NSAIDs

Actions due to:
1) Inhibition of cyclo-oxygenase enzymes (Cox-1 & Cox-2)
2) Inhibition of fatty acid amide hydrolase (breaks down N- arachidonoylethanolamine)
3) Inhibition of cyclooxygenation of 2-arachidonoylglycerol

Anti-inflammatory actions – dec. in PGE2 & PGI2, less vasodilation, less edema

Analgesic effect – dec. PGs, less sensitization of nociceptic nerve endings to bradykinin & 5-hydroxytryptamine, dec. in PG-induced vasodilation

Antipyretic effect – dec. in PGE2, made in response to IL-1. PGE2 elevates hypothalamic setpoint for temp. control

HOWEVER, most non-selective NSAIDs lead to some forms of gastropathy and/or nephropathy due to inhibition of Cox-1

simple, competitive, reversible inhibitors that compete with arachidonic acid for binding to the Cox active site.
Ibuprofen, naproxen, acetaminophen

competitive, time dependent, reversible inhibitors that bind to the Cox active site in an initial phase, forms reversible enzyme inhibitor complex, which, if retained for a sufficient time, causes a non-covalent conformational change in the protein, tighter binding.
Indomethacin, flubiprofen, diclofenac, meclofenamic acid

competitive, time dependent, irreversible inhibitors that form an enzyme inhibitor complex after covalent conformational change in the protein.
Aspirin

metabolizes anandamide to Arachidonic acid. Anandamide is our natural cannabinoid bliss molecule.

Interference with neutrophil-endothelial cell adherence, decreases expression of L-selectin

Asprin Specific Effects
Inhibition of NF-kB dependent transcription
Inhibition of iNOS expression
--Effects exerted at the level of translational/posttranslational modifications & directly upon catalytic activity of iNOS

Apoptosis

Most act by reversibly inhibiting both Cox-1 and Cox-2 (except acetylsalicylate, irreversible)
Inhibit platelet activation and lower cardiac mortality
React with nucleophilic groups on proteins resulting in acetylation.
Carboxylate anion required for anti-inflammatory activity
Substitution on the carbonyl or hydroxyl groups change the potency or toxicity.
Metabolized by glucuronidation.
Isolated in 1838 (extracted from willow bark), artificial synthesis of acetylsalicylic acid, 1897, 1899 commercially available

Complete blockade of Cox-1
Partial blockade of Cox-2

Production of ATL
Protective in animal models of:
1. Ischemia-reperfusion injury
2. Peritonitis
3. Asthma
Inhibits PMN recruitment
Enhances macrophage phagocytosis of apoptotic PMNs
Increases macrophage phagocytosis of bacteria
Decreases inflammatory cytokine production

Gastrointestinal ulceration and hemorrhage
Nephrotoxicity
Hepatic injury
Aspirin-induced airway hypersensitivity in asthmatics (perhaps due to increased LT levels, decrease immunosuppressive effect of PGE2)
Reye’s syndrome (Hepatic encephalopathy & liver steatosis in children)

Acetaminophen, active metabolite of Phenacetin (phenacetin not available in US)
Analgesic and antipyretic

Main analgesic mechanisms of action:
APAP metabolite: N-acetyl-p-benzoquinone imine (NAPQI)
agonist for TRPA1 (transient receptor potential cation channel subfamily A member 1) receptor, mediates analgesia, fever

APAP metabolite, p-aminophenol, crosses blood brain barrier and is metabolized to N-(4-hydroxyphenyl)-5Z, 8Z, 11Z, 14Z - eicosatetraenamide (AM404) --
potent agonist for TRPV1 (transient receptor potential vanilloid 1) receptor (elicits antinociception) in the midbrain & medulla and spinal dorsal horn
acts as an agonist of CB1 receptors in the brain
inhibits uptake of endogenous cannabinoids

Weak inhibition of Cox-1
Weak anti-platelet activity
No GI toxicity

Weak anti-inflammatory action
(works best with low levels of AA)

Inhibits PG production by acting as reducing peroxidase cosubstrate

Considered only a “modulator” of Cox activity
Influenced by antioxidant enzymes, GSH, hydroperoxides

Hepatotoxicity

Better tolerated, COX inhibitors, used to treat gout, lupus, general pain, osteo- and rheumatoid arthritis.
Ibuprofen (Motrin, Advil) – 1st to come into general use, S-isomer more active
Flurbiprofen (Ansaid)
Naproxen (Aleve) –
20X more potent than aspirin
Long plasma ½ life
Directly inhibits leukocyte function
Brain specific prodrugs synthesized

PGs that mediate inflammation, fever and pain are produced solely by COX-2
PGs important in gastrointestinal & renal function are produced solely by COX-1

Toxicity of NSAIDs in GI and renal systems due to lack of selectivity with respect to COX-1 & COX-2, SO design a drug specific for COX-2 to minimize adverse side effects

Sulfonic acid derivatives
Oxidation state of sulfur important, sulfones & sulfonamides selective for COX-2, sulfoxides and sulfides are not.
2 classes – carbocyclic & heterocyclic
100X more selective for COX-2
Anti-inflammatory, antipyretic, analgesic similar to non-selective NSAIDs
No antiplatelet activity
Only celecoxib (Celebrex) is approved in the US, etoricoxib (Arcoxia) and lumiracoxiab (Prexige) approved overseas.

Thrombogenicity
Hypertension
Renal failure
Cardiac failure
Wound healing