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Pharmacology > NSAIDs & Cannabis - Steph > Flashcards

NSAIDs & Cannabis - Steph Flashcards

1
Q

characteristics of protective inflammatory events

A
  • localized, self limiting
  • quick resolution
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2
Q

what are some cases in which inflammation is harmful

A
  • misdirection (allergies, autoimmune disease)
  • failure to be self limiting (chronic inflammation, fibrosis)
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3
Q

primary tissues of inflammation

A

blood vessels: allow migration and extravasation of WBC to site of injury
white blood cells: release inflammatory molecules

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4
Q

pain associated with inflammation is caused by

A

inflammatory mediators, drop in tissue pH, stimulate nociceptors in tissue

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5
Q

2 arachidonic acid metabolites that are also inflammatory mediators

A

protaglandins, leukotrienes

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6
Q

production of arachidonic acid

A
  • released from membrane phospholipids by action of phospholipases
  • AA mediators synthesized by cyclooxygenases and lipoxygenases (produce leukotrienes and lipoxins)
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7
Q

function of prostaglandins (PGD2 PGE2)

A
  • vasodilation and increased vascular permeability
  • inflammation, pain, fever
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8
Q

function of prostacyclin

A
  • vasodilation
  • inhibits clotting
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9
Q

funtion of thromboxane

A
  • vasoconstriction and promotes clotting
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10
Q

and imbalance between ______ and _______ promotes thrombus formation

A

An imbalance between prostacyclin and thromboxane
promotes thrombus formation.

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11
Q

what do NSAID drugs act on?

A

COX 1 and 2 (cyclooeygenase) enzymes to inhibit prostaglandin production

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12
Q

COX1

A
  • constitutive
  • produces protanoids with homeostatic function
  • gastric mucosa: increases mucus production, enhances local blood flow
  • kidneys: maintains adequate. renal perfusion
  • platelets: generates thromboxane, increases plateket activation
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13
Q

COX 2

A
  • primarily induced by inflammatory cytokines
  • produces prostanoids associated with inflammation, fever and pain
  • gastric mucosa: once damaged, plays important role in ulcer healing
  • kidney: plays a role in maintaining adequate renal perfusion
  • platelets: generates protacyclin, decreases platelet activation
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14
Q

are COX 1 and COX 2 mutually exclusive

A

no, the division between constitutive (COX 1) and inducible (COX 2) is not 100%!

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15
Q

characteristics of prostanoids

A
  • mostly autocrine or paracrine –> potent but LOCAL effect
  • effect is prostanoid, receptor and location dependant
  • short half life
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16
Q

general clinical uses of NSAIDs

A
  • anti-inflammatory
    -analgesic
  • antipyretic
  • treatment of septic shock
  • antithrombotic
  • anticancer in some cases
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17
Q

how does COX inhibition cause an analgesic effect

A
  • cox inhibition reduces the peripheral and central effects of prostaglandins
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18
Q

role of peripheral prostaglandins and how cox inhibition carries out its analgesic effect

A

peripheral prostaglandins sensitize nociceptors increasing the response to noxious stimuli - COX inhibition reduces the effect of prostaglandins

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19
Q

role of central prostaglandins and how cox inhibition carries out its analgesic effect

A

COX 1 and 2 expressed in spinal chord
- cox 2 is upregulated in response to peripheral inflammation leading to PGE2 release –> lowers spinal depolarization thresholds –> more frequent action potentials in 2nd order neurons “wind-up”/sensitization to analgesia

COX inhibition: inhibits all these effects

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20
Q

Antipyretic effects through NSAIDs/COX inhibition

A
  • normal: increased PGE due to COX 2 induction in hypothalamus resets the body’s thermal set point
  • COX inhibition: decreases PGE –> lowers thermal set point –> reduces fever
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21
Q

3 phases of septic shock

A
  1. non progressive - compensatory mechanisms are activated to maintain perfusion of vital organs
  2. progressive - worsening tissue perfusion and metabolic abnormalities, lactic acidosis due to tissue hypoxia
  3. irreversible - the body has sustained sufficient cell/tissue damage that even if hemodynamic abnormalities are corrected survival is not possible
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22
Q

how are NSAIDs used in the treatment of septic shock

A
  • improves the clincial parameters in patients with septic shock
  • mechanism not fully understood: likely COX inhibition and inhibition of TNF, caspase, and other inflammatory mediators
  • NSAIDs DO NOT bind endotoxin
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23
Q

in patients with poor perfusion, what should be considered when using NSAIDs to treat septic shock

A

benefits of NSAIDs may not outweight the risks in patients with poor perfusion

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24
Q

typical NSAID used to treat septic shock symptoms in cows and horses

A

flunixin - may help alleviate hemodynamic effects of sepsis (vasodilation,increased vascular permiability, decreased organ perfusion)

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25
Q

how does flunixin help in patients with septic shock symptoms

A

may help alleviate hemodynamic effects of sepsis (vasodilation,increased vascular permiability, decreased organ perfusion)

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26
Q

how do NSAIDs help in antithrombotic effects

A

COX-1: mediates thromboxane synthesis - increases platelet activation and aggregation

both non-selective and COX-2 selective NSAIDs have some COX-1 inhibition

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27
Q

Aspirin low dose effects

A

selectively and irreversibly inhibits COX-1 –> antithrombotic effect

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28
Q

mechanism for NSAID use in anticancer effect

A
  • CoX-2 up regulated in some tumors (transitional cell carcinoma, squamous cell carcinoma, melanoma)
  • NSAIDS may supress certain tumors via: restoring apoptosis, inhibit angiogenesis
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29
Q

NSAIDS that have some efficacy against transitional cell carcinoma in dogs

A

COX 2 inhibitors:
- firocoxib, meloxicam, deracoxib

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30
Q

NSAID that is sometimes used against squamous cell carcinoma in horses

A

piroxicam (non selective COX inhibitor)

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31
Q

pharmacokinetic properties of NSAIDs

A
  • highly protein bound
  • well-absorbed orally
  • metabolized in liver
  • half-life and dose varies dramatically between species
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32
Q

name the potential adverse effects of NSAIDs

A
  • GI irritation and ulceration
  • renotoxicity
  • hepatotoxicity
  • hemorrhage
  • blood dyscrasias
  • delayed partuition
  • delated soft tissue healing
  • delayed fracture healing
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33
Q

describe the mechanism behind the use of NSAIDs on GI irritation/ulceration

A
  • COX 1 has gastroprotective effects
  • COX 2 may be involved in healing ulcers
  • some NSAIDs are GI irritants - may see GI ulcers in patients who receive IV NSAIDs

inhibition of PGE –> decrease in bicarb and mucous secretion in stomach –> dec. in mucous protective layer

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34
Q

which type of NSAID is less ulcerogenic?

A

COX-2 selective (but NOTE: GI ulceration has occured after administration of highly COX-2 selective NSAIDs)

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35
Q

in additition to COX inhibition, what are other ulcerogenic effects related to NSAIDs

A
  1. direct GI irritation (NSAIDs = weak acids, aspirin precipitates out in acidic environments and may cause physical irritation
  2. enterohepatic recycling (drug excreted in bile –> resorbed in small intestine –> invreases duodenal and systemic exposure to NSAID)
  3. prolonged plasma half-life: icreased GI an renal adverse effects
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36
Q

clinical signs of GI irritation/ulceration in dugs

A

vomitting, melena and inappetance

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37
Q

clinical signs of GI irritation/ulceration in horses

A

inappetance, colic and diarrhea

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38
Q

most common site of NSAID GI adverse effects in horses

A

right dorsal common

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39
Q

why is there no NSAIDs labelled for long term use in cats

A

cats are particularly susceptible to NSAID-induced gastrointestinal ulcers

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40
Q

how do NSAIDs cause renotoxicity

A

prostaglandins maintain renal bloodflow and glomerular filtration rate in conditions of hypovolemia, hypoatremia and hypotension, in Diabetes mellitus patients and adrenocortical dysfunction
- inhibition of prostaglandins can cause ischemia of renal medulla
- renal papillary necrosis
- can cause acute renal failure during anesthesia or in hypovolemic/dehydrated patients
- COX-2 also crucial for renal development

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41
Q

how do NSAIDs cause clotting inhibition adverse effects

A
  • inhibition of thromboxane (COX-1) reduces platelet aggregation
  • aspirin of particular concern (irreversible, platelets have no nucleus so cant make more COX-1)
  • NO NOT use in patients at risk of hemorrhage
42
Q

describe the mechanism behind NSAIDs and their adverse effects in bone and soft tissue healing

A
  • COX-2 plays a role in wound healing and fracture repair
  • there is SOME evidence that NSAIDs may slow healing but this is not proven
43
Q

what is the COX-1/COX-2 ratio
- higher ratio vs lower ratio

A

ratio of the concentration of drug nescessary to inhibit 50% COX-1 activity/ the concentration of drug nescessary to inhibit 50% of COX-2 activity

higher ratio = more COX2 specific

44
Q

key adverse effects of ketoprofen, tolfenamic acid

A
  • gastroduodenal injury with multiday use
  • platelet effects
45
Q

key adverse effects of carprofenyl

A

idiosyncratic hepatopathy

46
Q

key adverse effects of meloxicam

A
  • rare acute renal failure when given peri-op
  • gastroenteropathies and blood dyscrasias may occur
47
Q

key adverse effects of dercoxib

A
  • more gastrduodenal injuries than other COX2 selective NSAIDs
  • do not give peri-op analgesic dose (3-4mgs/kg) long term
  • narrow therapeutic index
48
Q

key adverse affects of Robenacoxib

A
  • hepatopathies
  • long term use in cats associated with weight loss, renal failure, cardiac changes
49
Q

key adverse effects of Firocoxib

A
  • toxic to young dogs; do not use in puppies <7months old
  • gastroenteropathies can occur
50
Q

common NSAIDS used in Dogs**

A
  • Grapiprant
  • carprofen
  • deracoxib
    -firocoxib
    -meloxicam
    -robenacoxib
51
Q

common NSAIDs used in cats**

A
  • meloxicam
  • robenacoxib
52
Q

common NSAIDs used in horses ***

A
  • aspirin
  • dipyrone
  • firocoxib
    -funixin
  • ketaprofen
    -meloxicam (not approved)
    -phenylbutazone
53
Q

common NSAIDs used in cattle

A
  • aspirin
    -flunixin
    -meloxicam
    -ketoprofen
54
Q

considerations when choosing which NSAID to use

A
  • species differences, adverse effects
  • individual differences in response
  • type of pain
  • formulation
  • owner preference
  • vet. experience
  • compliance with regulations
55
Q

clinical considerations when using NSAIDs

A
  • anti-inflammatory effects work best when given early or pre-emptively
  • effective analgesics
  • age effects metabolism/excretion; slower in very young and very old
  • adequate hydration very important to avoid adverse renal effects
  • adverse effects vary with COX inhibition with species (cats mroe susceptible)
56
Q

which NSAIDs can be used in dogs for soft tissue surgery (which are the best choices)

A
  • carprofen, meloxicam are best choices
  • firocoxib, robenacoxib labelled for pre-operative use
57
Q

which NSAIDs can be used for soft tissue surgery in cats

A
  • robenacoxib has best evidence
  • meloxicam is widely accepted as post-op analgesic
58
Q

what is an important consideration for using NSAIDs peri-operatively

A

may delay tissue healing, avoid if posssible when doing GI surgery in small animals as their use increases risk of dehiscence

59
Q

timing of meloxicam and carprofen effects when given to dogs IV vs subq

A

meloxicam
IV: immediate
SQ: 2-6 hours to have clinically relevant analgesic effects

carprofen and robenacoxib: analgesic effect within 1 hour after subq administration

60
Q

which NSAIDs should be used in dogs for orthopaedic surgery

A

carprofen: best evidence for immediate post-op analgesic efficacy
NOTE: evidence for other nsaids = weak, probably not sufficient as the sole post-ortho surgery analgesic

61
Q

which NSAIDs are the best for othopedic surgury in cats

A

robenacoxib shown to be efficacious but limited evidence
meloxicam efficacious at 0.2 or 0.3 mg/kg

62
Q

best NSAIDs to use in dogs for MSK/osteoarthritis pain

A

meloxicam, firocoxib and carprofen are best choices among NSAIDs
firocoxib = most effective

63
Q

best NSAIDs to use in cats for MSK/osteoarthritis pain

A

meloxicam = best choice (reduce dose for longterm use)
robenacoxib may have more adverse effects in long term use in cats

64
Q

which NSAID is best for MSK pain in horses

A

phenylbutazone and flunixin
- firocoxib may be warranted for longterm use

65
Q

best NSAID to use for laminitis

A
  • endotoxin: aspirin may help to improve blood flow to foot
  • acute: non selective NSAID may help prevent neuropathic pain
  • Chronic: transition to COX2 selective to reduce adverse effects
66
Q

best NSAID to use for gastrointestinal pain/surgery

A

flunixin

67
Q

best NSAID to use in foals

A

AVOID as much as possible. if one must be used, selective NSAIDs are safer with GI toxicity

68
Q

clinical uses for NSAIDs in cattle

A
  • associated with increased cure rates for coliform mastitis and decreased culling for non-coliform mastitis
  • may help with welfare when treating lameness
  • meloxicam and flunixin reduce dehorning and castration pain
69
Q

Grapiprant mechanism

A

prostaglandin E2 EP4-receptor antagonist
- decreases PGE2’s inflammatory effects and reduces pain

70
Q

grapiprant use

A

labelled for treating osteoarthritis in dogs not responding to other NSAIDs
- Ep4 receptors in dogs not involved in pyrexia, therefore not an antipyretic

71
Q

what should you not do with Grapiprant

A

avoid use with other NSAIDs
not studied in dogs younger than 9m/o or in pregnant lactating females

72
Q

what considerations should you make when switching NAIDs

A
  • allow one week washout between NSAIDs to reduce confusion of adverse drug reactions occur
  • 10 half lives is usually considered the point at which the drug is fully cleared
73
Q

considerations when giving NSAIDs simultaneously

A

DONT DO IT GIRL

74
Q

considerations when giving NSAIDs with steroids

A

DONT DO IT GIRL

75
Q

unapproved NSAIDs that clients will ask you about

A
  • aspirin (acetylsalicyclic acid)
  • ibuprofen
  • acetaminophen (technically not an NSAID)
  • naproxen
  • piroxicam
76
Q

aspirin mechanism and use

A
  • often used because OTC, cheap, can help with dogs with osteoarthritis or prevention of thromboemboli (treatment for heartworm)
  • cats with hypertrophic cardiomyopathy or saddle thrombus
  • irreversible, non selective COX inhibitor (prolonged effect because more COX needs to be synthesized before effects go away
77
Q

considerations when giving aspirin

A
  • should not be given to patients with risk of hemorrhaging
78
Q

why should you not use ibuprofen in small animals

A

causes serious renal and GI toxicity in small animals

79
Q

acetominophen mechanism

A

central COX inhibitor (does not inhibit peripheral COX, therefore not an anti-inflammatory/not an NSAID)

80
Q

acetominophen uses

A

reduces pain and fever, not considered to be anti-inflammatory

81
Q

is acetominophen toxic to cats and dogs

A
  • few adverse effects in dogs at appropriate doses (toxic in high doses)
  • very toxic to cats at low doses (signs of toxicity include: facial edema, cyanosis, nethemoglobinemia, anemia, hemoglobinuria, icterus
82
Q

Naproxen uses in animals

A
  • sometimes used in horses
  • has been used for chronic OA tx in dogs but undergoes extensive enterohepatic recirculation and high incidence of adverse affects
  • little evidence to reccomend this drug over other NSAIDs
83
Q

Piroxicam clinical uses

A

throught to have an antitumor effect, used in treatment of transitional cell carcinoma in dogs and squamous cell carcinoma in horses
- high adverse side effects

84
Q

is Gabapentin an NSAID

A

not an NSAID, but often used as a non-SAID analgesic option

85
Q

Gabapentin mechanism

A

structurally similar to gaba but does not primarily act on GABA-R
- binds to Ca2+ channels to inhibit excitatory neurotransmitter release (anti-epileptic)

86
Q

gabapentin clinical uses

A
  • pain relief: often in conjunction with opioids, pre and post op
  • sometimes used as a non NSAID analgesic option in treatment of chronic pain
  • EVIDENCE FOR ANALGESIC IS LIMITED
  • reduce acute fear response/anxiety in companion animals
87
Q

active compounds in canabis

A
  • tetrahydrocannabinol (THC)
  • cannabidiol (CBD)
  • cannabinol
88
Q

cannabis receptors

A

CB1 and CB2

89
Q

endogenous cannabinoids

A
  • anandiamide
  • 2-arachidonylglycerol
90
Q

mechanism of THC

A
  • main psycotropic compound in cannabis
  • interacts directly with endocannabinoid receptors (CB1 in brain) which modulates dopamine signalling (both excitatory and inhibitory)
91
Q

THC proposed therapeutic uses

A
  • treatment of anorexia/energy metabolism disorders
  • reduces pain/inflammation
  • neuroprotection
  • anti-epileptic
  • anti-anxiety
  • antiemetic
    -anti-diarrheal
  • broncodialator
  • reduces intraocular pressure in glaucoma patients
  • anti-neoplastic
92
Q

THC pharmacokinetics in humans

A
  • poor bioavailability (very water insoluble
  • inhaled (10-30%) rapid T max
  • oral (5-20%) first pass effect, slower Tmax
  • extremely lipophilic (distributes rapidly to brain, sequesters to fat –> prolonged detection, if taken orally with fatty meals –> delays Tmax but triples AUC
93
Q

metabolization of THC `

A

CYP450 to active metabolites (11-OH-THC)

94
Q

why are dogs more susceptible to adverse CNS affects of THC than humans

A

hve more endocannabnoid receptors in CNS than humans

95
Q

cannabidiol (CBD) suggested effects

A

anxiolytic, antidepressant, antipsychotic, antoconvulsant, antinausea, antioxidant, anti-inflammatory, anti-arthritic, antineoplastic

96
Q

what does CBD protect against in animal models

A

in CNS is protective of epilepsy, anxiety, psychosis, parkinsons and huntingtons

97
Q

CBD mechanism of action in animals

A

low affinity for CB1 receptors
weak inverse agnoism at CB2 receptor (binds but induces opposite response)
- may act as weak CB1/CB2 agonists via inhibition of anandamide metabolism increasing 2-archidonylglycerol (endocannabinoid) levels

  • also interacts with large number of non-cannabinoid system molecular targets
98
Q

CBD pharmacokinetics in dogs

A
  • poor bioavailability (less than 19% oral administration)
  • T1/2 = 5-13 hours
  • extremely lipophilic
  • much less likely to cause toxicosis than THC
99
Q

CBD metabolism in dogs

A

metabolized by CYP450, excreted in feces and urine

100
Q

possible farmacological uses of CBD for vet med

A
  • epilepsy
  • anxiety
  • pain
  • antineoplastic effects
101
Q

CBD mechanism of action to attenuate seizures in animal models

A

pilocarpine: muscarinic agonist/cholinergic - causes seizure foci in brain
- CBD given prior to seizure induction reduced occurence of seizures
penicillin G: antagonizes GABA receptors in CNS - direct administration to brain causes seizures
- CBD given prior reduced severity and lethality

102
Q

mechanism of action for CBD and pain

A

multimodal analgesia:

  • inhibition of anandamide breakdown –> CB-R activation
  • activation/ desensitization of TRPV1 channels and TRPA1 channels
  • activation of seratonin receptors
  • inhibition of adenosine transporters –> increased adenosine signalling –> reduced inflammation
  • reduced cytokine levels –> reduced inflammation
  • glycine receptor activation

Pharmacology (11 decks)

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