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Adverse Drug Events
Judith Coombes
Neil Cottrell
School of Pharmacy,
University of Queensland
Objectives
• What an adverse drug reaction is
• Organisations and history
• Morbidity and mortality
• Classification
• Understanding of establishing Causality
• Reporting schemes
• The role of the Pharmacist
Adverse Drug Reaction - ADR
• A response to a drug that is noxious and
unintended and occurs at doses normally
used in man for the prophylaxis, diagnosis
or therapy of disease or for modification of
physiological function.
WHO 1975
Adverse Drug Event - ADE
• • Injury resulting from administration of a
drug.
• Event is often not solely due to the drug
but to events surrounding its use
– Unintended administration
• Mivacurium (muscle relaxant) instead of
metronidazole (antibiotic) – same packaging
• Lasix (diuretic) given instead of losec (anti ulcer) –
similar name
• An entire days worth of iv heparin given in 1
hour
Year
Event
2000 BC A physician who caused the death of a patient
should lose his hand – Babylonian code
950 BC Many drugs were excellent when mingled and
many were fatal’ – Homer
1700s
‘They poured drugs of which they knew little
into bodies of which they knew less’– Voltaire
1877
British medical association met to investigate the
sudden deaths due to chloroform
1937
Sulfonamide elixir containing diethylene glycol
given to 353 people – 105 deaths
1952
First book on adverse drug reactions – Myers
1961
Phocomelia due to thalidomide reported McBride
Thalidomide
• Released 1956
• Used for morning sickness during
pregnancy and as sleep aid
• Reports of phocomelia in 1961
• Germany 477 reports
• Drug withdrawn 1961
• Date Organisation
1962 Food and Drug Administration (FDA) to review
all investigational drugs before release –
safe as well as effective – USA
1963 Australian Drug Evaluation Committee (ADEC)
1964 Reports of ADRS requested in Australia
1964 Committee on Safety of Drugs - UK
1967 International system to monitor ADRs –WHO
1970 Adverse Drug Reactions Advisory Committee
(ADRAC) - Australia
Type of ADRs
• • Type A
– Predictable
•Type B
– Idiosyncratic/ bizarre
Type A
• Occur at therapeutic dose
– BUT if increase dose ++ will definitely occur
• Accentuation of normal drug effect
- Bradycardia (↓ heart rate) with a beta blocker
– Hypotension (↓ blood pressure) with perindopril
• Common –
– ~ 75% of all ADRs
– ~ 80% of all hospital admissions due to an ADR
• High Morbidity
• Low Mortality
Mechanisms of Type A
• Excessive therapeutic effect
– Decreased Clearance = drug accumulation
– Increased sensitivity target organ
• Pharmacological effect at an undesired
location
– Beta blocker eye drops ↓ heart rate
• Another pharmacological action of the
drug becomes significant
– Anticholinergic effects of tri-cyclic
antidepressants
Type B (bizzare)
• • Not dose related
• Unrelated to normal drug effect
– Quinine and thrombocytopenia (↓ platelets)
– Penicillins and hypersensitivity
• Sudden and dramatic in onset
• Rare ~ 25% of all ADRs
• Low Morbidity
• High Mortality
Mechanisms of Type B
• Immunological
– Allergic reactions – anaphylaxis, rash, organ
damage (bone marrow, kidneys, liver)
• Pharmacogenetic
– Factor predisposes the individual to the
effect
• glucose-6-phosphate dehydrogenase
deficiency
• ototoxicity with gentamicin
Nature of the reactions
• Troublesome
– Cough, vomiting
• Incapacitating
– Rash
• Life threatening
– Organ damage
• Bone marrow
• Exfoliating rash (skin falls off)
• Kidney failure- dialysis
Causality
• Previous experience
• Alternative causes
• Patient background
• Timing of events
• Characteristics of ADR
• Stopping the drug
• Rechallenge
At risk patients
• Extremes of age
• Patient history – multiple allergy
• Genetic polymorphism
• Impaired organ function – renal/ hepatic
• Polypharmacy – taking lots of drugs
• Lack of knowledge
– Carbimazole and sore throat
Pre-Marketing Surveillance
• Human Clinical Trials
• Phase I
– Volunteers – serious ADRS rare
• Phase II
– Patients – minor events
• Phase III
– Targeted for ‘minor events’
• All have small numbers – total ~ 1400
• Need 65,000 participants for ADR 1 in 10,000
Post-Marketing Surveillance
• After drug available
• Good source for rare reactions
• May identify incidence
• Spontaneous reporting
• Identify risk factors
Post-Marketing Study in USA
JAMA 2002;287:2215-20
• 548 drugs on market from 1975-1999
• 16 (3%) withdrawn in first 2 years
• 45 (8.2%) serious adverse reaction
identified.
Benefits Spontaneous reporting
• All medicines
• Whole population
• Early warning
• Does not affect prescribing habits
• Characterise reactions
Disadvantages Spontaneous
Reporting
• Low numbers - 60% reporting rate
• No control group for absolute incidence
• Causality can be difficult to prove
• Problems if long lag for effect
• Are they really drug related?
What to report
• All suspected reactions to NEW DRUGS or
drugs of current interest
• All suspected drug interactions
• Reactions that cause the following
– Death
– Danger to life
– Admission to hospital
– Prolongation of hospitalisation
– Absence from productive activity
– Increased investigational or treatment costs
– Birth defects
Role of the Pharmacist
• Identify drugs with high risk
• Patients with risk factors
• Ensure appropriate monitoring
• Patient education
• Identify previous risk/ exposure
• Encourage reporting from all
• Advise on management of ADRs
Respiratory
• Amiodarone
– ADRAC 2004 17/31 ADR reports were pulmonary
– 8 Pulmonary fibrosis
– Although onset maybe fast usually it is slow- limit
dose
• COX 2 inhibitors
Rofecoxib and celecoxib
• ADR
– Increased heart attack and stroke with
rofecoxib
• Rofecoxib withdrawn
• celecoxib caution in heart disease or with
risk
factors for heart disease.
Glitazones (used in type 2 diabetes)
Rosiglitazone, pioglitazone
• ADR
– Increased incidence of heart failure
– Increased incidence of heart attacks
• Heparin
– HITTS
– Heparin induced thrombotic thrombocytopenia
• Clozapine
– Used with monitoring of White Blood Cell count
– neutropenia
Nephrotoxic agents
Which drugs cause renal failure?
Which part of the kidney is affected?
Classification of Drug Induced Renal Failure
1. Pre-renal
2. Direct toxicity
(Intra-renal)
3. Immunological
damage (Intra-renal)
4. Obstructive
uropathy (Post-renal)
1. Pre-renal Failure
Number of different mechanisms :
a) Volume depletion
e.g. diuretics or cytotoxic therapy
b) Prostaglandin inhibition
e.g. NSAID’s or
c) ACEI (bilateral renal artery disease)
Renal Artery Stenosis –
Angiotensin II vital to maintain filtration
pressure. If give ACEI – Acute renal failure
NSAID induced renal impairment
Which patients are at risk?
Age > 60 yrs
Sex F > M
Underlying renal disease
Concurrent medication esp. if nephrotoxic
Decrease in effective circulating blood volume
-
CCF
Cirrhosis
nephrotic syndrome
volume depletion e.g. diuretics, cytotoxics
2. Direct Toxicity (Intra-renal)
a)
•
ATN : actue tubular necrosis – common (80% of
all DIRF).
Direct chemical insult to proximal tubule e.g.
Aminoglycosides, amphotericin, acyclovir.
cyclosporin and cisplatin
b) Interstitial damage – papillar necrosis rare
(analgesic nephropathy)
•
Chronic exposure to analgesics or analgesic /
antipyretic mixtures (aspirin + paracetamol)
•
Ingestion > 1 – 3 kg (6 tabs/day for 3 years)
3. Immunological damage (Intra-renal)
a)
•
Immunological damage
Allergic vasculitis
Rare, part of generalised allergic reaction caused by thiazides,
penicillamine
•
Acute interstitial nephritis
Hypersensitivity reaction + extra renal involvement
e.g. rash, arthralgia, fever
Recovery usually associated with drug removal
Causes = gold, penicillins, allopurinol, loop & thiazides
•
Glomerular damage
Immune-mediated – Ag / Ab complex
Causes = thiazides, gold, pnicillamine, captopril, NSAID
4. Obstructive uropathy
•
•
•
•
Retroperitoneal haemorrhage
e.g. anticoag’s or fibrinolytic agents
Retroperitoneal fibrosis
overgrowth fibrous tissue – methyldopa
Ureteric obstruction
2 analgesic nephropathy
Tubular blockage
crystalluria – uric acid / sulphonamides
calcium ppt – high serum calcium
Hb – drug-induced haemolysis
Liver ADRs
• Similar findings to viral hepatitis
– hepatocellular toxicity
• paracetamol overdose, halothane, ???
– drugs can also cause cholestasis
• ALP & GGT increase
• flucloxacillin, chlorpromazine, ???
– drugs can also induce enzyme production without
causing liver damage
• phenytoin, barbiturates, acute alcohol intake