Drug Safety: Adverse Drug Reactions, Drug Interactions & Medication Errors

Adverse Drug Reactions (ADRs) and Pharmacovigilance

Definition and Classification

• An Adverse Drug Reaction (ADR) is defined by the WHO as “any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function”. This definition excludes overdose, drug abuse, treatment failure, and administration errors.
• An Adverse Drug Event (ADE) is a broader term encompassing “any untoward medical occurrence presenting during the administration of a drug”. All ADRs are ADEs, but not all ADEs are ADRs.
• Pharmacovigilance is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects and other possible drug-related problems.
• Traditional Classification of ADRs:
  • Type A (Augmented) Reactions:
    • Usually an exacerbation of the drug’s known pharmacological effects.
    • Dose-dependent and predictable based on known pharmacology.
    • Generally have a high incidence but are associated with less morbidity and mortality.
    • Example: Insulin-induced hypoglycemia.
  • Type B Reactions: Not explicitly detailed in the provided text beyond being a traditional category, in contrast to Type A.

Epidemiology of ADRs

• ADRs are a considerable burden to society, both financially and in terms of human suffering.
• Incidence in Hospitalised Patients:
  • A median of 5.8% of hospital admissions result from adverse reactions (based on 25 studies).
  • A US study showed 6.7% incidence of serious ADRs among hospitalised patients, with 0.3% being fatal, making ADRs a leading cause of death (4th to 6th) in the USA.
  • A UK study found 6.5% of hospital admissions were ADR-related, accounting for 4% of bed capacity, with approximately 70% of reactions considered avoidable.
    • Commonly implicated medicines: NSAIDs, diuretics, warfarin, ACE inhibitors.
  • An Indian study (Mumbai, 2007) reported 6.9% of hospital admissions caused by ADRs, with 60% deemed avoidable. Average hospital cost was Rs 6197 (US$150/patient).
    • Most commonly suspected medicines in India: anti-tuberculosis drugs, anti-epileptics, anti-malarials, anti-coagulants.
  • An older Indian study (Chandigarh, 2001) found 5.9% of medical emergency department visits were drug-related, with ADRs accounting for 45% of these events.
• ADRs account for approximately 5% of all hospital admissions and occur in 10–20% of hospitalised patients.
• They increase healthcare costs and adversely affect patients’ quality of life.

Predisposing Factors

Patients with one or more of the following factors are at high risk of developing an ADR:

• Polypharmacy: Increased risk with multiple drug therapy due to interactions or synergistic effects.
• Multiple and Intercurrent Diseases: Patients with various diseases, especially with impaired hepatic or renal function, are at high risk. Example: Aminoglycoside nephrotoxicity in renal impairment.
• Age: Elderly and paediatric patients are more vulnerable due to physiological changes and multiple chronic diseases in the elderly, and altered drug handling capacity in children (especially neonates).
  • Example: Nitrate/ACE inhibitor-induced postural hypotension in elderly, grey baby syndrome with chloramphenicol in neonates.
• Drug Characteristics: Highly toxic drugs (e.g., cytotoxic anti-cancer drugs causing nausea/vomiting) or drugs with a narrow therapeutic range (e.g., digoxin, gentamicin) increase ADR risk.
• Gender: Women are generally reported to be more susceptible to ADRs than men due to physiological, pharmacokinetic, pharmacodynamic, and hormonal reasons.
  • Examples: Chloramphenicol-induced aplastic anaemia and phenylbutazone-induced agranulocytosis are more common in women.
• Race and Genetic Factors: Genetically predisposed individuals are at higher risk (e.g., G6PD deficiency and haemolysis from primaquine).
• Previous Allergic Reactions: Patients who have had previous allergic reactions are at higher risk.
• Inappropriate Doses and Prolonged Therapy: Also increase risk.

Mechanisms of Type A ADRs

Type A reactions in an individual may be attributed to one or more of the following mechanisms:

• Pharmaceutical Causes: Changes in drug quantity or release properties due to formulation (e.g., griseofulvin particle size, doxycycline salt formulation causing oesophageal damage).
• Pharmacokinetic Causes: Alterations in absorption, distribution, metabolism, or elimination of drugs can change drug concentration at the site of action, leading to therapeutic failure or toxicity.
  • Absorption: Rate and extent of absorption (influenced by formulation, GI motility, first-pass metabolism, drug interactions, GI mucosa capacity) can affect plasma concentration.
  • Distribution: Factors like regional blood flow, membrane permeability, and protein/tissue binding affect distribution. (Clinical significance of distribution changes for ADRs is yet to be fully proven).
  • Metabolism: Reduced metabolic rate can lead to drug accumulation and increased ADR risk, while enhanced metabolism can cause therapeutic failure. Influenced by genetic, environmental, and other factors.
• Pharmacodynamic Causes: Direct or exaggerated pharmacological effects (e.g., increased blood pressure from vasopressors) or drug-induced changes in physiological processes.
• Genetically Determined ADRs:
  • G6PD deficiency: Haemolysis from drugs like primaquine, sulphones, sulphonamides, chloramphenicol, quinine, quinidine.
  • Other examples: Methhaemoglobinemia (nitrates), porphyria (sulphonamides, barbiturates), malignant hyperthermia (halothane, suxamethonium).
• Immunological Reasons (Allergic Drug Reactions):
  • Primary cause of most qualitatively abnormal drug responses.
  • Symptoms not correlated with known pharmacological effects.
  • Usually a delay between first exposure and reaction development.
  • Very small doses can elicit reaction if allergy is established.
  • Reaction disappears upon cessation and reappears upon re-exposure.
  • Often recognisable as rash, angioedema, serum sickness, or anaphylaxis.
  • Occur in a very few patients.
  • Possibility of desensitisation.
  • Patients with atopic or allergic disorders are at high risk.

Detection and Data Collection

• Vigilance: Healthcare professionals should be vigilant, always considering ADRs in differential diagnosis.
• Monitoring High-Risk Patients: Patients at high risk should be closely monitored (e.g., those with renal/hepatic impairment, on narrow therapeutic index drugs, with previous allergies, on multiple drugs, pregnant/breastfeeding women).
• Sources of Clues: Ward rounds, patient chart review, patient counselling, medication history interview, and communication with other healthcare professionals can provide clues.
• Data to Collect: Patient demographic information, presenting complaints, past medication history, comprehensive drug therapy details (including OTC and current medications), lab data (haematological, liver, renal function tests), and details of the suspected ADR (onset, duration, nature, severity, suspected drug details, plasma concentration, other causes/risk factors).
• Sources of Information for Data Collection: Patient’s case notes and treatment chart, patient interview, laboratory data sources, and communication with other healthcare professionals.

Causality Assessment

• Definition: Method to estimate the relationship between a drug and a suspected reaction.
• A temporal or possible association is sufficient for an ADR report.
• Assessment is often highly subjective, based on individual clinician’s judgment.
• Steps: Collect all relevant data (demographics, medications including OTC, comprehensive ADR details, treatment/outcome of reaction, investigation reports). Use this data to correlate and categorise the relationship between the suspected drug and ADR using causality assessment scales.
• Every suspected ADR should be assessed for causality and documented in the patient’s medical record as a useful reference.

Under-reporting

• A major deficiency of spontaneous reporting programmes is the failure of health professionals to identify and report drug-related injuries.
• Strategies to improve reporting: Easier reporting methods (online, improved forms), acknowledgement of reports, feedback to clinicians (journals, bulletins), participation in educational meetings, collaboration with Drug and Therapeutics Committees, and involvement of various healthcare professionals and patients.

Communicating ADRs

• Health professionals need access to information on benefits and risks of medicines.
• Knowledge about rational and safe use needs to be provided through: basic training, continuous education, Drug Information Centres, package inserts, patient counselling, and mass media campaigns.
• Messages must be adapted to target groups, and resources should be allocated for unbiased information on benefits and risks, as irrational drug use is the most frequent cause of ADRs.

Documentation and Prevention

• Documentation: Complete documentation in the patient medical record (including alert cards/sheets) is essential to avoid re-exposure. In-house documentation for future reference is also necessary.
• Communication: Medical staff, including the original prescriber, must be notified of suspected ADRs.
• Pharmacists’ involvement in the ADR reporting system has a positive impact, assisting busy medical practitioners in managing suspected reactions.

Safety Monitoring of Herbal Medicines

• Traditional herbal medicines are widely used, often in combination with allopathic medicines.
• Their composition can vary, and many active ingredients are unidentified, making it difficult to pinpoint causative factors in ADRs.
• It is important that traditional medicines are also covered by the ADR reporting system.
  • Examples of identified interactions/toxicities: Hypericum perforatum (St. John’s wort) interaction with enzyme systems, Kava-Kava withdrawn due to liver toxicity, Aristolochia sp due to nephrotoxicity and carcinogenic potential.

Role of Pharmacists in ADRs

• Pharmacists play a vital role in the detection, prevention, and management of ADRs due to their extensive knowledge of medication use.
• Key roles:
  • Monitoring high-risk patients and drugs likely to cause ADRs.
  • Assessing and documenting patient’s previous allergic status and appropriateness of drug therapy.
  • Assessing possible drug interactions in multiple therapies.
  • Assisting healthcare professionals in detection and assessment of ADRs.
  • Encouraging/stimulating healthcare professionals to report ADRs.
  • Documenting suspected reactions and following up with patients.
  • Educating healthcare professionals, patients, and the public about ADRs.
  • Communicating with other healthcare professionals (nurses, community pharmacists).
  • Disseminating information on reported ADRs (e.g., through publications).
• The pharmacist’s involvement in the ADR reporting system has had a positive impact.

Drug Interactions

Definition

• Drug-drug interactions occur when two or more therapeutically active substances produce enhancement or diminution of the therapeutic effect or side effects of one or both drugs.
• Drug-food interactions occur when food or a food constituent interferes with a drug and the expected effect of the medicine is modified.

Mechanisms of Drug Interactions

• Pharmacokinetic Interactions: Involve alterations in absorption, distribution, metabolism, or elimination of drugs, leading to changes in drug concentration at the site of action.
  • Metabolism:
    • Occur through the induction or inhibition of drug metabolism, especially via cytochrome P450 (CYP450) isoenzymes (e.g., CYP2D6, CYP3A4, CYP2C9, CYP2C19, CYP1A2, CYP2B6, CYP2C8, CYP2E1, CYP3A5, CYP3A7).
    • Liver and intestinal wall are important sites for these interactions.
    • Example: Displacement of methotrexate or warfarin from protein binding by aspirin/NSAIDs, where altered metabolism (warfarin) and renal excretion (methotrexate) are the significant mechanisms.
  • Drug Transporter Interactions:
    • Drug transporters (e.g., P-glycoprotein or P-gp) carry drugs across cell membranes, into (uptake) or out of (efflux) cells.
    • P-gp pumps drugs out of cells. In the intestine, P-gp can transport digoxin molecules out of enterocytes back into the gut lumen, reducing absorption.
• Pharmacodynamic Interactions: Occur when drugs have an additive or antagonistic effect on each other’s pharmacological actions.
  • Knowledge of pharmacology can help predict many of these.
  • Pharmacological Synergism: Two drugs with similar pharmacological or side effects given together produce an additive effect.
    • Can be exploited for benefit (e.g., opiates + tricyclic antidepressants for pain) or be hazardous (e.g., ACE inhibitor + spironolactone leading to hyperkalemia).

Information Sources on Drug Interactions

Given the vast number of potential interactions, it’s crucial to consider both theoretical potential and clinical information.

• In Vitro and Animal Data:
  • Helpful in identifying the mechanism for an interaction (e.g., CYP450 isoenzyme system research).
  • Cannot reliably predict interactions in humans due to physiological differences.
• Case Reports:
  • Often the first way interactions are identified (published in journals or reported to pharmacovigilance programmes).
  • Reliability requires careful evaluation, as they may not be peer-reviewed.
  • Should be used cautiously (e.g., paracetamol-warfarin interaction).
• Clinical Trials:
  • Provide the most reliable evidence.
  • Allow control of extraneous factors and statistical testing.
  • Special considerations: Small subject numbers may underestimate statistical significance (Type II error), often use “healthy, young males” not reflecting at-risk patients, single-dose studies may miss chronic effects, and statistical significance doesn’t always imply clinical significance.
• Reviews, Monographs, and Handbooks:
  • Published in pharmacy literature (e.g., Pharmaceutical Journal, Annals of Pharmacotherapy) to educate pharmacists.
  • Useful compilations (e.g., Martindale, Meyler’s Side Effects of Drugs, Stockley’s Drug Interactions, Hansten and Horn’s Drug Interactions: Analysis and Management).
  • Require checking for quality, completeness, and recent updates.
• Tables, Charts, and Datasheets:
  • Quick reference sources (e.g., British National Formulary (BNF) tables, wall charts, pocket-sized charts, dispensing computer warnings) for rapid identification of known interactions.
  • Product data sheets from regulatory agencies (USA, UK, Australia, Canada, New Zealand) provide useful, reviewed information.
  • Disadvantage: May lack in-depth information needed to assess clinical significance.
• Interaction Websites:
  • Many sites cover specific drug classes or conditions (e.g., HIV/AIDS medicines, herbal medicines).
  • Subscription services (e.g., Stockley’s Drug Interactions online) offer reliable information.
  • Free web-based information requires careful assessment of reliability.

Identifying an Adverse Drug Interaction

• Pharmacists are frequently asked to identify if an event is medicine-related, requiring a systematic and reliable approach to identify likely interactions and exclude other causes.
• Medication and Reaction History:
  • Identify all medicines and therapeutically active substances (including OTC, herbal).
  • Note starting/stopping dates, doses, formulations, event observation date, reaction description, supporting lab tests.
  • Document dechallenge (stopping a medicine) and rechallenge (re-introducing) results.
• Using Drug Interaction Literature:
  • Reliable references may not cover recent information.
  • Search medical literature for new drugs or infrequent interactions if reliable texts are insufficient.
  • Be aware of differences in medicine availability between countries.

Managing an Adverse Interaction

• Management depends on severity, patient risk, and dose/timing importance.
• A classification system like ORCA (OpeRational ClassificAtion of drug interactions) can help guide appropriate action.
• Example: Erythromycin and terfenadine interaction (Class 1, avoid due to risk of torsade de pointes).

Screening Patients’ Medication to Prevent Drug Interactions

• Can occur during medicine review or before a new medicine is started.
• High-risk patients: Frail, malnourished, with renal/hepatic impairment, or multiple pathologies are at greater risk.
• High-risk drugs: Pose greater risk due to inherent toxicity, non-linear pharmacokinetics, or potent enzyme-inducing/inhibiting ability (e.g., cancer chemotherapy, carbamazepine, digoxin, lithium, warfarin, phenytoin, rifampicin, theophylline, valproic acid, protease inhibitors).
• Tools: Ready reference systems (tables, pocketbooks, computer programmes) assist screening.
• Order of Administration: Important consideration (e.g., lithium and bendrofluazide).
• Newly Introduced Medicines: Require additional monitoring and caution when combined with high-risk medicines.

Interactions With Food and Herbal Medicines

• Drug-Food Interactions:
  • Some are well-known and dangerous (e.g., MAO inhibitors and tyramine-containing foods causing hypertensive crisis).
  • Can lead to therapeutic failure (e.g., phenytoin with enteral feeding) or toxicity (e.g., high-fibre diet increasing warfarin activity by impairing vitamin K absorption).
  • Grapefruit juice inhibits GI metabolism of CYP3A4 substrates.
  • Often under-recognised and infrequently reported.
• Drug-Herbal Interactions:
  • Recently recognised importance; reviews are available for limited remedies.
  • In India, with its strong tradition of herbal/traditional medicine, this is a particularly important area for investigation.

Role of Pharmacists in Drug Interactions

• Pharmacists play an important role in preventing and detecting interactions, and providing reliable advice on management.
• Their expertise is valued by other health professionals.
• They contribute to screening for interactions and advising on management at the bedside, during dispensing, or with OTC sales.
• Pharmacists have contributed to key texts and documented interactions in literature.
• Requires a good understanding of pharmacology, reliability of information sources, likely clinical significance, and risk vs. benefit.
• Pharmacists can make a valuable contribution to patient management.

Medication Errors and Adverse Drug Events (ADEs)

Medication Use System

• The use of medicines in healthcare is a system with many related steps.
• Typically described as having five major steps, each involving different healthcare professionals:
  1. Selecting and procuring: Establishing a formulary.
  2. Prescribing: Assessing patient, determining need, ordering medicine.
  3. Preparing and dispensing: Purchasing, storing, reviewing, preparing, distributing.
  4. Administering: Reviewing dispensed medicine, assessing patient, administering.
  5. Monitoring: Assessing patient response, reporting reactions and errors.
• These steps involve many people and “hand-offs,” creating potential for errors.

Medication Errors

• A medication error is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medicine is in the control of the healthcare professional, patient or consumer.
• Historically, pharmacists defined medication error as “any deviation from the prescriber’s order”.
• ASHP Categories of Medication Errors:
  • Prescribing errors
  • Omission errors
  • Wrong time errors
  • Unauthorised drug errors
  • Improper dose errors
  • Wrong dosage form errors
  • Wrong drug preparation errors
  • Wrong administration or technique errors
  • Deteriorated drug errors
  • Monitoring errors
  • Compliance errors
  • Other medication errors
• Incidence:
  • Historically, drug administration error rates in hospitals were 10% or higher.
  • Medication errors in most hospitals are approximately 10%.
  • Error rates ranged from 4.4% to 59.1% (with wrong time errors) or 0.4% to 24.7% (excluding wrong time errors) in observation-based studies.
  • Lowest reported rate (0.6%) was in hospitals with pharmacy-coordinated unit dose and drug administration programmes.
• Causes of Medication Errors (Systems Failures):
  • Analysis of ADEs and potential ADEs identified 16 major systems failures.
  • Most common (29%): Failure in dissemination of drug knowledge, particularly to prescribers.
  • Second most common (18%): Inadequate availability of patient information (e.g., lab tests).
  • Seven failures accounted for 78% of errors, all improvable by better information systems.
  • Stages of Medication Use Process where errors occur: Prescribing (39%), Drug administration (38%), Dispensing (11%).
  • Common error types: Wrong dose (28%), wrong drug (9%), known allergy (8%), missed dose (7%), wrong time (7%).
  • Specific factors associated with prescribing errors: Decline in renal/hepatic function (13.9%), patient allergy to same class (12.1%), wrong drug name/dosage form/abbreviation (11.4%), incorrect dose calculations (11.1%), critical dosage frequency considerations (10.8%).
• Error-Prone Abbreviations: Prescribing terms and abbreviations can be misinterpreted, leading to dosing errors and even death (e.g., ‘qd’ vs ‘qds’, ‘u’ for units, ‘µg’ for ‘mcg’).

Adverse Drug Events (ADE) and Potential Adverse Drug Events

• An ADE is an injury resulting from medical interventions related to a medicine.
• Most ADEs are dose-dependent and potentially predictable.
• A potential ADE is a medication error with the potential for injury, but no injury occurs.
• ADEs can result from medication errors or from ADRs where no error occurred.
• Distinction from ADR: An ADR is harm directly caused by the drug at normal doses during normal use (e.g., nausea from chemotherapy). An ADE is a broader term, including harm from medication errors (e.g., death from prescribed overdose due to errors).
• Relationship: All ADRs are ADEs. Medication errors can lead to ADEs or potential ADEs. Not all ADEs are ADRs (some ADEs are due to errors).

Epidemiology of Medication-related Problems

• Medication-related problems are common.
• Error rates are influenced by the drug distribution system.
• Unit dose systems are safer than floor stock systems.
• Automated Dispensing Cabinets (ADCs) can be less safe if not properly configured and linked to computerised medication profiles with pharmacist review.

Tools to Measure Performance of the Medication Use Process

• Voluntary Reporting Systems:
  • Often focus only on drug administration, potentially missing errors at other steps.
  • Can miss many errors but are not time-consuming and engage staff.
  • Staff may be reluctant to admit errors due to fear of punishment.
• Observation-based Studies:
  • More effective than voluntary systems in detecting improvements.
  • Can be perceived as “catching people doing things wrong”.
• Criteria-based Audits (Medication Use Evaluation/DUE):
  • Quantitative assessment of problems through chart review.
  • Useful for identifying specific issues like wrong lab tests for monitoring or inappropriate treatment.
• Computerised Detection Programmes:
  • Effective in detecting medication errors and ADEs by integrating clinical and drug information.
  • “Trigger tool” approach: Alerts based on certain lab tests or drug orders (e.g., naloxone, vitamin K orders trigger ADE alerts).
  • Limitations: Only detect events resulting in abnormal lab values or antidote use; miss other ADEs.

Prevention Strategies

• Traditional Methods:
  • Unit Dose Drug Distribution Systems: Medications packaged, labelled, and distributed to point-of-care, typically a 24-hour supply or less. Demonstrated to be significantly safer than floor stock systems (reduced error rates by at least twice).
  • Intravenous Admixture Systems: Pharmacy-based preparation of IV solutions reduces error rates (e.g., from 21% with nurses to 7.24% with pharmacy). Pharmacists make fewer dosage calculation errors than physicians/nurses. Safer systems include manufacturer-prepared premixed/frozen minibags, point-of-care activated, and pharmacy-based IV admixture systems.
• Clinical Pharmacy Programmes:
  • Pharmacist participation in medical rounds (e.g., in ICU, general medicine units) has significantly reduced preventable ADEs and prescribing errors (e.g., 72% in ICU, 78% in general medicine).
  • Pharmacists identify incomplete orders, wrong dose/frequency, inappropriate choice, duplicate therapy, drug allergies, and recommend alternatives.
• Application of Technology:
  • Computer Prescription Order Entry (CPOE): Prescriber orders entered electronically. Compares orders against dosing standards, checks for allergies/interactions, warns prescribers. Addresses common systems failures: lack of drug knowledge and patient information.
  • Bar Code Systems: Aid in verification during dispensing and administration.
  • Smart Cards: Enable storage and transfer of large quantities of clinical information.
• Standardisation and Double Checks:
  • Standardise doses, drug concentrations, and administration procedures.
  • Pharmacists should prepare high-risk drug doses.
  • Require independent double-checks and documentation for high-alert medicines (e.g., IV pump settings).
  • Standardise IV medication administration to minimise interruptions, focus on one patient, use accurate records, and two patient identifiers.
  • Maintain high procedural standardisation and double checks (e.g., reviewing transcription, rescheduling missed doses).
• Information Availability:
  • Pharmacists should provide readily usable drug information to physicians.
  • Standard operating procedures for communication at patient transition points to ensure continuity of care and medication reconciliation.

Implications for Pharmacists in India

• India may lack resources for expensive technologies like CPOE and bar code systems.
• Variations in healthcare provision (allopathic, homeopathic, ayurvedic) can lead to more interaction-related errors.
• Many Indian pharmacists do not practice in settings with close collaboration with prescribers or nurses.
• Potential System-Based Causes of Medication Errors in India:
  • Dispensing without patient name or directions.
  • Returning original prescriptions to patients.
  • Transcription of hospital orders onto prescription forms.
  • Recording drug administration on separate stationery.
  • Treatment charts lacking space for drug allergies/ADRs or route of administration.
  • Separate medical records for inpatient/outpatient visits.
  • Lack of drug information references/guidelines on wards.
• Recommendations for Indian Pharmacists:
  • Acknowledge that errors and ADEs occur and study the problem.
  • Declare improving medication safety as a serious aim, integrating into coursework and professional discussions.
  • Identify common errors causing harm and focus on system improvements (e.g., removing concentrated solutions from floor stock, managing warfarin in outpatients).
  • Examine each step of the medication use process in their setting and identify areas for minimisation of risk.
  • Make improving medication use safety an individual pharmacist’s duty, day by day and patient by patient.
  • With appropriate education and training, graduate pharmacists can help improve medication use through services like drug therapy monitoring, patient counselling, drug information, ward round participation, and ADR reporting/monitoring.