Lecture 13; Adverse drug reactions Flashcards
Whats the definition of an adverse drug reaction?
A noxious or unintended response to a drug, which occurs at doses normally used in humans for the prophylaxis, diagnosis or treatment of diseases or for the modification of physiological function
What is the significance of adverse drug reactions?
- Common (9-28% of hospitalised patients)
- Associated with long term disability and death
What are the types of adverse drug reactions?
Type A : Augmented pharmacological effect
Type B: Bizarre ; unrelated to main action
Type C: Chronic effects ; Long term therapy related
Type D: Delayed effects ; Effects long time after treatment
Type E: End of treatment effects ; Withdrawal
Type F: Failure of treatment
Expand on Type A reactions:
Related to the main pharmacological action of a drug or its metabolites
- > Predictable
- > Dose related
Give some examples of type A reactions:
- Bleeding with warfarin
- Hypoglycaemia with insulin
- Confusion and drowsiness with nortiptyline
Describe type A reactions relating to cytotoxicity:
- Drug or reactive metabolites may directly damage cells
- Form covalent or non-covalent interactions with target molecules
- Hepatic metabolism generates high number of metabolites can lead to hepatotoxicity
- Polar drugs / metabolites are concentrated within the nephron -> Nephrotoxicity
Describe paracetamol hepatotoxicity as a type A adverse reaction
Paracetamol hepatotoxicity
- Converted by hepatic CYPs to toxic alkylating intermediate (NABQ1)
- Metabolite inactivated by conjugating to reduced glutathione
- In overdose, glutathione rapidly depleted
- Excess metabolite binds covalently to liver macromolecules causing cell damage and acute hepatic necrosis
- Prevented by N-acetylcystiene that facilitates glutathione synthesis
Describe gentamicin nephrotoxicity as a type A adverse reaction:
Gentamicin nephrotoxicity
- Aminoglycoside antibacterial ribosomal protein synthesis inhibitor
- Excreted unchanged in urine by Glomerular filtration
- Cytotoxicity at high concentrations to PT causing nephrotoxicity
- Gentamicin dose needs to be adjusted according to blood level monitoring and renal function
Write some notes on type B adverse drug reactions:
- Bizarre
- Not related to the main pharmacological action of a drug
- Not predictable
- Not dose related
- Allergic reactions of pharmacogenetic variability
Write some notes on type B adverse drug reactions ; allergic reactions:
- Initial exposure and sensitisation
- Allergic reaction occurs on repeated exposure
- Symptoms and signs resemble allergic disease
- i.e Antibiotics, NSAIDS, radio-contrast agents, anaesthetic agents
Describe the benzylpenicillin allergy ; type B reaction:
Benzylpenicillin allergy
- Skin rash; 1:10, Anaphylaxis, 1:5000, Death 1:50k
- ABs directed to penicilloyl-protein complex or penicillin polymers
- Many types of allergic reactions i.e
- > Acute anaphylaxis, haemolytic anaemia, serum sickness, rash
Describe carbamazepine skin reaction, type B reaction:
Carbamazepine skin reaction
- > Na channel blocker used for epilepsy
- > Occasional life threatening severe skin reactions
- Toxic epidermal necrolysis
- Skin blistering leads to dehydration, sepsis, organ Failure
- Immune mediated
- Genetic
Describe type C adverse drug reactions:
- Long term treatment may alter receptor expression and/or tissue sensitivity to drugs
- Adverse drug reactions can occur during therapy or after withdrawal of the drug
Describe a clinical example of a type C adverse drug reaction:
Haloperidol-induced dyskinesia
- Dopamine receptor antagonist used for psychosis
- Long term use can result in tardive dyskinesia that persists after cessation of treatment.
- Involuntary movements of the lips, jaw and tongue
- Possibly due to compensatory increase dopaminergic system
Write some notes on type-E adverse drug reactions:
- Withdrawal reaction
- Abrupt cessation of treatment can cause symptoms b/c of the unopposed change in receptor expression or tissue sensitivity
