NSAID/Cannabis Pharmacology Flashcards
How are inflammatory mediators created
- cell lipid bilayer through phospholipase to arachidonic acid
Lipoxygenase will metabolize arachidonic acid to leukotrienes/lipoxin
- increased vascular permeability
- leukocyte adhesion, activation, chemotaxis
COX1 and 2 will metabolize arachidonic acid to prostanoids
- prostaglandin: PG D2 and E2 = vasodilation, fever, pain
- prostacyclin = vasodilation, reduced clotting
- thromboxane = vasodilation, increased clotting
What levels does steroids and NSAIDs act on in the inflammatory mediator production cycle
steroids inhibit phospholipase
- which normally converts cell lipid bilayer to arachidonic acids
NSAIDs inhibit COX1 and/or COX2
Compare the functions of COX1 and 2
COX 1
- homeostatic functions, meaning it is constitutively active
- makes thromboxane and prostaglandins
COX2
- active during inflammation from macrophages and inflammatory cells
- prostaglandin and prostacyclin
both can impact each other
NSAIDs are typically non-specific
Compare the effects of COX
1 and 2 on gastric mucosa, kidney, platelet, vascular endothelium
gastric mucosa
- cox 1 = increase mucus and perfusion
- cox 2 = post damage ulcer healing function
kidneys - both types act to maintain perfusion
platelet
- cox 1 = increase thromboxane and increase clotting
- cox 2 = increase prostacyclin which reduces clotting
What are 3 main characteristics of prostanoids and how does COX receptors influence?
local effect via paracrine or autocrine signalling
short half life
their effect depends on the type of prostanoid, receptor, location
COX1 - typically associated with prostanoids associated with
- GI mucosal integrity
- platelet function
- vascular function
- homeostasis
COX2 - typically associated with prostanoids
- fever
- pain
- inflamm
What are 6 applications for NSAID use
anti-inflammation
anti-pyretic
septic shock
antithrombotic
anti-cancer
analgesic
How do NSAIDS cause anti-inflammatory effect
prostaglandins cause positive feedback due to vasodilation and an increase in inflammatory cytokines
NSAID will act to reduce prostaglandin synthesis
How do NSAIDS cause the analgesic effect
peripherally it will remove prostaglandins that will sensitize nociceptors
centrally it will affect COX 1 and 2 in the spinal cord
- normally when COX2 is upregulated it releases PG E2 resulting in a reduced depolarization threshold = wind up/ hyperalgesia/sensitization
NSAIDS can act synergistically with opioids
How do NSAIDS have an anti-pyretic effect
increased PG E2 results in a hypothalamus set point change
Reduced PGE2 will lower/normalize that set point
What is septic shock? What are the phases?
bacterial/LPS/endotoxin causes active inflammation
- mediators cause immunosuppression/vasodilation/increased vascular permeability/reduced perfusion/fever/reduced inotropy/metabolic disorder/thrombosis
all can cause hypotension and multiorgan failure
- non-progressive shock - perfusion is maintained to vital organs
- progressive shock - poor perfusion/metabolite abnormalities/lactic acidosis
- irreversible
How does NSAID impact septic shock?
NSAIDs don’t bind the endotoxin but may improve septic shock
- may not be worth the reduced perfusion NSAIDs can cause
What is commonly used to treat septic shock in cows
flunixin
What is the anti-thrombotic mechanism of NSAIDS
COX2 selective and non-selective NSAIDs can have an impact on COX1 receptors
COX 1 receptors increase thromboxane = increased platelet aggregation/activation
aspirin selectively and irreversibly inhibit COX1
What is the mechanism of action of anti-cancer use of NSAID
Tumors can sometimes upregulate COX2
- usually TCC/SCC/melanoma
NSAID restores apoptosis and reduced angiogenesis
Which NSAID are commonly used to treat TCC in dogs
firocoxib
meloxicam
deracoxib
they are COX2 selective
Which NSAID are commonly used to treat SCC in horses
piroxicam
non-selective
What are the pharmacokinetic features of NSAIDS
they are highly protein bound
- varied volume of distribution, consider drug interactions
good PO absorption - lipophilic weak acids
liver metabolism
varied half life
- species and individual variation
ex. aspirin in cows = 32min/cat = 22-45h
List the adverse effects associated with NSAID administration? There are 2 main ones
mainly
- GI irritation/ulcers
- renotoxicity
hepatotoxicity
hemorrhage
blood dyscrasia/clotting inhibition
delay parturition
delay soft tissue healing
delayed fracture healing
specific drug warnings
- deracoxib (narrow therapeutic index)
- firocoxib (not for young)
no adverse cardiovascular effects
How does the mechanism of action of GI irritation/ulceration of NSAIDS
COX1 = GI protection
COX2 = ulcer healing
ulceration due to NSAIDs are acidic
NSAIDs also undergo enterohepatic recycling causing increased exposure in the duodenum
high plasma half life so if you are switching NSAIDs give 5-7d, if not = increase irritation
What are the clinical signs associated with GI ulcers in dogs and horses
dog
- vomiting
- melena
- reduced aappeetite
horses
- diarrhea
- colic
- reduced appetite
What is the mechanism of action of NSAIDS on renotoxicity
it is not a problem if the patient is healthy/hydrated
causes renal papillary crest necrosis and acute renal failure due to decreased PGE2
higher risk if used
- during anesthesia
- hypovolemia
- dehydrated
In what animals are NSAIDS contraindicated in? Why?
COX2 is needed for renal development
not for neonate or pregnant
shouldn’t use post-GI anastomosis sx
avoid in foals
- if you have to then use COX2 selective
How is COX1 vs COX 2 selectivity assessed
COX 1 / COX 2 ratio
drug concentration needed to inhibit 50% of COX1 / drug concentration needed to inhibit 50% COX2
higher ratio = more COX2 specific
there is lots of species variation
What is the mechanism of action of the clotting inhibition of NSAIDs
it can inhibit thromboxane which reduces clotting
What is the mechanism of action of the delayed soft tissue healing and fracture healing of NSAIDs
reducing inflammation can reduce healing
COX2 has role in healing
shouldn’t use post-GI anastomosis sx
- require fast healing
What NSAIDs are commonly used in dogs
carprofen
deracoxib
firocoxib
meloxicam
robenacoxib
What NSAIDs are commonly used in cats
meloxicam
robenacoxib
no on-label use labelled
What NSAIDs are commonly used in horses
flunixin meglumine - main
firocoxib
phenylbutazone
What NSAIDs are commonly used in cow
ketoprofen - main
flunixin
meloxicam
aspirin
What 4 factors should you consider when giving NSAIDS
anti-inflam effects are more effective when given early
age
hydration
species (cats are more susceptible)
Scenario: soft tissue sx in dogs and cats what NSAIDs should you give
dog
- carprofen (works in 1h if SC) or meloxicam (if IV - immediate, SC = 2-6h) given pre-op
cat
- robenacoxib or meloxicam pre-op
Scenario: orthopedic sx in a dog or cat what NSAIDs should you give
dog
- carprofen post op
cat
- robenacoxib or meloxicam
+ additional analgesics
Scenario: osteoarthritis/MSK pain in a dog or cat what NSAIDs should you give
dog
- firocoxib (most effective)
- meloxicam
- carprofen
cat
- meloxicam
- reduce dose if using long term
- robenacoxib increases in adverse effects if used long term
Scenario: osteoarthritis/MSK pain in horses what NSAIDs should you give
phenylbutazone for MSK pain + flunixin for visceral pain = short term
firocoxib = long term tx
Scenario: laminitis pain in horses what NSAIDs should you give
if endotoxic - aspirin may increase perfusion to foot
acute - non-selective can prevent neuropathic pain
chronic - transition from non-selective to COX2 selective
Scenario: GI pain/sx in horses what NSAIDs should you give
flunixin
In what animals is phenylbutazone not allowed
food animals
if cows have coliform mastitis/lameness/dehorning/castration use meloxicam or flunixin
meloxicam
half life IV/PO - 17-26h
flunixin
half life IV = 4-7h
What is the mechanism of action of grapiprant?
PGE2 EP4 receptor antagonist
What is grapiprant commonly used for?
OA pain
What other considerations should you think about when giving grapiprant
not for pyrexia treatment
- EP4 receptors not involved with pyrexia
dont use with other NSAIDs
there is no evidence in pregnant or lactating or animals under 9mo
How should you switch NSAIDs
give 1 week washout
- may need an alternate tx in that time
10 half lives for drug clearance
do not give 2 at same time
- because highly protein bound = competitive for protein results in increased active drug in system (displace from protein)
do not give with steroid
What is the mechanism of action of aspirin? What is the use for it?
acetylsalicylic acid
irreversible COX 1 and 2 inhibitor with varied half life
increased hemorrhage risk
cat with FATE/HCM
heartworm tx dog
What is ibuprofen used for
nothing
GI/renotoxic
What is acetaminophen? What is its mechanism? How is its used?
not technically an NSAID
central COX inhibitor - reduced pain/fever but not anti-inflam
dogs - ok
cats - toxic
glucuronidation
What animals are naproxen used in? What animals is it not used in?
horse sometimes - but rare
not dogs
- highly enterohepatic recirculation = more adverse
What is piroxicam used for?
anticancer
- TCC dog
- SCC horse
lots of adverse effects
What is gabapentin? What is its mechanism?
not an NSAID
similar structure to GABA but doesn’t act on a GABA receptor
binds Ca channels and inhibit neurotransmitter release
- antiepileptic
What is gabapentin used for mainly
pain treatment with an opioid - pre or post op
chronic pain
reduced FAS (cats esp.)
limited evidence of analgesic effect
What receptors do cannabinoids act on
cannabinoid receptor 1 or 2 in CNS
there are endogenous cannabinoids that act on them
- anandamide
- 2- archidonylglycerol
What are the 3 main cannabinoids
tetrahydrocannabinol THC
cannabidiol
cannabinol
What is the mechanism of action of THC
It is the main psychotropic element
interact with endocannabinoid receptors
- mainly CB1 in brain
- also CB2 in immune cells (some brain)
modulate dopamine signalling - excitation and inhibition
What are the proposed uses for THC
anti
- epileptic
- anxiety
- emetic
- diarrheal
- neoplasia
anorexia tx
metabolism disorder tx
bronchodilator
reduce intraocular pressure for glaucoma
What are the pharmacokinetics of THC in humans
It has reduced bioavailability - it is water insoluble
- inhale = 10-30% absorb
- PO = 5-20% absorb
lipophilic = can enter and stay in brain/fat
- if eaten with lots of fat = slower release (increase AUC)
metabolized by CYP450 and hepatic recirculation
excretion in feces and urine
half life can vary depending on frequency of use
What are the pharmacokinetics of THC in dogs
similar to humans but 1000x more CB1 and 2 receptors
cause toxicity
- high morbidity
- low mortality
What is the mechanism of action of cannabidiol
It is the main non-psychotropic component
It has reduced CB1 receptor affinity
weak inverse agonist for CB2
weak CB1 and 2 agonism through anandamide metabolism and increased endogenous cannabanoid (like 2 archidonyl glycerol)
there are many drug targets
What are the pharmacokinetics of cannabidiol
It is poorly bioavailable
a half life of 5-13h
cytochrome P450 metabolism
it is very lipophilic
few adverse effects associated - long term administration may be associated with ALP with no other liver signs
What are the proposed uses for cannabidiol
antiepileptic
antianxiety
analgesia
anti-neoplasia
What is the mechanism for analgesia from cannabidiol
increased endogenous cannabanoid
desensitize TRPV1 and TRPA1 channel
activate serotonin receptor
inhibit adenosine transporter
- adenosine increased and reduced inflammation
reduced cytokine signalling
glycine receptor signalling
What are veterinarians in Canada allowed to do about cannabis
they can’t prescribe
provide education for clients (can advise) - ensure they know the risks
Can manage cases and management if the owner has gotten iit on their own
There are no animal product
What things must you consider if advising an owner giving cannabis
practice within the scope of clinical competence
weight evidence with other options
consider known risks
obtain informed consent
monitor and be available to treat adverse events
aware of misuse and abuse of product
