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D&D Unit 2 > NSAIDs (complete) > Flashcards

NSAIDs (complete) Flashcards

1
Q

What is arachidonic acid?

A
  • a phospholipid, omega-6 fatty acid
  • stored as an ester
  • cleaved by esterases to become activated/processed into descendants
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2
Q

Describe the biosynthetic pathway for production of prostaglandins

A

Arachidonic acid —> endoperoxide – cyclic intermediate (using COX-1 and COX-2) —-> prostaglandins E2, D2, F2a (using endoperoxide isomerases)

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3
Q

Describe the biosynthetic pathway for production of prostacyclins

A

Arachidonic acid —> endoperoxide – cyclic intermediate (using COX-1 and COX-2) —-> prostacyclin I2 (prostacyclin synthase)

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4
Q

Describe the biosynthetic pathway for production of leukotrienes

A

Arachidonic acid —> leukotriene A4 (5-lipoxygenase) —> LTB4 and LTC C4/D4/E4

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5
Q

Compare cyclooxygenase 1 and 2

A

COX enzyme critical for prostaglandin and thromboxane production

Both catalyze synthesis of cyclic endoperoxide, PGH2 (unstable intermediate)

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6
Q

Where is COX-1 expressed?

A

Ubiquitously

1) GI tract
2) Platelets
3) Kidneys
4) Vascular smooth muscle
5) Bone

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7
Q

What is COX-1’s role in GI tract?

A
  • Decreases gastric acid secretion
  • Increases mucosal secretion (protects!)
  • Promotes smooth muscle contraction
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8
Q

What is COX-1’s role in platelets?

A

Have a pro-aggregatory effect

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9
Q

What is COX-1’s role in the kidneys?

A

Promotes increased renal blood flow

Increased diuresis

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10
Q

What is COX-1’s role in vascular smooth muscle?

A

For prostaglandin/prostacyclin pathway: vasodilation

Tromboxane: vasoconstriction

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11
Q

What is COX-1’s role in the bone?

A

Stimulates formation/resorption

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12
Q

Where is COX-2 expressed?

A

When induced by cytokines, shear stress, GFs

When up-regulated as needed for specialized functions

Located in inflamed/activated tissues:

1) Areas of pain/inflammation
2) Hypothalamus
3) Kidneys
4) Endothelial cells
5) Uterine smooth muscle
6) Ductus arteriosus

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13
Q

What is COX-2’s role in areas of pain/inflammation?

A

Enhance edema formation

Enhance leukocyte infiltration via vasodilation

Increase bradykini pain-producing activity

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14
Q

What is COX-2’s role in the hypothalamus?

A

FEVER!

Increased heat generation

Decrease in heat loss

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15
Q

What is COX-2’s role in the kidneys?

A

Maintains renal blood flow (stresses can alter that)

Critical in elderly, when renal function deteriorates

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16
Q

What is COX-2’s role in endothelial cells?

A

Endos are upregulated by blood flow stress

Vasodilation and anti-aggregatory platelet effects

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17
Q

What is COX-2’s role in uterine smooth muscle?

A

Contributes to labor contractions near parturition

A COX inhibitor would cause a lot of problems in the third trimester

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18
Q

What is COX-2’s role in the ductus arteriosus?

A

Maintains patent ductus arteriosus via vasodilation

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19
Q

What are the effects of prostaglandins on vascular smooth muscle?

A

PGE2 causes vasodilation

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20
Q

What are the effects of prostaglandins on platelets?

A

No effect

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21
Q

What are the effects of prostaglandins on GI tract smooth muscle/secretory cells?

A

PGE2/PGI2 inhibit HCl secretion

Increase mucous secretion

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22
Q

What are the effects of prostaglandins on kidney cells?

A

PGE2/PGI2 increase renal blood flow

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23
Q

What are the effects of prostaglandins on uterine cells?

A

PGF2a induces contractions

24
Q

What are the effects of prostaglandins on inflammatory cells?

A

PGE2/PGI2 potentiates …

1) pain
2) edema
3) fever

25
Q

What are the effects of leukotrienes on inflammatory cell function?

A

LTB4 is chemoattractice for neutrophils

Induces endothelial cells and neutrophils to express adhesion proteins

26
Q

What are the effects of leukotrienes on pulmonary cells?

A

Intense contraction in bronchial smooth muscle

ASTHMA!

27
Q

What are the effects of leukotrienes on vascular smooth muscle?

A

Intense vasodilation —> edema

Promotes leukocyte margination/adhesion

28
Q

Describe the functional interactions between prostacyclin and thromboxane on vascular smooth muscle and platelets.

A

Prost: vasodilation, disaggregation

Throm: vasoconstriction, aggregation

They are opposites!!!

29
Q

What are the effects of aspirin on COX-1 and 2? (Therapeutic uses)

A

Irreversibly inactivates COX-1 and 2

Uses:

1) Analgesic
2) Antipyretic
3) Anti-inflammatory
4) Anti-platelet

30
Q

What are the effects of NSAIDs on COX-1 and 2? (Therapeutic uses)

A

Reversibly inactivates COX-1 and 2

Uses:

1) Analgesic
2) Antipyretic
3) Anti-inflammatory

NOT ANTI-PLATELET

31
Q

What are the effects of acetaminophen on COX-1 and 2? (Therapeutic uses)

A

CNS reversibly inactivates COX2

Uses:

1) Analgesic
2) Antipyretic

NOT ANTI-INFLAMMATORY or ANTI-PLATELET

32
Q

What are the effects of COX-2 selective inhibitors on COX-1 and 2? (Therapeutic uses)

A

Inhibits only COX2 activity

Uses:

1) Analgesic
2) Antipyretic
3) Anti-Inflammatory

NOT ANTI-PLATELET

33
Q

What are the adverse rxns from aspirin?

A

1) GI upset
2) Bleeding
3) Decreased renal function
4) Decreased labor contractions

DOES NOT increase clotting

34
Q

What are the adverse rxns from NSAIDs?

A

1) GI upset
2) Bleeding
3) Decreased renal function
4) Decreased labor contractions

DOES NOT increase clotting

35
Q

What are the adverse rxns from acetaminophen?

A

Unlike NSAIDs/aspirin NO…

1) …GI upset
2) …Bleeding
3) …Decreased renal function
4) …Decreased labor contractions
5) …Increased clotting

Potential for hepatotoxicity

36
Q

What are the adverse rxns from COX-2 inhibitors?

A

1) Decreased renal function
2) Decreased labor contractions
3) Increased clotting
4) Increase risk of cardio thrombotic events

NO GI UPSET or BLEEDING

37
Q

Why is low dose aspirin able to exhibit anti-thrombotic/cardioprotective effect unlike high dose?

A

Aspirin inhibits platelet aggregation — low dose is COX-1 specific

B/c it’s irreversible platelets cannot produce COX-1 (no nucleus) —- TXA2 synthesis inhibited for life of platelet (>8 days)

At high dose, the aspirin no longer concentrates around just platelets, also endothelial cells — these have COX-2 (normally anti-thrombotic)

38
Q

How is the low dose aspirin effect associated with COX-2 selective inhibitors?

A

COX-1 inhibition is favored over COX-2

Therefore the inhibition of pro-clotting is favored over that of anti-clotting

39
Q

Again, what are the therapeutic uses of aspirin?

A

Low dose inhibits thrombus formation

Results from irreversible inhibition of COX-1&2

Analgesic, antipyretic, anti-inflammatory, anti-platelet

40
Q

Describe the metabolism and excretion of aspirin

A

M: rapid absorption from stomach/sm intestine — ASA rapidly hydrolyzed to salicylate by esterases

E: Salicylate more slowly eliminated by glycine/glucuronide conj. — high dose = zero order kinetics

41
Q

What are the side effects of aspirin?

A

1) Gastric irritation
2) Increased bleeding time
3) Renal dysfunction

42
Q

What happens when a pt overdoses on aspirin?

A

Mild intox:
tinnitus, headache, dizziness, diarrhea, seeing probs, thirt

Acute intox-overdose:
uncoupling of oxidative phosphorylation, respiratory alkalosis, metabolic acidosis

43
Q

What are the contraindications for aspirin?

A

1) pts w/ gastric ulcers
2) pts on oral anticoags
3) pregnant pts
4) pts w/ hypersensitivity (allergy)
5) children s syndrome

44
Q

What drugs interact w/ aspirin?

A

1) Warfarin (inhibit platelet function)

2) Alcohol (add’l gastric irritation/bleeding)

45
Q

What is a lethal dose of aspirin?

A

10-30 grams

46
Q

Again, what are the therapeutic uses of traditional NSAIDs?

A

Anti-inflammatory, antipyretic, analgesic

Sometimes used for arthritis, dysmenorrhea

47
Q

What are the side effects of NSAIDs?

A

1) gastric irritation if taken w/o food

2) platelets transient/reversible

48
Q

What happens when you overdose on NSAIDs?

A

Rapid onset of renal failure, nausea, vomiting, GI pain/upset

Generally better tolerated and safer in overdose than aspirin

49
Q

What are the contraindications for NSAIDs?

A

Safety for use in pregnancy not established

50
Q

What are the therapeutic uses of acetaminophen?

A
  • A Cox 2 inhibitor only in the CNS
  • Analgesic, antipyretic, less anti-inflammatory

Compared w/ aspirin:

  • Does not upset stomach
  • Weak effect on platelets/clotting time
  • Minimal renal effects
  • no Reyes
  • considered safe in pregnancy
51
Q

Describe the metabolism and excretion of acetaminophen

A
  • Absorbed in GI
  • Metabolized to inactive sulfate and glucuronide (phase II conj)
  • Large doses —» toxic product in liver
  • t1/2 = 2-3 hrs
52
Q

What are the side effects of acetaminophen?

A
  • mild ^ in hepatic enzymes, reversible
  • larger dose: dizziness, excitement, disorientation
  • toxicity
53
Q

What happens when you overdose on acetaminophen?

A

Glutathione stores are depleted —» can’t inactivate toxic metabolite —» liver damage (death if untreated)

t1/2 of Ac ^ 2-3 fold

54
Q

What are the therapeutic uses for Celicoxib?

A

A COX-2 specific inhibitor

  • Anti-inflammatory, antipyretic, analgesic
  • Used for arthritis, menstrual pains, acute pain
55
Q

Describe the metabolism and excretion of Celicoxib

A

M: well absorbed, metabolized by liver (CYP2C9)

E: renal — long half-life allows for 1/2 daily doses

56
Q

What are the side effects of Celicoxib?

A

1) Renal

2) Increased risk of adverse CV event

57
Q

What are the contraindications for Celicoxib?

A

Do not use in pregnant women (blocks uterine contractions)

Do not use in people who are prone to cardiovascular issues!! BADDD

A sulfa drug —» watch out for allergies

D&D Unit 2 (10 decks)

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