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NSAIDs: general description
  • decrease production of inflammatory mediators (prostaglandins), possess anti-inflamm, analgesic, anti-pyretic effects
  • most work best for mild to moderate pain
  • safer than corticosteroids for LT use
  • common SE: mild/mod GI irritation, hepatotox, nephrotox in high doses or susceptible patients
  • block cyclooxygenase enzymes to inhibit production of proinflammatory prostanoids
inflammatory reaction: Phase 1
  • at inflamm sites, endothelial cells are activated and release/express molecules to attract circulating leukocytes
  • leukocytes bind endothelial cells and activate, infiltrate into interstitia of damaged area
inflammatory reaction: Phase 2
  • leukocytes are either activated for phagocytosis or for release of lysosomal enzymes, arachidonic acid metabs or oxygen derived metabs (free radicals)
inflammatory reaction: Phase 3
  • all these processes mediate endothelial injury and tissue damage
  • amplify inflammatory stimulus
  • can lead to pain and discomfort
  • NSAIDS block the amplification
Cyclooxygenase enzymes
  • COX-1: constitutively expressed; housekeeping enzyme in most cells
  • COX-2: inducible enzyme; important role in inflammation, facilitates inflamm response
  • COX-3: splicing form of COX-1; func unknown
Effects of COX inhibitors/NSAIDS:
  • smooth muscle
vascular smooth muscle: vasoconstriction

GI: deactivate smooth m. 

Airways: 
  • PGs contract
  • TXA2 & PGF relax

Overall: increase tone and blood flow if COX is blocked!
Effects of COX inhibitors/NSAIDS: 
  • gastric epithelial cells
  • decrease protection (acid production is no longer decreased!)
  • decreased secretion of mucin, bicarb (protective agents)
  • can lead to GI upset & ulcers
Effects of COX inhibitors/NSAIDS: 
  • platelets and blood cells

  • Baby aspirin inhibits thromboxane A2 formation in platelets
  • thus, it is "cardio-protective"
Effects of COX inhibitors/NSAIDs
  • kidney
  • reduce renal function
  • vasodilation (blocking thromboxane A2 action)
  • no increase in renin release
  • ↓GFR, ↑BP!
Effects of cox inhibitors/NSAIDs
  • reproductive organs
  • ↓contractions in uterus
  • decrease pain with period
Effects of cox inhibitors/NSAIDs 
  • C/PNS
  • Blocking would increase NE activity and release
Pharmacology of NSAIDS
  • Organic acids (exc nabumetone)
  • are reversible (except aspirin: effects longer than predicted; COX must be re-synth*)
  • Some short acting <6hr, some long acting >10hr half life
  • organic acids accum @ inflamm sites; drugs targeted here
  • most are well absorbed
  • metab by liver
  • renal excretion (some biliary)
  • highly albumin bound (>98%)
Therapeutic effects of NSAIDS
  • Antipyretic
  • analgesic
  • antiinflammatory
  • **exc Tylenol: NO antiinflammatory action - acts in brain as antipyretic & analgesic)
Analgesic effect of NSAIDS
  • low to mod pain
  • doesn't change perception of sensory modalities exc pain
  • chronic post op pain, pain from inflamm well controlled
  • localized musculoskeletal sx's tx-ed best
  • pain from hollow viscera (except menstruation pain) is not relieved
Antipyretic effects of NSAIDS
  • all antipyretic
  • even COX-2 selective agents
  • Aspirin CI in child w/ viral fever
Anti-inflammatory effects of NSAIDS
  • tx: RA and other chronic disorders
  • symptomatic relief only; doesn't stop progression of disease
Tylenol has NO anti-inflamm action
Other assorted effects of NSAIDS
  • Can treat: Period cramps due to prostanoids, Bartter's syndrom (renal prostaglandins), Gout
  • Assoc: reduces colon cancer by 50% (D/t COX-2)
  • baby aspirin prophylactic for CAD to prevent thrombosis
  • tx gout: increased clearance of urate! (except tolmentin & aspirin)
GI disturbances d/t NSAIDS
  • GI distress + bleeding
  • COX-1: mucosal protective actions,controls acid secretion; COX-2 selective agents and p-aminophenol derivs are less harmful to stomach
  • add prostaglandin analogs (like misoprostol)
  • Tylenol avoids this
Platelet Function Disturbances d/t NSAIDS
  • TXA2 stimulates aggreg of platelets - NSAIDS prevent aggregation - tx CAD
  • COX-2 selective have no effect on TXA2; but suppress 80% PGI2 formation
  • PGI2 normalls acts to suppress platelet activation: inhibition of PGI2 can cause over activation of platelets and cause thromosis!
  • this is why Vioxx and bextra were withdrawn
Respiratory Complications d/t NSAIDS
  • bronchospasm, dyspnea, wheezing in pts with asthma
  • single exposure could induce lung function deterioration
  • Not allergic HS rxn, but caused by excessive production of cysteinyl leukotrienes
NSAIDS exacerbate some conditions:
  • hypertension
  • congestive heart failure
NSAIDS & Prolongation of gestation
  • Prostaglandins initiate and progress labor
  • NSAIDS prevent preterm labor!
NSAIDS and premature closure of patent ductus arteriosus
  • high dose of indomethacin
  • useful in premature babies!
Renal function disruptions d/t NSAIDS
  • Non selective & COX-2 selective
  • ↓ renal blood flow & GFR can result in acute renal failure
  • edema from salt retention
  • papillary necrosis and chronic interstitial nephritis
Non selective COX inhibitors that are Salicylic Acid derivatives
  • Acetylsalycylic acid (aspirin)
  • Methyl salicylate (ben gay..)
  • Diflunisal (Dolobid)
  • Sulfasalazine (Azulfidine)
Aspirin hypersensitivity
  • like anaphylactic shock
  • not immunological
  • all agents
Aspirin (general description)
  • readily absorbed, rapidly converted (T1/2aspirin=15 min, T1/2salicylicacid=2-9 hrs)
  • hydrolysis not required
  • irreversible COX inhibitor
  • COX-1>>>COX-2
  • metab is saturable; toxic levels can be reached
  • alkalinization of urine increases excretion
Aspirin (Anti inflammatory effects)
  • due to COX inhibition
  • possibly interfering with leukocyte adhesion
Aspirin (analgesia effects)
  • reduce inflammation
  • decreased PGE, PGF (cause hyperalgesia)
Aspirin (antipyretic effects)
  • fever via inhibition of COX in hypothalamus
  • Inhibition of IL-1
Aspirin (Antiplatelet effects)
  • via irreversible acetylation of COX-1→ blocks TXA2 formation
  • Platelets can't aggregate
  • No NSAIDS before surgery!
  • In CAD; increased MI
  • irreversible inhibition in platelets (8-11d; life of platelet)
  • prolonged bleed time normal w/in 36 hr but 7d recommended (need 30% of platelet pool to be un-exposed to aspirin)
Clinical Uses of Aspirin
  • Analgesia, antipyresis, antiinflamm
  • mild to mod pain (non visceral): HA, arthritis, dysmenorrhea
  • w/opioids (percodan) severe pain
  • RA, OA, 3g/day
  • prophylactic CAD; selective TXA2 blocking: low dose (but assoc. w/ increased MIs in established CAD)
Aspirin intoxication
  • Fatal @ high amt - 10-30g or less
  • Salicylism: HA, dizzy, tinnitus, hearing loss, dim vision, mental confusion, lassitude, sweat, thirst, hyperventilation, nausea
  • severe at high doses: convulsions, coma, skin eruptions, A-B disruptions, fever, dehydration
  • CNS depression, CV collapse and resp failure - death!
Tx for aspirin intoxication
  • CV & respiratory support
  • reomval of agent via activated charcoal
  • correct A-B abnormalities
  • alkalinization of urine to facilitate excretion
Adverse effects of aspirin
  • in asthma: acute bronchoconstriction
  • can worsen gout
  • CI: kids (Reye's syndrome)
  • avoid in GI disease
  • avoid in head trauma (bleeding)
  • caution in renal failure
  • only if nec in pregnancy; excreted in breast milk
Diflunisal (Dolobid)
  • Salicylic acid derivative
  • not converted to salicylic acid
  • more potent anti-inflam vs. aspirin
  • analgesic & antipyretic actions
  • less auditory, GI, platelet SE's
  • topical or systemic for: pain (dental, cancer), ointment for oral lesions, OA, RA
Non-selective COX inhibitors (not salicylic acid derived)
  • Acetominophen
  • Indomethacin
  • Sulindac
  • Ibuprofen
  • Naproxen
  • Fenoprofen
  • Ketoprofen
  • Flurbiprofen
  • Tolmetin
  • Ketorolac
  • Piroxicam
Acetaminophen (Tylenol) general description
  • alternative to aspirin: for antipyretic & analgesic effects
  • no anti-inflammatory action
  • blocks COX-1,2,3 in CNS - analgesia by elevation of pain threshold & antipyresis via hypothalamic heat-regulating center
  • no peripheral inhibition; no platelet aggregation inhib, no severe GI problems
  • recommended for old and young
pharmacology of Acetaminophen
  • rapidly absorbed
  • t1/2 2hr
  • 20-50% protein bound
  • hepatic metab via conjugation & hydroxylation to N-acetyl-benzoquinoneimine which builds up with high doses
Therapeutic uses of Acetaminophen
Analgesia & antipyresis
  • children with viral infx (to avoid Reye's), adjunct in gout, salicylate toxicities
  • when aspirin is CI with peptic ulcer or bleeding problems
Toxicity of acetaminophen
  • early: N/V/D/pain 1st 2 days
  • high doses/chronic: fatal hepatic necrosis, acute renal failure
  • NAPQI accumulates in liver - hepatotox - and kidney - nephrotox.  causes tissue necrosis
  • leads to depletion of glutathione in liver
  • 10-15g hepatotoxic; 25g fatal
  • Care in: alcoholics with liver damage (less is toxic)
Treatment of acetaminophen toxicity
  • immediate!
  • gastric lavage
  • addition of sulfhydryl compounds replenish glutathione (N-acetylcysteine)
Indomethacin (Indocin) general description
  • oral/IV/suppos/ophthal
  • more potent than aspirin, not more efficacious
  • non-selective COX-1,2 inhibitor
Indications of indomethacin
  • RA, OA, acute gouty arthritis, eye pain
  • to facilitate closure of patent ductus arteriosus in preemies
Adverse effects of Indomethacin
  • d/t high potency
  • higher doses, 1/3 of pts need to stop
  • GI pain/hemorrhage
  • DIA, pancreatitis, HA, psychosis, hallucinations, renal problems
Sulindac (clinoril)
  • oral: 1/2 potent as indometh
  • pro-drug → active sulfide 16.5 hr half life: single daily dose
  • non selective COX1,2 inhib
  • anti inflam, analgesic, antipyretic
Indications for Sulindac
  • Rheumatic disease
  • suppresses familial intest polyposis
  • may inhibit development of colon, breast, prostate CA
Adverse effects of Sulindac
  • GI (less than others)
  • thrombocytopenia
  • agranulocytosis
  • nephrotic syndrome
Other non-selective COX inhibitors
  • Ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen
  • better tolerated than aspirin & indomethacin
  • indicated for alleviation of pain/inflamm in many disorders
  • may inhibit leukocyte function as well
  • naproxen has adv in analgesia and tolerability
Ibuprofen
  • 1200-3200mg/d; with food to ↓GI effects; 1/2 life 2 hr
  • 5-15% stop d/t GI
  • not rec in pregnancy, breast feeding
  • toxicity like salicylism
  • less antiinflamm than other NSAIDS
  • indometh alt for patent ductus arteriosus
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