An ABC of Drug-Related Problems RHB Meyboom, M Lindquist, ACG Egberts Drug Safety 2000;22:415-23

Introduction The percentage of hospital admissions due to adverse drug reactions in some countries is about or more than 10% Br J Clin Pharmacol 1998, 45(3), Thèrapie, 1999, 54(1) Ad Drug React Toxico Rev., 1998, 17(1), Norway11.5%, France13%, UK 16%

6.7% of hospital patients have serious adverse drug reactions (medication error excluded) Lazarou J. Pomeranz BH, Corey PN. JAMA 1998;279: % of hospital admissions are drug-related Therapeutic failure 54.8% Adverse reactions32.9% Overdose12.3% Avoidable49.3% Nelson KM, Talbert RL. Pharmacotherapy 1996;16:701-7

Some countries spend up to 15-20% of their hospital budget dealing with drug complications. – White T et al. Counting the cost of drug-related adverse events. Pharmacoeconomics, 1999, 15(5)

Type A adverse effects Drug actions Interactions Type B adverse effects Patient reactions Type C adverse effects Statistical effects Ineffectiveness Poisoning Noncompliance Medication error Dependence Late effects Carcinogenesis Organ selective injury Risk situations The Zodiac of Drug-Related Problems

Type A adverse effects - Drug actions Pharmacological side effects Common (> 1 %) Dose relationship Suggestive time relationship (kinetics) Reproducible Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Type A adverse effects - Drug actions Examples: Sedation Constipation Diarrhoea Urinary retention Impotence Hypoglycaemia (antidiabetics) Hypokalaemia (diuretics) Baldness (oncolytics) Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations Type A adverse effects - Drug actions Organ selective injury Long-term use effects Carcinogenesis Risk situations, e.g. - childhood - elderly - pregnancy - lactation - renal failure - haemodialysis Interactions

Type A adverse effects - Drug actions Methods of study: Clinical trial / follow-up study Spontaneous reporting Prescription event monitoring Hospital studies Experiments Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations Type B adverse effects - Patient reactions  Rare (< 1 %)  No dose relationship  Unexpected  Mechanism uncertain  Causality uncertain  Not reproducible  Characteristic, serious  Suggestive time relationship  Low background frequency

Type B adverse effects - Patient reactions  Immunoallergic reactions  Pseudoallergy  Metabolic intolerance  Idiosyncrasy Examples: Anaphylaxis Stevens-Johnson syndrome Blood dyscrasias Hepatitis Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations Type B adverse effects - Patient reactions Methods of study: Spontaneous reporting Prescription event monitoring Case control surveillance Large databases / record linkage

Type C adverse effects - 'statistical effects' Increased frequency of 'spontaneous' disease High background frequency Less typical for a drug reaction No suggestive time relationship Often long latency Mechanism unknown Not reproducible Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Type C adverse effects - 'statistical effects' Examples: Thromboembolic events GI haemorrhage Pancreatitis Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations Type C adverse effects - 'statistical effects' Methods of study: Follow up studies (large scale, long-term) Case control studies Large databases / record linkage Spontaneous Reporting of limited use

Ineffectiveness 55% of drug related problems Limited efficacy Noncompliance Pharmaceutical defect (counterfeit; generic) Interaction Resistance Tolerance Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations Inappropriate use Wrong dose Wrong duration Wrong indication Wrong administration Wrong patient Wrong attitude or expectations - Noncompliance - Medication error - Negligence (contraindication) - Failure of information, counseling or monitoring

Medication Error > 7000 deaths per year from medication error in the USA To Err is Human: Building a Safer Health System. National Academy Press, 1999

Inappropriate use Methods of study: Spontaneous reporting Questionnaire Hospital studies Follow-up studies Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Dependence hidden not only narcotics Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Poisoning (overdose) iatrogenic accidental intentional Drug actions Type A adverse effects Interactions Patient reactions Type B adverse effects Statistical effects Type C adverse effects Non-compliance Overdose Therapeutic failure Dependence Organ selective toxicity Delayed effects Special situations

Type A adverse effects Drug actions Interactions Type B adverse effects Patient reactions Type C adverse effects Statistical effects Ineffectiveness Poisoning Noncompliance Medication error Dependence Late effects Carcinogenesis Organ selective injury Risk situations The Zodiac of Drug-Related Problems

Definitions (WHO) Side Effect: any unintended effect of a drug occurring at normal doses, which is related to the pharmacological properties of the drug Adverse Event: any untoward medical occurrence that may present during treatment with a drug but does not necessarily have a causal relationship Adverse Reaction: any response to a drug which is noxious and unintended and occurs at normal doses  Often only suspicions! Edwards IR, Biriell C. Drug Safety 1994;10:93-102