Pharmacology - Nsaids

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General information about NSAIDs

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- group of agents w/ antipyretic, analgesic, and anti-inflammatory activities
- aspirin = prototype
- MOA involves inhibition of COX --> inhibition of synthesis of PGs and thromboxanes

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COX-1

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- COX-1 = enzyme involved in tissue homeostasis
- generates prostanoids for 'housekeeping' such as gastric epithelial cytoprotection
- gastric damage = inhibition of COX-1

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COX-2

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- COX-2 = induced by growth factors, tumor promoters, and cytokines
- major source of prostanoids in inflammation and cancer
- constitutive in kidney and brain
- endothelial COX-2 = primary source of vascular prostacyclin
- kidney COX-2 generates prostanoids that are important for normal renal dev't and function
- anti-inflamm action of NSAIDs = inhibition of COX-2

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Aspirin & Salicylates - General

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- irreversibly acetylate (and thus inactivate) COX
- other NSAIDs are reversible

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Aspirin & Salicylates - Actions

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- reduce inflammation
- reduce pain
- reduce fever

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Aspirin & Salicylates - Anti-inflammatory Actions

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- inhibition of COX --> dec synthesis of PG

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Aspirin & Salicylates - Analgesic Actions

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- PGE2 sensitizes nerve endings to the action of chemical mediators released by the inflammatory process, so by decreasing PGE2 syn, NSAIDs repress the sensation of pain!

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Aspirin & Salicylates - Antipyretic Actions

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- Fever b/c prod of PG in the CNS in response to bacterial pyrogens and b/c of the effect of IL-1 on the hypothalamus (IL-2 produced by macrophages and released during inflamm responses)
- Aspirin reduces elevated temp (normal body temp is only slightly affected)

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Aspirin & Salicylates - Respiratory Actions

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- Salicylates uncouple oxidative phosphorylation --> elevated CO2 and increased respiration
- Higher doses stimulate respiratory center --> hyperventilation
- Toxic levels --> central respiratory paralysis

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Aspirin & Salicylates - GI Effects

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Gastric damage by 2 mechanisms:
- inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective PG, especially PGI2 and PGE2
- NSAIDs or aspirin may cause ulceration by local irritation of gastric mucosa

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Aspirin & Salicylates - Effect on Platelets

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- TXA2 --> platelet aggregation
- Aspirin irreversibly inhibits TXA2 prod in platelets
- Aspirin also inhibits COX in endothelial cells, but these cells can synthesize new COX (platelets lack nuclei)
- Decreased TXA2 = prolonged bleeding time

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Aspirin & Salicylates - Actions on Kidney

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- Decrease in Renal Blood Flow [decreased PGE2 -->increased sodium and water retention; decreased PGI2 --> hyperkalemia and ARF]
- Acute Interstitial Nephritis [Type I Hypersensitivity]
- Analgesic Nephropathy [Chronic interstitial nephritis b/c of prolonged analgesics: renal papillary necrosis --> chronic interstitial nephritis --> CRF]

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Aspirin & Salicylates and Risk of Colon Cancer

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- long-term use of aspirin at low dosage --> LOWER incidence of colon cancer
- used in pts w/ familial adenomatous polyposis

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Aspirin & Salicylates - Uses

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Aspirin
- mild-moderate pain; NOT effective for severe visceral pain
- combined with opioids for tx of cancer pain

Salicylates
- effective for tx of rheumatic fever, rheumatoid arthritis, and other inflammatory joint conditions

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Aspirin & Salicylates - Cardiovascular

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- Aspirin inhibits platelet aggregation so low doses are used for cardioprotective effects

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Aspirin & Salicylates - Niacin

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- Niacin = antihyperlipidemic
- Niacin is usually poorly tolerated b/c it induces intense flushing which is mediated by release of PGD2 from teh skin
- Flushing inhibited by aspirin

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Aspirin & Salicylates - Dosage

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- Salicylates: low dose = analgesic/antipyretic, high dose = anti-inflammatory
- Aspirin: low dose = cardioprotective

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Aspirin & Salicylates - Fate

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- aspirin hydrolyzed to salicylate and acetic acid by esterases in tissue and blood
- low dose salicylate converted by liver into hydrosoluble conjugates and excreted by kidney [first-order kinetics; t1/2 = 3.5 hrs]
- higher doses (>1g) of aspirin: conjugation enzymes saturated --> zero-order kinetics w/ increased t1/2 [half-life of salicylate lengthens as dose of aspirin increases]

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Aspirin & Salicylates - AE

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- GI - epigastric distress
- Blood - prolonged BT
- Hypersensitivity - inc leukotrienes (diversion of arachidonate to lipoxygenase metabolism as a consequence of COX inhibition)
- Reye's syndrome - increased incidence if aspirin taken during viral infection (esp in kids; kids should be given acetaminophen to reduce fever)

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Aspirin & Salicylates - Uricosuric effects

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- Low dose aspirin compete w/ uric acid for secretion into tubular fluid and so reduce uric acid secretion
- Large doses compete with uric acid for reabsorption and thus increase uric acid excretion in the urine

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Aspirin & Salicylates - Hepatic Effects

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- Salicylates cause hepatic injury in pts treated w/ high doses (after several months of tx)
- Reversible upon discontinuation
- Salicylates CONTRAINDICATED in pts w/ chronic liver disease

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Aspirin & Salicylates - Pregnancy

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- Aspirin = Category C during trimester 1 and 2 and Category D during trimester 3
- Salicylates excreted in breast milk

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Salicylate Intoxication

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- Salicylism = mild chronic salicylate intox; headaches, dizziness, tinnitus, mental confusion, sweating, thirst, hyperventilation, nausea, vomiting
- Acute salicylate overdose = mixed respiratory alkalosis and metabolic acidosis
- Prolonged exposure to high doses leads to depression of the medulla w/ central resp depression and circulatory collapse
- Resp failure = usual cause of death

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COX-2 Selective Inhibitors (Coxibs)

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- similar to NSAIDs but have fewer GI side effects
- dont affect platelet aggreg (mediated by COX-1) so arent cardioprotective
- cause renal toxicities similar to NSAIDs
- assoc w/ cardiovascular thrombotic events

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COX-2 Selective Inhibitors - Drugs

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- Celecoxib is only one available in USA; AE = sulfonamide and can cause HS rxns (rashes)
- Rofecoxib and valdecoxib were w/drawn due to their assoc w/ thrombotic events
- Etoricoxib - available around the world (not USA)
- Meloxicam - not as selective for COX-2

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Clinical Uses of NSAIDs

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- mild-moderate pain
- Indomethacin (an NSAID) is commonly used in intial tx of gout and is also the DOC for closure of the PDA

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Drug Interactions

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- ACE-inhibitors = act partly by preventing breakdown of kinins that stimulate PG production; NSAIDs may diminish the antihypertensive effect by blocking prod of vasodilator and natriuetic PGs
- Corticosteroids - NSAIDs may increase frequency or severity of GI ulceration when combined w/ corticosteroids
- Warfarin - NSAIDs may increase risk of bleeding in pts receiving warfarin

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Acetaminophen

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- analgesic and antipyretic drug
- no anti-inflamm or anti-platelet effect
- not tech an NSAID
- DOC for pain relief in osteoarthritis, for children with fever and flulike symptoms, and for short-term tx of fever and minor pain during pregnancy
- alone not enough for rheumatoid arthritis but can be used as an adjunct

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Acetaminophen - AE

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- therapeutic doses - acetaminophen has negligible toxicity
- overdose or pts w/ severe liver impairment - drug is dangerous hepatoxin
- prompt admin of ACETYLCYSTEINE (a sulfhydryl donor) may be lifesaving after an overdose