Adverse Drug Reactions Flashcards
What is an ADR?
any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or treatment
How can the onset of an ADR be classified?
- Acute= within 60 minutes and presents with bronchoconstriction
- Sub-acute= 1-24 hours and presents with rash, serum sickness
- Latent= >2 days and presents with eczematous eruptions
How can the severity of an ADR be classified?
- Mild: bothersome but requires no change in therapy i.e metallic taste with metronidazole
- Moderate: requires change in therapy, additional treatment, hospitalisation i.e amphotericin induced hypokalemia
- Severe: disabling or life-threatening i.e kidney failure
How can ADRs be classified?
- Type A: Augmented
- Type B: Bizarre
- Type C: Chronic
- Type D: Delayed
- Type E: End of Treatment
- Type F: Failure of Treatment
Describe type A ADRs.
- dose related
- predictable
- easily reversible
- most common
- not usually life threatening
Describe type B ADRs
- idiosyncratic
- unpredictable
- rare
- cause serious illness/death
- unidentified fro months/years
- unrelated to dose
- not readily reversible
What are the predisposing factors relating to ADRs?
- multiple drug therapies
- renal/hepatic impairment
- Race and genetic polymorphisms
- age
- sex
What causes type A reactions?
- Excess pharmacological action
- they may be due to the secondary pharmacology of a drug unrelated to the therapeutic effect
What are the 2 types of type A ADRs?
- augmentation of the primary effect
- secondary effect
Reasons for Type A ADRs
- too high a dose
- pharmaceutical variation
- pharmacokinetic variation
- pharmacodynamics variation
What factors affect pharmacokinetic variation?
Absorption (dose, formulation, GI motility, first pass metabolism)
- distribution
- metabolism (enhanced/impaired)
- elimination (renal disease, reduced GFR)
Describe pharmacogenetics in ADRs.
- a number of drugs are metabolised via acetlyation which is under genetic control
- 1 in 10 have slow metabolism
- prone to drug toxicity
- peripheral neuropathy with isoniazid
How can disease impact ADR?
- renal and hepatic impairment can lead to increased toxicity if drug is not excreted
- Cardiac failure reduces the drug absorption from the gut due to oedema. There is poor renal perfusion and decreased GFR which leads to hepatic congestion.
When are type B ADRs more likely to occur?
-more common with macromolecules such as proteins, vaccines and polypeptides
-patients with asthma or eczema
Presence of particular HLA increases risk
What is the mechanism of type B?
-drug allergy or hypersensitivity
-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
Define idiosyncratic
- inherent abnormal response to a drug
- due to genetic abnormality such as enzyme deficiency or abnormal receptor activity
How can differences in response to a drug be considered?
- genetic
- immunological
Describe an 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 a receptor abnormality.
malignant hyperthermia with general anaesthetics
Describe hypersensitivity reactions.
- due to antigen-antibody interaction
- first dose acts as the antigen
- body produces the antibody
- subsequent antigen-antibody reaction
Describe type C ADRs.
- related to duration of treatment
- does not occur with a single dose
- semi-predictable
Give examples of Type C reactions.
- Iatrogenic Cushings disease
- Steroid induced osteoporosis
- opiate dependence
- tardive dyskinesia with neuroleptic drugs
- analgesic nephropathy due to paracetamol or NSAIDa
Describe type D reactions.
- adverse effects occur a long time after treatment
- teratogenesis- the children of treated patients
- carcinogenesis- treated patients years after treatment has stopped
Give examples of type D reactions.
- second cancers in those treated with alkylating agents or immunosuppressive agents (cyclophosphamide, alkylating agents)
- craniofacial malformations in children whose mothers were treated with isotretinoin
What is teratogenesis?
abnormal congenital malformations in the fetus following in utero exposure due to maternal medication use during 1st trimester of pregnancy
Name 5 teratogenic agents.
- cytotoxics
- vitamin A
- antithyroid drugs
- steroids
- oral anticoagulants
Give examples of type E reactions.
- 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
- alcohol
When does rebound phenomena occur?
-when a drug is suddenly stopped
Describe type F reactions.
-failure of therapy
-common
-dose related
frequently caused by drug interactions
-failure of the OCP when administered with hepatic enzyme inducers/antibiotics
How are ADRs diagnosed?
- differential diagnosis
- medication history
- assess time of onset and dose relationship
- lab investigations inc. plasma conc. measurement and allergy tests
