MS - Pharm (Part 1: Arachidonic Acid Products)

Question 1

What metabolic pathway yields leukotrienes?

Answer 1

Lipoxygenase pathway yields Leukotrienes; Think: “L for Lipoxygenase and Leukotriene”

Question 2

What function does LTB4 serve?

Answer 2

LTB4 is a neutrophil chemotactic agent; Think: “Neutrophils arrive ‘B4’ others”

Question 3

In what 4 processes/roles does LTC4 function? What other 2 leukotrienes also share these roles?

Answer 3

LTC4, D4, and E4 function in (1) bronchoconstriction, (2) vasoconstriction, (3) contraction of smooth muscle, and (4) increased vascular permeability

Question 4

What main function does PGI2 serve?

Answer 4

PGI2 inhibits platelet aggregation and promotes vasodilation; Think: “PGI2 = Platelet-Gathering Inhibitor”

Question 5

Again, what function does LTB4 have?

Answer 5

Neutrophil chemotaxis

Question 6

What main effect do LTC4, LTD4, and LTE4 have?

Answer 6

Increased bronchial tone

Question 7

What 4 effects does prostacyclin have? What is another name for it?

Answer 7

(1) Low platelet aggregation (2) Low vascular tone (3) Low bronchial tone (4) Low uterine tone; Prostacyclin (PGI2)

Question 8

What are 2 examples of prostaglandins? What are 2 of their major effects?

Answer 8

Prostaglandins (PGE2, PGF2alpha); (1) High uterine tone (2) Low bronchial tone

Question 9

What are 3 effects of thromboxane (TXA2)?

Answer 9

(1) High platelet aggregation (2) High vascular tone (3) High bronchial tone

Question 10

Draw a diagram indicating the mechanism of action of the following drugs in the arachidonic acid pathway: (1) Corticosteroids (2) NSAIDs, aspirin, acetaminophen, COX-2 inhibitors (3) Zafirlukast, Montelukast (4) Zileuton.

Answer 10

See p. 439 in First Aid 2014 for visual

Question 11

Draw the pathway from Membrane lipid (e.g., phosphatidylinositol) to Hydroperoxides. What are the final products of this pathway?

Answer 11

See p. 439 in First Aid 2014 for visual; Leukotrienes (LTB4 v. LTC4, LTD4, LTE4)

Question 12

Draw the pathway from Membrane lipid (e.g., phosphatidylinositol) to Endoperoxides. What are the final products of this pathway?

Answer 12

See p. 439 in First Aid 2014 for visual; Prostacyclin (PGI2), Prostaglandins (PGE2, PGF2alpha), Thromboxane (TXA2)

Question 13

What reaction does Phospholipase A2 catalyze in the arachidonic acid product pathway?

Answer 13

Membrane lipid (e.g., phosphatidylinositol) => Arachidonic acid

Question 14

What reaction does Lipoxygenase catalyze in the arachidonic acid product pathway?

Answer 14

Arachidonic acid => Hydroperoxides (HPETEs) (which is the precursor to Leukotrienes (LTB4 vs. LTC4, LTD4, LTE4))

Question 15

What reaction does Cyclooxygenase (COX-1, COX-2) catalyze in the arachidonic acid product pathway?

Answer 15

Arachidonic acid => Endoperoxides (PGG2, PGH2) (which is the precursor to Prostacyclin [PGI2], Prostaglandins [PGE2, PGF2alpha], Thromboxane [TXA2])

Question 16

What are the mechanism and effects of Aspirin?

Answer 16

Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) by covalent acetylation, which decreases synthesis of both thromboxane A2 (TXA2) and prostaglandins

Question 17

What effect does Aspirin have on bleeding time, and in what context? What effect does it have on PT and PTT?

Answer 17

Increased bleeding time until new platelets are produced (~7 days); No effect on PT, PTT.

Question 18

What type of drug is Aspirin?

Answer 18

A type of NSAID.

Question 19

What are the clinical uses for the following doses of Aspirin: (1) Low (2) Intermediate (3) High? For each of these, give the dosage amount that pertains to it.

Answer 19

(1) Low (< 300 mg/day): low platelet aggregation (2) Intermediate dose (300-2400 mg/day): antipyretic and analgesic (3) High dose (2400-4000 mg/day): anti-inflammatory

Question 20

What are 8 toxicities associated with Aspirin?

Answer 20

(1) Gastric ulceration, (2) Tinnitus (CN VIII). Chronic use can lead to (3) acute renal failure, (4) interstitial nephritis, and (5) upper GI bleeding. Risk of (6) Reye syndrome in children treated with aspirin for viral infection. Also stimulates respiratory centers, causing (7) hyperventilation and (8) respiratory alkalosis.

Question 21

What are 3 toxicities specifically associated with chronic use of Aspirin?

Answer 21

Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding.

Question 22

What toxicity is associated with Aspirin use in children, and in what context?

Answer 22

Risk of Reye syndrome in children treated with aspirin for viral infection.

Question 23

What major process/area does Aspirin effect, and what 2 toxicities may this yield?

Answer 23

Also stimulates respiratory centers, causing hyperventilation and respiratory alkalosis.

Question 24

What are 5 examples of NSAIDs?

Answer 24

(1) Ibuprofen (2) Naproxen (3) Indomethacin (4) Ketorolac (5) Diclofenac

Question 25

What are the mechanisms of NSAIDs?

Answer 25

Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block PG synthesis.

Question 26

What are 3 general clinical uses for NSAIDs? Which NSAID has a particular clinical use, and what is it?

Answer 26

Antipyretic, Analgesic, Anti-inflammatory. Indomethacin is used to close a PDA.

Question 27

What are 3 toxicities of NSAIDs?

Answer 27

Interstitial nephritis, Gastric ulcer (PGs protect against mucosa), renal ischemia (PGs vasodilate afferent arteriole).

Question 28

What is an example of COX-2 inhibitors?

Answer 28

COX-2 inhibitors (Celecoxib)

Question 29

What are the mechanism and effects of COX-2 inhibitors?

Answer 29

Reversibly inhibit specifically the cyclooxygenase (COX) isoform 2, which is found in inflammatory cells and vascular endothelium and mediate inflammation and pain;

Question 30

What mechanism do COX-2 inhibitors NOT have, and what effects does this have?

Answer 30

Spares COX-1, which helps maintain gastric mucosa. Thus, should not have the corrosive effects of other NSAIDs on the GI lining. Spares platelet function as TXA2 production is dependent on COX-1.

Question 31

What are 4 clinical uses for COX-2 inhibitors (celecoxib)?

Answer 31

Rheumatoid arthritis and Osteoarthritis; Patients with Gastritis or Ulcers.

Question 32

What are 2 toxicities of COX-2 inhibitors (celecoxib)?

Answer 32

Increase risk of thrombosis. Sulfa allergy.

Question 33

What is the mechanism of acetaminophen? Where does this mostly happen? Where is it inactivated?

Answer 33

Reversibly inhibits cyclooxygenase, mostly in CNS; Inactivated peripherally

Question 34

What are 2 clinical uses for Acetaminophen? How does it contrast to NSAIDs use?

Answer 34

Antipyretic, analgesic, but NOT anti-inflammatory.

Question 35

What is special consideration for clinical use of Acetaminophen versus Aspirin in pediatric populations?

Answer 35

Used instead of aspirin to avoid Reye syndrome in children with viral infections

Question 36

What is the main toxicity of Acetaminophen? What is the mechanism by which this occurs? What is the antidote for this, and how does it work?

Answer 36

Overdose produces hepatic necrosis; Acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue adducts in liver. N-acetylcysteine is antidote - regenerates glutathione.