Pharmacology of NSAIDs and Muscle relaxants - Lecture 1- Dr. Hengen

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VASUpharm14
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Pharmacology of NSAIDs and Muscle relaxants - Lecture 1- Dr. Hengen
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2013-04-08 18:21:11
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she's fun :) Describe the synthetic pathway, mechanism of action, and effects of prostaglandins  Describe the mechanism of action of NSAIDs  Describe the side effects and drug interactions of NSAIDs  Describe the mechanism of action and side effects of skeletal muscle relaxants
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  1. pathway of prostraglandins
    • arachidonic acid (AA) from cell membrane --> phospholipase A2 (PLA2) carries AA --> AA oxygenated by 1. COX, LOX, P450 epoxygenase
    • (focus on COX)
    • AA --> PGG2 --> PGH2
  2. 2 COX isoenzymes
    • 1. Cox 1 - constitutive - "housekeeping"
    • 2. Cox 2 - inducible - upregulated
  3. MOA of PGs
    • short half-lives (autocrine/paracrine)
    • effects depends on receptors expressed
    • G- PROTEIN COUPLED
  4. biological effects of PGs/TXA2: smooth muscle
    • vascular: TXA2 - vaso CONSTRICT
    •    - PGI2, E2, D2 - vaso DILATION
    • GI tract: all CONTRACT in the tract
    • airways: RELAXED E2, I2
    •   - CONTRACT D2,F2A,TXA2
    • uterus: all CONTRACT
  5. biological effects of PGs/TXA2: platelets
    • TXA2 - platelet aggregation
    • PGs - inhibit platelet aggregation
  6. biological effects of PGs/TXA2: kidney
    • COX-2 derived
    • E2, I2 vaso DILATE --> maintain renal blood flow and GFR
    • glomerulonephritis: TXA2 --> intrarenal vaso CONSTRICT --> decline in renal function
  7. biological effects of PGs/TXA2: central/peripheral NS
    • fever: PGs INCREASE body temp by activating PG receptors in the HYPOTHALAMUS
    • Pain perception: PGs sensitize --> DECREASE pain threshold
  8. biological effects of PGs/TXA2: GI Tract
    • cox-1 derived
    • cyto PROTECTION of gastric epithelium
  9. biological effects of PGs/TXA2: eye
    PGE, PGF lower intraocular pressure
  10. biological effects of PGs/TXA2: inflammation/immunity
    • PGs promote acute inflammation
    • E2,I2 primary --> increase local blood flow, vascular permeability, and leukocyte infiltration
    • D2 (from mast cells) --> inflammation in allergic response (lungs)
  11. biological effects of PGs/TXA2: cancer
    E2 --> tumor infiltration, progression, metastasis (increase angiogenesis, decrease apoptosis, modulates immune responses).
  12. NSAIDs ADME
    • absorbed well orally
    • highly bound to plasma proteins
    • accumulate at inflammation sites
    • elimination via glomerular filtration and tubular secretion
  13. NSAIDs metabolism
    hepatic
  14. NSAIDs MOA
    • competitive, reversible, active site inhibitors of COX enzymes
    • - except: aspirin - acetylates and irreversible
    • no LOX pathway = no suppression of LT formation
  15. NSAIDs duration of action
    • depends on time of elimination
    • -except: aspirin - synthesis of new COX enzymes. 8-12 days for full recovery of platelets after aspirin stop
  16. shortest half life NSAID
    diclofenac
  17. longest half life NSAID
    piroxicam
  18. 3 effects of all NSAIDs
    • 1. antipyretic
    • 2. analgesic
    • 3. anti-inflammatory (not in acetaminophen)
  19. therapeutic uses of NSAIDs (4)
    • 1. Fever - COX2 - use faster onset NSAIDs
    • 2. Pain - low-to-moderate (arthritic - inflammation), (menstrual pain/cramps - release of PGs).
    • 3. Inflammation - tx RA, OA, ankylosing spondylitis, gout, arthropaties, localized m/s syndroms (sprains, strains, low back pain)
    • 4. other - cardioprotection (low dose aspirin <100mg/d), niacin - flushing - PGD2 from skin). fetal circulatory system - PGs maintain ductus arteriosus (treat with indomethacin, ibuprofen, other NSAIDs to close); cancer chemoprevention - increased COX2 in tumors, 50% decrease in colon cancer
  20. Side Effects of NSAIDs (9)
    • 1. GI - most common - n/dyspepsia/abdominal pain/gastric and duodenal ulcers/cox 1 inhibition = dec. I2, E2 --> dec mucosal blood flow and dec mucus production (pick COX 2 selective)
    • 2. CNS - h/a, dizziness, confusion
    • 3. vascular effects - COX2 selective - INC risk of MI, stroke, thrombosis (I2 counteracts effects of prothrombotic/atherosclerotic stimuli
    • 4. bp/renovascular - fluid retention, HYPER tension, edema (E2,I2 - important for renal blood flow, GFR for CHF, chronic kidney disease or HYPO volemia)
    • 5. Hematologic - dec platelet function, bruising, rare thrombo/neutropenia
    • 6. pulmonary - bronco CONSTRICTION (LOX)
    • 7. Hepatic - abnormal LFTs and rarely liver failure
    • 8. skin - rash, pruritis, flushing
    • 9. Reye's syndrome - enceph + liver dysfunction + fatty infiltration of liver (<20 yo)
  21. Drug interactions - NSAIDs (5)
    • 1. corticosteroids/SSRIs + NSAID --> INC frequency of severity of GI SE
    • 2. Warfarin + NSAIDs --> INC risk of bleeding
    • 3. ACEi/diuretics + NSAIDs --> DEC effectiveness of ACEi/diuretics
    • 4. NSAIDs displace other drugs from plasma protein binding sites
    • 5. Li + NSAIDs --> INC Li levels with piroxicam, DEC Li levels with sulindac
  22. muscle spasm
    • increase in tonic stretch reflexes with muscle weakness
    • sustained lesions fo upper motor neuron and descending corticospinal pathway (pyramidal tract)
  23. skeletal muscle relaxants (spasmolytic drugs) used in
    • 1. muscle spasms
    • 2. cerebral palsy
    • 3. multiple sclerosis
    • 4. stroke
    • 5. brain trauma
  24. MOA of muscle spasm
    damage to UMN (pyramidal neurons in motor cortex) and corticospinal pathway (UMN axons form synapses with LMN in spinal cord) --> removal of INHIBITORY influence of UMN --> reflexes HYPER active and muscle tone INCREASE = muscle spasm
  25. Skeletal muscle relaxants targets reflex arc 3 ways
    • 1. decrease excitatory neurotransmission in spinal cord
    • 2. increase inhibitory 
    • 3. direct action on skeletal muscle
  26. MOA: GABA a receptor modulator
    • R activation leads to increase CL- conductance --> membrane HYPER polarization
    • Diazepam
    • GABAergic skeletal muscle relaxants
  27. MOA: GABA b receptor agonist
    • Gi-PCR 
    • R activation leads to INC K+ = membrane HYPER polarization and DEC Ca2+ = DEC release of glutamate from presynpatic
    • Baclofen (b for b)
  28. SE of GABAergic skeletal muscle relaxants: diazepam
    sedation
  29. SE of GABAergic skeletal muscle relaxants: baclofen
    • sedation (tolerance develops)
    • overdose: blurry vision, HYPO tension, cardiac and respiratory depression, coma
    • withdrawal: taper or get acute HYPER spasticity, rhadomyalisis, delirium, fever
  30. MOA: a2 adrenergic receptor agonist (related to clonidine)
    • a2R activation leads to DECREASE release of glutamate from presynaptic nerve terminals in spinal cord = DEC muscle spasms
    • Tizanidine
  31. SE of Tizanidine
    sedation, HYPO tension, dry mouth
  32. MOA: blocks Ca channel in SR - ryanodine receptor 1 (RyR1)
    • reduces skeletal muscle strength interfering with excitation/contraction coupling in the muscle fibers
    • normally: AP --> NMG --> Ca2+ from SR --> muscle contraction
    • Dantrolene
    • Skeletal muscle relaxant affecting muscle
  33. SE of Dantrolene
    generalized muscle weakness, sedation, rarely hepatitis

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