Analgesics

Question 1

Describe the metabolism of salicylate

Answer 1

aspirin is hydrolyzed into salicylic acid in GI, once absorbed, majority is metabolized by 4 hepatic pathways, 1 pathway via urine that is pH dependent (depending on pH this pathway is 10-50% elimination)
- at high levels of toxicity, urine becomes main route of elimination (hepatic is saturated)
- urinary alkalization increases urinary elimination by 20-30x

Question 2

Describe ion trapping by alkalization in serum and urine

Answer 2

By treating with sodium bicarb, we raise pH in plasma and urine, this means that salicylate is ionized in the both the circulation, preventing it from entering tissue and CNS, as well as preventing reabsorption in the tubules.
(can still be filtered through glomeruli in both forms)

Question 3

What is the mechanism of salicylate toxicity?

Answer 3

Uncouples oxidative phosphorylation and inhibits key dehydrogenase enzyme in Krebs
- which interferes with glucose and fat metabolism
- results in hyperthermia and decreased ATP production
- results in increased peripheral glycolysis (lactic acidosis, hypoglycemia) and increased fatty acid metabolism (ketoacidosis)
- also stimulates resp center in brain

Question 4

What are the manifestations of salicylate poisoning?

Answer 4

Gastroenteritis (remember, inhibits COX1 AND COX 2)
Mixed resp alkalosis and metabolic acidosis
CNS toxicity
cardiac toxicity
acute resp. distress syndrome

Question 5

What is reyes syndrome

Answer 5

acute noninflammatory encephalopathy
- also causes sudden and severe liver failure

Question 6

What tests should we run for salicylate poisoning?

Answer 6

Standard lab tests
- ABG
- blood glucose
- PTT
- anion gap/ electrolytes
- lactate
Plasma salicylate level

Question 7

How do we treat salicylate poisoning?

Answer 7

prevent absorption: lavage, make them vomit with medication, charcoal
Supportive care: fluid and electrolytes, treat hyperthermia by cooling
Enhance elimination:
- urinary alkalization (suspected salicylate toxicity and symptoms; high plasma salicylate levels)
- hemodialysis (very severe)
- hemoperfusion

Question 8

What is the MOA of acetaminophen

Answer 8

analgesic : competitively inhibits COX 3 in CNS -> decreased prostaglandin
- weakly inhibits COX 1 and 2 -> doesn’t lead to gastritis and inhibited platelet like aspirin

antipyretic: direct effect on heat-regulating centers in brain -> sweating and vasodilation

Question 9

Describe APAP metabolism

Answer 9

majority is metabolized into a sulfate form and a glucuronide form (some in urine)
- rest is metabolized into NAPQI (toxic) which is metabolized into non-toxic form if glutathione present

Question 10

How does APAP overdose and liver injury occur?

Answer 10

if both sulfation and glucuronidation pathways are saturated, APAP is metabolized into NAPQI, if Glutathione is depleted, excess NAPQI binds to SH groups in cellular proteins and cause cell injury -> leads to centrilobular hepatic necrosis

Question 11

What level of glutathione is needed for safety?

Answer 11

APAP toxicity occurs when hepatic GSH falls to less than 30% of baseline

Question 12

What are risk factors for APAP toxicity?

Answer 12

1. induction of CYP2E1 CYP3A4 liver enzymes increases formation of NAPQI, induction occurs by excess alcohol and long term treatment with enzyme inducing drugs
2. depletion of glutathione such as malnourished, eating disorders, alcoholism, AIDS

Question 13

How does APAP poisoning present?

Answer 13

4 stages
1 (0-24hrs) : GI irritation, nausea vomiting, liver tests normal
2 (18-48hrs): latent period, RUQ pain, AST/ALT increase, transient resolution of GI symptoms
3 (72-96hrs): maximal hepatotoxicity, vomiting reappears, AST/ALT/ PT/ bilirubin peak, sudden and severe liver failure (jaundice, hemorrhage), sometimes renal and pancreatic failure
4(5days - 3 weeks): resolution or death, resolution or progression to multiple organ failure

Question 14

How is the decision of antidote treatment for APAP determined? When is it not applicable?

Answer 14

based on timed plasma APAP concentration using Rumack-matthew nomogram (if over line, treat)
- only used for SINGLE acute ingestion
- sample must be collected over 4 hrs after ingestion (assume complete absorption and peak plasma level)

Cant use when:
- ingestion over 24hrs ago
- unknown time of ingestion
- extended release APAP
- chronic overdose

Question 15

Describe the MOA of NAC

Answer 15

N-acetyl cysteine can
- directly detoxify NAPQI
- increase syntheses and availability of glutathione
- act as substrate for sulfation pathway
-

Question 16

What are additional treatments for APAP besides NAC

Answer 16

activated charcoal to reduce absorption (must be within 1st hour of OD)
supportive treatment: liver transplant, fluid replacement etc.