Toxicity onwards

Question 1

Therapeutic index

Answer 1

TI=LD50/ED50
Larger number, the safer
over 10 is safe

Question 2

Adverse drug reactions percentage of mobidity and mortality

Answer 2

about 20%

Question 3

Classification of ADRs (2)

Answer 3

Type 1 = predictable

Type 2 = not predictable

Question 4

NSAID GI toxicity

Answer 4

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)

Question 5

Toxicity of paracetamol due to…

Answer 5

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

Question 6

Biomarker

Answer 6

Readily measurable marker of response (eg drop in BP)

Repeated meas possible
Cheap, high content info, rapid indication of
HIGH INFORMATION

Question 7

Surrogate endpoint

Answer 7

Biomarker used for reg approval (reduced viral load etc)

Question 8

Outcome

Answer 8

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

Question 9

Problem of biomarkers

Answer 9

Something like BP rarely predicts individual beneficial clinical outcome - only small % of patients will ahve death/disability prevented
LARGER percentage will have adverse effects

Question 10

Advantages of surrogate endpoints

Answer 10

High information
Low cost
“accepted” to be strongly correlated to outcome

CHEAPER and SHORTER clinical trials

Question 11

Phases of drug development (purpose of each)

Answer 11

0 = prediction for humans (animals)
1 = tolerability 
2 = Effectiveness (diseased)
3 = Safety
4 = Post-marketing

Question 12

Suxamethonium

Answer 12

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

Question 13

6-mercaptopurine

Answer 13

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)

Question 14

Perhexilline

Answer 14

Anti-angina drug that when not metabolised (CYP2D6) accumulates in lysosomes resulting in hepatotoxicity and neuropathy

Taken off market in most of world

Question 15

Most common penicillin reactions

Answer 15

Nausea, vomiting, diarrhoea, black hairy tongue

CAN ALSO cause haemolytic anaemia, leucopenia etx (assoc with high doses of parenteral penicillin)

Question 16

Cimetidine and Warfarin

Answer 16

Cimetidine inhibits warfarin metabolidm - blood levels increased to toxic levels

Question 17

Ethanol and Paracetamol

Answer 17

Eth induces enzyme that bioactivates psaracetamol, so don’t drink and take paracetamol

Question 18

Bad side effect of Baycol

Answer 18

More frequent than usual cases of rhabdomyolosis

Question 19

2 methods of decresing absorption of toxin

Answer 19

1. Ipecac

2. Activated Charcoal

Question 20

Mechanism of Ipecac

Answer 20

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

Question 21

Mechanism of Activated Charcoal

Answer 21

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

Question 22

Neutralise the chemical (2)

Answer 22

1. Iron and Deferoxamine

2. Paracetamol and N-Acetyl-Cysteine

Question 23

Iron and Deferoxamine

Answer 23

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

Question 24

Paracetamol and N-Acetyl-Cysteine

Answer 24

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

Question 25

Enhanced elimination method:

Answer 25

Salicylate and urinary alkalisation

Question 26

Salicylate and urinary alkylisation

Answer 26

Aspirin readily hydrolysed to salicylate (BAD - tinnitus, hyperventilation)

Sodium bicarbonate used to raise the urinary pH >7.5 (weak acids that undergo significant urinary excretion become trapped)

pH must be well monitored in order to prevent too high, impairs cardiac contractility, hypernatremia, fluid overload

used WITH activated charcoal

Question 27

Heroin with……?

Answer 27

Naloxone

Question 28

Naloxone:

Answer 28

(Heroin)
Antagonist at mu, kappa and delta opioid receptors

Shorter half life than heroin, take repeatedly>

May precipitate heroin withdrawal, so risk to healthcare professionals

Question 29

Warfarin and….?

Answer 29

Vitamin K

Question 30

Vitamin K

Answer 30

(Warfarin)
In overdose, blood in stools, excessive bruising

Vitamin K may be required for weeks to months until coagulation returns to normal (prothrombin)

Question 31

Organophosphates and…

Answer 31

Pralidoxime

Question 32

Pralidoxime

Answer 32

(Organophosphates, sarin)
Give atropine to antagonise ACh
Pralidoxime to remove phosphate group from choliesterase and regenerate catalytic activity

Most effective less than 24h after organophosphate exposure, as phosphorylation becomes ages and irreversible