Clinical Pharmacology of Adverse Drug Reactions

Comprehensive Study Notes

Learning Objectives

  • Apply pathophysiologic principles underlying side effects (pharmacological and patient-related effects)
  • Characterize ADRs using different classification formats (A/B categories, DoTS)
  • Discuss patient factors that increase risk for developing side effects
  • Understand special considerations for pediatric and geriatric populations

Concept Definition

Adverse Drug Reaction (ADR): Every unwanted effect occurring during treatment with a drug.

Quiz: True or False?

1. An adverse drug reaction is every unwanted effect occurring during a treatment. (True)
2. Dose-dependent adverse drug reactions are most of the time not serious. (False - They can be serious)
3. Whether an adverse drug reaction occurs, depends on individual sensitivity. (True)
4. There is always a pharmacological explanation available for an adverse drug reaction. (False - Not always)
5. Based on risk factors it is predictable which patients will develop an adverse drug reaction. (False - Not fully predictable)

Classification of ADRs

1. Pharmacologically Explainable ADRs

Type Example Toxicity Mechanism
Pharmaceutical Phenytoin Phenytoin toxicity (ataxia, nystagmus) Increased bioavailability due to formulation change
Pharmacokinetic Digoxin Digoxin toxicity (nausea, arrhythmias) Decreased elimination with impaired renal function
Pharmacodynamic Indomethacin Left ventricular failure Water and sodium retention
Genetic Nortriptyline Confusion Reduced hepatic elimination (CYP2D6 deficiency)
Drug-drug interactions Lithium + NSAIDs Lithium toxicity Inhibition of lithium excretion

2. A-F(G) Classification System

Type Characteristics Action
A(ugmented) Pharmacological effect, dose-related, frequent, predictable, low mortality Withdrawal or dose reduction
B(izarre) Rare, unpredictable, idiosyncratic, high mortality Withdrawal; avoid in future
C(hronic) Rare, cumulative dose related Withdrawal (longer period) or dose reduction
D(elayed) Rare, mostly dose-related, sometimes only after withdrawal Varies
E(nd of use) Rare/unpredictable, rapid after withdrawal Restart and tapering
F(ailure) Frequent, dose-related, result of interactions Dose increase, effect comedication
G(enetic) Pharmacokinetic or pharmacodynamic Dose adjustment or withdrawal and avoidance

Key Differences: Type A vs Type B Reactions

Type A (Augmented): Pharmacological effect, dose-dependent, occurs frequently, often detected in clinical trials.

Type B (Bizarre): Idiosyncratic, rare, not dose-dependent, serious, not detected in clinical trials.

Examples of Type B Reactions

  • Blood: Serious blood disorders
  • Liver: Hepatitis
  • Kidney: Nephritis
  • Lung: Pneumonia, alveolitis
  • Skin: Urticaria, angioedema, anaphylaxis
  • Allergic/Immunological: Anaphylaxis, various skin manifestations, blood count abnormalities, immune-complex disease

DoTS Classification System

A newer approach classifying ADRs based on:

  • Do - Dose relatedness
  • T - Time relatedness
  • S - Susceptibility factors

Dose Relatedness

  • Supra-therapeutic doses: Toxic effects
  • Standard therapeutic doses: Collateral effects
  • Subtherapeutic doses: Allergic reactions (in susceptible patients)

Time Relatedness

  1. Time-independent: Can occur anytime, independent of treatment duration
  2. Time-dependent:
    • Rapid reactions: Only when drug administered rapidly (e.g., Red man syndrome with vancomycin)
    • First-dose reaction: Particularly at first dose (e.g., hypotension with ACE inhibitors)
    • Early reaction: Early in treatment then disappears through adaptation (e.g., nitrate-dependent headache)
    • Intermediate reaction: Occurs after a few days (e.g., 5th day rash with antibiotics)
    • Late reaction: Risk increases with time (e.g., osteoporosis with corticosteroids)
    • Delayed reaction: After prolonged use or repeated exposure (e.g., breast carcinoma risk with estrogen)

[Graph: Dose-response curves showing Type A (analgesic effect of morphine) and Type B (allergic reaction) reactions with margin of safety]

[Graph: Probability of ADR vs Time after administration for high, medium, and low susceptibility]

Individual Susceptibility Factors

Source of Susceptibility Examples Implications
Genetic Porphyria, Succinylcholine sensitivity, Malignant hyperthermia, CYP polymorphisms Screen for abnormalities; avoid specific drugs
Age Neonates (chloramphenicol), Elderly (hypnotics) Adjust doses according to age
Sex Alcohol intoxication, Mefloquine neuropsychiatric effects, ACE inhibitor cough Use different doses in men and women
Physiology altered Phenytoin in pregnancy Alter dose or avoid
Exogenous factors Drug interactions, Food interactions (grapefruit juice with CYP3A4 substrates) Alter dose or avoid co-administration
Disease Renal insufficiency (lithium), Hepatic cirrhosis (morphine) Screen; avoid specific drugs; use reduced doses

Special Populations: Pediatrics

Note: ADRs in children show different patterns compared to adults, sometimes with higher frequency (e.g., liver failure with valproate, Stevens-Johnson Syndrome with lamotrigine).

Pharmacokinetics in Children

  • Absorption:
    • Higher stomach acidity due to milk buffering
    • Less absorbed: phenobarbital, phenytoin, carbamazepine, indinavir
    • Increased absorption: doxapram
    • Variable gastric emptying rate (decreased in newborns, increased in toddlers)
    • Caution with absorption through skin
  • Distribution:
    • Percentage of fat: 15% in newborns, similar to adults at puberty
    • Extracellular volume: 45% in newborns vs 15% in adults
    • Lower protein binding in newborns
  • Metabolism:
    • CYP450 system activity is low
    • Glucuronidation still slow (chloramphenicol → gray-baby syndrome)
    • Reduced acetylation (isoniazid more toxic)
    • Possible intrauterine enzyme induction (anticonvulsants)
    • Not fully developed: drugs may have longer half-life
  • Excretion:
    • Glomerular filtration fully developed at 2.5-5 months
    • Tubular function fully developed at 7 months

Pharmacodynamics in Children

  • Increased or decreased sensitivity to drugs
  • Antihistamines: central stimulating effects
  • Benzodiazepines: paradoxical effects
  • Ketotifen: aggressive/hyperactive behavior
  • Cyclosporine: High immunosuppressive response
  • Effect of growth and development on drug response

Special Populations: Geriatrics

Key Challenges: Aging differs among individuals, multiple morbidity, polypharmacy (interactions), long-term drug use, compliance issues, practical problems.

ADRs in Elderly: Frequency by Drug Class

  • Cardiovascular drugs: 26.0% of ADRs
  • Antibiotics/anti-infectives: 14.7%
  • Diuretics: 13.3% (22.1% preventable)
  • Nonopioid analgesics: 11.8%
  • Anticoagulants: 7.9% (10.2% preventable)
  • Hypoglycemics: 6.8% (10.9% preventable)
  • 6% of all hospital admissions in elderly are due to preventable ADRs

Pharmacokinetic Changes in Elderly

  • Absorption: Reduced esophageal motility, slower gastric emptying, longer intestinal transit time
  • Distribution:
    • Decreased muscle mass → decreased lean body mass
    • Lipophilic substances: greater Vd → initially low plasma concentration
    • Hydrophilic substances: smaller Vd → higher toxicity risk
    • Albumin concentration: may decrease due to underlying disorders
  • Hepatic elimination:
    • Liver volume decreases, reduced phase I reactions
    • Enzyme levels decreased (especially CYP1A2 and 3A4)
    • Reduced hepatic blood flow → reduced clearance of high first-pass drugs (propranolol 45%↓, morphine 35%↓)
  • Renal elimination:
    • 1/3 of elderly: no renal function deterioration
    • 2/3: changes due to cortical area ↓, glomeruli ↓, proximal tubuli ↓, vascular changes
    • Inulin clearance decreases with age (graph showing decline from ~120 to ~60 mL/min/1.73m² from age 20 to 90)

Pharmacodynamic Changes in Elderly

  • Changes in receptor density, structure, signal propagation
  • Increased sensitivity to: psychiatric drugs, opioids, dopamine agonists, parasympathicolytics
  • Decreased sensitivity to: β-blockers, insulin

Specific ADR Risks in Elderly

  • Falls: Due to orthostatic effects (α/β-blockers), EPS effects (benzodiazepines), psychoactive agents
    • Benzodiazepines: OR 1.48 (95% CI 1.23-1.77)
    • Antidepressants: OR 1.66 (95% CI 1.38-2.00)
    • Neuroleptics: OR 1.50 (95% CI 1.25-1.79)
  • Orthostatic effects: Inadequate vasodilatory response, reduced baroreceptor function, insufficient fluid intake
  • Thermoregulation problems: Changed homeostasis, reduced shivering ability, risk for hypothermia (antipsychotics increase risk!)
  • Cerebral function impairment: Loss of cholinergic neurons/receptors, stroke history, anticholinergic drugs have greater effect

Key Principles

"Dosis sola facit venenum" - Paracelsus (1493-1541)

"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."

  • ADR classification helps in understanding mechanism and management
  • Individual susceptibility factors significantly influence ADR risk
  • Special populations (pediatrics, geriatrics) require specific considerations
  • Preventable ADRs account for significant morbidity and healthcare costs
  • Pharmacovigilance is essential for medication safety across all age groups