Non-Selective Cox Inhibs, Cox-2 Selective, Dmards, Etc...

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What are the 7 common Non-selective Cyclooxgenase Inhibitors?

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1. Acetylsalicyclic acid (Asprin)
2. Methy Salicylate (Ben Gay)
3. Diflunisal
4. Sulfasalazine
5. Acetaminophen (tylenol)
6. Indomethacin
7. Sulindac

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Acetylsalisylic acid (Asprin, ASA)

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-readily absorbed from the stomach and upper SI, rapidly--> acetic acid & salicylate (T1/2 2-19hrs)
-hydolysis not required
-IRREVERSIBLE COX INHIB, way more selective for COX-1 over COX-2
-metab is saturable--> toxic fast

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Acetylsalisylic acid (Asprin, ASA)

Anti-Inflammatory effects are due to?

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-COX inhibition
-Possibly interfering w/ leukocyte adhesion

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Acetylsalisylic acid (Asprin, ASA)

Analgesia is due to?

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-reduced inflammation and a decrease in PGE and F which cause hyperalgesia

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Acetylsalisylic acid (Asprin, ASA)

Antipyretic effects?

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1. Reduces elevated temp (normal temp not really affected)
-through inhib of COX in hypothalmus
-Inhib of IL-1

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Acetylsalisylic acid (Asprin, ASA)

Antiplatelet effects?

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-IRREVERSIBLE ACETYLATION of COX-1 blocks TXA2 formation
-blocks prostacyclin but clinically the TXA2 effect predominates
-IRREVERSIBLE INHIB IN PLATELETS IS LONG (8-11 DAYS)

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Acetylsalisylic acid (Asprin, ASA)

Clinical Uses

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-analgesia, antipyresis, anti-inflam
-mild to moderate pain
-RA, OA, etc
-Prophylactic use for CAD etc (Selective blocking of TXA2 in platelets [low dose 40-80 mg/day])

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Aspirin Intoxication

aka salicylism

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-fatal if high amounts are ingested (10-30 gms; 300-350 ug/ml)
-symptoms: headaches, dizzy, tinnitus, hearing loss, dimness of vision, mental confusion, sweating, thrist, hyperventilation and nausea
-CNS: CV collapse, resp failure

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Tx for Aspririn Intoxication

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-CV and respiratory support
-removal of agent from stomach w/ act charcoal
-correcting A-B abnormalities
-alkalinization of urine to facilitate excretion

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Acetylsalisylic acid (Asprin, ASA)

Adverse Effects

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-asthma--> acute bronchocons
-worsen gout
-Reye's synd linked to aspirin given to children w/ viral infx and fever
-avoid in GI disease and head trauma, renal failure
-only in pregos if necessary

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Diflunisal

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-derivative of salicyclic acid but is not converted to it
-more potetent anti-inflam than aspirin
-used as analgesic w/ less auditory, GI and platelet side effects

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Topical or Systemical Clinical Uses of Diflunisal

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-mild to mod pain (dental/cancer)
-ointment for oral lesions
-Osteoarthritis
-RA

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Acetaminophen (tylenol)

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-alt to ASA for analgesia & antipyresis
-NO ANTI-INFLAM ACTIONS
-therapeutic actions due to inhib of COX 1,2,3 in CNS where it produces analgesia by elev of pain thresh and antipyresis thru action on hypothal heart-reg center

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Acetaminophen (tylenol) -

Peripheral actions

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-does not inhib periph COX enzymes and therefore doesn't inhib platelet aggregation nor does it cause severe GI problems like other NSAIDs
-thus recommended for old/young pts

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Acetaminophen (tylenol)

Pharmacology

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-rapidly absorbed w/ a T1/2 2hrs and 20-50% protein binding
-hepatic metab through conj and hydroxylation
-N-acetyle-benzoquinoneimine builds up w/ high dose)

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Acetaminophen (tylenol)

Therapeutic uses

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-analgesia, antipyresis
-children w/ viral infx, adjunct in gout, salicylate toxicities
-if aspirin is CI w/ peptic ulcer or bleeding problems

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Acetaminophen (tylenol)

Toxicity

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-few minor problems like rashes but at high does or w/ chronic use FATAL HEPATIC NECROSIS AND POSSIBLY ACUTE RENAL FAILURE CAN OCCUR (due to oxidative metabolite, NAPQI)
-15 g hepatox, 25 g fatal, much less in alcoholics due to liver dam

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Indomethacin (Indocin)

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-oral, IV, suppository, or ophthalmic
-Anti-inflam, analgesic, antipyretic actions sim to salicyclates but more potent than aspirin, NOT more efficacious
-non-selective COX -1 and 2 inhib

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Indomethacin (Indocin)

Indications

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-prim for RA, OA, acute gouty arthritis, eye pain
-used to facilitate closure of patent ductus arteriosus in premature babies

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Indomethacin (Indocin)

AEs

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-at higher doses 33% of pts taking drug
-GI pain + hemorrhage, diarrhea, pancreatitis, headache, rarely psychosis, hallucinations and some renal problems can occur

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Sulindac (Clinoril)

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-oral form, 1/2 as potent as indomethacin
-pro-drug metab to the active sulfide which has a T1/2 of 16.5 hrs
-non select COX-1, 2 inhib

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Sulindac (Clinoril)

Indications

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-Rheumatic disease, suppresses familial intestinal polyposis and may inhib the development of colon, breast and prostate cancers

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Sulindac (Clinoril)

AEs

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-GI, thrombocytopenia, agrunolocytosis, nephrotic syndrome

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What are some non-selective COX inhibitors that may also inhibit leukocyte function?

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-Ibuprofen (motrin, Advil)
-Naproxen (Aleve, Naprosyn)
-Fenoprofen
-Ketoprofen
-Furbiprofen

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What are the non-selective COX inhibitors that may also inhibit leukocyte function indicated for?

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-alleviation of pain and inflam in RA, OA, ankylosing spondyltitis, gouty arthritis, tendonitis, bursitis, and dysmenorrhea

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Ibuprofen

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-w/ food to reduce GI effects, T1/2 = 2hrs, injectable form available
-not recommended for pregos
-toxicity sim to salicylism
-less anti-inflam act than other NSAIDs
-alt to inomethacin for patent ductus arteriosus

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Naproxen

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-ful abs 2-4hrs, w/ antacids > abs time
-T1/2 = 14 hrs (2xs higher in old pts)
-very sim to ibuprofen
-FDA study suggested long term use associated w/ increase CV risk compare to placebo

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Fenoprofen

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-closely associated w/ interstitial nephritis, rarely used

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Ketoprofen

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-High potency propionic acid derivative
-may also antagonize bradykinin
-relative high percentage of pts (30%) complain of GI effects generally mild

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Flurbiprofen

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-Complex MOA, also inhibs TNF-a & NO synthesis
-ophthalmic form to inhbit interop miosis
-off label to preserve bone around dental implants
-rarely assoc w/ cogwheel rigidity, ataxia, tremor, myoclonus

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Tolmetin

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-better tolerated than aspirin
-used for arthritis, may be 5 days or longer before benefit observed
-rheumatic disease + juvenile form
-AE sim to others w/ some CNS effects like nervousness and anxiety

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Ketorolac

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-potent analgesic and mod effective anti-inflam, used for short term tx of pain (postop), can be used in place of opioids (just as efficacious)
-more freq renal toxicity, AE GI and platelets
-also topically for inflamm of eye

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Piroxicam

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-advantage is long T1/2 so only single daily dose

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Celecoxib

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-similar efficacy as other NSAIDs w/ fewer adverse GI effects
-not as much prothrombic effects as seen w/ use of Vioxx
-Rofecoxib and Valdecoxib removed from market b/c of CV effects

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Diclofnac

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-relatively high potency agent w/ selectivity for COX-2 over COX-1
-long tx of RA, OA, ank spondy
-3 formulations
-Arthrotec: combined formulation w/ misoprostol (prosta analog, reduces GI problems
-severe hep rxns may occur

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Meloxican

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-may be slightly more selective for COX-2

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Etodolac

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-slightly more selective for COX-2 adn useful for post op pain
- may be assoc w/ some temporary renal problems

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Disease Modifying Anti-Rheumatic Drugs (DMARD's)

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-target underlying causes of RA and represent a new generation of therapeutics designed to reduce symptoms and disease progression
-can take weeks-months so they may combined w/ NSAIDs initially to provide more immed relief of pain/inflammation

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Methotrexate

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-immunomodulation by inhib of AICAR transformylase, thymidylate sythetase, and polymorphonuclear chemotaxis decrease autoimmune destruction
-used greatly for RA, but also for psoriasis, progressive MS, subacute lupis, giant cell arteritis

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Methotrexate AEs

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-cytotox at high doses (chemo)
-leucorvin inhibs, thus rescue agent
-nausea, mucosal ulcers, hepatotox
-concurrent use of NSAID's decreases clearance--> rapid toxicity (BM supression) and death

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Cyclophosphamide

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-metab to phosphoramide mustard which cross-links DNA & decreases cell replica to suppress immune resp
-dose-dep infertility and BM suppression are potential problematic AEs along w/ cytotox at higher doeses

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Cyclosporine

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-regs gene trans, decreasing IL-1 and IL-2 receptor prod; alters T-cell macro interaciton to decrease T-cell dep B cell fxn
-sign risk of nephrotoxicity
-drugs that inhib CYP3A enzyme may increase tox & avoid drinking grapefruit juice

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Azthioprine

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-converted to mercaptopurine to exert immuno-suppression by disrupting purine NA metab
-more freq used for transplant than RA due to AEs: BM suppression, anemia, hep dysfunction

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Rituximab

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-monoclonal Ab that binds to the Ag CD20 which is expressed on surf of B-lymphocytes--> B-cell lysis
-RA in combo w/ methotrexate in pts who had inad response to TNF antagonist therapies (infusion)

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TNF Alpha Inhibitors:

Adalimumab

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-recombinant human anti-TNF monocolonal that prevents soluble TNF from interacting w/ p55 & p75 receptors--> decrease T-cell activity
-can be in combo w/ methotrexate
-injected, expensive, opp infx risk, uncertain if long term use = maligs

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TNF Alpha Inhibitors:

Infliximab

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-25%mouse/75% human, sim to adalimumab (potent macro inhib)
-IV dosing ~ 8 weeks
-antichimeric Abs dev in 62% of pts
-combo w/ methotrex reduces this and increases efficacy

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TNF Alpha Inhibitors:

Infliximab AEs

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-Severe hepatic rxns--> death or liver transplantation
-serious blood dyscrasias
-some pts Abs against infliximab can be seen & inc allergic responses
-*reports of worsening of demylinating syndromes like MS

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TNF Alpha Inhibitors:

Entanercept

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-recomb fusion prot containing regions of TNF receptor linked to the Fc fragment of human IgG1
-blocks act of both TNF-a and B
-also inhibs lymphotoxin - a
-SubQ inj 2x/wk, slow ab/long dur

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TNF Alpha Inhibitors:

Entanercept Indications/AEs

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-RA alone or w/ methotrexate
-juvenile arthritis
-ulcerative colitis
-AE concern about opp infx and lymphomas

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Abatacept MOA

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-fusion prot that comprises the EC domain of CTLA4 and a frag of Fc domain of IgG1
-mimics endog CTLA4, competes w/ CD28 for CD80 and 86 binding, thus preventing deliv of 2nd costim signal req for optimal T cell act--> prevents release of cytokines/act of macros

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Abatacept

Indications and AEs

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-pts who did not adequately respond to one or more DMARDs
-AE: RTIs
-DO NOT combine w/ anti-TNF agents due to increased risk of infx

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Sulfasalazine

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-reduces IgA and IgM
-suppresses T-cell activity
-metab by gut flora to bioactive metab sulfapyridine
-30% discontinue due to tox, N/V, headache, rash, neutropenia (1-4%)

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Leflunomide

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-act metab A77-1726 inhibs dihydroortate DH --> decrease ribonucleotide synth w/ subseq red in T-cell prolif and auto-Ab prod by B-cells
-efficacy in RA = methotrex and sulfasalazine (NO combine w/ methotrex)

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Gold formulations

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-alters macro act to reduce several cytokines
-highest bioavail after IM injection
-high efficacy against RA and assoc disorders but rarely used to tox concerns (heme abnorms, nephro syndr, aplastic anemia)

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Antimalarials

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-chloroquine and hydrocloroquine
-suppress T-lymphocytic responses to mitogens
-improve RA symptoms but lower efficay than other DMARDs