MOA: suppress prostaglandin synthesis in the CNS that is stimulated by pyrogens and thereby reduces fever
*COX-1:* totally shut down, so platelet can’t make more
*COX-2:* turns enzyme into lipoxygenase, converted to 15-Lipoxin A4, which is an anti-inflammatory compound
– better at inhibiting COX-1 than COX-2, meaning it’s better at preventing CV events in people who are at risk of CVD. However, not in people who are not at risk
– COX-2 event, so Aspirin effects water/salt retention
COX-2 inhibition in the kidney leads to -> retention of water and sodium which can lead to -> hypertension
– Release of prostaglandins necessary for homeostatic function is disrupted, as is release of prostaglandins involved in inflammation.
– also, little to no anti-platelet effect since COX-1 is not inhibited as strongly, if at all
Examples: Celecoxib, Rofecoxib, Valdecoxib
– Drug interaction: Celecoxib is metabolized by same CYP450 enzyme as warfarin
– Valdecoxib: increased CVD in bypass patients -> removed from market
– Rofecoxib: increased edema, HTN, and mortality -> removed from market
– The irreversible action of aspirin results in a *longer duration* of its antiplatelet effect and is the basis for its use as an antiplatelet drug
– Activation of peripheral pain sensors may be diminished as a result of reduced production of prostaglandins in injured tissue
-a central mechanism is operative.
– Most important, they reduce prostaglandin-mediated cytoprotection in the GI tract and autoregulation of renal function
– GI: particularly important how NSAIDs cause increased acid secretion and decreased mucus secretions -> ulcers
– Salicylate is a reversible nonselective inhibitor of cyclooxygenase. Duration of activity is longer than pharmacokinetic half-life of drug due to irreversible COX inhibition
– Elimination of salicylate is first order at low doses, with a half-life of 3-5 h. At high doses, half-life increases to 15 h or more and elimination becomes zero order.
– Excretion is via the kidney.
– half-life of about 2 h, is relatively safe
– GI toxicity, nephrotoxicity hypersensitivity due to increased leukotrienes
– Drug Interaction: interference with aspirin’s antithrombotic action
– many other conditions, including dysmenorrhea, headache, and patent ductus arteriosus in premature infants.
– reduce polyp formation in patients with primary familial adenomatous polyposis. Long-term use of NSAIDs reduces the risk of colon cancer.
– only NSAID available in a *parenteral* formulation.
– Chronic use can result in gastric ulceration, upper GI bleeding, and *renal damage* including acute failure and interstitial nephritis.
– increases bleeding time
– aspirin hypersensitivity
– Reye’s syndrome
– there’s no specific antidote for aspirin
– This type of hypersensitivity to aspirin precludes treatment with any NSAID.
– respiratory alkalosis
– risk of *renal damage* with any of the NSAIDs, especially in patients with preexisting renal disease. Because these drugs are cleared by the kidney, renal damage results in higher, more toxic serum concentrations.
– Use of parenteral *ketorolac* is generally restricted to 72 h because of the risk of GI and renal damage with longer administration.
– Serious hematologic reactions have been noted with *indomethacin*
– same risk of *renal damage,* presumably because COX-2 contributes to homeostatic renal effects.
– TXA2 has opposite effects
– still available in some other countries.
– only a *weak COX-1 and COX-2 inhibitor* in peripheral tissues, which accounts for its lack of anti-inflammatory effect; does not directly inhibit PGH2 synthase, it binds a substrate that makes the enzyme work so it *interferes with PG synthesis*
– may inhibit a third enzyme, COX-3, in the CNS
– lacks anti-inflammatory or antiplatelet effects
– used in hemophiliacs
– when taken in overdose or by patients with severe liver impairment -> dangerous *hepatotoxin*
– mechanism of toxicity: involves oxidation to cytotoxic intermediates by *phase I CYP450,* which occurs when the body has low amounts of substrates for phase II conjugations (acetate and glucuronide). Prompt administration of *acetylcysteine,* a sulfhydryl donor, required
– People who regularly consume 3 or more alcoholic drinks per day are at increased risk of acetaminophen-induced hepatotoxicity
– called disease-modifying drugs because some evidence shows slowing or even reversal of joint damage, an effect never seen with NSAIDs.
– also called slow-acting antirheumatic drugs because it may take 6 wk to 6 mo for their benefits to become apparent.
– However, too toxic for routine chronic use
– reserved for temporary control of severe exacerbations and long-term use in patients with severe disease not controlled by other agents.
– Acute and Chronic
Two Goals of Treatment:
1. Treat inflammation
2. Treat cause
– Treatment strategies include:
1. reducing inflammation during acute attacks with colchicine, NSAIDs, or glucocorticoids
2. accelerating renal excretion of uric acid with uricosuric drugs such as probenecid or sulfinpyrazone
3. reducing the conversion of purines to uric acid by xanthine oxidase, using allopurinol or febuxostat
– inhibited by allopurinol and febuxostat
– effective in inhibiting the inflammation of acute gouty arthritis.
– reduce prostaglandin formation
– inhibit crystal phagocytosis by macrophages
– along with glucocorticoids, reduce the synthesis of inflammatory mediators in the gouty joint
– reduces leukocyte migration and phagocytosis
– may also reduce production of leukotriene B4 and decrease free radical formation.
– since it reacts with tubulin and interferes with microtubule assembly, it’s a general *mitotic poison.* Tubulin is necessary for normal cell division, motility, and many other processes.
– Lower doses are used to prevent attacks of gout in patients with a history of multiple acute attacks.
– also of value in the management of *familial Mediterranean fever*
– managed by colchicine
– Short courses of glucocorticoids can cause behavioral changes and impaired glucose control.
– Because colchicine can severely damage the liver and kidney, dosage must be carefully limited and monitored. Overdose is often fatal.
– *Probenecid and sulfinpyrazone* are weak acids that compete with uric acid for reabsorption by the weak acid transport mechanism in the proximal tubules and thereby *increase uric acid excretion*
– At low doses, may also compete with uric acid for secretion by the tubule and occasionally can elevate, rather than reduce, serum uric acid concentration.
– Elevation of uric acid levels by this mechanism occurs with aspirin (another weak acid) over much of its dose range.
Uricosuric drugs are used orally to treat chronic gout. These drugs are of no value in acute episodes.
– These are *sulfonamides,* so may share allergenicity with other classes of sulfonamide drugs like diuretics, antimicrobials, and oral hypoglycemic drugs
– increased uric acid in kidney tubules can precipitate and form stones; must drink lots of water to prevent this.
– increased UA in plasma is a risk factor for CVD
– converted to *oxypurinol* or *alloxanthine* by xanthine oxidase; *alloxanthine is an irreversible suicide inhibitor* of the enzyme
– allopurinol and alloxanthine inhibit other enzymes involved in purine and pyrimidine metabolism
– *more selective* and *more efficacy* than allopurinol and alloxanthine, but no evidence that it will prevent next gout attack any better
– takes longer for mobilization to be acheived, so need to wait longer after the first attack before starting this
– decreases [uric acid] (less soluble) -> *less precipitation of uric acid crystals in joints and tissues*
– Clinical trials suggest that febuxostat is more effective than allopurinol in lowering serum uric acid.
– Like uricosuric agents, these drugs are usually withheld for 1-2 weeks after an acute episode of gouty arthritis and are administered in combination with colchicine or an NSAID to avoid an acute attack.
– Allopurinol is also used as an adjunct to cancer chemotherapy to slow the formation of uric acid from purines released by the death of large numbers of neoplastic cells.
– rarely may cause peripheral neuritis, vasculitis, or bone marrow dysfunction including aplastic anemia.
– interferes with anti-cancer drugs and warfarin clearance
– Febuxostat can cause liver function abnormalities, headache, and GI upset.
– contains polyethylene glycol, which extends efficacy
– for people who don’t respond to other treatments
– inject every 2-4 weeks
– “chews up” uric acid in plasma
– use prednisone, antihistamine because the body recognizes the pig enzyme as foreign
2. anaphylaxis, so it’s only given in hospital setting
3. caution using in people with CVD
– has nothing to do with uric acid!
– IL-1 is an important mediator in gout,
– this drug *”gobbles up” IL-1*
– used in chronic gout, but it’s expensive
– only in people unable to be treated by other methods