biosyn of prostaglandins
- cell membrane phospholipids
- phospholipase A2 (PLA2)
- AA
- Cyclooxygenase (COX)
- prostaglandin (PG) H2
- tissue-specific isomerases
tissue specific isomerases- uterus, GI, renal a, BVs, platelets, CT
- uterus- PGF2alpha, PGE2
- GI- PGE2
- renal a- PGE2
- BVs- PGI2
- platelets- TxA2
- CT- PGE2
excess of PGs in inflamed tissue causes what?
- heat
- redness
- swelling
- pain
prostaglandins- effects on vasculature, CNS, PNS
- PGI2- vasodilation
- PGE2- permeability
- PGE2 in CNS- Temp (Fever)
- PGE2 in PNS- pain sensitization
aspirin and salicylate- anti-infl effects at?
higher doses (2-3 g/day)
- aspirin metabolized to salicylate by liver
- high dose ASA- pro-drug for anti-infl doses of salicylate
aspirin and salicylate- toxicities
COX-indep:
- acid-base disturbance
- tinnitus
- hypersensitivity
- Reye’s syndrome
aspirin and salicylate- 6-20 g- toxicity
- early- resp alkalosis
- later- metabolic acidosis
- fever, dehydratino
progression of aspirin/salicylate toxicity
- salicylates uncouple mitochondrial ox phos in CNS
- resp center registers dec in ATP fas hypoxemia- responds with hyperventilation
- hyperventilation blows off CO2- causes resp alkalosis- prompts kidney to deplete bicarbonate
- organic acids accum b/c ATP is no longer generated thru Krebs cycle
- metabolic acidosis- life-threatening
Aspirin- contraindications
Fever in children/adolescents!!!
- anyone < 19 yo with a fever- risk of Reye’s syndrome!!!
- alternative- acetaminophen
traditional NSAIDs- drugs
- Ibuprofen
- Indomethacin
- Naproxen
- Diclofenac
Coxibs- drugs
-Celecoxib
Salicylates- drugs
- Salicylate
- Aspirin
- Diflunisal
NSAIDS- moa
- inhibit COX- inhibit prostaglandin syn- reduce local edema, vascular permeability (swelling), and pain
- anti-infl, analgesic, and anti-pyretic
COX-1 and 2- similarities
- use same substrates (AA)
- make same products (PGs)
- role in infl
- role in renal fxn
COX-1
- constitutive- in all tissues
- PROMINENT role responding to physiological stimuli
- also has a role in responding to pathological stimuli that release AA from cells
COX-2
- distinctive physiological role in kidney!!
- COX-2 expression is induced- PROMINENT role responding to pathological stimuli
COX1, PGs, and inflammation
- infl stim AA release
- COX-1 converts AA into PGE2
- PGE2 causes sx’s- erythema, edema, pain
COX-2 induction in inflammation
- infl induces COX-2 expression
- COX-2 converts AA into PGE2
- COX-2 derived PGE2 amplifies sx’s!!! (worse erythema, edema, pain)
tNSAIDS and salicylate- do what
- inhibit COX
- lower PG formation
- relieve sx’s
traditional NSAIDs and salicylates- moa
-competitive, reversible, non-selective!!! (COX-1 and 2)
NSAIDS- anti infl indications
- MSK- osteoarthritis, other arthritides, bursitis, gout flare, ankylosing spondylitis
- other- dysmenorrhea, headache
traditional NSAIDs- complications
- ulcer (inhibits mucosal integrity- PGE2)
- bleeding (inhibits homeostasis- blood platelets- TxA2)
- peripheral edema, inc BP (inhibits Na, H20 excretion- PGE2 and PGI2-)
NSAIDs- not indicated when?
- asthma
- gut infl (gastritis, colitis, pancreatitis, hepatitis)
- infectious infl/fever
COXIBs- moa
(celecoxib)
-selective inhibition of COX-2
