Autocoids, Analgesics, NSAIDS

NSAID: *Very Potent --> Increased SE (Pancreas)

also inhibits Phospholipase A and PMN migration

*Used to close Patent Ductus Arteriosus (as are other NSAIDs)

All are reversible inhibitors and all have the similar side effects

GI: pain, ULCER, Pancreatitis, Diarrhea

NSAID: Specific COX-2 inhibitor
*Reversible

Shifts PG synthesis to COX-1 --> Thromboxanes become predominant and increase platelet aggregation and vasoconstriction --> INCREASE RISK OF MI AND STROKE

Contraindicated in GI, Renal, CV disease, Bowel Ischemia

Antipyretic/Analgesic - NOT ANTI-INFLAMMATORY (not used to treat RA)

*Metabolized by liver - NAPQI toxic metabolite causes *Dose Dependent Hepatic Necrosis*
-potentiated by EtOH

DOC for child with fever (not aspirin which can cause Reye's)

Gastric emptying within 4 hours

Forced Diuresis

*N-acetylcysteine (mucomyst) binds free radicals (administer parenterally)

PGE1 - Misoprostol is a PGE1 analogue to decrease gastric acid secretion in ulcers

Thromboxane Production: Platelet aggreagation and vasoconstriction

Constitutively produced: GI protection from stomach acid*

Chemotaxis, Bronchoconstrictino `

Prostacyclin PGI synthesis in ENDOTHELIAL CELLS

It is inducible (microsomal)

Doesn't truly affect platelet aggreagration - but when inhibited PG ratio is shifted to TXA which increases platelet aggregatino

PGE2 - used for abortion, facilitating labor and dysmenorrhea

*all prostaglandins are contraindicated in pregnancy due to abortion potential

Prostaglandin PGE1: Treatment of ED

May cause priapism (like Trazodone)

PGs keep PDA patent

Tx of Pulmonary HTN via vasodilation

Bosentan and Sildenafil tx pulmonary HTN as well

PGF2a analogue: Topical Tx of Glaucoma

Increases uveoscleral resorption of aqueous humor
-additive effect when used with Timolol

SE: iridial discoloration (like amiodarone, Thioridazine), Conjunctival Hyperemia, eyelash GROWTH

*PGE1 analogue*

Reduces gastric acid secretion in ulcers

*PGE1 is the most GI protective*

Lipoxygenase Inhibitor

Tx of Asthma because LTC4 increases bronchial tone

Leukotriene Receptor Inhibitor

Treatment of Asthma

ASA *Prototype NSAID*
IRREVERSBLE COX1 and COX2 inhibitor

4 Effects: Analgesia, Antiinflammatory, Antipyretic, Platelet Inhibition

Weak Acid --> Eliminated by alkaline urine (Sodium Bicarb)

Tox:
Asthma: Shunts Eicosonoid synthesis to bronchoconstricting leukotrienes

Gout - competes with uric acid for excretion

Epigastric Distress - ULCERS - inhibition of PGE1

Renal Damage --> inhibition of prostaglandins which are used to vasodilate/offset effects of angiotensin

Low doses --> 1st order kinetics
High doses--> 0 order kinetics

PUD, Bleeding Disorders, Vit K deficiency

MANY drug interactions:
*displaces warfarin from plasma proteins --> increases bleeding*

Also competes with penicillin and other acids for plasma protein binding

Aspirin Toxicity characterized by tinnitus and vertigo --> leads to deafness

Skin eruptino and CNS problems

Salicylate "Jag" - resembles drunk

Induced by giving aspirin to children with viral infections

uncouples oxidative phosphorylation

DOC for child with fever: Tylenol

Less effecte than aspirin

COX inhibition is reversible

oil of Wintergreen

irritates skin/mucosa

some salicylates are keratolytic --> wart removal

Siacylic acid derivative NOT metabolized to salicylic acid thus NOT A PRODRUG

No significant antipyretic effects

Dicolfenac (potent NSAID)

+

Misoprostol (PGE1 anologue) GI protectant

NSAID: Potent COX inhibitor

SE: mostly GI, thus administer with misoprostol (= arthrotec when combined)

Most Potent NSAID*

Thus good analgesic for POST-OP PAIN

*Can only use for 5 days - Gastric Ulceration*

Minutes - very short

Motrin and Advil

*First Choice NSAID because decreased SE, but also decreased potency*

*Short t1/2 - requires multiple daily doses*

NSAID w/ longest t1/2 - 13 hours

"take a LONG NAP"

NSAID: inhibits PMN migration and decreases free radicals

Long t1/2

Prodrug NSAID

requires conversion to active metabolite

Long enough t1/2 for 1x daily admin

Very Potent NSAID - not available in the US

Serious GI and BM Side Effects

Similar to Piroxicam NSAID

Less nephrotoxic than other NSAIDS

Severe GI SE and Pancreatitis