Adverse effects 24-25 (1)

INTRODUCTION TO ADVERSE DRUG EVENTS (ADE)

  • Statistics:

    • Annually, 1.3 million ED visits and 350,000 hospitalisations due to ADEs.

    • Associated healthcare costs: $3.5 billion yearly (40% preventable).

MAIN CAUSES OF ADE

  • Incidence: 4 instances per 1000 users.

  • Common Drugs Associated:

    • Antibiotics (16% of ADEs):

      • 1 in 1000 risk of ADE (common allergy).

    • Anticoagulants (32% in >65 years):

      • Warfarin, rivaroxaban, dabigatran are common causes.

    • Opioid Analgesia:

      • Higher death rate than heroin.

DESIRABLE VS UNWANTED EFFECTS

  • Opiates:

    • Unwanted: Constipation (when treating pain).

  • Anti-histamines (H1 antagonists):

    • Unwanted: Drowsiness (for allergies).

TYPES OF TOXICITY MECHANISMS

  • Pharmacological Toxicity (Predictable):

    • This type of toxicity is directly related to the drug’s main action and is usually dose-dependent, meaning higher doses increase the risk.

    • Example: Aspirin has anti-inflammatory effects but can also cause bleeding due to its impact on blood clotting, which is an alternative pharmacological action. Similarly, antihistamines can bind to multiple receptors, sometimes leading to unintended effects like drowsiness.

  • Non-Pharmacological Toxicity (Unpredictable):

    • This toxicity is not related to the drug’s primary action and is more difficult to predict.

    • Example: ACE inhibitors, which are commonly used for hypertension, can sometimes cause a persistent cough. This effect is unrelated to the drug’s main action of lowering blood pressure and is considered unpredictable.

  • Overdose Toxicity:

    • Occurs when a drug is taken in excessive amounts, either accidentally or intentionally.

  • Idiosyncratic Toxicity:

    • This is a rare, dose-independent type of toxicity that occurs unpredictably in a small number of people.

HISTORICAL CASES OF ADE

  • Thalidomide:

    • Marketed in 1957 as a sedative and anti-emetic (prevent nausea)

    • Withdrawn for teratogenic effects (foetal abnormalities)in 1961. Caused shortening of limbs

  • Diethylstilbestrol (DES):

    • Approved in 1941 to prevent miscarriages

    • Identified as teratogen by 1971, leading to increased risk of cancer

SOURCES OF ADE

  • Active Pharmaceutical Ingredient (API):

    • API-Mediated Toxicity Causes:

      • Species-Specific Effects: ADEs may vary by species and could emerge only in humans after approval.

      • Metabolite Toxicity: Harmful by-products from drug metabolism may cause ADEs.

      • Rare Reactions: Some ADEs appear only in a small number of patients, often discovered post-market.

  • Contaminants:

    • Issues from manufacturing or API degradation over time.

METABOLISM OF DRUGS

  • Toxicity often due to metabolites which are usually unknown prior to use.

CASE STUDIES

  • Paracetamol:

    • Requires replenishment of glutathione (GSH)

    • N-acetylcysteine is an orally active form and gets converted to GSH.

POLY-PHARMACY

  • Multiple medications often necessary due to co-morbidities.

  • requires careful drug selection and dosage adjustments

  • Too many possible interactions; rational approach based on metabolic pathways and commonly co-administered drugs

CONTAMINANTS AND DEGRADATION STUDIES

  • Contaminants may vary by batch, affecting safety.

  • Degradation can reduce API and create toxic by-products.

GENERICS AND BIOEQUIVALENCE

  • Generic Drugs:

    • Cheaper alternatives; differences may lie in synthesis, formulation, and contaminants.

    • Not made to the same standard as branded product

  • Bioequivalence:

    • Bioequivalence measures (Cmax, AUC) between two products

    • Generic drugs only need to show bioequivalence in a small number of healthy volunteers

CLINICAL TRIAL RECRUITMENT AND RACE

  • P IIII Studies:

    • Target specific demographics who will likely be successful

    • Often does not reflect real world patient

  • Race/Genetic Variability:

    • Variance in drug response may lead to tailored dosing recommendations.

PRECISION MEDICINE

  • Tailoring drugs to individuals can improve effectiveness but increases costs and reduces market size.

DOCTOR-RELATED ERRORS

  • Contributing factors include inadequate training, knowledge gaps, and communication failures.

RMP VS REMS

  • Both strategies monitor drug risks but differ in approaches and implementation.