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DEN 7203 Pharmacological Concepts > NSAIDs > Flashcards

NSAIDs Flashcards

Lecture 6

1
Q

Describe the arachidonic acid pathway

A
  1. Phospholipids broken down into Arachidonic acid pathway by Phospholipase A2
  2. Arachidonic acid broken down into Prostaglandins (cyclooxygenase) and Leukotrienes (Lipoxygenase)
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2
Q

Prostaglandins lead to ____
Leukotrienes lead to ____

A

Pain; airway reactivity

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3
Q

What are prostaglandins?

A

Ubiquitous, lipid soluble molecules derived from arachidonic acid

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4
Q

What is arachidonic acid?

A

Fatty acid liberated from cell membrane phospholipids through the cyclooxygenase pathway

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5
Q

What do prostaglandins contribute to?

A
  • Vasodilation
  • Capillary permeability
  • Phagocytic activity of leukocytes
  • Pain and fever that accompanies inflammation
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6
Q

Another product of the cyclooxygenase pathway, ____, promotes platelet aggregation and vasoconstriction

A

Thromboxane A2

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7
Q

Prostaglandins have a protective effect on:

A

GI system

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8
Q

How do prostaglandins protect the GI system?

A
  • Inhibits the activation of neutrophils
  • Inhibits leukocyte-endothelial interaction
  • Inhibits acid secretion and increases mucus production
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9
Q

COX-1 is a ____ enzyme

A

Cyclooxygenase

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10
Q

What is COX-1 responsible for?

A

Physiologic production of prostaglandins

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11
Q

COX-1 is a house-keeping enzyme that regulates normal cellular processes (via production of PGs) such as:

A
  • Gastric cytoprotection
  • Vascular homeostasis
  • Platelet aggregation
  • Kidney function
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12
Q

Where is COX-2 constitutively expressed?

A

Brain, kidney, bone

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13
Q

COX-2 expression is inducible at other sites by:

A
  • Oxidative stress
  • Injury
  • Ischemia
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14
Q

What is COX-2 responsible for?

A

Elevated production of prostaglandins in inflammation

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15
Q

Classical NSAIDS inhibit ____ and are associated with ____

A

COX-1 and COX-2; Adverse effects of peptic ulceration and dyspepsia (indigestion)

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16
Q

Newer NSAIDs selectively inhibit ____, fewer gastric side effects but reported increased risk for ____

A

COX-2; heart attack, stroke, thrombosis due to relative increase in thromboxanes in platelets

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17
Q

What are the 3 main pharmacologic effects of NSAIDs?

A
  • Anti-pyretic
  • Analgesic effect
  • Anti-inflammatory
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18
Q

NSAIDS inhibit:

A

Prostaglandin synthesis

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19
Q

How does set point temperature increase in the hypothalamus?

A

During inflammation, IL-1 increases –> inc. COX-2 –> inc. PG –> inc. set point temp in hypothalamus

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20
Q

NSAIDs inhibit PG production in the hypothalamus and as a result ____

A

Resets temperature (anti-pyretic)

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21
Q

How do NSAIDs provide analgesic effect?

A

Decrease the PGs that sensitize pain receptors

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22
Q

NSAIDs can work in combination with ____ and ____

A

Opioids; lessen the required opioid dose

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23
Q

How do NSAIDs provide headache pain relief?

A

NSAIDs decrease PGs which result in less vasodilation of cerebral vasculature

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24
Q

How do NSAIDs work as anti-inflammatory?

A
  • NSAIDs decrease PG synthesis by COX-2 in inflammatory cells
  • Decrease vasodilation, cell adhesion, migration, stabilizes lysosomes
  • Decreased vascular permeability and therefore less edema
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25
Q

NSAIDs are weak organic ____ that are ____ absorbed

A

Acids; well

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26
Q

NSAIDs are metabolized by:

A

CYP3A and CYP2C family of cytochrome P450 enzymes in the liver

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27
Q

NSAIDS undergo final ____ excretion but also ____ excretion and reabsorption. They are excreted ____ or ____ soluble metabolites

A

Renal; Biliary; unchanged; H2O

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28
Q

NSAIDs are ___ bound, usually to ____

A

Protein; albumin

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29
Q

Non-selective COX inhibitors are ____ potent or at least ____ inhibitors of COX-1 (vs COX-2) which can lead to adverse effects

A

More; equipotent

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30
Q

NSAIDs like Ibuprofen, Naproxen, and aspirin are more selective for which COX?

A

COX 1

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31
Q

____ is 100x more selective inhibitor of COX1 than COX2

A

Aspirin (still inhibits both)

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32
Q

True or false: Aspirin has a much greater affinity for COX1 compared to Naproxen or Ibuprofen

A

True (refer to bar graph)

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33
Q

____ is one of the most consumed drugs in the world

A

Aspirin

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34
Q

Aspirin inhibits:

A

COX1 and COX2 (nonselective and irreversible)

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35
Q

____ causes irreversible acetylation of a serine on COX-1 and COX-2

A

Aspirin

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36
Q

True or false: All NSAIDS are irreversible competitive inhibitors of COX1 and COX2

A

False - only aspirin does this

37
Q

Aspirin is a weak organic ____, so favors absorption in the ____

A

Acid; stomach

38
Q

True or false: aspirin is rapidly and completely absorbed

A

True

39
Q

Aspirin is rapidly hydrolyzed into ____ by ____

A

Acetic acid and salicylate; gastric and plasma esterases

40
Q

____ is the active metabolite of aspirin

A

Salicylate

41
Q

Aspirin has a ____ half-life
Salicylate has a ____ half-life at low doses and ____ at high doses

A

15 min; 2-3 hour; 12 hour

42
Q

Aspirin acetylates COX in _______ while salicylate is a ____ of COX in platelets

A

Platelet irreversibly; Reversible inhibitor

43
Q

Platelet life span

A

8 days

44
Q

Low dose of aspirin is effective in:

A
  • Prevention of transient ischemic attacks
  • unstable angina
  • coronary artery thrombosis with MI
  • Thrombosis after coronary artery bypass grafting (due to block of COX1 in platelets)
45
Q

____ is associated with use of aspirin during a viral infection, often ____ or ____

A

Reye’s syndrome; influenza; varicella

46
Q

What is Reye’s syndrome?

A

Acute childhood illness that produces acute encephalopathy and liver disease

47
Q

Symptoms of acute encephalopathy

A
  • Lethargy
  • Agitation
  • Delirium
  • Seizures
48
Q

Without aggressive treatment, ____ of Reye’s syndrome cases end in death

A

80-90%

49
Q

With heroic treatment, mortality rate of Reye’s syndrome can still exceed ____, and survivors are left with ____

A

30%; brain damage

50
Q

What should you to to prevent Reye’s syndrome?

A

NO ASPIRIN for children/teenagers with fever, including flu, chicken pox, and maybe also gastroenteritis, respiratory infection

51
Q

Is acetaminophen associated with Reye’s syndrome?

A

No

52
Q

____ hyperreactivity can occur in asthmatic patients taking NSAIDs

A

Airway

53
Q

Airway hyperreactivity - is it immune mediated?

A

No, but resembles drug allergy

54
Q

Airway hyperreactivity is more common in patients with:

A

Asthma or nasal polyps

55
Q

Possible cause of Airway hyperreactivity

A
  • When COX enzymes are blocked, arachidonic acid pathway shifts, reducing bronchodilating PGs (PGE2)
  • Produces leukotrienes that constrict bronchioles, mimicking asthmatic attack
  • May include urticaria and angioedema
56
Q

For patients with airway reactivity, use:

A

Acetaminophen

57
Q

Adverse effects of NSAIDs

A
  • Occult bleeding
  • Possible increases in intraoperative and postoperative hemorrhage in oral surgery
  • Renal issues
58
Q

What is occult bleeding?

A

Hidden amounts of blood in stool

59
Q

How does occult bleeding occur?

A
  • Direct capillary and mucosal damage as aspirin disintegrates
  • COX1 inhibition interferes with cytoprotective mechanisms and platelet aggregation
60
Q

NSAIDs are contraindicated in patients with ____, leads to dangerous _____

A

Ulcers; GI hemorrhage

61
Q

In oral surgery, higher doses of aspirin may lead to:

A

Possible increases in intraoperative and postoperative hemorrhage

62
Q

In oral surgery, with very high doses of NSAIDs, what is recommended to do?

A

Med consult and platelet function assay

63
Q

Low dose therapy in oral surgery

A

Accepted practice is to not stop low-dose aspirin therapy for dental procedures but to consider local control measures if necessary (suturing, collagen in socket)

64
Q

Normal renal function is dependent on:

A

PG synthesis

65
Q

COX 1 and COX 2 produce the PGs that reduce ____ at the ascending loop of Henle and maintain proper dilation of renal vasculature

A

Water and Na+ reabsorption

66
Q

Following inhibition of PGE2 synthesis in the kidneys, what happens?

A

Water and Na+ retention results in peripheral edema, elevation in blood pressure, and possible congestive heart failure

67
Q

Acute renal failure is more likely with:

A
  • Pre-existing renal insufficiency
  • Congestive heart failure
  • Dehydration

(in these cases, renal arterioles are more dependent on PGs to maintain normal perfusion)

68
Q

NSAIDs that inhibit COX 2 cause ____ GFR in the kidney

A

Reduced

69
Q

Ibuprofen is a ____ COX inhibitor

A

Non-selective

70
Q

Ibuprofen has ____ anti-inflammatory properties

A

Good

71
Q

All propionic acids are:

A

Extensively and reversibly protein bound (99%)

72
Q

Ibuprofen is a ____ derivative

A

Propionic acid

73
Q

Ibuprofen can be administered in what forms for post surgical dental pain?

A
  • Oral tablet
  • Liquid
  • IV
  • Topical creams for osteoarthritis
  • Liquid gels
74
Q

____ has a lower incidence of side effects vs aspirin due to being less selective for COX 1 and less GI side effects

A

Ibuprofen

75
Q

Ibuprofen interaction with anticoagulants is:

A

Uncommon (No irreversible inhibition of COX in platelets)

76
Q

Chronic use of Ibuprofen

A
  • Nausea
  • Dyspepsia
  • GI ulceration
  • Headache
  • Hypertension
  • Increase in liver enzymes
77
Q

Naproxen (Aleve) is more or less irritating to the GI tract than ibuprofen>

A

More (likely due to greater selectivity for COX 1)

78
Q

Naproxen half life

A

15 hours

79
Q

COX2 selective inhibitors reduce ____ while minimizing ____

A

Inflammation and pain; undesirable GI adverse effects

80
Q

Why are COX-2 inhibitors selective for COX-2?

A

Larger than non-selective COX inhibitors, so too bulky to access hydrophobic channel of COX-1, so less inhibition of COX1

81
Q

Which COX-2 selective inhibitors have potential cardiovascular effects?

A

Vioxx and Bextra

82
Q

COX-2 selective inhibitors are prescribed for:

A

Osteoarthritis, rheumatoid arthritis

83
Q

____ is the only FDA-approved highly selective COX-2 inhibitor in the US

A

Celecoxib

84
Q

Celecoxib is 10x more selective for ____ than ____

A

COX2 than COX1

85
Q

Celecoxib effects

A

Decreases inflammation and pain with minimal GI problems and reduced effect on platelet aggregation

86
Q

Celecoxib may cause allergic rxn due to:

A

Sulfonamide group

87
Q

True or false: for dental pain, Celecoxib is superior to ibuprofen

A

False

88
Q

start slidd 29

A

DEN 7203 Pharmacological Concepts (7 decks)

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