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PDA Block 2 > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

3 general properties of NSAIDs

A
  • anti-inflammatory
  • anti-pyretic
  • analgesic
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2
Q

 In general, when you think about PGs and inflammation,
think about________

(is it COX 1 or COX2)

A

COX2

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3
Q

Does acetaminophen have anti-inflammatory properties

A

NO

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4
Q

What is the general mechanism of all NSAIDs

A

inhibition of cyclooxygenase however not all inhibit COX1 and or COX2 some are specific

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5
Q

Mechanism of Action of Aspirin

A
  • it is an IRREVERSIBLE inhibitor of COX1 and COX2

- It does this by acetylating a serine moiety

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6
Q

How many NSAIDs are irreversible inhibitors of COX1 and COX2

A

ONLY ASPIRIN

then rest are reversible inhibitors

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7
Q

Therapeutic implications of irreversible inhibition of COX1 and COX2

A

the only way to overcome irreversible inhibition is to synthesize new COX enzymes.

Platelets don’t have a nucleus so they cant synthesize new COX enzymes so once they are knocked out that platelet is done. Fortunately platelets regenerate in about 7 days. So when new platelts are formed those new platelets will have OCX function

  • this is why you only need a low dose of aspirin in CV disease.
  • whereas in endothelial cells they have a nucleus so they can re-synthesize COX quickly
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8
Q

describe the pharmacokinetics of aspirin

-how is it absorbed and what limits the absorption

A
  • oral absorption that is limited by dissolution rate. therefore if you chew the aspirin you can increase the absorption rate
  • It is hard on the stomach so it can have an enteric coating or buffer to help make is dissolve in the intestines instead of the stomach
  • highly bound to plasma proteins
  • crosses the BBB
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9
Q

Does aspirin cross the BBB

A

YES

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10
Q

Describe the metabolism of Aspirin

A
  • It is deacetylated into Salicylic acid
  • Salicyclic acid is then broken down via
  • Phase I oxidation (4%)
  • Phase II glucuronidation (34%)
  • hase II glycination (49%)
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11
Q

How is aspirin eliminated

A

renal and it is dose dependent. Normally it is about 2-3 hours, but can be up to 30 hours when the dose is high enough because the metabolism enzymes saturate and there is a build up of Salicylic acid

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12
Q

unique effects specific to aspirin that are unrelated to COX inhibition

A
  • Uric acid excretion
  • CNS effect (bc crosses BBB)
  • Respiratory effect
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13
Q

Explain why gout is a contraindication for aspirin

A
  • gout is a build up on uric acid
  • low dose aspirin: decrease uric acid excretion
  • small secretory component for urate that is sensitive to low concentrations of salicyclates
  • large dose aspirin- increase uric acid secretion

-usually people take low dose aspirin so if someone ahs gout and they take a low dose aspriing they already have ab build up of uric acid and now they will decrease uric acid excretion, further increasing th build up of uric acid

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14
Q

Effect of PGs on Uric acid excretion

A

PGs have no effect on uric acid excretion, but aspirin does.

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15
Q

CNS effects of Aspirin

A

tinnitus, high-tone deafness, confusion, dizziness, delirium, psychosis, coma

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16
Q

What is the major limitation to long term therapy with NSAIDs (especially aspirin)

A

GI side effects

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17
Q

Effects of PGs on GI system

A
  • major PGs that effect the GI system are PGE2 and PGI2 (which are formed by COX1 bc that is the constitutive one and COX2 is the inducible one that is associated with injury and inflammation )
  • PGE2 and PGI2 promote secretion of the cytoprotective mucus in the intestine and inhibit acid secretion by the stomach
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18
Q

NSAID GI side effects

A

block the production of cytoprotective PGs

  • GI ulceration and irritation
  • chronic use of NSAIDs increases risk by 3x
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19
Q

PGs and platelets

A
  • PGI2 inhibits platelet aggregation

- TXA2 stimulates platelet aggregation

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20
Q

NSAID effects on platelets

A

ALL NSAIDs increase bleeding time by inhibiting platelet TXA2

a single dose of 80 mg aspirin inhibits bleeding time for one week bc platelets lack a nucleus and will only get a new COX with new platelets bc ASA irreversible inhibition of COX

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21
Q

NSAID hypersensitivity

A
  • intolerance to aspirin and other NSAIDS
  •  NOT an IgE-mediated mechanism
  • proposed mechanism: Blocking COX causes all Arachidonic acid to be shuttled in the leukotriene pathway. these are responsible for allergy bronchoconstriction and mucus production
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22
Q

PGs and the KIdney

A
  • COX-1
  • Role for COX-2 as well especially in disease states
  • PGE2 and PGI2 increase renal blood flow
  • increase Na and water excretion
23
Q

NSAID renal side effect

A
  • decrease renal blood flow
  • promote salt and water retention
  • effects more prominent in individuals dependent on vasodilatory PGs (ie people who have CHF, renal disease and ELDERLY)
24
Q

PGs and the uterus

A
  1. pregnant uterus
    - PGF2a=contraction
    - PGE2=contraction
    - PGI2=dilation (early pregnancy)
  2. maintina patent ductus arteriosus (PDA) in fetus
  3. Non pregnant uterus
    - PG mediated effects on contraction
    - hyperalgesia
25
Q

NSADIs and pregnancy

A
  • prolongation of gestation
  • prolonged labor
  • increased risk of postpartum hemorrhage: TXA2/platelets/clotting
  • intratuterine closure of PDA

-but thought that low doses don’t case harm to fetus

26
Q

NSAIDs and the non-pregnant uterus

A

decrease pain associated with primary dysmennorhea

27
Q

Salicyclism

A

aspirin poisoning

-symptoms are a lot of the CNS toxicity bc at high doses more will cross the BBB

28
Q

Reye Syndrome

A

-specific to aspirin use in children (6-11 years) and often follows a virus like chicken pox or influenza B

  • clinical characteristics:
  • acute encephalopathy
  • liver degeneration

-mandates warning that all children under the age of 19 are at risk of reye syndrome

29
Q

Therapeutic uses of aspirin

A
  • fever, pain, inflammatory disorders
  • CV disease
  • low dose: CV disease
  • intermediate dose: low intensity pain/fever
  • high dose: chronic inflammatory disease/rheumatoid arthritis
30
Q

low dose aspirin

A

CV disease

31
Q

intermediate dose aspriin

A

low intensity pain/fever

32
Q

high dose aspirin

A

chronic inflammatory disease/rheumatoid arthritis

33
Q

Side effects associated with ALL NON- SELECTIVE (COX-1 AND COX-2) NSAIDS

A
  • GI irritation
  • Inhibition of platelet aggregation/increased risk of bleeding
  • Decrease in RBF in patients dependent of vasodilatory PGs
  • hypersensitivity
34
Q

COX 2 is the major isoform associated with

A

inflammation

35
Q

Theory behind development of COX-2 inhibitors

A

_Cox2 is the isoform associated with inflammation

  • Major limitation of conventional NSAIDd was GI-related side effects
  • COX1 responsible for synthesis of cytoprotective
  • so if we only block COX-2 then we can treat inflammation whiheout risk of GI side effects

-unfortunately this didn’t pan out and we still get GI side effects for an unknown reason

36
Q

What is the only selective COX-2 inhibitor

A

Celecoxib

37
Q

Celecoxib and allergies

A
  • contains a sulfonamide side chain
  • this is important for allergic reactions bc some people are allergic to sulfa drugs. this is a true antigen antibody allergic reaction unlike the NSAID hypersensitivity we previously talked about
38
Q

Celecoxib mechanism of action

A
  • reversible inhibitor of COX2

- COX 2 specific bc the binding site that it binds to does not exist in COX 1

39
Q

Celecoxib is metabolized by what?

A

CYP2C9

40
Q

Adverse effects of Celecoxib

A 
-hypersensitivity
Increased risk of adverse
CV thrombotic events, like
MI/stroke 
- Increase risk of GI irritation,
ulceration, bleeding
41
Q

Contraindications

A 
-Pre-existing CV risk factors
or disease 
-Patients with a sulfonamide
toxicity 
-Prior NSAID hypersensitivity 
-Following coronary artery
bypass graft surgery 
-Deficiency of CYP2C9
42
Q

FDA recommendations for NSAIDs

A

-package insert for all NSAIDs, including Celecoxib
•  Exception is aspirin
-risk of serious, and potentially life-threatening, gastrointestinal bleeding.

43
Q

What are the 2 reversible COX inhibitors that can be orally administered and what are their major differences

A

Ibuprofen and Naproxen
-the major difference is half life, naproxen is taken once a day and ibuprofen is take 3-4 times a day

-they have less GI effects than aspirin

44
Q

What is the NSAID that can be given . orally or via IV and what is it used for

A

Indomethacin

  • reversible inhibition of COX1 and COX2
  • used for gout, preterm labor, to close patent ductusarteriosus (IV)
  • not routinely used to treat pain or fever
45
Q

Ketorolac

A
  • reversible inhibitor of COX1 and COX2
  • oral, IV and IM administration
  • rapid onset short duration
  • **-used as alternative for opioid analgesics in the treatment of post-operative pain*****
  • oral or injection
  • short term aka less than 5 days
  • much more effective for pain than inflammation-important!!!!!!!
46
Q

Piroxicam

A

-Reversible inhibitor of COX1 and COX2
-oral administration once a day
-metabolized by CYP2C9
-EXTREMELY LONG HALF LIFE
-and osteoarthritis
Therapeutic use
*Symptomatic treatment of acute and chronic rheumatoid arthritis

47
Q

Acetaminophen

A

reversible COX inhibitor not NSAID

48
Q

Acetaminophen may not work in cells or tissues that ______

A

have high levels of peroxide

49
Q

Metabolism of acetaminophen

A

-partially metabolized by liver microsomal system (phase I)
*CYP2E1, CYP1a2, CYP3A4
- Mainly undergoes (phase II) glucoronidation and sulfation (95%
of total)

50
Q

How is acetaminophen excreted

A

renal excretion

51
Q

What is the plasma half life

A

about 2 hours

52
Q

Adverse effect/toxicity of acetaminophen

A
  • None to little GI issues

- Most serious is hepatic toxicity

53
Q

Toxicity of acetaminophen explanation and treatment

how does alcohol play a role

A

-too much acetaminophen leads to more acetaminophen being metabolized by CYP2E1 into NAPQI which leads to hepatotoxicity
- Treatment is N-acetylcysteine (replenishes
glutathione stores) preferably within 36 hours
-Alcohol induces the enzyme CYP2E1 so that more acetaminophen in converted to NAPQI which leads to hepatotoxicity

54
Q

therapeutic uses of acetaminophen

A
  • acute pain and fever

- NO ANTI-INFLAMMATORY EFFECTS

PDA Block 2 (13 decks)

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