MSK 01: Pharmacology of NSAIDs, Acetaminophen, and Select DMARDs Flashcards
How do prostaglandins contribute to inflammation and pain?
- involved in pathogenesis of painful inflammatory conditions due to elevated levels during tissue inflammation
- directly activate nociceptors to cause pain and sensitization
How are prostaglandins synthesized?
- arachidonic acid released from cell membranes through action of phospholipases
- converted by cycloxygenase (COX) to prostaglandins and thromboxanes
What are the 5 main types of prostaglandins and their receptors?
(all receptors are GPCRs)
- PGE2: EP(1-4)
- PI2 (prostacyclin): IP
- PGD2: DP(1, 2)
- PGF2𝛼: FPA,B
- TXA2: TPAB
What is the effect of activation of PGE2 binding to receptor EP(1-4)?
inflammation, pain (peripheral, spinal cord), inhibit gastric acid secretion, promote GI mucus secretion, mediate fever and muscle pain associated with viral infection
What is the effect of activation of PI2 binding to receptor IP?
pain, vasodilator and angiogenesis, increase renal water and Na+ clearance
What is the effect of activation of PGD2 binding to receptor DP(1,2)?
bronchoconstrictor, promotes sleep induction
What is the effect of activation of PGF2𝛼 binding to receptor FPA,B?
vasoconstrictor, bronchoconstrictor increase flow of aqueous humor (eye pressure)
What is the effect of activation of TXA2 binding to receptor TPAB?
potent vasoconstrictor and bronchoconstrictor, promote platelet aggregation and angiogenesis
What is the general structure of prostaglandins?
20-carbon, cyclopentano-fatty acid
- cyclopentane (ring)
- COOH (Acid)
What are eicosanoids?
class of bioactive compounds that include prostaglandins, thromboxanes, prostacyclins, and leukotrienes
What is the biologic activity of PGE1?
increases secretion of bicarbonate ion and gastric mucus
What is the biologic activity of PGE2?
protects GI epithelia from acid degradation, reduces secretion of gastric acid and increases mucus secretion
What is the biologic activity of PGi2?
potent inhibitor of platelet aggregation, reduces secretion of gastric acid
What is the biologic activity of TXA2?
potent inducer of platelet aggregation
Describe the structure of COX enzymes.
- catalytic region in hydrophobic channel near enzyme core
- cycloxygenase site binds to arachidonate
- peroxidase active site contains heme group (protoporphyrin IX) near protein surfacem binds to peroxide (PGG2)
- Arg120 provides ionic interaction with anionic carboxylate group of arachidonic acid
- Ser530 (COX1)/Ser516 (COX2) lies near opening of cyclooxygenase site, but does not participate in reaction – site of acetylation by aspirin
Describe the structural difference between COX1 and COX2.
COX1:
- Ile at residue position 523
COX2:
- Val at residue position 523
Describe the functional difference between COX1 and COX2.
COX1:
- expressed constitutively in most cells – stomach, intestine, kidney, platelets, CNS
- produces prostaglandins involved in normal cellular activity (ie. protection of gastric mucosa and maintenance of kidney function)
COX2:
- expressed at low levels in ‘resting’ cells of vascular smooth muscle, fibroblasts, monocytes, macrophages, and vascular endothelium
- expression can be induced in many cells by pro-inflammatory cytokines (ie. IL-1, TNF-alpha), depending on certain stimuli (ie. inflammation or tissue injury)
- constitutively expressed in kidney
Both:
- similar enzyme mechanism (active site)
What are natural COX inhibitors?
w-3 FAs (PUFAs)
- found in cold water fish
- eicosapentaenoic acid, docosohexaenoic acid
- compared to w-6 in arachidonic acid (double bond at line 6, backwards from carbon 20)
