Adverse drug effects

What is an Adverse Drug Reaction (ADR)?

Any response to a drug that is noxious, unintended and occurs at doses normally used for prophylaxis, diagnosis or treatment.

What is an Adverse Drug Event (ADE)?

Any harmful event occurring during drug treatment, whether or not it is caused by the drug.

What is a side effect?

A secondary effect of a drug occurring in addition to the intended therapeutic effect.

How does an ADR differ from an ADE?

An ADR is caused by the drug; an ADE may or may not be caused by the drug.

What does the modern ADR definition include?

Reactions from normal use, overdose, misuse, abuse, medication errors, off-label use and occupational exposure.

Why are ADRs important?

They cause morbidity, mortality, hospital admissions and increase healthcare costs.

Which drugs are commonly associated with ADR-related hospital admissions?

NSAIDs, diuretics, warfarin, ACE inhibitors, antidepressants, beta-blockers, opiates, digoxin and corticosteroids.

What is a serious adverse reaction?

A reaction causing death, life-threatening events, hospitalization, disability, congenital abnormalities or other medically significant conditions.

What is a Type A ADR?

Augmented reaction that is dose-related and predictable from the drug's pharmacology.

80% are caused by this

Key features of Type A ADRs

Common, predictable, dose-related and usually low mortality.

Examples of Type A ADRs

Digoxin toxicity, hypoglycaemia from insulin, bleeding with warfarin.

How are Type A ADRs often prevented?

Dose adjustment, monitoring and avoiding interactions.

What is a Type B ADR?

Bizarre reaction that is unpredictable and not related to normal pharmacology.

Key features of Type B ADRs

Uncommon, unpredictable and associated with higher mortality.

Examples of Type B ADRs

Penicillin anaphylaxis, malignant hyperthermia and idiosyncratic liver injury.

What is a Type C ADR?

Chronic reaction occurring because of long-term treatment.

Example of a Type C ADR

Cushing's syndrome from prolonged corticosteroid use.

What is a Type D ADR?

Delayed reaction appearing after drug exposure, sometimes years later.

Examples of Type D ADRs

Teratogenicity, carcinogenicity and tardive dyskinesia.

What is a Type E ADR?

End-of-use reaction caused by withdrawal of therapy.

Examples of Type E ADRs

Beta-blocker withdrawal causing angina or myocardial infarction.

What is a Type F ADR?

Failure of therapy.

Examples of Type F ADRs

Oral contraceptive failure due to enzyme induction by St John's Wort.

What does DoTS stand for?

Dose, Time and Susceptibility.

Who developed the DoTS classification?

Aronson and Ferner.

What are the three DoTS components?

Dose, Time and Susceptibility.

What is the advantage of DoTS?

It explains ADRs more comprehensively than Type A-F and can classify all ADRs.

What are the three dose categories in DoTS?

Subtherapeutic, therapeutic and supratherapeutic doses.

What reaction can occur at subtherapeutic doses?

Hypersusceptibility reactions such as penicillin anaphylaxis.

What reaction can occur at therapeutic doses?

Collateral effects such as morphine-induced nausea.

What reaction can occur at supratherapeutic doses?

Toxic effects such as paracetamol overdose.

What are toxic effects?

Adverse effects occurring at high drug concentrations.

What are collateral effects?

Adverse effects occurring at normal therapeutic concentrations.

What are hypersusceptibility reactions?

Adverse effects occurring at unusually low concentrations in susceptible individuals.

According to DoTS, are ADRs dose related?

Yes, all ADRs are considered dose related.

What is a first-dose reaction?

An ADR that occurs after the first dose of a medicine.

Example of a first-dose reaction

Anaphylaxis with penicillin.

What is an early reaction?

An ADR occurring soon after treatment begins.

Example of an early reaction

Nitrate-induced headache.

What is an intermediate reaction?

An ADR occurring after days or weeks of therapy.

Example of an intermediate reaction

Toxic epidermal necrolysis.

What is a late or long-term reaction?

An ADR developing after prolonged treatment.

Example of a late reaction

Corticosteroid-induced Cushing's syndrome.

What is a delayed reaction?

An ADR appearing after exposure has finished.

Example of a delayed reaction

Cancer following exposure to certain medicines.

What is a withdrawal reaction?

An ADR resulting from stopping a medicine.

Example of a withdrawal reaction

Paroxetine withdrawal syndrome.

What factors affect susceptibility to ADRs?

Genetics, age, sex, disease, physiological factors and drug interactions.

Genetic susceptibility example

G6PD deficiency causing haemolysis after certain drugs.

Age-related susceptibility example

Elderly patients developing Parkinsonism with prochlorperazine.

Sex-related susceptibility example

ACE inhibitor cough being more common in women.

Disease-related susceptibility example

Gentamicin toxicity in patients with renal impairment.

Why are elderly patients at greater risk of ADRs?

Polypharmacy, frailty, reduced renal function and multiple comorbidities.

Why are children at greater risk of ADRs?

Immature organ systems and altered drug handling.

How should pharmaceutical care be modified for renal impairment?

Adjust doses, monitor renal function and avoid nephrotoxic drugs.

How should pharmaceutical care be modified for liver disease?

Consider reduced metabolism, lower doses and enhanced monitoring.

How should pharmaceutical care be modified during pregnancy?

Assess fetal risk and avoid teratogenic medicines.

What is causality assessment?

The process of determining whether a drug caused an adverse reaction.

Why is causality assessment important?

It supports patient safety and regulatory decisions.

What is dechallenge?

Stopping a suspected medicine to see if the reaction resolves.

What is rechallenge?

Reintroducing the medicine to see if the reaction recurs.

What is usually the strongest evidence for causality?

A positive rechallenge.

What is the Bradford Hill criterion of Strength?

A strong association is more likely to be causal.

What is the Bradford Hill criterion of Consistency?

The association is repeatedly observed in different studies and populations.

What is the Bradford Hill criterion of Specificity?

A particular exposure causes a specific effect.

What is the Bradford Hill criterion of Temporality?

The drug exposure must occur before the adverse effect.

What is the Bradford Hill criterion of Biological Gradient?

A dose-response relationship exists.

What is the Bradford Hill criterion of Plausibility?

A biologically reasonable mechanism exists.

What is the Bradford Hill criterion of Coherence?

The association fits established scientific knowledge.

What is the Bradford Hill criterion of Experiment?

Experimental evidence supports the relationship.

What is the Bradford Hill criterion of Analogy?

Similar drugs cause similar effects.

Which Bradford Hill criterion is considered essential?

Temporality.

What information is assessed when evaluating ADR causality?

Temporal relationship, dose relationship, dechallenge, rechallenge, alternative causes and pharmacological plausibility.