an abc of drug-related problems · type c adverse effects - 'statistical effects'...
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An ABC of Drug-Related Problems
RHB Meyboom, M Lindquist, ACG EgbertsDrug Safety 2000;22:415-23
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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
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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
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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
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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)
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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
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Kinetics and age• Sulfamethoxypyridazine
– Newborn– 1 month-2 years– 2 - 12 years– Adults– Elderly
• T½(h)
– 136– 54– 51– 63– 98
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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