Toxicity onwards Flashcards
Therapeutic index
TI=LD50/ED50
Larger number, the safer
over 10 is safe
Adverse drug reactions percentage of mobidity and mortality
about 20%
Classification of ADRs (2)
Type 1 = predictable
Type 2 = not predictable
NSAID GI toxicity
Induce lesions by interacting with phosphatidyl choline and reducing gastric mucosa’s ability to protect itself (COX cycloprotective so initial lesion results in overt damage)
Toxicity of paracetamol due to…
Saturation of detoxification pathways
Toxic metabolite quinoneimine (reacts with sulfhydryl groups in critical cellular proteins) Loss of intra Ca disrupts mitochondria and leads to necrotic cell death
Adult dose >200mg/kg or 10g in acute dose
Biomarker
Readily measurable marker of response (eg drop in BP)
Repeated meas possible
Cheap, high content info, rapid indication of
HIGH INFORMATION
Surrogate endpoint
Biomarker used for reg approval (reduced viral load etc)
Outcome
What patient feels / functions / survives (pain, hospital admission, surgery, DEATH)
SUBJECTIVE (pain)
Often happens only once (death)
Can take MANY YEARS for evident differences
LOW INFORMATION
Problem of biomarkers
Something like BP rarely predicts individual beneficial clinical outcome - only small % of patients will ahve death/disability prevented
LARGER percentage will have adverse effects
Advantages of surrogate endpoints
High information
Low cost
“accepted” to be strongly correlated to outcome
CHEAPER and SHORTER clinical trials
Phases of drug development (purpose of each)
0 = prediction for humans (animals) 1 = tolerability 2 = Effectiveness (diseased) 3 = Safety 4 = Post-marketing
Suxamethonium
Lack of detox results in enhanced pharmacological activity
used for muscle relaxation during surgery
Normally lasts 2-6 minutes
USUALLY hydrolysed by plasma eserases. 1/3500 caucasians reduced activity : prolonged muscle paralysis and apnea
6-mercaptopurine
Undergoes s methylyation catalysed by thiopurine methyl transferase
1/300 at risk of potentially fatal haematopoeitic toxicity due to accum of thioguanine nucleotides in haematopoeitic tissues.
10-15fold reduction in dose
(Genotype people prior to administration)
Perhexilline
Anti-angina drug that when not metabolised (CYP2D6) accumulates in lysosomes resulting in hepatotoxicity and neuropathy
Taken off market in most of world
Most common penicillin reactions
Nausea, vomiting, diarrhoea, black hairy tongue
CAN ALSO cause haemolytic anaemia, leucopenia etx (assoc with high doses of parenteral penicillin)
Cimetidine and Warfarin
Cimetidine inhibits warfarin metabolidm - blood levels increased to toxic levels
Ethanol and Paracetamol
Eth induces enzyme that bioactivates psaracetamol, so don’t drink and take paracetamol
Bad side effect of Baycol
More frequent than usual cases of rhabdomyolosis
2 methods of decresing absorption of toxin
- Ipecac
2. Activated Charcoal
Mechanism of Ipecac
Cephaeline stimulates vomiting centre
Emetine activates sensory receotprs in proximal small intestine
Only useful over SHORT timeframe (before absorption). Limits ability to use other strategies
Mechanism of Activated Charcoal
Drug adsorb onto charcoal and prevent absorption (too big)
Creates conc gradient such that drug/metabolite is eliminated faster
Dose usually 1-2g/kg orally or naso-gastric tube
Neutralise the chemical (2)
- Iron and Deferoxamine
2. Paracetamol and N-Acetyl-Cysteine
Iron and Deferoxamine
Large amt iron overwhelms GI resulting in massive iron absorption
When serum iron levels exceed the capacity of the binding protein transferrin, severe toxicity mac occur
Free iron causes toxicity to intestines, generates free radicals
DEFEROXAMINE is antidote for iron poisoning
Chelates the free iron to form feroxamine but does not remove iron from proteins such as transferrin, ferritin, Hb
Feroxamine excreted unchanged in the liver
Paracetamol and N-Acetyl-Cysteine
NAC is antidote for paracetamol overdose
Paracetamol is metabolised to quinoneimine that can react with the sulfhydryl groups in proteins (high doses, liver failure and death)
NAC is precursor for glutathione synthesis and so boosts resynthesis of vital intracellular agent and thus prevents liver damafe.
NAC antioxidant
