Pharm 4: Adverse Effects of Drugs

ADVERSE EFFECTS OF DRUGS

Lecturer Information

  • Name: Dermot Cox

  • Email: dcox@rcsi.ie

  • Institution: School of Pharmacy and Biomolecular Sciences

  • Date: October 2025

LEARNING OBJECTIVES

  • Predictable/Pharmacological Adverse Effects:

    • Describe the characteristics and examples of predictable adverse effects that are pharmacological in nature.

  • Unpredictable/Non-Pharmacological Adverse Effects:

    • Describe the nature and examples of unpredictable adverse effects that are non-pharmacological.

  • Idiosyncratic/Dose-Independent Adverse Effects:

    • Explain idiosyncratic effects that occur independent of drug dose, including their causes.

  • Therapeutic Index (TI):

    • Define the therapeutic index and discuss management strategies for drugs with a low TI.

  • Drug-Drug Interactions:

    • Discuss the two primary mechanisms of drug-drug interactions: plasma protein binding and cytochrome P450-mediated interactions.

  • Special Considerations for Populations:

    • List populations requiring special considerations during prescribing, including the differences in drug response.

ADVERSE DRUG EVENTS (ADE)

  • Prevalence of Medication Use:

    • 82% of American adults take at least one medication.

    • 29% take five or more medications.

  • Impact of ADEs:

    • 1.3 million emergency department visits annually due to ADEs.

    • 350,000 hospitalizations annually due to ADEs.

    • $3.5 billion spent on additional medical costs associated with ADEs each year.

    • Approximately 40% of ADEs are preventable.

MAIN CAUSES OF ADE

  • Incidence Rate:

    • Overall incidence of ADEs: 4 per 1000 patients.

  • Specific Drug Classes and Associated Risks:

    • Antibiotics:

    • Account for 16% of ADEs.

    • 1 in 1000 risk of an ADE, with allergy being the most common reaction.

    • 1 in 4000 chance of avoiding a serious complication of upper respiratory tract infection.

    • Anticoagulants:

    • Involved in 32% of ADEs for patients over 65 years, with warfarin, rivaroxaban, and dabigatran among the top causes.

    • Opioid Analgesia:

    • Associated with a higher death rate than heroin.

    • Insulin:

    • Additional risk for adverse events.

US EMERGENCY DEPARTMENT (ED) VISITS FOR ADVERSE DRUG EVENTS (2013-2014)

  • Table summarizing emergency department visits and characteristics of ADEs:

    • Patient Age Group:

    • ≤5 years: 5133 cases; estimate of 9.7% hospitalized.

    • 6-19 years: 846 cases; estimate of 10.5% hospitalized.

    • 20-34 years: 3452 cases; estimate of 6.8% hospitalized.

    • 35-49 years: 571 cases; estimate of 8.9% hospitalized.

    • 50-64 years: 5638 cases; estimate of 13.7% hospitalized.

    • 65-79 years: 667 cases; estimate of 10.2% hospitalized.

    • ≥80 years: 5928 cases; estimate of 14.3% hospitalized.

    • Sex Distribution:

    • Female: 23,934 cases (57.1%); 6754 hospitalized.

    • Male: 18,651 cases (42.9%); 5844 hospitalized.

    • Number of Medications Implicated:

    • 1 medication: 35,142 cases (83.8%) with 9716 hospitalized.

    • ≥2 medications: 7443 cases (16.2%) with a hospitalization estimate of 2882.

    • Type of ADE:

    • Adverse effect: 12,081 cases (27.8%); 3957 hospitalized.

    • Allergic reactions: 10,435 cases (26%); 1080 hospitalized.

    • Supratherapeutic effects: 15,718 cases (37.2%); 6835 hospitalized.

    • Unsupervised ingesting by child: 2,604 cases (4.9%); 590 hospitalized.

UNWANTED VS DESIRABLE EFFECTS

  • Opiates Example:

    • Constipation is an unwanted effect when treating pain but a desirable effect when treating diarrhea.

  • Anti-histamines (H1 Antagonists):

    • Drowsiness is unwanted when treating allergies but desired when preventing travel sickness.

TYPES OF TOXICITY

  • Mechanisms of Toxicity:

    • Pharmacological Toxicity (Predictable):

    • Resulting from excessive pharmacological action and often relates to drug class.

    • Example: Aspirin has both anti-inflammatory and bleeding effects.

    • Non-Pharmacological Toxicity (Unpredictable):

    • Specific to a certain member of a drug class; often due to unintended drug actions.

    • Example: ACE inhibitors can cause a cough.

    • Idiosyncratic Toxicity:

    • Unpredictable effects not related to drug dose or mechanisms.

HISTORY OF ADE

  • Thalidomide Case Study:

    • Marketed as sedative and antiemetic (1957).

    • Withdrawn in 1961 due to identified teratogenic effects, recognized by William McBride and Widukind Lenz.

  • Diethylstilbestrol (DES):

    • A non-steroidal estrogen approved in 1941 for miscarriage prevention and other gynecological uses.

    • Identified as a teratogen in 1971, leading to increased cancer risks in DES Daughters.

SOURCES OF ADVERSE DRUG EFFECTS (ADE)

  • Active Pharmaceutical Ingredients (API):

    • Primary source with potential toxicity.

  • Contaminants:

    • Result from synthesis and degradation of APIs.

  • Excipients:

    • Usually well-characterized and deemed safe.

WHY ARE TOXIC DRUGS ALLOWED?

  • Pre-Approval Testing:

    • APIs undergo in vitro and in vivo testing, yet some toxicity arises from species-specific effects or unknown metabolites.

    • Toxicity may only emerge after extensive patient treatment.

METABOLISM

  • Drug Testing:

    • Majority of drugs are tested pre-approval; however, toxicity is largely from metabolites often uncharacterized prior to use.

  • Metabolism Concepts:

    • Commonly termed “detoxification,” but it may also result in increased toxicity (toxification).

CASE STUDY: PARACETAMOL

  • Mechanism:

    • Requires replenishing glutathione (GSH), which is not orally active.

  • Treatment:

    • N-Acetylcysteine is orally active and converted into GSH.

POLY-PHARMACY AND DRUG INTERACTIONS

  • Need for Multiple Drugs:

    • Many diseases necessitate concurrent prescription of several drug classes.

  • Phase III Studies:

    • Typically involve one drug class; Phase IV is used to include broader drug combinations and necessitate dosage adjustments.

  • Rational Approach:

    • Assessing existing prescriptions alongside metabolic interactions is vital for effective treatment.

ADVERSE DRUG REACTION REPORTING

  • Importance:

    • Allows identification of potential drug interactions and adverse effects.

    • Adverse reactions are reported at multiple levels: patients to doctors, doctors to authorities, etc.

PRESCRIBING ERRORS AND MEDICATION ERRORS

  • Categories of Medication Errors:

    • Preventable harm, non-preventable harm, and no harm associated with adverse drug events.

    • Common errors include wrong drug, dose, frequency, or patient mismatch.

POTENTIAL SOLUTIONS TO ERROR REDUCTION

  • Strive for Improved Systems:

    • Implement electronic prescribing, enhance patient education on medication, and utilize patient-friendly labeling.

    • Encourage reporting of medication errors for improved practices.

SPECIAL POPULATIONS & PRECISION MEDICINE

  • Clinical Study Considerations:

    • Patient selection for Phase III studies tends to exclude various demographics, potentially impacting real-world applicability.

CONCLUSION AND FUTURE OF PRECISION MEDICINE

  • Challenges and Considerations:

    • Personalized medicine has the potential for improved outcomes but raises questions about market size and drug pricing.