NSAIDs & Cannabis - Steph Flashcards
characteristics of protective inflammatory events
- localized, self limiting
- quick resolution
what are some cases in which inflammation is harmful
- misdirection (allergies, autoimmune disease)
- failure to be self limiting (chronic inflammation, fibrosis)
primary tissues of inflammation
blood vessels: allow migration and extravasation of WBC to site of injury
white blood cells: release inflammatory molecules
pain associated with inflammation is caused by
inflammatory mediators, drop in tissue pH, stimulate nociceptors in tissue
2 arachidonic acid metabolites that are also inflammatory mediators
protaglandins, leukotrienes
production of arachidonic acid
- released from membrane phospholipids by action of phospholipases
- AA mediators synthesized by cyclooxygenases and lipoxygenases (produce leukotrienes and lipoxins)
function of prostaglandins (PGD2 PGE2)
- vasodilation and increased vascular permeability
- inflammation, pain, fever
function of prostacyclin
- vasodilation
- inhibits clotting
funtion of thromboxane
- vasoconstriction and promotes clotting
and imbalance between ______ and _______ promotes thrombus formation
An imbalance between prostacyclin and thromboxane
promotes thrombus formation.
what do NSAID drugs act on?
COX 1 and 2 (cyclooeygenase) enzymes to inhibit prostaglandin production
COX1
- 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
COX 2
- 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
are COX 1 and COX 2 mutually exclusive
no, the division between constitutive (COX 1) and inducible (COX 2) is not 100%!
characteristics of prostanoids
- mostly autocrine or paracrine –> potent but LOCAL effect
- effect is prostanoid, receptor and location dependant
- short half life
general clinical uses of NSAIDs
- anti-inflammatory
-analgesic - antipyretic
- treatment of septic shock
- antithrombotic
- anticancer in some cases
how does COX inhibition cause an analgesic effect
- cox inhibition reduces the peripheral and central effects of prostaglandins
role of peripheral prostaglandins and how cox inhibition carries out its analgesic effect
peripheral prostaglandins sensitize nociceptors increasing the response to noxious stimuli - COX inhibition reduces the effect of prostaglandins
role of central prostaglandins and how cox inhibition carries out its analgesic effect
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
Antipyretic effects through NSAIDs/COX inhibition
- 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
3 phases of septic shock
- non progressive - compensatory mechanisms are activated to maintain perfusion of vital organs
- progressive - worsening tissue perfusion and metabolic abnormalities, lactic acidosis due to tissue hypoxia
- irreversible - the body has sustained sufficient cell/tissue damage that even if hemodynamic abnormalities are corrected survival is not possible
how are NSAIDs used in the treatment of septic shock
- 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
in patients with poor perfusion, what should be considered when using NSAIDs to treat septic shock
benefits of NSAIDs may not outweight the risks in patients with poor perfusion
typical NSAID used to treat septic shock symptoms in cows and horses
flunixin - may help alleviate hemodynamic effects of sepsis (vasodilation,increased vascular permiability, decreased organ perfusion)
how does flunixin help in patients with septic shock symptoms
may help alleviate hemodynamic effects of sepsis (vasodilation,increased vascular permiability, decreased organ perfusion)
how do NSAIDs help in antithrombotic effects
COX-1: mediates thromboxane synthesis - increases platelet activation and aggregation
both non-selective and COX-2 selective NSAIDs have some COX-1 inhibition
Aspirin low dose effects
selectively and irreversibly inhibits COX-1 –> antithrombotic effect
mechanism for NSAID use in anticancer effect
- CoX-2 up regulated in some tumors (transitional cell carcinoma, squamous cell carcinoma, melanoma)
- NSAIDS may supress certain tumors via: restoring apoptosis, inhibit angiogenesis
NSAIDS that have some efficacy against transitional cell carcinoma in dogs
COX 2 inhibitors:
- firocoxib, meloxicam, deracoxib
NSAID that is sometimes used against squamous cell carcinoma in horses
piroxicam (non selective COX inhibitor)
pharmacokinetic properties of NSAIDs
- highly protein bound
- well-absorbed orally
- metabolized in liver
- half-life and dose varies dramatically between species
name the potential adverse effects of NSAIDs
- GI irritation and ulceration
- renotoxicity
- hepatotoxicity
- hemorrhage
- blood dyscrasias
- delayed partuition
- delated soft tissue healing
- delayed fracture healing
describe the mechanism behind the use of NSAIDs on GI irritation/ulceration
- 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
which type of NSAID is less ulcerogenic?
COX-2 selective (but NOTE: GI ulceration has occured after administration of highly COX-2 selective NSAIDs)
in additition to COX inhibition, what are other ulcerogenic effects related to NSAIDs
- direct GI irritation (NSAIDs = weak acids, aspirin precipitates out in acidic environments and may cause physical irritation
- enterohepatic recycling (drug excreted in bile –> resorbed in small intestine –> invreases duodenal and systemic exposure to NSAID)
- prolonged plasma half-life: icreased GI an renal adverse effects
clinical signs of GI irritation/ulceration in dugs
vomitting, melena and inappetance
clinical signs of GI irritation/ulceration in horses
inappetance, colic and diarrhea
most common site of NSAID GI adverse effects in horses
right dorsal common
why is there no NSAIDs labelled for long term use in cats
cats are particularly susceptible to NSAID-induced gastrointestinal ulcers
how do NSAIDs cause renotoxicity
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
how do NSAIDs cause clotting inhibition adverse effects
- 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
describe the mechanism behind NSAIDs and their adverse effects in bone and soft tissue healing
- 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
what is the COX-1/COX-2 ratio
- higher ratio vs lower ratio
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
key adverse effects of ketoprofen, tolfenamic acid
- gastroduodenal injury with multiday use
- platelet effects
key adverse effects of carprofenyl
idiosyncratic hepatopathy
key adverse effects of meloxicam
- rare acute renal failure when given peri-op
- gastroenteropathies and blood dyscrasias may occur
key adverse effects of dercoxib
- more gastrduodenal injuries than other COX2 selective NSAIDs
- do not give peri-op analgesic dose (3-4mgs/kg) long term
- narrow therapeutic index
key adverse affects of Robenacoxib
- hepatopathies
- long term use in cats associated with weight loss, renal failure, cardiac changes
key adverse effects of Firocoxib
- toxic to young dogs; do not use in puppies <7months old
- gastroenteropathies can occur
common NSAIDS used in Dogs**
- Grapiprant
- carprofen
- deracoxib
-firocoxib
-meloxicam
-robenacoxib
common NSAIDs used in cats**
- meloxicam
- robenacoxib
common NSAIDs used in horses ***
- aspirin
- dipyrone
- firocoxib
-funixin - ketaprofen
-meloxicam (not approved)
-phenylbutazone
common NSAIDs used in cattle
- aspirin
-flunixin
-meloxicam
-ketoprofen
considerations when choosing which NSAID to use
- species differences, adverse effects
- individual differences in response
- type of pain
- formulation
- owner preference
- vet. experience
- compliance with regulations
clinical considerations when using NSAIDs
- 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)
which NSAIDs can be used in dogs for soft tissue surgery (which are the best choices)
- carprofen, meloxicam are best choices
- firocoxib, robenacoxib labelled for pre-operative use
which NSAIDs can be used for soft tissue surgery in cats
- robenacoxib has best evidence
- meloxicam is widely accepted as post-op analgesic
what is an important consideration for using NSAIDs peri-operatively
may delay tissue healing, avoid if posssible when doing GI surgery in small animals as their use increases risk of dehiscence
timing of meloxicam and carprofen effects when given to dogs IV vs subq
meloxicam
IV: immediate
SQ: 2-6 hours to have clinically relevant analgesic effects
carprofen and robenacoxib: analgesic effect within 1 hour after subq administration
which NSAIDs should be used in dogs for orthopaedic surgery
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
which NSAIDs are the best for othopedic surgury in cats
robenacoxib shown to be efficacious but limited evidence
meloxicam efficacious at 0.2 or 0.3 mg/kg
best NSAIDs to use in dogs for MSK/osteoarthritis pain
meloxicam, firocoxib and carprofen are best choices among NSAIDs
firocoxib = most effective
best NSAIDs to use in cats for MSK/osteoarthritis pain
meloxicam = best choice (reduce dose for longterm use)
robenacoxib may have more adverse effects in long term use in cats
which NSAID is best for MSK pain in horses
phenylbutazone and flunixin
- firocoxib may be warranted for longterm use
best NSAID to use for laminitis
- 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
best NSAID to use for gastrointestinal pain/surgery
flunixin
best NSAID to use in foals
AVOID as much as possible. if one must be used, selective NSAIDs are safer with GI toxicity
clinical uses for NSAIDs in cattle
- 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
Grapiprant mechanism
prostaglandin E2 EP4-receptor antagonist
- decreases PGE2’s inflammatory effects and reduces pain
grapiprant use
labelled for treating osteoarthritis in dogs not responding to other NSAIDs
- Ep4 receptors in dogs not involved in pyrexia, therefore not an antipyretic
what should you not do with Grapiprant
avoid use with other NSAIDs
not studied in dogs younger than 9m/o or in pregnant lactating females
what considerations should you make when switching NAIDs
- 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
considerations when giving NSAIDs simultaneously
DONT DO IT GIRL
considerations when giving NSAIDs with steroids
DONT DO IT GIRL
unapproved NSAIDs that clients will ask you about
- aspirin (acetylsalicyclic acid)
- ibuprofen
- acetaminophen (technically not an NSAID)
- naproxen
- piroxicam
aspirin mechanism and use
- 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
considerations when giving aspirin
- should not be given to patients with risk of hemorrhaging
why should you not use ibuprofen in small animals
causes serious renal and GI toxicity in small animals
acetominophen mechanism
central COX inhibitor (does not inhibit peripheral COX, therefore not an anti-inflammatory/not an NSAID)
acetominophen uses
reduces pain and fever, not considered to be anti-inflammatory
is acetominophen toxic to cats and dogs
- 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
Naproxen uses in animals
- 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
Piroxicam clinical uses
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
is Gabapentin an NSAID
not an NSAID, but often used as a non-SAID analgesic option
Gabapentin mechanism
structurally similar to gaba but does not primarily act on GABA-R
- binds to Ca2+ channels to inhibit excitatory neurotransmitter release (anti-epileptic)
gabapentin clinical uses
- 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
active compounds in canabis
- tetrahydrocannabinol (THC)
- cannabidiol (CBD)
- cannabinol
cannabis receptors
CB1 and CB2
endogenous cannabinoids
- anandiamide
- 2-arachidonylglycerol
mechanism of THC
- main psycotropic compound in cannabis
- interacts directly with endocannabinoid receptors (CB1 in brain) which modulates dopamine signalling (both excitatory and inhibitory)
THC proposed therapeutic uses
- 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
THC pharmacokinetics in humans
- 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
metabolization of THC `
CYP450 to active metabolites (11-OH-THC)
why are dogs more susceptible to adverse CNS affects of THC than humans
hve more endocannabnoid receptors in CNS than humans
cannabidiol (CBD) suggested effects
anxiolytic, antidepressant, antipsychotic, antoconvulsant, antinausea, antioxidant, anti-inflammatory, anti-arthritic, antineoplastic
what does CBD protect against in animal models
in CNS is protective of epilepsy, anxiety, psychosis, parkinsons and huntingtons
CBD mechanism of action in animals
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
CBD pharmacokinetics in dogs
- poor bioavailability (less than 19% oral administration)
- T1/2 = 5-13 hours
- extremely lipophilic
- much less likely to cause toxicosis than THC
CBD metabolism in dogs
metabolized by CYP450, excreted in feces and urine
possible farmacological uses of CBD for vet med
- epilepsy
- anxiety
- pain
- antineoplastic effects
CBD mechanism of action to attenuate seizures in animal models
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
mechanism of action for CBD and pain
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
