Pharmacology and Toxicology

Question 1

Principles of management of salicylate toxicity

Answer 1

Specific Mx:

*Decontaminate : 50g charcoal ( 1g/kg paeds) if within 8 hours of ingestion and safe airway. Can be repeated if levels increasing suggesting bezoar

*Eliminate: urinary alkalinisation with sodium bicarbonate, aiming urine pH 7-8 ( increased weak acid ion trapping in tubules for excretion)

*Haemodialysis: if severe toxicity, or if former methods not successful

Supportive care:

ABCS - protect airway, if intubating beware need for high MV, monitor UECs, replace K, fluids and vasopressors for hypotension

Question 2

Clinical + biochemical features of salicylate toxicity

Answer 2

Neuro: tinnitus, drowsy, delirium, seizures, encephalopathy

Resp: Resp Alkalosis due to direct stimulation of resp centres

CVS: hypotension if significant volume loss, and due to acidosis, ECG widened QRS

GI: N+V, Abdo pain

Metabolic: acidosis (lactic acidosis due to uncoupling of oxidative phosphorylation -> can result in fever), K may be low

Haem: thrombocytopenia ( COX1 mediated), hypoprothrombinaemia

Question 3

When assessing a patient with salicylate toxicity, how would you interpret a declining serum salicylate level?

Answer 3

Declining salicylate level may mean different things so clinically useless:
*salicylate is highly protein bound - knowing the level tells you nothing about the free fraction
*salicylate level doesn’t correlate well with toxicity
*level going down may indicate urinary clearance OR, drug is being taken up intracellularly in acidaemia with worsening toxicity

Question 4

Mechanism of toxic effects of aspirin

Answer 4

Aspirin Kinetics:
A: oral absorption, rapid
D: small Vd. Weak acid. pK 3. >95% PB
M: Hepatic metabolism, first -> zero order kinetics when pathways saturated in overdose
E: renal clearance

Effects:
- Direct stimulant of resp centre -> Resp Alkalosis
- Direct mucosal irritation causing vomiting, Indirect CNS CTZ triggering N+V
- Uncoupling of oxidative phosphorylation -> lactic acidosis HAGMA

*NB gas machine might give mistaken NAGMA as salicylate ions are mistaken for Cl ions

Question 5

When is the Delta Ratio useful

Answer 5

*Delta ratio = increase in anion gap (from 12) / serum decrease in HCO3 (from 24)

*Useful in the presence of a HAGMA to determine if it is a ‘pure’ HAGMA or if there is coexistent normal anion gap NAGMA or metabolic alkalosis.

*Involves incorrect assumption that all buffering is by bicarb and that this happens in ECF - i.e. that for one mole of acid added, there will be one mole of bicarb used up

*Interpretation:

< 0.4 -> NAGMA - hyperchloraemia

0.4-0.8 -> NAGMA + HAGMA

1-2 -> HAGMA ( Delta ratio usually ~ 1.6 for lactic acidosis)

> 2 coexistent metabolic alkalosis - high Bicarb to start with, may have had pre-existent compensated resp acidosis