NSAIDS

Question 1

Describe the biosynthetic pathways for production of prostaglandins, prostacyclin, thromboxane, and leukotrienes, including the source of the precursor arachidonic acid and the specific enzymes involved.

Answer 1

The phospholipid membrane at the site of injury is broken down by phospholipases and is converted into arachidonic acid.

COX-1/COX-2 converts arachidonic acid into PGH2.

PG Endoperoxide Isomerases convert PGH2 into prostaglandins.
Thromboxane Synthase converts PGH2 into thomboxanes.

Prostacyclin PGI2 Synthase conversts PGH2 into Prostacyclin PGI2.

5-Lipoxygenase converts ararchidonic acid into leukiotrienes and, via 12-lipoxygenase into lipoxins.

Question 2

Compare and contrast the biochemistry and physiology of cyclooxygenase-1 and cyclooxygenase-2 with regards to expression, tissue locations, physiologic role, inducers, and inhibitors.

Answer 2

COX-1: Constitutively expressed, located ubiquitously, including GI tract (decrease acid and pepsin secretion, increase mucous and bicarbonate production), platelets (Pro-aggregatory effect), kidneys (increase renal blood flow, promotes diuresis), vascular smooth muscle (Vasolidate with PGI2 and PGE2, vasoconstrict with TXA2), and bone (stimulates bone formation and resorptioin). Inhibited by NSAIDS

COX-2: Induced by cytokines, shear stress, and growth factors, or upregulated as needed . Located in inflamed or activated tissues:

Areas of pain/inflammation: (induced) enhance edema formation and leukocyte infiltration via vasodilation potentiation of bradykinin pain-producing activity

Hypothalamus: (induced) causes fever by increasing heat generation and decreasing heat loss.

Kidneys: (constitutively upregulated) adaptation to stresses via maintenance of RBF, most critical in elderly-deteriorating renal function.

Endothelial cells: (upregulated by shear stress) vasodilation and anti-aggregatory platelet effects.

Uterine smooth muscle: (induced) contributes to labor contractions near parturition

Ductus arteriosus: (induced) maintenance of patent ductus arteriosus via vasodilation.

Question 3

Side effects related to inhibition of COX

Answer 3

GI ulceration, bleeding (COX1 in gastric cells)
Increased bleeding risk (COX-1 in platelets)
Renal dysfunctinon (COX-1 and COX-2 in kidney cells)
Delay labor (COX-2 in uterine smooth cells)
Increased thrombotic events (COX-2 in endothelial cells)

Question 4

Describe the effects of leukotrienes on inflammatory cell function and pulmonary / vascular smooth muscle.

Answer 4

LTB4: neutrophil chomotaxis, aggregration, and transmigration through endothelium.

LTC4/D4/E4: Increased vascular permeability, bronchoconstriction, vasoconstriction

Question 5

Describe the functional interaction of prostacyclin and thromboxane A2 with relation to physiologic effects on vascular smooth muscle and platelets.

Answer 5

Prostacyclin activates a Gs receptor protein, increasing cAMP production, thereby decreasing platelet aggregation. Prostacyclin also promotes vasodilation.

Thomboxane A2 activates a Gi receptor protein, decreasing cAMP production, thereby increasing platelet aggregation. Thomboxane A2 also promotes vasoconstriction

Question 6

Aspirin

Answer 6

Irreversible COX-1 and COX-2 inhibitor

Therapeutic uses:
Pain
Fever
Inflammation
Antiplatelet

Adverse reactions
GI ulceration, bleeding
Increased Bleeding
Renal dysfunction
Delay labor
Close DA
Reye's syndrome
asthmatic rxn
tinnitus

Question 7

Traditional NSAIDs

tNSAIDs

Answer 7

Reversible COX-1 and COX-2 inhibitor

Therapeutic uses:
Pain
Fever
Inflammation

Adverse reactions
GI iritation
Increased bleeding
renal dysfunction
delay labor
close DA

Question 8

Acetaminophen

Answer 8

CNS COX-2

Therapeutic uses:
Pain
Fever

Adverse rxns:
hepatotoxic in larger doses

Question 9

Celecoxib

Answer 9

Reversible COX-2 inhibitor

Therapeutic uses:
Pain
Fever
Inflammatioin

Adverse rxns:
Renal dysfunction
Increase clot formation
delay labor
close DA

Question 10

Describe the mechanism whereby low-dose, but not high-dose, aspirin is able to exert an anti-thrombotic / cardioprotective effect. Relate this effect to potential cardiovascular toxicity associated with use of COX-2 selective agents.

Answer 10

Inhibits platelet aggregation

Low dose aspirin is essentially platelet COX-1 selective via 2 mechanisms:

1) Platelets cannot synthesize new COX-1 enzyme, thus TXA2 synth is inhibited for life of platelet, COX-2 prostacyclin synthesis recovers faster.
2) Largest concentration of acetylsalicylic acid is presystemic in portal vein, thus greater effect on circulating platelet COX-1 (TXA2 synth) relative to tissue endothelial cell COX-2 (prostacyclin synth)-> decreased tendency for clotting

COX-2 inhibitors:
Selectively inhibit PGI2 synthesis–> alters TXA2:PGI2 ratio in prothrombotic direction (increases platelet aggregation)