Drug Safety 2024
Copyright Notice
Commonwealth of Australia Copyright Regulations 1969 Material reproduced under Part VB of the Copyright Act 1968 (the Act) Subject to copyright; further reproduction may be protected Instructor: Dr. Johnson Liu, Contact: johnson.liu@unsw.edu.au Course: PHAR2011 - Introductory Pharmacology & Toxicology
Core Concepts
Drug Properties: Key aspects that define drug functions.
Pharmacodynamics: "What the drug does to the body".
Pharmacokinetics: "What the body does to the drug".
Dose/route of administration influences absorption.
Distribution impacts drug concentration in the body.
Metabolism indicates how drugs are degraded.
Excretion refers to drug removal from the body.
Drug Binding and Safety: Importance of selective binding to protein targets.
Drug Types: Small molecules, peptides, proteins, RNA, and DNA.
Drug Action: Different types of actions categorized.
Learning Objectives
Describe basic concepts related to adverse drug effects.
Explain margin of safety and therapeutic index concepts.
Discuss common types of adverse drug reactions (ADRs).
Outline factors causing variable drug ADRs.
Explore ways to reduce ADRs.
Examine how drug safety is assessed.
Philosophical Context
Paracelsus (16th century): "The dose makes the poison" - highlights toxicity related to dosage.
Sir Derrick Dunlop (1960s): "Show me a drug with no side effects, and I will show you a drug with no actions" - questions absolute safety in drugs.
Adverse Drug Reactions (ADRs)
Definition: Any unintended, noxious response occurring at normal doses, excluding overdose or errors.
Drug Toxicity: Adverse effects arising from exceeding therapeutic dose or plasma concentration.
Serious Adverse Drug Reactions (SADRs)
Criteria for SADRs:
Fatal or life-threatening.
Causes significant disability.
Requires intervention to prevent permanent damage.
Prolongs hospitalization.
Causes congenital anomalies.
Margin of Safety
Concept: Evaluates the safe therapeutic range of drugs.
Minimum Toxic Concentration (MTC) and Minimum Effective Concentration (MEC).
A larger margin of safety indicates a safer drug.
Plasma Concentration
General Rule: Larger safety margin correlates with increased drug safety.
Beyond observed MTC, the likelihood of ADRs increases.
Therapeutic Index (TI)
ED50: Effective Dose at which 50% of population shows a therapeutic response.
TD50: Toxic Dose at which 50% of population experiences adverse effects.
Therapeutic Index Formula: TI = TD50/ED50 (Higher TI indicates greater safety).
Clinical Use of Drugs with Low Margin of Safety
Examples of drugs with small safety margins:
Warfarin (anticoagulant)
Lithium (mood stabilizer)
Digoxin (inotrope)
Drugs with larger safety margins include penicillin (antibiotic).
Theophylline Case Study
Usage: Administered for acute bronchoconstriction (e.g., asthma).
Dosage Concerns:
15 μg/ml: therapeutic effects.
25 μg/ml: mild side effects.
35 μg/ml: serious effects.
42 μg/ml: severe effects.
Margin of Safety: Very low (< 3 fold).
Assessing Drug Safety
Nothing is completely safe; benefits must outweigh risks.
Benefit-Risk Balance
Factors Influencing Assessment:
Seriousness of adverse reactions.
Frequency of adverse events.
Efficacy of the drug in treating conditions.
Drug interactions and safety profile.
Classification of ADRs
Type A: Augmented, predictable, linked to drug mechanism.
80% of ADRs fall into this category.
Type B: Bizarre, unpredictable, not mechanistically linked.
Higher mortality rates, much less common.
Type A ADRs Examples
Mechanistically linked adverse effects:
Enalapril: Hypotension.
Diazepam: Sedation.
Insulin: Hypoglycemia.
Type B ADRs Examples
Severe ADRs:
Hepatic, renal damage.
Immunological reactions.
Neurodegeneration and carcinogenesis.
Often detected post marketing.
Type B ADR Example - Cardiac Arrhythmia
Terfenadine Case: Linked to lethal arrhythmias.
Resulted in drug withdrawal.
Affects multiple drug classes, indicating broad risk.
Individual Susceptibility Impacts
Factors influencing ADE susceptibility need to be understood.
Sources of Altered Susceptibility to ADRs
Genetic: Conditions like G6PD deficiency.
Age & Sex: Neonates and gender responses.
Physiological: Drug effects in special conditions (e.g., pregnancy).
Exogenous Factors: Drug interactions, diseases impacting drug metabolism.
Genetic Susceptibility to ADRs
G6PD Deficiency:
Types of drugs can lead to hemolytic anemia.
Importance of avoiding certain triggers.
ADR Susceptibility Mechanisms
CYP450 Polymorphisms: Influence on drug metabolism and ADR risks.
Examples include risk factors for warfarin, antipsychotics, opioids, etc.
Preventing ADRs through Monitoring
Strategies: Identify subgroups, patient history, and pharmacogenomic markers to minimize risks.
Patient Management to Prevent ADRs
Safe prescribing practices and monitoring are crucial.
Co-administration to mitigate adverse effects.
Drug Safety Testing Importance
Safety testing is vital to protect against potential side effects.
Continuous process from preclinical to post-market.
Historical Context for Drug Safety Regulations
Various tragedies shaped drug safety laws (e.g., Thalidomide, Elixir Sulfanilamide).
Importance of Safety Testing in Development
Serious adverse events lead to compound abandonment.
Short and long-term testing required.
Reasons for Post-Market Pharmacovigilance
Clinical trials limitations in identifying rare ADRs.
Importance of monitoring broader patient populations post-marketing.
Role of Therapeutic Goods Administration (TGA)
Overseeing drug approval, post-market surveillance, and safety communication to health professionals.
Drug Discovery to Market Process
Overview of stages from drug discovery through clinical trials to post-marketing.
Recap of Learning Objectives
Same as previous section. Summary of what learners should achieve.
Practice Multiple Choice Question
MCQ assessing understanding of drug safety and marginals.
Practice Short Answer Questions
Topics include Type A and Type B ADRs, susceptibility to drugs, and reasons for pharmacovigilance.