Lecture 23 Flashcards
What is the simplest classification which places adverse reactions into one of two categories?
Type I: Predictable
Type II: Not predictable (and often ascribed and immunological cause)
What types of genetic polymorphism can lead to susceptibility to adverse drug reactions?
Ones that interfere with the drugs pharmacokinetic properties of ADME or the pharmacokinetic problems from receptors, ion channels enzymes and the immune system
How can inter-individual variability in drug metabolism lead to adverse events?
A lack of metabolism can lead to an enhanced plasma concentration and exaggerated pharmacological response
A lack of a metabolic pathway can lead to the drug becoming bioactivated by a different enzyme
A lack of a detoxification pathway leads to enhanced toxicity
Increased protein expression or catalytic activity may lead to a subsequent increase in the formation of toxic metabolites
How does suxamethonium lead to adverse drug reactions?
It is normally used for muscle relaxation during surgery lasting for 2-6 minutes as the drug is rapidly hydrolysed by plasma esterases however 1/3500 caucasian patients had reduced enzyme activity leading to prolonged muscle paralysis and potentially apnea
How can 6-Mercaptopurine lead to adverse drug reactions?
Usually this drug undergoes and said S-methylation catalysed by the enzymes thiopurine methyl transferase
89% of individuals have high activity of this and 11% have intermediate activity
1 in 300 patients are at high risk of potentially fatal haematopoietic toxicity as thioguanaine will accumulate of thioguanine nucleotides in hemopoietic tissues there must be a large (1–15 fold) reduction in dose
How does perhexiline lead to adverse drug reactions?
Perhixiline is an anti-angina drug that has cationic, amphiphilic properties
It is not metabolised by CYP2D6 then it will accumulate in lysosomes to cause hepatotoxicity and neuropathy
What are the adverse drug reactions to penicillins?
The most common reactions to oral dosage are nausea, vomiting, epigastric distress, diarrhoea and black hairy tongue
If the dosage is high then haemolytic anaemia, leucopenia, thrombocytopenia, neuropathy and nephropathy are also occasionally seen
What are the hypersensitivity drug reactions to penicillins?
skin eruptions urticaria laryngeal oedema anaphylaxis reactions resembling serum sickness including chills, fever, oedema, arthralgia and prostration
How can pharmacodynamic interactions lead to adverse drug effects?
Interactions tend to occur when there is overlapping action of two drugs to cause an increase in the pharmacological effect which is harmful
What is an example of pharmacological interaction leading to adverse drug reactions?
Ethanol has many pharmacological effects including acting at GABA(A) receptors if alcohol is drunk with sedatives then, hypnotics or some antihistamines then this can result in an additive effect leading to too much sedation which could cause a coma or even death
How can pharmacokinetics lead to adverse drug reactions?
Toxicity of a compound may increase if there is inhibition of the normal detoxification pathways so a higher plasma concentration
Inhibition of one pathway causes greater clearance through a bioactivation pathway
Inhibition of repair mechanisms
Induction of the enzymes that catalyze the bioactivation
What are 3 examples of pharmacokinetic interactions leading to an adverse drug reaction?
Warfarin has a narrow therapeutic index
Cimetidine can inhibit warfarin metabolism leading higher concentrations
Terfenadine is usually metabolized by CYP to fexofenaine but has a fatal interaction with ketoconazole as this inhibits CYP3A4 leading to increased plasma concentrations interfering with the cardiac slow K+ channel prolonging Q-T interval
Ethanol can induce an enzyme which bioactivates paracetamol to form a toxic metabolite
