Salicylate

Question 1

What is the therapeutic use of salicylate?

Answer 1

Anti-platelet (aspirin)
- Prevent thrombosis

Question 2

What is the mechanism of action of aspirin?

Answer 2

It is an NSAID, which inhibits prostaglandin biosynthesis (as COX inhibitors)

Question 3

What are the isoforms of cycloxygenase?

Answer 3

COX-1 (constitutive and good)
PG E2 - Renal function
Thromboxane A2 - Platelet fcn
Prostacycline - Gastric protection, vascular endothelium

COX-2 (inducible and bad) ➔ inflammatory stimuli
Pro-inflammatory PGs & other inflammatory mediators
Causes inflammation (pain, fever)

Question 4

What happens when NSAID inhibits COX isoforms?

Answer 4

COX-1
TAX2 - platelet dysfunction
PGE2 - Chronic kidney disease
Prostacycline (PGI2) - GI bleeding

COX-2
Therapeutic effects (pain relief)

Question 5

Describe salicylate metabolism.

Answer 5

Acetylsalicylic acid and methylsalicylic acid ➔ salicylic acid

1. Salicylic acid can be excreted unchanged in urine (~10%) [1st-order kinetics]
2. Salicylic acid can be oxidized into gentisic acid (~1%) [1st-order kinetics]
3. Salicylic acid can be converted into acylglucuronide (~5%) [1st-order kinetics]
4. Salicylic acid can be converted into phenolic glucuronide (~10%) [Michaelis-Menten kinetics]
5. Salicylic acid can be converted into salicyluric acid (~75%) [Michaelis-Menten kinetics]

1-5 occurs in liver

1st-order kinetics = nonsaturable kinetics
Michaelis-Menten kinetics = saturable kinetics

Question 6

At toxic levels of salicylate, renal excretion:

Answer 6

1. Becomes major route of excretion
2. Renal elimination is pH dependent from 10-50%
3. Urinary alkalization with sodium bicarbonate increases urinary elimination by 10-20x

Question 7

Why does urinary alkalization with sodium bicarbonate increases urinary elimination by 10-20x?

Answer 7

Salicylate is a weak acid (pKa 3.5), ionization is increased in an alkaline environment
- Salicylate ions cannot cross cell membrane

Alkalization shifts the equilibrium to the right which favours ionization
HA ➔ H + A

1. Both salicylic acid and salicylate ions can freely filter through glomeruli into renal tubules
2. Salicylate ions cannot be reabsorbed by renal tubules so it is trapped and excreted in the urine.

Question 8

Why is plasma alkalization used to eliminate salicylic acid?

Answer 8

Prevents salicylate from entering tissues and the CNS

Salicylate ion cannot cross cell membrane and blood-brain barrier, hence it is trapped in blood which allows more rapid excretion in the urine

Question 9

What is the mechanism of toxicity induced by salicylate overdose?

Answer 9

ALL METABOLIC EFFECTS
1. Uncouples oxidative phosphorylation

2. Inhibits key dehydrogenase enzymes in Krebs cycle
   - Interferes with glucose and fat metabolism
   - Pyruvate dehydrogenase connects the citric acid cycle and subsequent oxidative phosphorylation to the glycolysis, gluconeogenesis, and lipid and amino acid metabolism pathways

Question 10

What does a person do to compensate in salicylate toxicity?

Answer 10

Hyperventilation

Question 11

What are the metabolic effects of salicylate toxicity?

Answer 11

Inhibition of key dehydrogenase enzymes in Krebs cycle
1. Decreased ATP production
2. Ketoacidosis
3. Lactic acidosis
4. Hypoglycemia

Uncoupling of oxidative phosphorylation
1. Decreased ATP production
2. Hyperthermia

Question 12

What is Reye’s syndrome?

Answer 12

Children with acute febrile viral illness given Aspirin

Acetylsalicylic acid (ASA) a.k.a aspirin, should not be given to children, teenagers, young adults with chickenpox, influenza or flu-like symptoms

Question 13

What are the clinical manifestations of Reye’s syndrome?

Answer 13

1. Acute noninflammatory encephalopathy
2. Fulminant hepatic failure

Question 14

What can we do to test for salicylate poisoning?

Answer 14

Test plasma salicylate level
- 2 h for symptomatic patients
- 4 h for asymptomatic patients
Post ingestion

Question 15

Why should we be careful to intubate patients who have salicylate poisoning?

Answer 15

Their hyper ventilatory compensation is not maintained

Question 16

What are some ways we can manage salicylate poisoning?

Answer 16

1. GI contamination
2. Enhancing elimination - urinary alkalization, hemodialysis, hemoperfusion
3. Supportive care - fluid/electrolyte management, for hyperthermia ➔ fans, cold water submersion

Question 17

What are indications for urinary alkalization by bicarbonate in salicylate poisoning?

Answer 17

Proven or suspected salicylate toxicity and symptoms of salicylism
1. Tinnitus
2. Delirium
3. Fever
4. Metabolic derangements

High plasma salicylate levels
1. >2.9 mmol/L in acute toxicity
2. >2.2 mmol/L in chronic toxicity

Urinary alkalization should be considered as 1st-line treatment for moderately-severe salicylate poisoning

Question 18

What is the normal concentration of salicylate in the body?

Answer 18

0.3 - 2.1 mmol/L

Question 19

What are the indications for dialysis in salicylate poisoning?

Answer 19

Based on levels
1. >7 mmol/L in acute
2. >6 mmol/L in chronic
3. Rising levels despite optimal medical management

Based on toxicity
1. CNS Toxicity
2. ARDS
3. Renal failure