Adverse Drug Events and Their Causes

Adverse Drug Events (ADE)

• 82% of American adults take at least one medication, and 29% take five or more
• In 2016, the age-adjusted rate for drug-poisoning deaths for males (26.2 per 100,000) was almost double that of females (13.4)
• In 2020, 91,799 drug overdose deaths occurred in the United States (28.3 per 100,000 people)
• 75% of these involved opioids
• ADEs include medication errors, allergic reactions, and overdoses.

Other Causes of ADE

• The incidence of ADEs is 4 per 1000
• Antibiotics account for 16% of ADEs, with allergies being the most common
• Anticoagulants are responsible for 32% of ADEs in patients over 65 years of age
• Warfarin, rivaroxaban, and dabigatran are among the top 10 causes of ADEs
• Phenytoin (anti-seizure medication) exhibits zero-order kinetics
• Opioid analgesia has a higher death rate than heroin
• Insulin can also cause ADEs

Types of Toxicity - Mechanisms

• Pharmacodynamic toxicity (predictable)
  • Excessive pharmacological action
  • Alternative pharmacological action (e.g., Aspirin can cause bleeding while having anti-inflammatory effects)
  • Overdose toxicity
• Pharmacokinetic (unpredictable?)
  • Induction/inhibition/competition of P450 enzymes
• Idiosyncratic
  • Allergic response
  • Hyperthermia with general anaesthetics
• Withdrawal
  • Steroid, beta blocker, anti epileptic, PPI withdrawal

Thalidomide

• Marketed as a sedative in 1957 (Germany)
• Found to be an effective antiemetic (off-label use for morning sickness)
• Withdrawn in 1961 due to teratogenic effects (prevents angiogenesis)
• Not tested on pregnant animals (species dependent: mice less sensitive than humans)

Thalidomide Today

• Used as an immunomodulator to treat various conditions including:
  • Hansen’s disease (Leprosy)
  • Cancer
  • Graft versus host disease in children
  • HIV mouth ulcers & wasting
• Prescribed under a Risk Evaluation & Mitigation Strategy (REMS, FDA)

Diethylstilboestrol (DES)

• Non-steroidal oestrogen
• Approved by the FDA in 1947 to prevent miscarriage, treat oestrogen deficient states, and as a post-coital contraceptive
• Banned in chickens in 1959/66
• Classified as a teratogen in 1971

DES Teratogenicity

• DES Daughters:
  • Increased risk of developing clear cell adenocarcinoma (CCA) of the vagina and cervix, breast cancer
  • Pregnancy-related problems: miscarriage, stillbirth, ectopic pregnancy, premature labor, preeclampsia
• DES Sons and Grandsons:
  • Urogenital abnormalities (e.g., hypospadia)
• DES Grandchildren:
  • Infertility
  • Cerebral palsy

Drug Regulation in the 1950s

• Very little formal regulation, mostly at the discretion of pharmaceutical companies
• No teratogenicity studies required
• Thalidomide was not approved by the FDA (not used in the United States)
• The thalidomide incident changed the global regulatory environment.

Source of ADEs

• Active Pharmaceutical Ingredient (API)
  • API-mediated toxicity is due to a species-specific effect or a metabolite, possibly species-specific
  • Toxicity may only occur in a small number of patients (pharmacogenetics)
• Contaminants
  • Due to synthesis or degradation of API
• Excipients
  • Used to bulk up, stabilise, surface coat, colour, or flavour
• Propellants (e.g, CFCs)
  • Replaced with HFCs after the Montreal Protocol 1987

Cytochrome P450 (CYP) Enzymes

• CYP enzymes metabolise medications
• Chronic administration can induce hepatocytes to produce larger amounts of drug-metabolising enzymes
• Enzyme induction accelerates drug metabolism, requiring larger doses of the drug or potentially leading to overdose
• Apparent inhibition can occur with concurrent administration of two or more drugs that compete for the same metabolising enzymes

Bioequivalence

• Generics need to show bioequivalence with approved products in a small number of healthy volunteers
• Bioequivalence is usually measured by comparing Cmax and AUC between two products
• Defined as a confidence interval (CI) of test within 0.8 and 1.25 of reference
• Switching between generics with different AUC could significantly alter the effective dose for a patient, potentially leading to therapeutic failure or adverse effects.

Idiosyncratic Toxicity

• Dose-independent
• Often due to genetic polymorphisms (e.g., CYP polymorphisms)
• Difficult to identify

Coumarin

• High level of hepatotoxicity in rats, but low level of toxicity in humans (0.37%)
• Banned as a foodstuff by the FDA in 1954 (considered a carcinogen)
• Re-analysis of rat data suggests that the hepatic lesion was cholangiofibrosis (bile duct proliferation) and not cholangiocarcinoma

Generics

• After a drug’s patent lapses (20 years)
• Are generics the same as branded products?
• Bioequivalence refers to the absence of a significant difference in the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action

Contaminants

• While a very pure form of the API is used, by-products from synthesis might still exist. These can be batch specific or due to manufacturing changes
• API can degrade over time influenced by storage conditions (heat, light, humidity) leading to a reduced dose and potentially toxic by-products.

Ranbaxy & Dr Reddy

• Ranbaxy: Indian generic pharmaceutical company with multiple violations of regulations and product recalls.
• Dr Reddy: Found to have contaminated Ranitidine, Valsartan, Losartan, and Irbesartan products with N-Nitrosodimethylamine (NDMA), a known carcinogen.