Aspirin is an irreversible inactivator of cyclooxygenase enzymes

this is accomplished through acetylation of COX I & II

list the following NSAIDs in order of most to least potent:

Aspirin, Acetaminophen, ibuprofen, indomethacin

Indomethacin (0.1)

Ibuprofen (50)

Aspirin (164)

Acetaminophen (>1000)

values are concentrations (mcmol/L) needed for 50% enzyme inhibition

TNF and IL-1 stimulate fever by increasing synthesis of prostaglandins in the hypothalamus, which promote an increase in body temperature.

NSAIDs block this prostaglandin synthesis in the hypothalamus.  They thereby minimize the increase in body temperature, bringing the body back to (but not below) normal

Analgesic action is by blocking PGE2 synthesis.  PGE2 sensitizes nerve endings to the actions of bradykinin and other pain signals.

by irreversibly blocking cyclooxygenases, aspirin reduces platelet formation of TXA2 and endothelial formation of PGI2. 

Platelets cannot restore there supply of TXA2 (no transcription/translation machinery), whereas endothelial cells are capable of replenishing the lost PGI2.  Therefore PGI2 effects will dominate, favoring vasodilation and clot inhibition.

At high doses of aspirin, both TXA2 and PGI2 are inhibited equally and there is no effect from aspirin (no shift in the balance)

Beginning: as aspirin is absorbed it begins stimulating the respiratory center of the medulla, causing respiratory alkalosis with compensatory metabolic acidosis.

Late: continued aspirin absorption leads to depressed respiratory function and respiratory acidosis.  Increased aspirin(acidic) levels and its inhibition of TCA (organic acid buildup) also mean a furthering of the metabolic acidosis.

Make urine alkaline to help increase salicylic acid excretion

Also present: hyperthermia, abdominal cramps, nausea,

Mild= plasma salicylate 400-800

severe= plasmasalicylate > 800

1) salicylic acid

2) phenytoin

3) ethanol

Aspirin

NSAID

irreversible inactivator of COX-I, COX-II

moderate doses stimulate respiratory center in medulla and lead to decreased platelet aggregation, high doses depress respiratory center and also cause hypervolemia and a decreased GFR.

Also leads to erosive gastritis due to PGE inhibition.

(read: prolonged use of aspirin can lead to kidney problems and gastric ulcers)

Mesalamine

Sodium Salicylate

NSAIDS

 Salicylic Acid Derivatives

Mesalamine is the only NSAID indicated in the treament of Crohn's disease or ulcerative colitis.

also: ALL salicylates are contraindicated in G6P-DH deficiency because they may cause hemolytic anemia

"Advil"

NSAID

propionic acid derivative

Reversible inhibition of COX-I, COX-II

Similar effects to salicylates, but less pronounced gastrointestinal and CNS effects.

NSAID

propionic acid derivative (like ibuprofen)

NSAID

Acetic acid derivative

very potent (compared to aspirin, ibuprofen)

Inhibits cyclooxyganase pathway AND (to a lesser extent)lipoxygenase pathway.  greater anti-inflammatory efficacy than most NSAIDs

Used in acute musculoskeletal pain, inflammation of the eye, rheumatoid arthritis and ankyloasing spondylitis.

'feldene'

NSAID

of the oxicam family

one of the MOST POTENT inhibitors of the cyclooxyganase pathway.  Also inhibits PMN cell migration

meloxicam inhibits mainly COX-II

similar uses to diclofenac

most potent NSAID

highest efficacy

COX-I inhibited much more than COX-II

also inhibits phospholipase A2, thereby decreasing the synthesis of all eicosanoids and PMN migration.

uses: same as other NSAIDs,

also used to help close patent ductus arteriosus

*not indicated for general use as analgesic or antipyretic because of its toxicity.

analgesic-antipyretic drug but not anti-inflammatory ('Tylenol' or 'Paracetamol')

(no peripheral inhibition of prostaglandin synthesis)

use if NSAIDS are contraindicated (ex: hypersensitivity reaction), and if pain is not due to inflammation

Acetaminophen Poisoning: Hepatic toxicity due to intermediate (N-acetyl-p-benzoquinone)  Centrilobular necrosis.  Vomiting, abdominal pain, hepatic damage.

treatment: acetylcysteine administered w/in 16hrs protects from hepatotoxicity

1) decreased migration

2) decreased interleukin production (IL-2, TNF, IFN-g)

3) inhibition of histamine release

4) decreased fibroblast proliferation after IL-2 and growth factor inhibition

1) decreased phagocytizing ability

2) decreased interleukin production (IL-1, TNF)

3) decreased IL-1 leads to decreased TCell activation

1) Replacement therapy after surgical removal of adrenal ademona

2) Congenital adrenal hyperplasia

 3) All connective tissue disorders (arthritis, bursitis, rheumatics, lupus erythematosus, myasthenia)

 4) Cancers

5) Respiratory Distress Syndrome

6) myocarditis/pericarditis

7) cerebral edema

Epinephrine and IV glucocorticoids

Epinephrine blocks histamine release via beta-2 receptors, as well as dilating the bronchioles.  Glucocorticoids inhibit IgE synthesis and migration of inflammatory leukocytes.

a potent indole derived NSAID that is considered the drug of choice for acute attacks of gout

also drug of choice for closure of patent ductus arteriosus in newborns.  (common in premature infants)  This is achieve by the inhibition of vasodilatory prostaglandins: PGE1, 2, PGI2, which maintain the patency of the ductus.

Acetaminophen toxicity is due largely to its metabolic intermediates (N-acetyl-parabenzoquinone).  This is neutralized by the action of glutathione.  When acetaminophen is administered in toxic doses, the glutathione cannot keep up with toxic intermediate production and N-acetyl-parabenzoquinone accumulates.  It reacts with SH groups of hepatocyte proteins, causing damage to the cells and leading to centrolobular necrosis.  

Treatment involves administration of N-acetylcysteine, a compound with many SH groups that can help buffer the effects of N-acetyl-parabenzoquinone and give glutathione a fighting chance