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PHRM 825 > NSAIDs - 20,21 > Flashcards

NSAIDs - 20,21 Flashcards

1
Q

Inflammation

  • initiates ___ process
  • may injure normal tissues
  • too strong of a response ( ___ infection)
  • prolonged response ( ___ infection)
  • inappropriate response ( ___-antigens, ___ disease)
  • 5 signs
A
  • healing
  • severe
  • persistent/recurrent
  • self-antigens, autoimmune
  • heat (calor), redness (rubor), swelling (tumor), pain (dolor), loss of function (functio laesa)
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2
Q

Chemical mediators of inflammation

  • vasoactive ___ (histamine and ___ )
  • Eicosanoids (prostaglandins, ___, and lipoxins)
  • ___ activating factor (PAF)
  • Cytokines (TNF, IL-___, chemokines → ___ inflammation) (IFN-y → ___ inflammation)
  • complement components (C3a and C5a)
  • Coagulation and kinin systems (bradykin, thrombin, fibrinopeptides)
A
  • amines, serotonin
  • leukotrienes
  • platelet
  • 1, acute
  • chronic
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3
Q

What is this?

A

PAF

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4
Q

T or F: Eicosa means 30

A

False; 20, eicosanoids will have 20 or more carbons

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5
Q

Eicosanoids

4 types
PGE2- Blood vessel ___ , brochi ___ , uterus ___
PGF2a - blood vessels ___ , bronchi ___ , uterus ___
PGI2 - blood vessels ___ , platelets ___
TXA2 - blood vessles ___ , platelets ___

A
  • dilation, dilation oxytocic dilation
  • constriction, contriction, oxytocic constriction
  • dialtion, inhibits aggregation
  • constriction, aggregation (clotting)
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6
Q

prostaglandin = ___
leukotrienes = ___
lipoxin = ___

A
  • inflammation
  • allergies
  • anti-inflammatory
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7
Q

Eicosanoids

  • ___-lived mediators (seconds to minutes)
  • ___ and paracrine signaling
  • bind GPCRs in target cells (Gs and Gq)
  • Gs = ___
  • Gq = ___
A
  • short
  • autocrine
  • dilation
  • constriction
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8
Q

Arachidonic acid

  • 20-carbon polyunsaturated fatty acids
  • ___ fatty acids
  • most abundant and important ___ of eicosanoids
  • Released from membrane phospholipids by ___ (PLA2)
  • corticosteroids ___ the production of phospholipase A2
A
  • essential
  • precursor
  • phospholipase A2
  • suppress
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9
Q

Oxygenation of arachidonic acid

  • PGH synthase ( ___ ) pathway
  • Lipoxygenase pathway
  • Epoxygenase ( ___ ) pathway
  • Isoprostane pathway (free radical reaction)
A
  • COX
  • CYP450
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10
Q

PGH synthase

  • both COX and ___ activities
  • COX reaction: radical-mediated oxidation
  • ___ reaction: hydroperoxyl group (-OOH) to a hydroxyl group (-OH)
A

Hydroperoxidase

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11
Q

Isoforms of PGH synthase

PGH synthase-1
* COX-1: housekeeping ( ___ cytoprotection)
PGH synthase 2
* COX-2: expressed upon stimulus in inflammatory and immune cells.
* Stimulated by ___ , tumor promoters, and ___ .

Inhibited by ___

A
  • gastric
  • growth factors, cytokines
  • NSAIDs
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12
Q

Prostaglandins vs. thromboxanes

platelets = ___
vascular endothelia = ___

A
  • TXA2
  • PGI2
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13
Q

Eicosanoid drugs

Alprostadil
* type: ___
* relaxes smooth muscles and ___ blood vessels
* used for ___ by injection or suppository

A
  • PGE1
  • expands
  • ED

ouch, make sure they pee before

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14
Q

Eicosanoid drugs

Misoprostol
* ___ derivative
* Prevents ___
* when combined with ___ , terminates early pregnancy

A
  • PGE1
  • peptic ulcer
  • mifepristone
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15
Q

Eicosanoid drugs

Latanoprost
* topically active ___ derivative (prodrug)
* ___ blood vessels
* used for glaucoma

A
  • PGF2a
  • constrict
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16
Q

Eicosanoid drugs

Prostacyclin
* type: ___
* powerful ___
* inhibitor of ___
* used to treat pulmonary arterial hypertension by ___ injection or ___
* should not be used with ___

A
  • PGI2
  • vasodilator
  • platelet aggregation
  • IV, inhalation
  • anticoagulants
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17
Q

NSAID uses

  • Treatment of moderate pain, ____ , and inflammation from acute
    inflammation
    Treatment of early-stage rheumatoid arthritis and osteoarthritis
  • ___ prevention
A
  • fever
  • cancer
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18
Q

NSAID mechanism of action

Inhibition of prostaglandin endoperoxide H synthase (PGHS or COX), which catalyzes the formation of prostaglandins.
* Many NSAIDs ___ both COX-1 and COX-2.

A

inhibit

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19
Q

Classes of NSAIDs

A
  • Salicylates
  • Arylacetic acids
  • Arylpropionic acids
  • Non-carboxylate NSAIDs
  • COX-2 selective NSAIDs
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20
Q

Example of a salicylate NSAID?

A

aspirin

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21
Q

Example of aryl propionic acid NSAID?

A

ibuprofen

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22
Q

Example of aryl acetic acid NSAID?

A

Indomethacin

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23
Q

Example is non-carboxylate NSAID?

A

meloxicam

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24
Q

Example of COX-2 Selective NSAID?

A

Celecoxib

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25
Q

Side effects of NSAIDs

Gastrointestinal
* mild: dyspepsia, N/V
* severe: ulcer, blood loss
* the ___ of NSAIDs is the primary insult
* inhibition of ___ secondary insult
* inhibition of ___ (increased tendency of bleeding)

A
  • acidicty
  • PGEs
  • platelet aggregation
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26
Q

Side effects of NSAIDs

Blood coagulation
* ____ prolongs bleeding by irreverible inhibition of platelet COX - ___
* can be used in some patients with ___ disease to prevent blood coagulation

A
  • aspirin, 1
  • cardiovascular
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27
Q

T or F: aspirin before surgery or tooth extraction is recommended

A

‘FALSE; youll bleed like crazy.

contraindicated

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28
Q

Side effects of NSAIDs

renal
* renal failure in patients with cardiovascular, ___, and ___ diseases

A

heptic, renal

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29
Q

Side effects of NSAIDs

Hypersensitivity
* Characterized by skin rashes, hives, angioedema, and an asthma-like
syndrome (blocked by ___ inhibitors).
* Occurs in 0.3% of the population (___ % in asthmatics).

A
  • 5-lipoxygenase
  • 10%

theory: higher in asthmatics due to higher baseline leukotriene levels

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30
Q

Side effects of NSAIDs

Reye’s syndrome
* specific to ___
* ___ damage common in survivors
* occurs in children who have had the ___ or ___
* ___ should not be given to anyone under the age of ___ who has a ___

A
  • salicylates
  • brain
  • flu, chicken pox
  • aspirin 12, fever
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31
Q

Side effects of NSAIDs

CNS

A
  • tinnitus
  • dizziness
  • headache

tinnitus is ringing of the ears

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32
Q

Prevention of GI side effects

  • misoprostol __ analog (prevents ulcers)
  • esomeprazole ___ inhibitor (reduced acid secretion even in the absense of COX-1 activity)
  • combo products: naproxen/esomeprazole, naproxen/misoprostol, diclofenac/misoprostol

Misoprostol

A
  • PGE1
  • proton pump
33
Q

Drug interactions of NSAIDs

  • ___ % of NSAIDs are bound to ___
  • NSAIDs may ___ for serum albumin binding sites with other drugs

Example – combination with oral anticoagulants
* Increases the plasma concentration of free ___.
* The ability of salicylate to produce GI bleeding and inhibit the clotting
mechanism aggravates the problem.
* Necessitates a possible ___ in the dosage of anticoagulant.

A
  • 90-99%, albumin
  • compete
  • anticoagulant
  • decrease
34
Q

Structure-activity relationships in NSAIDs

  • commonly contains a __ group
  • acidic group located one carbon away from ___ or heteroaromatic ring
  • a methyl group on the carbon atom separating the acidic group from the aromatic ring tends to increase activity for “ ___ “
    A second area of lipophilicity (aromatic or alkyl) that
    is noncoplanar with the aromatic or heteroaromatic
    ring generally ___ activity.
A
  • acidic/carboxyl
  • “profens”
  • enhaces
35
Q

Salicylates

  • Absorbed as an ionic form from the small intestine and, to lesser extent, from the stomach as an ___ form.
  • Inhibits COX-1 and COX-2 ___.
  • May suppress COX-2 induction.
A
  • acid
  • reversibly
36
Q

Salicylates - aspirin

  • The only NSAID that ___ inhibits COX by acetylating a ___
    residue in the active site.
  • Absorbed largely as the intact form but hydrolyzed rapidly to salicylate by
    plasma ___.
  • Blocks platelet-aggregating factor TXA2 effectively; increases the risk of
    bleeding but also reduces the risk of myocardial infarction.
  • not ___ in solutions due to esters being sensitive to ___
A
  • irreversibly, serine
  • esterase
  • TXA2
  • stable
  • hydrolyzing
37
Q

Salicylates

Salsalate (Disalcid®)
* ___ of salicylic acid (prodrug)
* hydrolyzed into 2 ___ in the small intestine and ___
* does not cause ___

A
  • dimer
  • salicylates, absorbed
  • GI bleeding
38
Q

Salicylates

Diflunisal (Dolobid®)
* More ___ analgesic than
aspirin, but produces ___ side effects.
less ___ activity than aspirin
3-4 fold longer t1/2 than aspirin

A
  • potent
  • less
39
Q

Arylacetic acids

Indomethacin
* one of the most ___ NSAIDs
* high incidence of side effects
* not suitable for ___ use
* not stable in solution due to hydrolysis of ___

A
  • potent
  • long term
  • amide bond
40
Q

Arylacetic acids

Sulindac
* prodrug; the ___ group is reduced to the active sulfide intermediate in the circulatory system
* less ___ side effects
* suitable for ___ use to treat ___ inflammation

A
  • sulfoxide
  • GI
  • long term, chronic
41
Q

Arylacetic acids

Etodolac
* ___ acid
* As potent as ___.
* Somewhat selective for ___.
* Less ___ bleeding
* Suitable for ___ use to manage ___.

A
  • Pyranocarboxylic
  • indomethacin
  • COX-2
  • GI
  • long-term, osteoarthritis
42
Q

Arylacetic acids

Diclofenac
* The most widely used NSAID in the world.
* As potent as ___
* Somewhat selective for ___.
* Inhibits both COX and ___ pathways.
* good for long term

A
  • indomethacin
  • COX-2
  • lipoxygenase
43
Q

Arylpropionic acids

Ibuprofen (Advil® or Mortrin®)
* more potent than aspirin but less than indomethacon
* moderate gastric irritation
* ___ group enhances it activity and reduces many side effects.

Bioequivalent racemic mixture
* S-(+)-enantiomer possesses ___ activity in vitro.
* R-(-)-enantiomer is converted to S-(+)-enantiomer enzymatically in vivo.

A
  • α-Methyl
  • greater
44
Q

Arylpropionic acids

Naproxen (Aleve®)
* ___ (+) - enantiomer
* more potent than ibuprofen
* moderate ___
* used to treat ___ arthritis and osteoarthritis

A
  • S
  • gastric irritation
  • rheumatoid
45
Q

Arylpropionic

Ketorolac
* Cyclized heteroarylpropionic acid
derivative
* ___ management of
moderate to severe pain.
* Analgesic activity similar to
___ acting analgesics.
* Widely accepted alternative to
narcotic analgesics.

A
  • short term
  • centraly (like opiates)
46
Q

Non-carboxylates

Nabumetone
* nonacidic prodrug
* metabolized quickly to ___ which is a ___ inhibitor
* minimum ___ side effects
* Potent anti-inflammatory, but weak ___ activity.

A
  • 6-MNA, COX
  • gastric
  • analgesic
47
Q

Non-carboxylates

Meloxicam
* Belongs to the oxicam class,
which resembles the ___ intermediate in COX.
* Enolic acid
* ___ acting ; single daily dose.
* As potent as ___.
* Somewhat selective for ____.
* good more longe term use

A
  • peroxy radical intermediate
  • long
  • indomethacin
  • COX-2
48
Q

Consequences of COX-1 inhibition

  • Stomach irritation and ___
  • Blockade of platelet ___
  • Inhibition of uterine ___
  • Inhibition of ___ mediated renal function
  • ___ reactions

Preferential inhibition of COX-2 gives anti-inflammatory effects with
lower incidence of gastric ulceration.

A
  • ulceration
  • aggregation
  • motility
  • prostaglandin
  • hypsersensitivity
49
Q

What NSAIDs are good for long term use?

A
  • Etodolac
  • meloxicam
  • celecoxib
  • nimesulide
50
Q

What NSAIDs are good for long term use?

A
  • Etodolac
  • meloxicam
  • celecoxib
  • nimesulide
51
Q

Selective COX-2 Inhibitors

  • ___ in the NSAID binding site of COX-2 is substituted for ___ in that of COX-1.
  • Selective COX-2 inhibitors exploit the ___ NSAID binding site in COX-2 with larger and relatively rigid substituents.
  • “coxib”
A
  • valine, isoleucine
  • larger
52
Q

Side effects of selective COX-2 inhibitors

  • elevated ___ and atherogenesis
  • expression of COX-2 in endothelium is critical for ___ production
  • selective COX-2 inhibitors do not affect the production of ___ by COX-1 (heightedned thrombotic response on the rupture of artherosclerotic plaque)
  • increased risk for heart attack and ___
A
  • blood pressure
  • PGI2 (prostacyclin)
  • TXA2
  • stroke
53
Q

Celecoxib

Celebrex®
* First NSAID to be marketed as selective COX-2 inhibitor.
* Used for osteoarthritis and rheumatoid arthritis.
* Good efficacy against pain, inflammation, and fever.
* As potent as ___.
* Less risk of ___ side effects.
* No ___ activity.

A
  • naproxen
  • GI
  • antiplatelet
54
Q

Celecoxib

Celebrex®
* First NSAID to be marketed as selective COX-2 inhibitor.
* Used for osteoarthritis and rheumatoid arthritis.
* Good efficacy against pain, inflammation, and fever.
* As potent as ___.
* Less risk of ___ side effects.
* No ___ activity.

A
  • naproxen
  • GI
  • antiplatelet
55
Q

Acetaminophen

  • Analgesic and antipyretic effects similar to ___
  • Much weaker as an ___ agent.
  • mechanism of action: Does not inhibit ___ acid binding to ___.
  • Scavenges ___ required for PGH synthase activity
  • Peroxynitrite is the major oxidant for ___ synthase activity in the ___.
  • In inflammation, high concentrations of ___ are present, and acetaminophen scavenging is overwhelmed.
A
  • aspirin
  • anti-inflammatory
  • arachidonic, PGHS
  • peroxynitrite
  • PGH, CNS
  • peroxides
56
Q

Acetaminophen

  • Lower incidence of ___ and ___
  • Tolerated in patients with blood ___ disorders.
  • Not associated with ___ syndrome.
  • Does not cross-react with ___
  • Hepatotoxicity at toxic doses (CYP 450 mediated N-hydroxylation to form N-acetylimidoquinone
    which reacts with ___ ) .
  • Toxic doses overload the glutathione, and cell damage occurs in the liver.
A
  • GI disturbance and hypersensitivity
  • Reye’s
  • aspirin
  • glutathione

glutathione is a reducing agent in cells (detoxifying in liver)

57
Q

What is this?

A

Arachidonic acid

precursor of eicosanoids

58
Q

What is this?

A

Arachidonic acid

59
Q

What is this?

A

TXA2

60
Q

What is this?

A

PGI2 (prostacyclin)

61
Q

What is this?

A
62
Q

What is this?

A

PGF2

63
Q

What is this?

A

Alprostadil

PGE1

64
Q

What is this?

A

Misoprostol

PGE1 derivative

65
Q

What is this?

A

Latanoprost

PGF2a
derivative (prodrug)

66
Q

What is this?

A

Aspirin (ASA)

67
Q

What is this?

A

Salsalate

Salicylates

68
Q

What is this?

A

Diflunisal (Dolobid®)

Salicylates

69
Q

What is this?

A

Indomethacin

Arylacetic acids

70
Q

What is this?

A

Sulindac

Arylacetic acids

71
Q

What is this?

A

Etodolac

Arylacetic acids

72
Q

What is this?

A

Diclofenac

Arylacetic acids

73
Q

What is this?

A

Ibuprofen

Arylpropionic acids

74
Q

What is this?

A

Naproxen (Aleve®)

Arylpropionic acids

75
Q

What is this?

A

Ketorolac

Arylpropionic acids

76
Q

What is this?

A

Nabumetone

Non-carboxylates

77
Q

What is this?

A

meloxicam

Non-carboxylates

78
Q

What is this?

A

Celecoxib

Selective COX-2 Inhibitors

79
Q

What is this?

A

PHRM 825 (49 decks)

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