NSAIDs 1 - Slides 14-31

Question 1

What are salicylates?

Answer 1

Irreversible, noncompetitive

Non-selective inhibitors of Cox-1 and Cox-2

Question 2

Describe the pharmacodynamics of acetylsalicylic acid

Answer 2

Oral absorption
Hepatically conjugated then renal excretion
Able to cross the placenta and found in breast milk

Question 3

Describe dose-response relationship of acetylsalicylic acid

Answer 3

80-325 mg: Antiplatelet effects, can lead to bleeding

650-1000 mg: Antipyretic, analgesic - can lead to bleeding, GI, nausea, and hypersensitivity

3000 to 6000 mg: Antiinflammatory - can cause Tinnitus

6000 to 10,000 mg: Salicylism, hyperventilation/alkalosis

10-20,000 mg: Salicylism (fever, dehydration, metabolic acidosis)

20-30,000 mg: Salicylism (Shock, coma, respiratory and renal failure, death)

Question 4

Treatment for salicylism?

Answer 4

Gastric lavage
CV and respiratory support
Fluids, forced diuresis
Correct acid-base, electrolyte balance
Reduce body temperature
Dialysis

Question 5

Contraindications for salicylates?

Answer 5

Bleeding disorders (use with caution)

Pregnancy (low doses may be of benefit in hypertensive disorders but it can lead to pre-eclampsia/growth retardation of fetus)

Children with fever associated with a viral disease bc there’s increased risk of Reye’s syndrome

Question 6

What is Reye’s syndrome?

Answer 6

Fatty liver encephalopathy
Usually seen in children under the age of 15, mortality is 50%
Associated with aspirin use in children recovering from viral illness like influenza or chicken pox

1-3 days of persistent vomiting, stupor, progresses rapidly to convulsion and coma.
Enlarged liver
Increased aminotransferase, serum ammonia, prothrombin time, hypoglycemia, metabolic acidosis

Question 7

Treatment for Reye’s syndrome?

Answer 7

Glucose (to treat hypoglycemia)
Fresh frozen plasma (to increase clotting)
Mannitol (to prevent edema)

Question 8

What is Diflunisal?

Answer 8

A salicylate; competitive and reversible

Good anti-inflammatory (osteo and rheumatoid arthritis)
Good analgesic for mild to moderate pain
Less antipyretic effects (can mask fever at higher doses)

It can cause Stevens Johnson Syndrome

Question 9

What is Sulfsalazine?

Answer 9

Salicylate; converted by colonic bacteria into 5 aminosalicylic acid
Used in IBS

Question 10

What is Olsalazine?

Answer 10

Salicylate; converted by colonic bacteria into 5 aminosalicylic acid
Used in IBS

Question 11

Describe the pharmacodynamics of proprionic acid derivatives

Answer 11

Orally absorbed, high protein binding, more potent than salicylates
Hepatic conjugation and renal excretion (like salicylates)
Less severe GI side effects but more severe renal and hepatotoxicity

Used for arthritis, muscle pain, dysmenorrhea

Question 12

Name the proprionic acid derivatives. Which have the highest half lives?

Answer 12

Ibuprofen
Naproxen (14 hours)
Naproxen Na (14 hours)
Ketoprofen
Fenoprofen
Flurbiprofen
Oxaprozin (40-60 hours)

Question 13

Describe Cox-2 selective agents. Reversible or irreversible? What do they treat? Common side effects?

Answer 13

Reversible, selective for Cox-2
They mainly affect inflammation with limited GI side effects
Can cause dyspepsia, diarrhea

Only one on the market now is Celecoxib

Question 14

Describe the level of Cox-2 inhibition of the Cox-2 selective agents in order from most selectivity to least

Answer 14

(Most) Lumiracoxibe is equal to etoricoxibe
Valdecoxibe is equal to rofecoxibe
Celecoxib is the least

Question 15

Toxicities associated with Cox-2 inhibition?

Answer 15

Inhibiting PGI2 production causes more TXA2 production in epithelial cells of the blood vessels
This increases risk of MI and strokes, increases blood pressure, and decreases kidney function

Can also cause hypersensitivity and skin reactions

Question 16

Actions of acetaminophen?

Answer 16

Analgesic, Antipyretic
Poor anti-inflammatory/anticoagulant effects

Fewer GI/CV/respiratory side effects as a result

Question 17

Why is APAP able to treat fever and pain, but not inflammation like other NSAIDs?

Answer 17

More potent centrally
Inactivated by peroxidases found in inflamed tissue so has no anti-inflammatory effects
Fewer GI/CV/respiratory side effects as a result

Question 18

What happens when APAP goes into toxic ranges? What are these ranges?

Answer 18

10-15 g is toxic
25 g is fatal

Dose-dependent hepatic necrosis

Question 19

What are the 3 possible mechanisms of APAP?

Answer 19

COX 3 inhibitor (variant of COX1 found in canine brain, limited in humans)

NO synthase inhibitor - NMDA induced NO facilitates pain, no effect on cNOS or iNOS

Cannabinoid receptor - APAP is metabolized to p-aminophenol, which is conjugated w/ arachidonic acid by fatty acid amide hydrolase to form N-arachidonoylphenolamine which can inhibit the uptake of Amandamide (CB receptor agonist) and gate TRPV1 channels in cells

Question 20

Describe the TRPV1 theory of APAP mechanism

Answer 20

TRVP 1: Transient receptor potential vanilloid 1

Gated ion channels involved in sensory information transduction (heat and pain)
Channel activated by anandamide, if you inhibit the uptake of amandamide then you’ll have it activating the receptor longer, desensitizing it and keeping it open to decrease the pain pathway

Question 21

How is APAP metabolized?

Answer 21

APAP goes through 3 metabolic pathways:

Sulfate (renal excretion of metabolite)
Glucuronidation (renal excretion of metabolite)
and P450 to a toxic metabolite, that is usually further metabolized by glutathione and renally excreted

Glutathione is limited so any extra toxic metabolite goes to the liver and causes hepatic necrosis

Question 22

What is the toxic APAP metabolite?

Answer 22

N-acetyl-benzoquinoneimine

Question 23

How do you treat APAP toxicity?

Answer 23

Give N-acetyl-cysteine to replenish glutathione

However must be given in the first 8 hours of toxicity

Question 24

Is APAP toxicity damage reversible?

Answer 24

Yes but takes several months