NSAIDs 1 - Slides 14-31 Flashcards
(24 cards)
What are salicylates?
Irreversible, noncompetitive
Non-selective inhibitors of Cox-1 and Cox-2
Describe the pharmacodynamics of acetylsalicylic acid
Oral absorption
Hepatically conjugated then renal excretion
Able to cross the placenta and found in breast milk
Describe dose-response relationship of acetylsalicylic acid
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)
Treatment for salicylism?
Gastric lavage CV and respiratory support Fluids, forced diuresis Correct acid-base, electrolyte balance Reduce body temperature Dialysis
Contraindications for salicylates?
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
What is Reye’s syndrome?
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
Treatment for Reye’s syndrome?
Glucose (to treat hypoglycemia)
Fresh frozen plasma (to increase clotting)
Mannitol (to prevent edema)
What is Diflunisal?
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
What is Sulfsalazine?
Salicylate; converted by colonic bacteria into 5 aminosalicylic acid
Used in IBS
What is Olsalazine?
Salicylate; converted by colonic bacteria into 5 aminosalicylic acid
Used in IBS
Describe the pharmacodynamics of proprionic acid derivatives
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
Name the proprionic acid derivatives. Which have the highest half lives?
Ibuprofen Naproxen (14 hours) Naproxen Na (14 hours) Ketoprofen Fenoprofen Flurbiprofen Oxaprozin (40-60 hours)
Describe Cox-2 selective agents. Reversible or irreversible? What do they treat? Common side effects?
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
Describe the level of Cox-2 inhibition of the Cox-2 selective agents in order from most selectivity to least
(Most) Lumiracoxibe is equal to etoricoxibe
Valdecoxibe is equal to rofecoxibe
Celecoxib is the least
Toxicities associated with Cox-2 inhibition?
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
Actions of acetaminophen?
Analgesic, Antipyretic
Poor anti-inflammatory/anticoagulant effects
Fewer GI/CV/respiratory side effects as a result
Why is APAP able to treat fever and pain, but not inflammation like other NSAIDs?
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
What happens when APAP goes into toxic ranges? What are these ranges?
10-15 g is toxic
25 g is fatal
Dose-dependent hepatic necrosis
What are the 3 possible mechanisms of APAP?
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
Describe the TRPV1 theory of APAP mechanism
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
How is APAP metabolized?
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
What is the toxic APAP metabolite?
N-acetyl-benzoquinoneimine
How do you treat APAP toxicity?
Give N-acetyl-cysteine to replenish glutathione
However must be given in the first 8 hours of toxicity
Is APAP toxicity damage reversible?
Yes but takes several months
