Chapter 3  ·  Module 4  ·  Pharmacodynamics

Clinical Pharmacodynamics

Drug interactions at the effector, tolerance, and pharmacogenomics at a glance

High-Risk Pharmacodynamic Drug Interactions

Cardiac interaction

QT Prolongation → Torsades de Pointes

  • Drugs block cardiac potassium channels → delayed repolarization → prolonged QT
  • Corrected QT >500 ms: high torsades de pointes risk
  • Combining two QT-prolonging drugs = additive prolongation
  • Risk factors: female sex, hypokalemia, hypomagnesemia, bradycardia, congenital long QT
  • Classes: antiarrhythmics, macrolides, fluoroquinolones, azoles, antipsychotics, methadone
  • Management: baseline electrocardiogram; correct electrolytes; monitor corrected QT; hold if >500 ms

Central nervous system interaction

Additive Respiratory Depression

  • Opioids + benzodiazepines: synergistic respiratory depression
  • United States Food and Drug Administration black box warning (2016)
  • Gabapentinoids add further respiratory depression with opioids
  • Alcohol potentiates both classes
  • Interaction is at brainstem respiratory center, not plasma concentration
  • Prescribe naloxone for at-risk patients; cannot manage by monitoring plasma levels alone

Renal interaction

Cumulative Nephrotoxicity

  • Aminoglycoside + vancomycin: synergistic proximal tubule injury; daily creatinine monitoring
  • Triple whammy: nonsteroidal anti-inflammatory drug + angiotensin converting enzyme inhibitor or angiotensin receptor blocker + diuretic
  • Triple whammy removes three compensatory mechanisms for maintaining glomerular filtration rate simultaneously
  • High acute kidney injury risk in elderly and chronic kidney disease patients

Tolerance, Dependence, and Addiction — Three Distinct Concepts

ConceptDefinitionExamplesClinical implication
Tolerance Reduced drug effect at same dose; higher dose needed for same response Opioid analgesics, benzodiazepines, nitrates, beta-agonists Dose escalation needed; not a sign of addiction
Physical dependence Withdrawal syndrome on abrupt discontinuation; physiological adaptation Opioids, benzodiazepines, beta-blockers, glucocorticoids, clonidine Taper gradually; do not confuse with addiction
Addiction Compulsive drug-seeking despite adverse consequences; neurological disorder Can occur with or without tolerance or dependence Not an inevitable consequence of opioid prescribing for pain

Cross-Tolerance

Tolerance to one drug reduces sensitivity to others in the same class sharing the same receptor. Opioid cross-tolerance: patient on chronic high-dose opioids requires higher doses of all opioids including for surgical analgesia. Incomplete cross-tolerance between opioids = basis for opioid rotation. Benzodiazepine/alcohol cross-tolerance at gamma-aminobutyric acid type A receptor: alcohol-dependent patients need higher benzodiazepine doses for withdrawal management.

Pharmacogenomics — Pharmacodynamic Variability

Anticoagulation

Warfarin and Vitamin K Epoxide Reductase Complex 1

  • Vitamin K epoxide reductase complex 1 = warfarin’s target enzyme
  • Promoter polymorphism: variant allele = less enzyme = more sensitive to warfarin
  • Variant allele more common in East Asian populations → typically lower warfarin dose needed
  • Combined with cytochrome P450 2C9 (pharmacokinetics) explains 35–50% of dose variance
  • Food and Drug Administration-approved genotype-based dosing guidance

Heart failure

Beta-1 Receptor Polymorphism

  • More active receptor variant: stronger response to beta-blockade
  • Greater heart rate reduction, blood pressure lowering, and heart failure benefit
  • Less active variant: blunted response; may need higher beta-blocker doses
  • Routine genotype testing not yet standard; dosing based on hemodynamic response

Paradoxical pharmacodynamics

SCN1A and Dravet Syndrome

  • SCN1A mutation = loss-of-function in inhibitory interneuron sodium channels
  • Paradox: sodium channel-blocking antiepileptics WORSEN seizures in Dravet syndrome
  • Mechanism: further suppress already-compromised inhibitory interneurons
  • Carbamazepine, phenytoin, lamotrigine: CONTRAINDICATED in Dravet syndrome
  • Use instead: valproate, clobazam, fenfluramine, cannabidiol
  • SCN1A genetic testing now standard in infantile fever-triggered epilepsy