An ABC of Drug-Related Problems

RHB Meyboom, M Lindquist, ACG Egberts Drug Safety 2000;22:415-23

6.7% of hospital patients have serious adverse drug reactions (medication error excluded)
Lazarou J. Pomeranz BH, Corey PN. JAMA 1998;279:1200-5

16.2% of hospital admissions are drug-related Therapeutic failure 54.8% Adverse reactions 32.9% Overdose 12.3% Avoidable 49.3%
Nelson KM, Talbert RL. Pharmacotherapy 1996;16:701-7

The Zodiac of Drug-Related Problems

Type A adverse effects Drug actions Poisoning
Organ selective injury Late effects Carcinogenesis Risk situations

Dependence

Noncompliance Medication error

Interactions Type C adverse effects Statistical effects

Ineffectiveness

Type B adverse effects Patient reactions

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Type A adverse effects - Drug actions Pharmacological side effects Common (> 1 %) Dose relationship Suggestive time relationship (kinetics) Reproducible

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Type A adverse effects - Drug actions Examples: Sedation Constipation Diarrhoea Urinary retention Impotence Hypoglycaemia (antidiabetics) Hypokalaemia (diuretics) Baldness (oncolytics)

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

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

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Kinetics and age

Sulfamethoxypyridazine T(h)
Newborn 1 month-2 years 2 - 12 years Adults Elderly 136 54 51 63 98

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Type A adverse effects - Drug actions Methods of study: Clinical trial / follow-up study Spontaneous reporting Prescription event monitoring Hospital studies Experiments

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

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

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Type B adverse effects - Patient reactions Immunoallergic reactions Pseudoallergy Metabolic intolerance Idiosyncrasy Examples: Anaphylaxis Stevens-Johnson syndrome Blood dyscrasias Hepatitis

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Type B adverse effects - Patient reactions Methods of study: Spontaneous reporting Prescription event monitoring Case control surveillance Large databases / record linkage

Comparison Type A and Type B

A Pharmacologically predictable Dose dependant Incidence & morbidity Mortality Treatment Yes Yes High Low Decrease dose B No No Low High Stop

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

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

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Type C adverse effects - 'statistical effects' Examples: Thromboembolic events GI haemorrhage Pancreatitis

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

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

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Ineffectiveness
55% of drug related problems Limited efficacy Noncompliance Pharmaceutical defect (counterfeit; generic) Interaction Resistance Tolerance

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Inappropriate use
Wrong dose

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

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

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Inappropriate use
Methods of study: Spontaneous reporting Questionnaire Hospital studies Follow-up studies

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Dependence
hidden not only narcotics

Overdose Dependence

Drug actions Type A adverse effects

Interactions Therapeutic failure Non-compliance Delayed effects

Organ selective toxicity Special situations

Statistical effects Type C adverse effects

Patient reactions Type B adverse effects

Poisoning (overdose)
iatrogenic accidental intentional

The Zodiac of Drug-Related Problems

Type A adverse effects Drug actions Poisoning
Organ selective injury Late effects Carcinogenesis Risk situations

Dependence

Noncompliance Medication error

Interactions Type C adverse effects Statistical effects

Ineffectiveness

Type B adverse effects Patient reactions

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