Adverse Drug Reactions Flashcards by David Brennan

What is an adverse drug reaction (ADR)

Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or treatment

An appreciably harmful or unpleasant reaction

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What does an ADR result in

An intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product

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How many people are admitted annually due to ADR’s

1,000,000 (6.5% of all hospital admissions)

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How many inpatients suffer an ADR

10-20%

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How many deaths a year are due to ADR

5000 - 12,000

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What is the 4th leading cause of death

ADR

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What type of onset can ADR show

Acute
Sub-acute
Latent

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Describe acute ADR

Occur within 60 minutes (e.g. bronchoconstriction)

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Describe sub-acute ADR

Occurs within 1 to 24 hours

Can present with rash and serum sickness

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Describe latent ADR

Occurs after 2 days

May show eczematous eruptions

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What are the three classes of severity of ADR

Mild
Moderate
Severe

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Describe a mild ADR

It is bothersome but requires no change in therapy (e.g. metallic taste with metronidazole)

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Describe a moderate ADR

It requires change in therapy, additional treatment and hospitalization (e.g. amphotericin induced hypokalemia)

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Describe a severe ADR

Causes a disabling or life-threatening condition (e.g. kidney failure)

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How are ADRs classified (6)

Type A - Augmented
Type B - Bizarre
Type C - Chronic
Type D - Delayed
Type E - End of treatment   
Type F - Failure of treatment

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Describe a type A ADR

It causes normal but augmented response to the pharmacological actions of a drug
It is dose related and predictable

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Describe a type B ADR

It causes Bizarre effects

It is idiosyncratic and unpredictable

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What are predisposing factors to ADRs

Multiple Drug Therapy
Inter-current Disease (e.g. renal and hepatic impairment)
Race and Genetic Polymorphisms
Age (e.g. elderly and neonates)
Sex (e.g. ADRs more common in women)

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What are type A ADRs due to

Excess pharmacological action (e.g.
Bradycardia with beta-blockers or Hypoglycaemia with sulphonylureas or insulin)
The secondary pharmacology of a drug unrelated to the therapeutic effect.

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What type of ADR is the most common

Type A (account for 80% of all ADRs)

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How can type A be treated

Its easily reversible by reducing the dose or stopping the drug
Not usually life threatening

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What types of type A ADRs are there

Augmentation of the primary effect

Secondary effect

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What are the reasons for a type A ADR

Too high a dose
Pharmaceutical variation
Pharmacokinetic variation
Pharmacodynamic variation

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When do pharmacokinetic variation and pharmacodynamic variation occur

Normally due to a result of disease

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What can pharmacokinetic variation involve

Absorption (e.g. dose, formulation, GI motility, first pass metabolism) Distribution Metabolism (e.g. enhanced or impaired hepatic function) Elimination (e.g. renal disease, reduced GFR)

What do ADRs that arise from absorption mainly result in

Therapeutic failure

When is liver disease important

When drugs have a narrow therapeutic index

What is the importance of pharmacogenetics

A number of drugs are metabolised via acetylation which is under genetic control

Name some pharmacogenetic factors

10% of the population are slow metabolisers Prone to drug toxicity peripheral Neuropathy with isoniazid

What will renal and hepatic impairment have on drug use

Toxic drug levels may build up

What effect will cardiac failure have on drug usage

Drug absorption from the gut may reduce due to oedema Poor renal perfusion and decreased GFR Hepatic congestion

What are type B ADRs (8)

``` Bizarre Unpredictable Rare Cause serious illness or death Unidentified for months or years Unrelated to the dose Not readily reversed ```

What are type B ADRs commonly associated with

Macromolecules (e.g. proteins, vaccines and polypeptides)

Who can type B ADRs affect

Patients with a history of asthma or excema

Why is the HLA status important in type B ADRs

Presence of particular HLA increases risk of a type B reaction

What are the mechanisms for ADRs

Idiosyncratic | Drug allergy or hypersensitivity

Describe how the drug allergy or hypersensitivity present (5)

Immunological No relation to the pharmacological action of the drug Delay between exposure and ADR No dose response curve Manifests as rash, asthma, serum sickness

What is an idiosyncratic response

An inherent abnormal response to a drug due to genetic abnormalities such as enzyme deficiency or abnormal receptor activity It involves pharmacogenetics and pharmacodynamics

How can the responses to drugs be considered

Genetic | Immunological

Describe the ADR that occurs in patients with the enzyme abnormality, Erythrocyte glucose 6-phosphate dehydrogenase (G6PD) deficiency

Individuals with sex linked inherited deficiency of this enzyme are susceptible to red cell haemolysis when given drugs such as primaquine or sulphonamides

Describe the ADR that occurs in patients with the receptor abnormalities

Malignant hyperthermia with general anaesthetics

Why do drug allergy hypersensitivity reactions occur

Due to antigen- antibody interaction

How do drug allergy hypersensitivity reactions occur

The first dose acts as the antigen Body produces the antibody Subsequent antigen-antibody reaction

What are type C ADRs related to

The duration of treatment as well as the dose and does not occur with a single dose They are semi-predictable

Give examples of type C ADRs (5)

Iatrogenic Cushings disease Steroid induced osteoporosis Opiate dependence Tardive dyskinesia with neuroleptic drugs Analgesic nephropathy due to paracetamol or NSAIDs

What are type D ADRs

Averse effects which occur a long time after treatment

What can type D ADRs cause

Teratogenesis | Carcinogenesis in treated patients years after treatment has stopped (or children of treated patients)

In who can type D second cancers occur

In those treated with alkylating agents or immunosuppressive agents (e.g. cyclophosphamide or alkylating agents)

What kind of malformations can occur in children whose mothers were treated with isotretinoin

Craniofacial

What is teratogenesis

The abnormal congenital malformations in the fetus following in utero exposure due to maternal medication use during 1st trimester of pregnancy

Name some teratogenic agents

``` Cytotoxics Vitamin A Antithyroid drugs Steroids Oral nticoagulants ``` All drugs should be avoided during pregnancy unless they are safe or the benefit outweighs potential risk

What are type E ADRs

Adverse effects which occur when a drug treatment is stopped especially suddenly following long-term use (e,g, alcohol)

Give examples of what type E ADRs can cause

Unstable angina and MI when beta blockers are stopped. Addisonian crisis when long term steroids are suddenly stopped Withdrawal seizures when anti-epileptics are stopped

When does rebound phenomena occur

When a drug is suddenly withdrawn (e.g. alcohol, benzodiazepines, beta-blockers, corticosteroids)

Describe type F ADRs

Failure of therapy Common Dose related Frequently caused by drug interactions

Give an example of a type F ADR

The failure of the OCP when administered with hepatic enzyme inducers/ antibiotics

How can ADRs be diagnosed

Step 1: Differential diagnosis Step 2: Medication History (past & present) Step 3: Assess time of onset and dose relationship Step 4: Laboratory investigations (plasma concentration measurement, allergy tests)

Who are most at risk of ADRs (at least 5)

``` Children and elderly Multiple medications Multiple co-morbid conditions Inappropriate medication prescribing, use, or monitoring End-organ dysfunction Altered physiology Prior history of ADRs Extent (dose) and duration of exposure Genetic predisposition ```

What drugs are commonly involved in ADRs (at least 5)

``` Antibiotics Antineoplastics Anticoagulants Cardiovascular drugs Hypoglycemics Antihypertensives NSAID/Analgesics Diagnostic agents CNS drugs Opiates ```

How many fatal ADRs do antineoplastics, cardiovascular drugs and CNS drugs account for

69%

What body systems are commonly involved in ADRs (at least 5)

``` Haematologic CNS Dermatologic/Allergic Metabolic Cardiovascular Gastrointestinal Renal/Genitourinary Respiratory Sensory ```

When should ADRs be reported

All significant or unusual adverse drug reactions as well as unanticipated or novel events that are suspected to be drug related All ADRs affecting Black Triangle Drugs/Products

How can ADRs be reported

Using ADR yellow card scheme