Introduction to Clinical Pharmacy

Introduction to Adverse Drug Reactions (ADRs)

• Definition: Any drug providing therapeutic benefits can also produce unexpected, potentially adverse effects.

Historical Context of ADRs

• Chloroform Anaesthesia: Sudden death incidents reported in the late 19th century.

• Salvarsan (1922): Jaundice linked to treatment.

• 1937 Sulphanilamide Disaster: Diethylene glycol used as a solvent led to 107 deaths in the USA; resulted in the establishment of the FDA.

• 1961 Thalidomide Disaster: Led to the establishment of the Committee on Safety of Medicines (CSM).

• Chloramphenicol (1966): Caused blood dyscrasias leading to restricted use.

• Benoxaprofen (1982): Withdrawn due to liver damage.

• Aspirin (1986): Linked to Reye’s syndrome in children, resulting in restricted usage.

Recent Withdrawals and Concerns

• Cerivastatin (2001): Withdrawn due to safety concerns.

• Rofecoxib (2004): Withdrawn following safety issues.

• Paroxetine (Seroxat) (2004): Concerns regarding safety and efficacy.

• Sibutramine (2010): Concerns about cardiovascular safety led to withdrawal.

• Rosiglitazone (2010): Withdrawn due to safety risks related to heart disease.

Incidence of ADRs

• In-Patients: 10-20% suffer from an ADR.

• Hospital Deaths: 0.24-2.9% of hospital deaths are attributed to ADRs.

• Hospital Admissions: 0.3-5.0% of admissions are because of ADRs.

• Note: These statistics vary across literature and are averages.

Classification of ADRs

• Type A (Augmented):

  • Characteristics: Exaggerated pharmacological action, dose-related, occurs in everyone, predictable effects.

  • Common Examples:

  • Hypotension with blood pressure medications (e.g. atenolol, ramipril).

  • Headaches and flushing due to vasodilators.

  • Diarrhoea caused by magnesium-containing antacids.

• Type B (Bizarre):

  • Characteristics: Unpredictable and not related to dosage; can be caused by allergies or inherited tendencies.

  • Examples:

  • Severe skin reactions (e.g. Stevens-Johnson syndrome with Phenytoin).

  • Blood dyscrasias, such as thrombocytopenia and neutropenia linked to methotrexate and phenytoin.

  • Photosensitivity reactions with Tetracycline and amiodarone.

• Type C (Continuous): Long-term administration effects (e.g. Analgesic nephropathy).

• Type D (Delayed): Effects occurring later (e.g. teratogenesis, carcinogenesis).

• Type E (End of Use): Withdrawal reactions (e.g. from long-term use of antidepressants).

Relation of ADRs with Dose

• ADRs occurring above therapeutic range: e.g., bleeding with warfarin.

• ADRs occurring within therapeutic range: e.g., constipation with opioid analgesics, such as codeine.

• Hypersensitivity reactions occur below the therapeutic range (e.g. penicillin allergy).

Factors Influencing ADRs

• Time Course of Treatment: Immediate vs. delayed reactions.

• Patient-Specific Characteristics:

  • Genetic susceptibility.

  • Age (children and elderly).

  • Sex.

  • Physiological changes (e.g., pregnancy).

  • Diseases (renal or hepatic insufficiency).

  • Ethnicity.

Side Effects in the British National Formulary (BNF)

• The BNF lists clinically relevant side effects for most drugs, omitting those with negligible consequences.

• Side effects are categorized by frequency and body system, emphasizing serious effects.

Frequency of Side Effect Classification

• Very Common: >1 in 10.

• Common: 1 in 100 to 1 in 10.

• Uncommon: 1 in 1000 to 1 in 100.

• Rare: 1 in 10,000 to 1 in 1000.

• Very Rare: <1 in 10,000.

Strategies for Prevention of ADRs

• Drug History: Always check patient allergies and potential interactions with OTC and herbal medications.

• Use medications only with a clear indication, particularly in vulnerable populations like pregnant patients.

• Consider age, hepatic or renal disease, and genetic factors.

• Limit the number of prescribed drugs and ensure clear instructions, especially for the elderly.

• Prefer familiar drugs whenever possible.

• Warn patients of serious potential ADRs.

Understanding Drug Interactions

• Definition: Drug interaction occurs when the effect of one drug alters another, often resulting in adverse effects but can sometimes be beneficial.

• Clinical Importance: Approximately 4% of deaths due to ADRs are linked to interactions.

• Management Strategies:

  • Avoiding the interaction.

  • Detecting it upon occurrence.

  • Treating the effect if it occurs.

Mechanisms of Drug Interactions

• Pharmaceutical Interactions:

  • Occur in vitro when drugs inactivate each other without pharmacological principles; focus on simple chemistry.

• Pharmacokinetic Interactions:

  • Drug A alters the concentration of drug B reaching its action site.

• Pharmacodynamic Interactions:

  • Drug A modifies the effects of drug B without changing the drug B concentrations in tissue fluids.

Pharmaceutical Interactions

• Characteristics: Drugs mixed together may physically or chemically interact.

  • Physical Incompatibility: E.g., precipitation due to pH or concentration changes.

  • Chemical Incompatibility: E.g., degradation or inactivation due to chemical reactions.

• Predicting Incompatibility: Consider pH similarities, formulations, diluents, and concentrations using BNF and manufacturer literature.

Pharmacodynamic Interactions

• Characteristics: Occur when one drug alters another’s action, leading to toxicity or loss of effect.

• Types of Interaction:

  • Direct:

  • Two drugs act on the same site (e.g., potentiation and inhibition).

  • Indirect:

  • Drug interactions caused by physiological changes (e.g., warfarin and aspirin).

Examples of Pharmacodynamic Interactions

• Potentiating Effect:

  • Alcohol enhances effects of CNS-active drugs (e.g., antipsychotics).

• Inhibitory Effect:

  • β-adrenoceptor antagonists (e.g., propranolol) diminish efficacy of β-agonists (e.g., salbutamol).

Pharmacokinetic Interactions – Absorption

• Mechanisms Affecting Absorption:

  • pH changes, effects on gastric emptying, competition for absorption mechanisms, and gut bacterial flora changes.

Changes in pH of Gastrointestinal Fluids

• Mechanism: The ionization state of drugs affects solubility and hence absorption; influenced by drug pKa and gastric pH.

• Note: Antacids can impede absorption of other drugs; e.g., do not take simultaneously with other medications.

Absorption - Binding/Chelation

• Example: Drugs containing Ca²⁺, Mg²⁺, or Al³⁺ can form insoluble complexes with antibiotics like tetracycline, retarding absorption.

Changes in Gut Motility

• Effects of Agents:

  • Anticholinergics (e.g., atropine) slow gastric motility, while others (e.g., metoclopramide) speed it up.

Metabolism Interactions

• Overview: The liver is crucial for drug metabolism; includes Phase I reactions involving cytochrome P450.

Enzyme Induction vs. Inhibition

• Enzyme Induction: Drug A induces enzymes metabolizing Drug B, leading to decreased effect of Drug B, risking sub-therapeutic outcomes.

• Examples of Inducers: Rifampicin, phenobarbital, phenytoin, and St John's Wort.

• Enzyme Inhibition: Drug A inhibits the enzyme responsible for Drug B's metabolism, leading to increased effects and potential toxicity of Drug B.

• Examples of Inhibitors: Cimetidine, macrolides, quinolones, and grapefruit juice.

Pharmacogenomics and Personalized Medicine

• Definition: Uses personal history and genetic profiles to optimize treatment approaches and minimize ADR risk.

• Application: Pharmacogenomics assesses CYP450 enzymes to tailor drug dosing, improving outcomes and decreasing ADRs.

Distribution - Protein Binding Displacement Interactions

• Mechanism: Drugs that are highly protein bound can lead to increased concentrations of unbound active drugs upon displacement, often leading to enhanced effects or toxicity.

• Factors: Important parameters include high protein binding (>90%) and low apparent volume of distribution.

• Examples: Warfarin and phenytoin; toxicity can arise if displacement simultaneously decreases elimination.

Renal Excretion Interactions

• Mechanisms: Include altered protein binding, inhibition of tubular secretion, and changes in urinary pH.

Changes in Urinary pH

• Mechanism: The ionization state of drugs influences their excretion based on urine pH; weak acids may be more rapidly excreted in alkaline urine and vice versa.

• Example: Treating aspirin overdose involves alkalinizing urine with bicarbonate infusion to enhance drug elimination.

Inhibition of Tubular Secretion

• Example: Co-administration of NSAIDs with methotrexate raises toxicity risk due to diminished tubular secretion of methotrexate.

The Role of P-glycoprotein (P-gp)

• Definition: P-glycoprotein is an efflux transporter that expels drug molecules out of cells.

• Function in Humans: Initially described in tumor cells; reduces drug absorption and increases excretion in liver and kidney.

Clinical Implications of P-gp Inhibition

• Clinical Outcome: Inhibiting P-gp increases drug absorption, allowing greater plasma concentrations.

• Example with Digoxin: Co-administration of P-gp inhibitors (e.g., amiodarone) with digoxin can heighten digoxin toxicity, necessitating a dose reduction.

References

• Oxford Handbook of Practical Drug Therapy, Richards & Aronson.

• Oxford Textbook of Clinical Pharmacology and Drug Therapy, D.G. Grahame-Smith and J.K. Aronson.

• BNF - latest edition.

• Avery’s Drug Treatment, Trevor M. Speight.

• Rang and Dale’s Pharmacology, H.P. Rang, M.M. Dale, J.M. Ritter and R.J. Flower.

• Principles of Biochemical Toxicology, J.A. Timbrell.

• Horn, J.R., Hansten, P.D. Drug Interactions with Digoxin: The Role of P-glycoprotein. Pharmacy Times, 2004.

• Balayssac, D., et al., Does inhibition of P-glycoprotein lead to drug–drug interactions? Toxicology Letters, 2005.

• Por, E.D., et al., Evaluation of Pharmacogenomics Testing of Cytochrome P450 Enzymes in the Military Health System. Military Medicine, 2022.