an abc of drug-related problems · type c adverse effects - 'statistical effects'...

An ABC of Drug-Related Problems

RHB Meyboom, M Lindquist, ACG EgbertsDrug 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-relatedTherapeutic 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

Interactions

Type B adverse effects Patient reactions

Type C adverse effectsStatistical effects

Ineffectiveness

Poisoning

Noncompliance Medication error

DependenceLate effectsCarcinogenesis

Organ selective injury

Risk 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

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 actionsExamples:

•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

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

Kinetics and age• Sulfamethoxypyridazine

– Newborn– 1 month-2 years– 2 - 12 years– Adults– Elderly

• T½(h)

– 136– 54– 51– 63– 98

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

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

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

Comparison Type A and Type B

A B

Pharmacologicallypredictable

Yes No

Dose dependant Yes No

Incidence &morbidity

High Low

Mortality Low High

Treatment Decrease dose Stop

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

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

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

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

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

Inappropriate use• Wrong dose• Wrong duration• Wrong indication• Wrong administration• Wrong patient • Wrong attitude or expectations

- Noncompliance- Medication error- Negligence (contraindication)- Failure of information, counselingor 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

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 useMethods 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

The Zodiac of Drug-Related Problems

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

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