Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Flashcards
Nonsteroidal Anti-Inflammatory Drugs
diverse group of drugs which inhibit to some extent the Cyclooxygenase enzymes
Large chemical diversity exists among the NSAIDs, not all the same
NSAID Mechanism of Action
- Inhibition of Cycloxygenase (COX)
- Cox-1
- Cox-2
Prastaglandins
- Local regulation of organ and tissue function
- local control of vasculature of blood flow
- Local control of GI environment
- Local control of platelets
- Local control of Renin release
- Exception:
- Endotoxemia resulting in systemic release of prostaglandin and systemic effects
- Lipopolysaccharides (LPS) release from gram negative bacteria
- Endotoxemia resulting in systemic release of prostaglandin and systemic effects
Prostaglandins:
Cox-1
- “Constitutive” enzyme
- Local regulation in most cases
- PGE
- vasodilation
- sensitization of nociceptors
- Enhance inflammation
- Fever
- Gastroprotection
- mucous secretion, bicarbonate secretion, increased blood flow, inhibition of acid secretion
- Increase renal blood flow through vasodilation
- PGE
Prostaglandins:
Cox-1
PGF2a
Necessary for parturition in most animals
Lutalyse used to scencronize cattle
Prostaglandins:
Cox-1
TBX
Thromboxane
Platelet aggregation, vasoconstriction
Prostaglandins:
Cox-2
- “Inducible” enzyme
- local regulation in most cases
-
PGE:
- vasodilation, sensitization of nociceptors, inflammation, fever, maintain patency of ductus areteriosis, ovulation
- Release of renin
-
PGI:
- Prostacyclin: antagonist to Thromboxane
- Produced in blood vessel walls resulting in vasodilation and inhibition of platelet aggregation
- Sensitizes nociceptors
- Gastroprotective similar to PGE
-
PGE and PGI:
- Renal effects also include tubular effects
- Increase renal blood flow (Dogs, +/- cats and horses)
- Tubular release:
- increased sodium excretion
- Renal effects also include tubular effects
Prostaglandins:
Cox-2
“Inducible” Enzyme
- Up-regulated in some types of inflammation
- Up-regulated in some types of pain
- Up-regulated in gastric healing
- Up-regulated in renal vasculature during renal hyptension
- Cox-2 expressed in neoplastic tissue
- Angiogenesis? Inflammation?
- Constitutively expressed:
- GI tract - gastroprotective
- Renal - maintain renal blood flow and tubular functions
Lipoxygenase (LOX)
- Catalyzes formation of Leukotrienes
- Effects:
- Vasocontristion (Antagonistic to PGs)
- Decreases blood flow
- Increase Gastric Acid Secretion
- Pro-Inflammatory
- Activation, recruitment, migration, and adhesion of inflammatory cells
- Increased cytokine production (TNF-a, IL-1B)
- Bronchoconstriction
- Does nonselective COX inhibition increase leukotriense by shifting the AA pathway?
- yes
- Vasocontristion (Antagonistic to PGs)
Aspirin Triggered Lipoxin (ATL)
- Potent anti-inflammatory action
- Stimulate gastroprotective effects
- Modulate T-cells and Macrophages
- Aspirin induces Lipoxin formation by Cox-2
- Product to Acetylated Cox-2, therefore Cox-2 inhibitors prevent formation and beneficial effects
Nociceptive Stimulation
Cox-2 is the primary driver for the pain pathway
Non-selective COX inhibitor
Effect Cox-1 and Cox-2 the same
Cox-2 Selective Inhibitor
Effects Cox-2 with no effect on Cox-1
Cox-2 Preferential Inhibitor
Cox-2 is mostly effected, but there are small effects on Cox-1
GI Tract Adverse Effects (AE) from NSAIDs
- Vomiting, Diarrhea
- Gastritis, enteritis, GIT ulceration, death
- Right Dorsal Colitis in Horses
- Direct irritation of GIT
- Inhibition of both Cox-1 and Cox-2 produce greatest GIT adverse effects
- Cox-2 selective and preferential NSAIDs have less GIT adverse effects compated to nonselective inhibitors
- Except when there are underlying GI lesions
- Cox-2 selective and preferential NSAIDs have less GIT adverse effects compated to nonselective inhibitors
- Are GI adverse effects to in part to increases LT formation?
- Nonselective Cox and Lox inhibitor have low GIT adverse effects despite lack of Cox-2 selectivity
GIT Adcerse Effects from NSAIDs:
Cox-1
Mediates GIT homeostasis
GIT adverse effects from NSAIDs:
Cox-2
Also mediates GIT homeostasis
Needed for GIT healing
Lipoxin = gastroprotective
GIT Adverse Effects from NSAIDs:
Minimizing GI adverse effects
- Appropriate patent selection
- Avoid administration with corticosteroids and other NSAIDs
- Avoid in animals with underlying GI issues
- Avoid in animals with known sensitivity
- Gastroprotective therapies
- misoprostol (Synthetic Prostaglandin E)
- Acid suppression
- Proton Pump inhibitors
- Histamine H2 antagonist
- Sucralfate
Renal Adverse Effects form NSAIDs
- PGE is a local mediator renal blood flow
- Cox-1 mediates blood flow “in healthy kidneys” in some species (not dogs)
- In dogs, Cox-2 is constitutive in renal vasculature
- Cox-2 up-regulated due to renal ischemia/hypotension
- Renin release mediated in part by Cox-2
- increase Cox-2 maintains renal blood flow
- Increase Lox decreases renal blood flow
Renal Adverse Effects form NSAIDs:
Increased by:
- Hypotension
- Pre-existing renal disease
- Concurrent use of nephrotoxic drugs
- Congestive heart failure
- Sodium Depletion
- Cox-2 upregulated in macular densa
- Macula densa:
- Renin-angiotensin-aldosterone (reabsorb sodium/water from urine), maintain blood pressure
Hepatotoxicity
- Idiosyncratic
- can occur with any NSAId
- No breed predispostions identified
- Typically occurs whithin 21 days
- Not dose-dependent
- Often reversible with discontinuation of NSAID and supportive therapy
- severe cases can be fatal
- Unknown if reactions will occur with other NSAIDs
- Dose dependent toxicity
- overdose
- Caution clients about flavored formulations
Coagulation Inhibition
Primarily due to thromboxane inhibition
Cox-1 inhibition
Low dose aspirin irreversibly binds to thromboxane synthetase :anti-platelet effects”
Hypercoagulable State
Cox-2 selective inhibitors
Inhibition of PGI
Less of a problem in most animals
Myelosuppression
Rare, but serious
Associated primarily with:
Phenylbutazone - aplastic anemia
Dipyrone - Agranulocytosis
Special Considerations:
Gastrointestinal Surgery/Disease
- Enterotomy, gastrotomy, GDV
- Cox-1
- Gastroprotective
- Cox-2
- Upregulated in healing GIT
- Cox-1
Special Considerations:
Anesthesia
- Short Anesthesia, <20 mins, less risk
- Hypotension:
- renal blood flow increased by COx-2 mediated vasodilation in dogs and all species
- Fluids should be administered during anesthesia to animals on NSAIDs
Special Considerations:
Shock/ Trauma
- Increased adverse effects of NSAIDs
- GIT:
- blood flow already decreased due to shock
- Renal blood flow:
- Cox-2 dependant
- NSAID analgesia limited to mild-moderate pain
- GIT:
- Primary treatment of Pain/Shock
- crystalloids
- Colloids
- Opioids
Special Considerations:
Shock/ Trauma
- Increased adverse effects of NSAIDs
- GIT:
- blood flow already decreased due to shock
- Renal blood flow:
- Cox-2 dependant
- NSAID analgesia limited to mild-moderate pain
- GIT:
- Primary treatment of Pain/Shock
- crystalloids
- Colloids
- Opioids
Indications
Analgesic
Antipyretic
Ameliorate the effects of endotoxins
Antiplatelets
Anti-inflammatory
NSAID Efficacy
- Is very good for mild to moderate pain
- No NSAID has demonstrated a consistent increased efficacy compared to another NSAID
- However an individual patient may respond better to a specific NSAID
- Chronic and neuropathic pain may less responsive to NSAIDs
Client Instructions: Dog
- Recheck if:
- Vomiting / diarrhea/ anorexia
- Lethargy / depression
- Yellow eyes / gums
Client Instructions: Horses
- Rechecke if:
- poor performance
- colic
- diarrhea
- decreased appetite
- Weight loss
- Bruxism (Teeth grinding)
Concurrent Drug Use:
Adverse Effects
- Corticosteriods (GIT)
- Amphotericin (Renal)
- Cisplatin (Renal)
- Aminoglycosides (Renal)
- Diuretics (Furosemide, Renal)
- Serotonin Reuptake Inhibitors (GI, Bleeding)
Concurrent Drug Use:
Decreased Efficacy
- ACE inhibitors (Enalapril)
- Diurectics (Furosemide)
