-
- Aracidoni acid →
- 1. Lipoxygenase pathway
- - Leukotrienes
- 2. Cyclooxygnase pathway
- - Prostacyclin
- - Prostaglandins
- - Thromboxane
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Arachadonic acid products
Lipoxygenase pathway
- Lypoxygenase → Leukotrienes
- LTB4 → neutrophils (*"Neutrophils arrive B4 others")
- LTC4, D4, E4 functions: bronchoconstriction, vasoconstriction, contraction of smooth muscle, ↑ vascular permeability
-
Arachadonic acid products
Cyclooxygenase pathway: PGI2
- PGI2 inhibits platelet aggregation and promotes vasodilation
- *Platelet-Gathering Inhibitor
-
Aspirin
- Mechanism: Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) by acetylation
- -↓ synthesis of TXA2 and prostaglandins
- -↑ bleeding time
- -No effect on PT, PTT
- Clinical use:
- -Low dose (<300mg/day): ↓ platelet aggregation
- -Intermediate dose (300-2400mg/day): antipyretic and analgesic
- -High dose (2400-4000mg/day): anti-inflammatory
- Toxicity:
- -Gastric ulceration
- -tinnitus
- -Chronic use → renal failure, interstitial nephritis, upper GI bleeding
- -Reye's syndrome in children (when treated with ASA for viral infection)
- -Stimulates respiratory centers → hyperventilation, respiratory alkalosis
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NSAIDs
Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac
- Mechanism:
- -Reversibly inhibit cyclooxygenase (COX-1, COX-2)
- -Block prostaglandin synthesis
- Clinical use:
- -Antipyretic
- -Analgesic
- -Anti-inflammatory
- -*Indomethacin is used to close a PDA
- Toxicity:
- -Interstitial nephritis
- -Gastric ulcers (PGs protect gastric mucosa)
- -Renal ischemia (PGs vasodilate afferent arteriole)
-
COX-2 inhibitor
Celecoxib
- Mechanism: Reversibly inhibits COX-2
- -isoform found in inflammatory cells and vascular endothelium; mediates inflammation and pain
- -Spares COX-1; decrease GI effects
- -Spares platelet function (TXA2)
- Clinical use:
- -RA
- -Osteoarthritis
- -Pts with gastritis or ulcers
- Toxicity:
- -Increase risk of thrombosis
- -Sulfa allergy
-
Acetaminophen
- Mechanism:
- -Reversibly inhibits cyclooxygenase, mostly in CNS (inactivated peripherally)
- Clinical use:
- -Antipyretic
- -Analgesic
- -NOT anti-inflammatory
- -Used to avoid Reye's syndrome in children with viral infection
- Toxicity:
- -OD produces hepatic necrosis
- -metabolites deplete glutathione and form toxic tissue adducts in liver
- -N-acetylcysteine is antidote (regenerates glutathione)
-
Bisphosphonates
Alendronate, "-dronates"
- Mechanism:
- -Pyrophosphate analog
- -bind hydroxyapatite in bone, inhibits osteoclast activity
- Clinical use:
- -Osteoporosis
- -Hypercalcemia
- -Paget's disease of bone
- Toxicity:
- -Corrosive esophagitis
- -Osteonecrosis of the jaw
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Purine → Hypoxanthine → Xanthine → Uric acid
-
Chronic gout drugs
- Allopurinol
- Febuxostat
- Probenecid
- Colchicine
-
Acute gout drugs
- NSAIDs: Naproxen, indomethacin
- Glucocorticoids: oral or intraarticular
-
Allopurinol
- Inhibits xanthine oxidase
- ↓ conversion of xanthine to uric acid
- Other uses: lymphoma, leukemia (to prevent tumor lysis-associated urate nephropathy)
- **Increases concentration of azathioprine and 6-MP (both normally metabolized by XO)
-
Febuxostat
Inhibits Xanthine oxidase
-
Probenecid
- Inhibits reabsorption of uric acid in PCT
- also inhibits secretion of penicillin
-
Colchicine
- Binds and stabalizes tubulin to inhibit polymerization
- Impairs leukocyte chemotaxis and degranulation
- Side effects: GI (oral)
-
TNF-α inhibitors
Etanercept, infliximab, adalimumab
- All TNF-α inhibitors predispose pts to infection (including reactivation of latent TB)
- TNF blockade prevents activation of macrophages and destruction of phagocytosed microbes
-
Etanercept
- Mechanism:
- -Fusion protein (receptor for TNF-α + IgG1 Fc), produced by recombinant DNA
- -*Etanercept is a TNF decoy receptor
- Clinical use:
- -Rheumatoid arthritis
- -Psoriasis
- -Ankylosing spondylitis
-
Infliximab, adalimumab
- Mechanism:
- -Anti-TNF-α monoclonal antibody
- Clinical use:
- -Crohn's disease
- -Rheumatoid arthritis
- -Ankylosing spondylitis
- -Psoriasis
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