Week 3 Non narcotic analgesics

Question 1

Describe the mechanism of aspirin for analgesic effects.

Answer 1

• Inhibits cyclooxygenase irreversibly by transferring acetyl moiety to Serine hydroxyl grp that blocks approach of arachidonic acid to substrate site
• salicylate (broken down from aspirin) reversibly inhibits COX

Question 2

What is mechanism behind the antipyretic effect of aspirin?

Answer 2

• blocks action of pyrogens and Il-1 in hypothalamus by inhibiting prostaglandin synthesis
• resets temperature control of pre optic region, facilitates heat dissipation via vasodilation and sweating

Question 3

How does acute overdose toxicity of aspirin occur?

Answer 3

> 30g is potential lethal

• saturation of salicylate metabolizing enzymes in liver and limited ability of kidney to secrete salicylate
• Results in metabolic acidosis -uncoupled oxidative phosphorylating, increasing heat production, leading to more glycolysis->lactic acid and increased oxygen consumption and CO2 formation
• hyperventilation–>respiratory alkalosis (salicylate inhibits anion exchange in RBC)

Question 4

What is the therapy for aspirin poisoning?

Answer 4

• urine alkalization with sodium bicarbonate to increase salicylate excretion (brings pH up so that more salicylate in ionized form)
• also corrects metabolic acidosis
• potassium to treat hypokalemia

Question 5

Why is aspirin not given to children?

Answer 5

• for children, association between salicylate and Reye’s syndrome
• not given to children with chickenpox or influenza, but generally avoided also for children <12

Question 6

What are the actions of acetaminophen?

Answer 6

• analgesic and antipyretic action equal in potency to aspirin
• no anti inflammatory activity
• doesn’t inhibit COX, and doesn’t share side effects with NSAIDS

Question 7

What is the mechanism of hepatotoxicity of acetaminophen?

Answer 7

• usually >7.5 g as single overdose
• cytochrome p450 converts about 5% of drug into quinoneimine, normally conjugated by glutathione and renal excreted
• in overdose, glutathione is depleted and quinonemine isn’t converted, leading to cell necrosis
• delayed hepatic necrosis, so important to identify individuals who may develop hepatotoxicity early

Question 8

What are the antidotes for acetaminophen toxicity?

Answer 8

• N-Acetylcysteine is preferred choice. Converted to cysteine and is precursor for glutathione synthesis.
• agents that increase synthesis of glutathione
• glutathione itself isn’t effective because can’t cross cell membrane
• antidotes must be given in less than 8-10 hrs after ingestion, after 24 hrs is ineffective

Question 9

Compare aspirin and acetaminophen.

Answer 9

ASPIRIN
1. gastric irritation
2. inhibition of platelet aggregation
-acetaminophen is preferred prior to surgery but not useful for prevention of coronary diseases
3. displaces drugs from albumin
4. hypersensitivity rxn
5. uricosuric effects, not given to gout patients
6. children--Reye's syndrome assoc.
7. analgesic and antipyretic activities
8. good anti inflammatory activity
ACETAMINOPHEN
7. equal in potency, none of above