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
