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), 301-308.

• Thèrapie, 1999, 54(1) 21-27. • Ad Drug React Toxico Rev., 1998,

17(1), 19-50.• Norway 11.5%, France 13%, UK 16%

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

• 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). 445-458.

Type A adverse effects Drug actions

Interactions

Type B adverse effects Patient reactions

Type C adverse effectsStatistical effects

Ineffectiveness

Poisoning

Noncompliance Medication error

DependenceLate effectsCarcinogenesis

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 actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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 actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType C adverse effects

Non-compliance

Overdose

Therapeutic failure

Dependence

Organ selective toxicity

Delayed effects

Special situations

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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 actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType C adverse effects

Non-compliance

Overdose

Therapeutic failure

Dependence

Organ selective toxicity

Delayed effects

Special situations

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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 actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType C adverse effects

Non-compliance

Overdose

Therapeutic failure

Dependence

Organ selective toxicity

Delayed effects

Special situations

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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 actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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 actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType C adverse effects

Non-compliance

Overdose

Therapeutic failure

Dependence

Organ selective toxicity

Delayed effects

Special situations

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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

Ineffectiveness55% of drug related problems

• Limited efficacy• Noncompliance• Pharmaceutical defect (counterfeit; generic)• Interaction• Resistance• Tolerance

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType C adverse effects

Non-compliance

Overdose

Therapeutic failure

Dependence

Organ selective toxicity

Delayed effects

Special situations

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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 actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType C adverse effects

Non-compliance

Overdose

Therapeutic failure

Dependence

Organ selective toxicity

Delayed effects

Special situations

Dependence• hidden• not only narcotics

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType C adverse effects

Non-compliance

Overdose

Therapeutic failure

Dependence

Organ selective toxicity

Delayed effects

Special situations

Poisoning (overdose)• iatrogenic• accidental• intentional

Drug actionsType A adverse effects

Interactions

Patient reactionsType B adverse effects

Statistical effectsType 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 effectsStatistical effects

Ineffectiveness

Poisoning

Noncompliance Medication error

DependenceLate effectsCarcinogenesis

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