NSAIDs Flashcards by Mark Sutherland

The four main effects seen in NSAIDs

Anti-platelet, analgesic, anti-pyretic, anti-inflammatory

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Salicylic acid

Topical keratolytic agent. Not an NSAID

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Methyl salicylate

Topical for muscle aches (Ben Gay, Icy Hot, etc). Toxic if taken internally

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Aspirin

Acetyl-salicylic acid (ASA). Prototype NSAID, organic acid salicylate derivative

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What is the pKa of ASA?

3.5

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Does ASA affect COX-1 or COX-2 and reversibly or irreversibly?

Inhibits both irreversibly by acetylating them

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What are non-acetylated salicylates used for?

Anti-inflammatory effects used for osteoarthritis and rheumatoid arthritis

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Name four non-acetylated salicylates

Sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal

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Do the antiplatelet effects of ASA occur at low or high doses?

Quite low doses (60-80 mg daily)

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What is the mechanism for the antiplatelet effects of ASA?

Inhibiting Thromboxane A2 synthesis in platelets by inhibiting platelet COXs (persists for life of platelet, 8-12 days)

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How does ASA achieve analgesia in the periphery?

Inhibiting PG synthesis (PGI2 and PGE2 synergize with bradykinin and histamine to produce inflammation)

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How does ASA achieve analgesia in the CNS?

Inhibiting PG synthesis (PGE2 causes Ca influx resulting in release of pain NTs (sub P, aspartate, glutamate, CGRP))

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In what patients will ASA not lower body temperature?

Those that do not have a fever

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How does ASA achieve antipyresis?

Cytokines produce PGE2 in preoptic hypothalamic area which increases cAMP to increase set point. ASA inhibits PGE2 synthesis

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Do the anti-inflammatory effects of ASA occur at low or high doses?

High doses (3250 to 3900 mg)

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ASA has anti-inflammatory effects mainly through inhibition of PG synthesis. What non PG-dependent mechanisms does ASA use to fight inflammation?

Inhibit neutrophil chemotaxis, stabilize lysosomes, and prevent vascular permeability. These inhibit PMN and monocyte migration to site of inflammation

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Aspirin has a pKa of 3.5 Does the stomach absorb it when gastric pH is above or below 3.5?

Below 3.5

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How does ASA damage gastric mucosa?

It gets trapped their due to intracellular pH being above its pKa (while gastric pH is below). Then acidic properties of ASA damage cell

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What is ASA first metabolized to and by what?

To salicylate ion by tissue and plasma esterases

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Why is sustained release not a good option for ASA?

Because it is subject to high levels of first pass metabolism

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Salicylate is the first metabolite of ASA. To what is salicylate normally bound in blood?

Albumin

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Salicylate is the first metabolite of ASA. Does salicylate have any pharmacologic action?

Yes it is a reversible inhibitor of COX (ASA is an irreversible inhibitor of COX)

What property of distribution may increase the gastric effects of an NSAID?

Enterohepatic recirculation

Symptoms of NSAID hypersensitivity

Vasomotor rhinitis, angioedema, generalized urticaria (hives), bronchial asthma, layngeal edema, bronchoconstriction, flushing, hypotension, shock

Are individuals with ASA intolerance more likely to have hypersensitivity to other NSAIDs?

Yes. ASA intolerance is a contraindication for other NSAIDs

What plasma level of salicylate poisoning is consistent with overdose and what are the symptoms?

30 to over 160 mg/dL, hyperventilation, metabolic acidosis, hyperpyrexia, coma, renal vasomotor and respiratory failure

What can cause Reyes syndrome?

Use of NSAIDs in children with fever caused by viral illness (or given varicella virus vaccine). Reyes is very serious

Drug interactions of ASA

Anticoagulants (warfarin, heparin, etc), Alcohol (GI bleeding), Methotrexate (increases methotrexate toxicity)

For the following are they constitutive or inducible: COX-1 and COX-2

COX-1 is constitutive, COX-2 is inducible

Is COX-1 more related to the TXA pathway or PGI2 pathway, and what does that mean for its effects on coagulation?

More related to TXA pathway. Inhibiting solely COX-1 leads to excessive bleeding

Is COX-2 more related to the TXA pathway or PGI2 pathway, and what does that mean for its effects on coagulation?

More related to the PGI2 pathway (which inhibits platelet aggregation). Sole inhibition of COX-2 can lead to hypercoagulability (stupid Vioxx)

Which COX is found everywhere, and which is found mainly at sites of inflammation?

COX-1 found everywhere, COX-2 found mainly at sites of inflammation (and in kidney and endothelial cells)

Name two COXs that are variants of other COXs

COX-3 is variant of COX-1 and COX-2b is variant of COX-2

Which non-selective COX inhibitors are irreversible, and which are reversible

ASA is irreversible, all other salicylates and organic acid NSAIDs are reversible

What type of compounds are selective COX-2 inhibitors?

Organic sulfur containing compounds

Are selective COX-2 inhibitors reversible or irreversible?

Slowly reversible

Ibuprofen

Propionic acid derivative NSAID. 20x more potent inhibitor of COX as apirin

Naproxen

Propionic acid derivative NSAID. 20x more potent inhibitor of COX as apirin

Name some acetic acid derivative NSAIDs

Ketorolac (Toradol), Indomethacin, Sulindac, Nabumetone, Diclofenac, Etodolac, Tolmetin

What is the equivalency between potency (in dose) of ketorolac (IM) and morphine (IM)

30 mg ketorolac IM is equivalent to 6 to 12 mg morphine IM

What NSAID is used for patent ductus arteriosis and what are its other uses?

Indomethacin. Also used for arthritis (e.g. ankylosing spondylitis) and acute gout

Which acetic acid derivative NSAID is given as a prodrug?

Sulindac

Which NSAID suppresses familial intestinal polyposis?

Sulindac

What characteristics are unique about Nabumetone (Relafen)?

Less gastric effects (non-acidic prodrug), very little antiplatelet effects, once daily dosing

Name three selective COX-2 inhibitors

Celecoxib (Celebrex), Rofecoxib (no longer on market), Valdecoxib (Vioxx, no longer on market)

What are the effects of acetaminophen?

Anti-pyretic, analgesic (NOT ANTI-INFLAMMATORY)

What is the mechanism of acetaminophen?

Inhibition of COX-1 and COX-2 in CNS, but not in periphery. Also strong inhibition of COX-3

When do peak blood levels of acetaminophen occur and what is its half life?

30 to 60 min, half life is 2 hours

Metabolism of acetaminophen

95 percent goes glucuronidation and suflation, 5 percent goes CYP dependent glutathione (GSH) conjugation

What toxic metabolite is generated by acetaminophen, is it the primary or alternate pathway, and what clears this toxic metabolite?

NAPQI, alternate pathway (primary overwhelmed). Cleared by hepatic GSH, which can be depleted quickly in overdose

What treatment is given for acetaminophen overdose and why?

N-acetylcysteine, it increases hepatic stores of GSH. Does not reverse any liver damage that has already occurred

What nuclear receptor does acetaminophen activate, what does it do, and why is this a problem?

Activates Constitutive Androstane Receptor (CAR) which induces CYP1A2, 2E1 and 3A, increasing rate of NAPQI production

Drug interactions of acetaminophen

Warfarin (hypothrombinemic response with high doses of acetaminophen), Caffeine (may enhance analgesia)

Two main adverse reactions with acetaminophen

Hepatic necrosis and kidney necrosis (analgesic nephrophathy)