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PHARMACOLOGY - 1 > 13 – NSAIDs > Flashcards

13 – NSAIDs Flashcards

1
Q

Leaves and bark of willow tree

A
  • Anti-inflammatory properties
  • *contains SALICYCLIC ACID: pre-cursor to aspirin
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2
Q

5 cardinal signs of inflammation

A
  • Redness
  • Heat
  • Swelling
  • Pain
  • Loss of function
  • **caused by vasodilation, edema, nociceptive stimulation
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3
Q

If wanting to prevent peripheral inflammation, NSAIDs or steroids?

A
  • Can use either or
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4
Q

NSAID uses

A
  • Prevent or reduce inflammation
  • Reduce fever (anti-pyretic)
  • *Analgesic (central and/or peripheral effects)
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5
Q

NSAID: prevent or reduce inflammation

A
  • Block formation of inflammatory EICOSANOIDS
    o Ex. prostaglandins, thromboxane, leukotrienes
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6
Q

NSAID: reduce fever (anti-pyretic)

A
  • PGE2 (prostaglandin) is an endogenous pyrogen
    o Increase body T by re-setting the ‘set-point’ in hypothalamus
  • *if more prostaglandin expressed=increase T
  • *if decrease prostaglandin=decrease T
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7
Q

NSAID inflammation pathway: peripheral

A
  • Prevent AA from going to prostaglandins
    o Block COX1 and COX2
  • Do NOT get PGE2 or PGF2
  • *Immune-mediated products (ex. leukotrienes) are STILL PRODUCED!
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8
Q

NSAID analgesia

A
  • Reducing PERIPHERAL may decrease pain sensation
    o If due to swelling/pressure (same mechanism as with corticosteroids)
  • Prostaglandin ‘synergy’ with bradykinin and histamine
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9
Q

PG ‘synergy’ with bradykinin(BK) and histamine(HT)

A
  • PG can increase afferent neurone firing due to BK&HT-mediated stimulation of peripheral nociceptors
    o Hyperalgesia (increase effect of painful stimuli)
    o Allodynia (normally non-painful stimuli become painful)
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10
Q

What about Tylenol (ex. acetaminophen)?

A
  • Has lots of CENTRAL analgesia effect
    o Still lots of PGs being produced in CNS
  • Poor PERIPHERAL analgesia effect
  • Not much anti-inflammatory activity
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11
Q

‘central’ analgesia

A
  • Both cyclo-oxygenase isoforms (COX-1 and COX-2) are present in brain and spinal tissue
    o Produce PGs in neural tissues
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12
Q

What is the result of ‘central’ PGE formation?

A
  • Sensitizes central nociceptors (‘wind-up”)
  • Lowers spinal depolarization threshold
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13
Q

NSAIDs is one of most commonly classes of vet drugs

A
  • Efficacious
  • Relatively safe
  • Potential for profit (giving multiple times a day)
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14
Q

NSAIDs and reported adverse effects (‘pharmovigilance’)

A
  • Typically 10% of total adverse effects
  • Used a lot, so will see more adverse effects
  • Tend to use them in animals that are less healthy
    o Geriatric, perioperative, etc.
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15
Q

NSAIDs: GI adverse drug events

A

*60%
- Vomiting
- Diarrhea
- Ulcers
- Melena
- *PG usually protect
- *direct GI irritation (aspirin, meloxicam tablets)

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16
Q

NSAIDS: renal adverse events

A

*20%
- PG help maintain GFR
o NSAIDs: decrease GFR
- Renal papillary necrosis

17
Q

NSAIDs GI and renal adverse events

A
  • *DOSE-DEPENDENT in most cases
    o Use lowest dose that is still effective
18
Q

NSAIDs hepatic adverse events

A

15%
- Idiosyncratic hepatic necrosis/toxicity
- Increase liver enzymes: change in bile acids?
- *cats most susceptible, but can’t predict individual toxicity
- **probably dose-dependent, but dose-independent is (‘less) common’
o If see independent=liver

19
Q

NSAIDS hematologic adverse events

A

1%
- Prolonged bleeding time with aspirin and ketoprofen

20
Q

COX1

A
  • Constitutive (produced constantly)
  • Present under normal conditions in many cells
  • Produce ‘cytoprotective’ PGs (vasodilation, mucous)
    o *positive
21
Q

COX1 present under normal conditions in many cells

A
  • Platelets and endothelium
  • Mucosal cells (GI)
  • Renal tubule cells
  • Neural tissues
22
Q

COX2

A
  • Inducible (expressed in response to inflammatory mediators)
  • Often formed at sites of inflammation
    o *what we want to target
  • Constitutive in some tissues
23
Q

COX2 selective

A
  • Drugs that inhibit COX2 (but not COX1) at label dose
24
Q

COX2 preferential

A
  • Drugs that inhibit COX2 at lower drug concentrations than COX1
    o Some COX1 inhibition at label dose
25
Q

COX nonspecific

A
  • Both COX1 and COX2 are inhibited at label doses
26
Q

How to determine which category of NSAID? (‘older’ concept)

A
  • COX inhibition
  • IC50: drug concentration at which 50% of enzyme activity is inhibited
  • *lower IC means increased drug potency
27
Q

Wanted to get an NSAID where IC50 for COX1 was really high (older concept)

A
  • High number means LESS inhibition
  • COX1 is ‘spared’
28
Q

IC ratios problems

A
  • In vitro data does not pan out when given to animals
  • Species differences in IC values
  • Chirality
    *HARD TO COMPARE IC BETWEEN NSAIDs or SPECIES
29
Q

Overly-simplistic (and wrong) theory

A
  • COX1 is good, COX2 is bad
  • Higher COX1 : COX2 IC50 ration =better NSAID
    *past this point!
30
Q

COX2 is not all bad

A
  • Constitutive in some tissues (kidney, brain, SC)
  • Expressed near gastric ulcers=accelerates healing
31
Q

COX3

A
  • Derivative of COX1
  • Found in brain
  • Unknow function, but inhibited by older NSAIDs that ‘seem to work’
32
Q

PK/PD data and NSAID comparison of safety and efficacy

A
  • Cannot make decisions solely on PK/PD data
    o Need clinical trials! (not in vitro data)
33
Q

NSAID general PK properties

A
  • Generally good oral bioavailability
  • Primarily eliminated by HEPATIC metabolism
  • Highly protein bound (lead to low Vd)
    o Present at sites of peripheral inflammation
  • Usually weak acids (can be ion-trapped in cells)
  • *kinetics highly variable between species
    o Cats=poor glucuronidation (low clearance, long half-life)
34
Q

COXIB-specific drug properties

A
  • Varying degrees of COX2 selectivity
  • Generally, very LIPOPHILIC
  • Hepatic metabolism: CYP450
    o When use with other drugs, if both substrates for same enzyme=induction/inhibition
35
Q

VIOXX (first COXIB in human med)

A
  • Recalled
  • Increased risk of CV events (heart ailments, strokes)
    o Not an issue in dogs or cats
36
Q

Intravenous lipid emulsion (ILE) therapy

A
  • May be helpful in cases of lipophilic NSAID toxicosis
  • Concept: lipophilic drug distributes from CNS into lipid emulsion in vasculature=facilitates clearance (DRUG DISTRIBUTION)
  • BUT: limited efficacy (case reports, are NOT clinical trials)
    o One case of respiratory distress reported after ILE
37
Q

Washout periods

A
  • Time period when switching between 2 drugs
  • *allows 1st drug to be eliminated, increasing margin of safety when 2nd drug is administered
  • *very important for anti-inflammatory drugs
    o Even though different enzyme targets, it is the same pathway
38
Q

Is it a good idea to use a ‘washout period’ when switching between NSAIDs?

A
  • Yup!
39
Q

How do you know how long a washout period to use when switching NSAIDs?

A
  • *BE CAREFUL
  • Use some length (whatever is feasible for patient/owner)
  • Warn owner of risks!

PHARMACOLOGY - 1 (12 decks)

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