NSAIDs Flashcards
Describe the biosynthetic pathways for production of prostaglandins including the source of the precursor arachidonic acid and the specific enzymes involved.
AA is converted into a cyclic intermediate by cyclooxygenases (COX-1 and COX-2). This cyclic intermediate is further transformed by endoperoxide isomerases to prostaglandins E2, D2, or F2a
Describe the biosynthetic pathways for production of thromboxane including the source of the precursor arachidonic acid and the specific enzymes involved.
AA is converted into a cyclic intermediate by cyclooxygenases (COX-1 and COX-2). This cyclic intermediate is further transformed to thromboxane.
Describe the biosynthetic pathways for production of prostacyclin including the source of the precursor arachidonic acid and the specific enzymes involved.
AA is converted into a cyclic intermediate by cyclooxygenases (COX-1 and COX-2). This cyclic intermediate is further transformed to prostacyclin
Describe the biosynthetic pathways for production of leukotrienes, including the source of the precursor arachidonic acid and the specific enzymes involved.
Completely different pathway. AA is converted by 5-lipoxygenase to leukotriene A4 (LTA4); this is further enzymatically converted to LTB4 and LTC C4/D4/E4 (which are more or less interchangeable for our purposes).
Compare and contrast the biochemistry and physiology of cyclooxygenase-1 and cyclooxygenase-2 with regards to expression, tissue locations, physiologic role, inducers, and inhibitors: COX-1
Constitutively expressed pretty much everywhere- for the most part perform global, housekeeping functions. This means it has important normophysiological roles:
- GI tract: Decreases secretion of gastric acid, increases mucosal secretion (protective mechanism), promotes smooth muscle contraction.
- Platelets: show a pro-aggregation effect.
- Kidneys: promote increased renal blood flow, diuresis.
- Vascular smooth muscle:
- –Prostaglandin/prostacyclin: vasodilation.
- –Tromboxane: vasoconstriction
- Bone: stimulates formation/resorption.
Compare and contrast the biochemistry and physiology of cyclooxygenase-1 and cyclooxygenase-2 with regards to expression, tissue locations, physiologic role, inducers, and inhibitors: COX-2
Induced by inflammatory cytokines (IL-1, IL-2, IFN-gamma; also LPS); it is not expressed (mostly) without induction by those cytokines. The important exception is in the endothelial cells, in which COX-2 is expressed all the time to prevent intravascular clotting.
- Pain: potentiates bradykinin-mediated nociception (pain).
- Inflammation: enhances ‘leakiness’ of vessels (pro-edema and leukocyte infiltration).
- Fever: Resets ‘normal point’ of body temperature in hypothalamus- increase heat production and decrease heat loss.
- Kidneys: Maintain steady renal blood flow.
- Uterine: During pregnancy, the one place where you absolutely have to have an AA derivative– live birth is more or less impossible without it. PGE F2a induces uterine contractions.
- –This means that if you give a COX inhibitor to a pregnant woman in the third trimester, you can cause a lot of problems with labor and delivery.
- –Notice that the fetus also uses PGE E2 and PGI to keep the ductus arteriosus open– with COX inhibitors, can cause the ductus to close (which is not a good outcome for the fetus).
List the effects of prostaglandins on vascular smooth muscle and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
PGE2 causes vasodilation
List the effects of prostaglandins on platelets and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
No effects noted
List the effects of prostaglandins on GI tract smooth muscle and secretory cells and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
PGE2/PGI2 inhibit HCl secretion, increase mucous secretion.
List the effects of prostaglandins on kidney cells and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
PGE2/PGI2 increase renal blood flow
List the effects of prostaglandins on uterine cells and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
PGF2a induces contractions
List the effects of prostaglandins on inflammatory cells and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
PGE2/PGI2 potentiate pain, edema, and fever
Describe the effects of leukotrienes on inflammatory cell function
LTB4 is chemoattractive for neutrophil- induces endothelial cells and neutrophils to express adhesion proteins.
