Adverse Drug Reactions Flashcards
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
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
How many people are admitted annually due to ADR’s
1,000,000 (6.5% of all hospital admissions)
How many inpatients suffer an ADR
10-20%
How many deaths a year are due to ADR
5000 - 12,000
What is the 4th leading cause of death
ADR
What type of onset can ADR show
Acute
Sub-acute
Latent
Describe acute ADR
Occur within 60 minutes (e.g. bronchoconstriction)
Describe sub-acute ADR
Occurs within 1 to 24 hours
Can present with rash and serum sickness
Describe latent ADR
Occurs after 2 days
May show eczematous eruptions
What are the three classes of severity of ADR
Mild
Moderate
Severe
Describe a mild ADR
It is bothersome but requires no change in therapy (e.g. metallic taste with metronidazole)
Describe a moderate ADR
It requires change in therapy, additional treatment and hospitalization (e.g. amphotericin induced hypokalemia)
Describe a severe ADR
Causes a disabling or life-threatening condition (e.g. kidney failure)
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
Describe a type A ADR
It causes normal but augmented response to the pharmacological actions of a drug
It is dose related and predictable
Describe a type B ADR
It causes Bizarre effects
It is idiosyncratic and unpredictable
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)
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.
What type of ADR is the most common
Type A (account for 80% of all ADRs)
How can type A be treated
Its easily reversible by reducing the dose or stopping the drug
Not usually life threatening
What types of type A ADRs are there
Augmentation of the primary effect
Secondary effect
What are the reasons for a type A ADR
Too high a dose
Pharmaceutical variation
Pharmacokinetic variation
Pharmacodynamic variation
When do pharmacokinetic variation and pharmacodynamic variation occur
Normally due to a result of disease
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
