Adverse Drug Events

Judith CoombesNeil 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 andunintended and occurs at doses normallyused in man for the prophylaxis, diagnosisor therapy of disease or for modification ofphysiological function.WHO 1975

Adverse Drug Event - ADE

• • Injury resulting from administration of adrug.• Event is often not solely due to the drugbut to events surrounding its use– Unintended administration• Mivacurium (muscle relaxant) instead ofmetronidazole (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 Event2000 BC A physician who caused the death of a patient

should lose his hand – Babylonian code

950 BC Many drugs were excellent when mingled andmany were fatal’ – Homer

1700s ‘They poured drugs of which they knew littleinto bodies of which they knew less’– Voltaire

1877 British medical association met to investigate thesudden deaths due to chloroform

1937 Sulfonamide elixir containing diethylene glycolgiven 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Used for morning sickness duringpregnancy and as sleep aid• Reports of phocomelia in 1961• Germany 477 reports• Drug withdrawn 1961

• Date Organisation1962 Food and Drug Administration (FDA) to reviewall investigational drugs before release –safe as well as effective – USA1963 Australian Drug Evaluation Committee (ADEC)1964 Reports of ADRS requested in Australia1964 Committee on Safety of Drugs - UK1967 International system to monitor ADRs –WHO1970 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 undesiredlocation– Beta blocker eye drops ↓ heart rate• Another pharmacological action of thedrug becomes significant– Anticholinergic effects of tri-cyclicantidepressants

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, organdamage (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 USAJAMA 2002;287:2215-20• 548 drugs on market from 1975-1999• 16 (3%) withdrawn in first 2 years• 45 (8.2%) serious adverse reactionidentified.

Benefits Spontaneous reporting

• All medicines• Whole population• Early warning• Does not affect prescribing habits• Characterise reactions

Disadvantages SpontaneousReporting

• 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 ordrugs 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 withrofecoxib• Rofecoxib withdrawn• celecoxib caution in heart disease or with riskfactors 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 agentsNephrotoxic agents

Which drugs cause renal failure?Which part of the kidney is affected?

1.Pre-renal

2.Direct toxicity(Intra-renal)

3.Immunological damage (Intra-renal)

4.Obstructive uropathy (Post-renal)

Classification of Drug Induced Renal Failure

1. Pre-renal Failure

Number of different mechanisms :

a) Volume depletione.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 filtrationpressure. If give ACEI – Acute renal failure

Which patients are at risk?

Age > 60 yrsSex F > M Underlying renal diseaseConcurrent medication esp. if nephrotoxicDecrease in effective circulating blood volume

- CCF- Cirrhosis- nephrotic syndrome- volume depletion e.g. diuretics, cytotoxics

NSAID induced renal impairment

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 nephritisHypersensitivity reaction + extra renal involvemente.g. rash, arthralgia, feverRecovery usually associated with drug removalCauses = gold, penicillins, allopurinol, loop & thiazides

• Glomerular damageImmune-mediated – Ag / Ab complexCauses = thiazides, gold, pnicillamine, captopril, NSAID

4. Obstructive uropathy

• Retroperitoneal haemorrhagee.g. anticoag’s or fibrinolytic agents

• Retroperitoneal fibrosisovergrowth fibrous tissue – methyldopa

• Ureteric obstruction2 analgesic nephropathy

• Tubular blockagecrystalluria – uric acid / sulphonamidescalcium ppt – high serum calciumHb – 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