preventing and Managing Drug Interactions

Medication Review and Screening

• Conduct comprehensive medication reviews, including prescription drugs, over-the-counter medications, and herbal supplements
  • Perform medication reconciliation at each healthcare visit and hospital admission/discharge
  • Encourage patients to maintain an up-to-date medication list, including non-prescription products
• Utilize drug interaction screening software and databases to identify potential interactions during prescription
  • Implement electronic prescribing systems with built-in interaction checking
  • Consult reliable drug interaction resources (Micromedex, Lexicomp) for detailed information

Patient Education and Monitoring

• Educate patients about potential drug interactions and the importance of adherence to medication schedules and dietary restrictions
  • Provide written information on significant drug interactions and foods/herbs to avoid
  • Teach patients to recognize signs and symptoms of potential drug interactions
• Monitor patients closely for signs of drug interactions, especially when starting new medications or changing doses
  • Schedule follow-up appointments or laboratory tests to assess drug effectiveness and safety
  • Encourage patients to report any unusual symptoms or side effects promptly

Clinical Management Strategies

• Consider alternative medications or dosing strategies when clinically significant interactions are identified
  • Choose drugs with lower interaction potential within the same therapeutic class
  • Adjust dosing schedules to minimize interactions (separating interacting drugs by several hours)
• Implement therapeutic drug monitoring when appropriate to assess drug levels and adjust dosages accordingly
  • Monitor serum concentrations of drugs with narrow therapeutic indices (digoxin, phenytoin)
  • Use pharmacogenetic testing to identify patients at higher risk for certain drug interactions
• Collaborate with pharmacists and other healthcare providers to optimize medication regimens and minimize interaction risks
  • Consult clinical pharmacists for complex medication regimens or high-risk patients
  • Establish interdisciplinary teams to review and manage medication-related problems in healthcare settings