Adverse Drug Reactions & Poisoning Flashcards
What does the clinical effectiveness of a first order drug after its been stopped depend on?
Therapeutic window
Minimal effective [drug]plasma
How is paracetamol metabolised?
60% conjugated with glucuronide
30% conjugated with sulfate
10% oxidised by CYP450 to NAPQI (toxic)
NAPQI conjugated with glutathione to inactive metabolites
What causes the toxic effects in paracetamol overdose?
Metabolism via gluronide & sulfate is saturated
Conjugation of NAPQI with glutathione is saturated
Build up of NAPQI causing liver damage (via free radicals)
What is the treatment for paracetamol overdose?
1hr = ?activated charcoal (reduced absorption, disgusting)
4-8hrs and less than 12g or 150mg/kg = consult [paracetamol]
8hrs+ (or time and amount unknown) = start treatment immediately
Replace glutathione to reduce NAPQI concentration by giving N-acetylcysteine
note: can discontinue treatment after consulting [paracetamol] graph
note: more at risk of liver damage if mixed overdose/concurrent alcohol
How would you calculate the loading dose required for a dose of phenytoin (92% salt given) for a 100kg man when the volume of distribution is 0.7l/kg and the [drug]target at steady state is 20mg/l?
(Loading dose = Vd x [drug]target at steady state)
Vd = 0.7l/kg [drug]target at steady state = 20mg/l
Vd = 0.7l/kg x 100kg = 70l
Loading dose = 70l x 20mg/l = 1400mg
1.4g/0.92 = 1.5g loading dose required
How does the volume of distribution and clearance differ in children and the elderly?
Children:
- higher apparent volume of distribution
- higher clearance
Elderly:
- clearance reduced —> longer half life —> longer elimination time
Give an approximation for the effect of reduced GFR on the clearance of a drug exclusively eliminated by the kidneys.
When GFR is halved, the half life roughly doubles
e. g. assuming t1/2 = 4hrs at GFR = 90ml/min/1.73m2
note: in CKD this can be compensated for better than AKI
What are some common areas of actions and modes of action of drugs?
- cell surface receptors
- nuclear receptors
- enzyme inhibitors
- ion channel blockers
- transport inhibitors
- inhibitors of signal transduction proteins
Define potency. How can it be calculated for agonists?
POTENCY = dose required to produce the desired biological response OR different doses of two drugs required to exact the same effect
Agonists: compare to agonist with 100% efficacy in vitro and add antagonist until EC50 is reached
What is the effect on the dose response curve when increasing the [agonist] when competitive antagonists are present?
Dose response curve shifts to the right
i.e. EC50 changes but the maximal effect is the same
What is the therapeutic index of a drug?
Range of doses that can effectively treat a condition whilst still remaining safe
EC50(adverse effect)/EC50(desired effect)
How do changes in drug absorption effect drug ADME?
- changes in gut motility e.g. opiates, atropine both reduce gut motility
- interference with absorption e.g. Fe2+ and chelating agents, food and alcohol (reduced absorption —> reduced effect of drug)
How do changes in drug distribution affect drug ADME?
- drugs with low volume of distribution more likely to interact with drugs that also have a low volume of distribution (and vice versa) due to competition at binding sites
Where do drugs with low and high volumes of distribution distribute?
Low Vd:
- blood
- intracellular spaces
High Vd:
- muscle
- fat
- extracellular spaces
How do changes in drug excretion affect drug ADME?
- reduced protein binding —> increased free [drug] —> increased excretion
- inhibition of tubular secretion —> increased [drug]plasma ———–> reduced excretion