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Phase I > Arthritis/NSAIDs > Flashcards

Arthritis/NSAIDs Flashcards

1
Q

Radiographic signs of OA

A
  • Osteophytosis
  • Enthesophytosis
  • Effusion
  • Soft tissue swelling
  • Subchondral sclerosis
  • Intra-articular mineralization
  • Subchondral cyst
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2
Q

Arachidonic Acid pathway

A

Cell membrane phospholipids - (phospholipase A2)-> Arachidonic Acid
-AA -> COX-1/2 -> PGG2 -> PGH2 => Thromboxane A2 (vasoconstriction, platelet aggregation), PGI2 (vasodilation, inhibit platelet agg), PGD2/PGE2 (vasodilation, inc vascular permeability)

-AA -> 5-Lipoxgenase => Leukotriene A4-E4

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3
Q

COX isoforms

A

COX-1: Generally constitutive form - prostaglandins important for physiologic functions (GI cells, platelets, endothelial cells, renal cells)
COX-2: Generally inducible - expression regulated under basal conditions, upregulated in presence of inflammation

*Oversimplification - COX2 constitutive in brain & kidney

Selectivity denoted by COX-1:COX-2 ratio

*COX inhibition may increase lipoxygenase pathway with more leukotrienes (LTB4)

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4
Q

NSAID adverse effects

A

-Cartilage: Conflicting results - in vitro inhibition (aspirin) vs stimulation proteoglycan synthesis. Carprofen, ketoprofen, piroxicam possible chondroprotective effects.

-GI: GI adverse effects usually due to ulceration due to inhibtion of COX-1 stimulated PGE-2 mediated bicarb & mucus secretion, epithelialization, and increased blood flow. Control of gastric acid secretion, mucus & bicarb secretion, and mucosal epithelialization/blood flow decreased.
Breakdown of small blood vessels due to mucus deficiecny may be inciting lesion. Salicylates cause local damage via “back diffusion” of acid - injury to mucosal cells & submucosal capillaries. Impaired platelet activity may also contribute. Enhanced LT synthesis from AA shunted away from COX pathway exacerbates.

-Hematopoetic: All cause impaired platelet activity d/t impaired thromboxane synthesis (COX1 selective action). Aggregation defects caused by aspirin can last up to 1 week. Can cause bone marrwo dyscrasias.

-Renal: Vasodilatory & tubuloactive prostoglandins are protective, ensuring medullary vasodilation & UOP continue during states of renal arterial vasoconstriction. COX 1&2 mediated renal effects of prostoglandins. Loss of protective effect important in patients with renal compromise.
COX1&2 constitutively expressed, COX-2 potentially more important
COX-2 inhibition causes Na & K retention in salt-depleted individuals

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5
Q

Carprofen

A
  • MOA not completely understood, unclear if eicosanoid synthesis inhibition is major action
  • COX2 selective with 1:2 ratio of 17
  • Possible stimulation of sulfated glycosaminoglycan synthesis at lower doses (10ug/mL or less), inhibition at higher.
  • Subjective and objective improvement in limb function in OA, minimal GI side effects reported
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6
Q

Deracoxib

A
  • Coxib class of NSAIDs
  • Bioavailability best with food
  • COX ratio not listed in JT, should be COX2 selective
  • Hepatic metabolism, excreted in feces but up to 1/5 in urine
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7
Q

Etodolac

A
  • Indole acetic acid derivative
  • Inhibits COX1 & 2 - in some whole blood assays, primarily cox1
  • Biliary excretion with enterohepatic recirculation
  • Possible association with KCS, in addition to standard renal/hepatic/hematologic concerns
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8
Q

Firocoxib

A
  • Pyridylsulfone COX-2 specific
  • COX1:2 ration ~342-430 (therapeutic COX 2 levels below any ihibition of cox1)
  • Studies show “non-inferiority” to carprofen, etodolac; possible superiority to etodolac
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9
Q

Ketoprofen

A
  • Propionic acid class of carboxylic acid derivatives
  • COX1 selective
  • Limited published data on safety/efficacy, not labeled for prolonged treatment
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10
Q

Mavacoxib

A
  • COX-2 selective (ratio ~21)
  • Very slow clearance: therapeutic levels maintained for ~1 month from single dose once at steady state
  • Primarily biliary excretion, unchanged
  • 5% of dogs display delayed clearance (half life 80d instead of 40) => recommend 2 doses 14d apart followed by dose q30d for 6.5mos, then 2 month washout
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11
Q

Meloxicam

A
  • Oxicam class, COX2 selective (ratio ~3)
  • Clinical use/research shows low GI/renal toxicity, attenuate CS of chemically induced stifle synovitis. Compares favorably to other NSAIDs.
  • Only NSAID labeled for long-term use in cats
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12
Q

Phenylbutazone

A
  • Slightly COX2 selective (2.64)
  • Limited literature regarding use for OA in dogs, wide dose ranges listed
  • Toxicity include hemorrhage, biliary stasis, hepatitis, renal failure, blood dyscrasias
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13
Q

Robenacoxib

A
  • Coxib class, highly COX2 (140); no effect on cox1 at therapeutic doses
  • Extensive hepatic metabolism, biliary excretion (minor renal excretion)
  • “targeting” with persistence of drug longer at sites of inflammation
  • Now labeled for cats - not listed in JT at time of publication
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14
Q

Tepoxalin

A
  • Non-selective COX inhibitor but also 5-lipoxygenase inhibitor
  • Leukotriene inhibition may minimize GI toxicity (10% rate of GI upset)
  • In vitro shown to ameliorate degradation of cartilage in catabolism
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15
Q

Tolfenamic acid

A
  • NSAID labeled in europe for use for 3d followed by 4d washout
  • Not feasible for long-term OA mgmt
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16
Q

Amantadine

A
  • NMDA receptor antagonist
  • First used as antiviral agent, then for parkinson’s, then chronic/neuropathic pain
  • Only study looking at use in OA in dogs showed possible benefit of meloxicam + amantadine over meloxicam alone
17
Q

Gabapentin

A
  • GABA analogue, originally used as human antiepileptic
  • Exact MOA unknown, thought to involve voltage gated N-type Ca++ channels
  • Renal excretion - may require less frequent dosing with renal insufficiency
  • No peer reviewed data on use in dogs/cats for OA
18
Q

Acetaminophen

A
  • DO NOT USE IN CATS
  • MOA unclear - central inhibitory action on COX1 splice variant? possible serotinergic activity on descending inhibitory pain pathways?
  • High safety factor
19
Q

Codeine

A

-Prodrug metabolized to morphine & codeine-6-glucuronide (small amount norcodeine & hydro)

20
Q

Corticosteroids

A
  • Controversial for use in OA, used intra-articularly (long-active preparations: methylprednisolone acetate, triamcinolone preparations)
  • While potent anti-inflammatory effects and some evidence for cartilage protection, concern for long-term suppression of cartilage matrix synthesis
  • Recommend limited repeated use in same joint - in humans max once per 6 weeks, 3-4 per year
21
Q

Polysulfated glycosaminoglycans

A
  • MOA unknown, in vitro study showed maintenance of chondrocyte viability and division, protection against ECM degradation
  • Decrease serum cartilage oligometric matrix protein concentrations?
  • Adequan - IM injections, moderate evidence to support use
22
Q

Pentosan Polysulfate

A
  • Semisynthetic glycosaminoglycan, similar to heparin (structurally) and has anticoagulant properties
  • In vitro: retard articular cartilage degradation and stimulate hyaluronan synthesis by synovial cells and proteoglycan by chondrocytes
  • Fibrinolytic & thrombolytic agent
  • Moderate evidence for use
23
Q

Chondroitin sulfate

A
  • 5% oral bioavailability, debate about whether it reaches articular cartilage intact
  • No reports or studies looking at use as sole agent for OA. Newer reports in human OA show declining evidence for use/bias in older studies.
  • Not currently sufficient evidence to recommend use
24
Q

Glucosamine

A
  • 90% oral absorption & diffuses into articular tissues
  • In vitro stimulation of chondrocyte metabolism & stimulate proteoglycan synthesis
  • Stimulate production of monomeric proteoglycans capable of assembling into large aggregates, increase aggrecan core protein mRNA
  • Separate study showed detrimental effects on cell viability & glycosaminogylcan production
  • Limited veterinary studies, suspected bias in older human studies with less evidence ot support in more recent ones.
25
Q

Essential fatty acids

A
  • EFA are polyunsaturate fatty acids, principal ones being linoleic acid and alpha-linoleic acid
  • AA is an n-6 fatty acid
  • N-3 and n-6 compete as substrates for COX1&2, 5-lipoxygenase => n-6 result in production of imflammatory prostaglandins, leukotrienes, thromboxanes
  • n-3 EFAs (esp. eicosapentaenoic acid) reduced mRNA levels for cartilage-degrading proteinases (ADAMTS-4 & -5, MMP-3 & -13 ) and COX2 (but not 1) & inflammatory cytokines (TNF-a, IL-1a/b)
  • In vivo studies showed diet of n-3 EFA (fish oil derived) decreased proMMP-2 & -9 expression, increased TIMP-2 expression in synovium, decreased plasma AA
  • Clinical study showed improved peak vertical force over 90d in dogs supplemented fish oil omega-3 fatty acids

Phase I (5 decks)

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