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Describe the mechanism of action of NSAIDs

Block production of prostaglanding by blocking COX conversion of arachidonic acid to PGG2


Compare COX 1 and 2

- COX1: constitutive, always present, maintain turnover cells, required for life
- COX2: inducible, active in response to inflammatory stimulus, invoke production of PGs that are not usually there (PGE2)


Where are COX1 found?

- Intestines
- Platelets
- Stomach
- Kidney


Where are COX2 found?

- Macrophages
- Leukocytes
- Fibroblasts
- Endothelial cells


Outline some equine specific problems with NSAIDs

- Thrombophlebitis wih pheynbutazone if have perivascular injection
- Prescription of phenylbutazone only done when this can be entered into passport immediately


Give examples of suggested equine specific effects of NSAIDs that have

- Inflammation
- Pyrexia
- Oedema
- Endotoxaemia
- Ileus
- Adhesion formation (tenuous evidence)
- Thrombosis


Discuss the effect of NSAIDs on wound healing

- Some compromise to healing
- However pain has more significant impact on wound healing so administration of NSAIDs still positive


Outline the pharmacokinetics of NSAIDs

- Hepatic metabolism and renal excretion
- High protein binding, low vol of distribution
- Significant individual variation in response and susceptibility to toxicity
- Effects often outlive the plasma half life


Compare the risks of NSAIDs in ponies and horses

Ponies more susceptible to phenylbutazone toxicity than horses


Explain the adverse effects of NSAIDs regarding the kidney

- Reduce renal blood flow as this is mediated by prostaglandins in the medulla
- Hypotension + NSAID = renal damage
- Some concern regarding pre/peri-operative use bu several NSAIDs licensed for this


Explain the adverse effects of NSAIDs regarding the GI system

- Prostaglandins cytoprotective in the GIT
- GI side effects most common with chronic use
- Direct irritation and PG inhibition are the cause of these signs
- Some require administration with food, others on empty stomach


List the serious GI side effects of NSAIDs

- Vomiting (small animals)
- Colic
- Inappetance
- Diarrhoea
- Protein losing enteropathy (PLE), secondary anaemia
- Ulceration
- Death


Explain the role of prostaglandins in the GIT

- Cytoprotective
- Decrease volume, acidity and pepsin content in the stomach
- Stimulate bicarbonate secretion
- Promote mucosal blood flow and repair and turnover of cells


Compare the adverse effects of NSAIDs on the GI system of young and adult hoses

- Young: more susceptible to gastric ulceration
- Adults: more susceptible to right dorsal colitis


Describe the long term adaptation of the GI system to NSAID use

- Increased mucosal blood flow
- Increased mucosa cell regeneration
- Decreased inflammatory cell infiltrate
- From 14 days


Explain the role of enterohepatic recycling in the GI safety of NSAIDs

- Excretion into intestine from bile
- Leads to repeated exposure of the duodenum to the drug
- Directly correlates to toxicity


Give examples of ways in which the GI safety of NSAIDs can be improved

- Protective strategy
- Sucralfate sucrose (aluminium sulphate)
- H2 agonists
- Protein pump inhibitors
- Newer coxibs
- Different formulation of NSAIDs sometimes tolerated better by different individuals


How does hepatotoxicity occur as a consequence of NSAID use?

Type I and type III reactions


List the adverse effects of NSAID use in cats

- Hyperthermia
- Respiratory alkalosis
- Metabolic acidosis
- Methaemoglobinaemia
- Haemorrhagic gastro-enteritis
- Renal failure
- Hepatic injury


Which NSAID is particularly dangerous in cats?



Outline the dosing and frequency of administration of NSAIDs in cats

- Titrate to lowest effective dose
- Dose to lean/ideal body weight in obese animals
- Reduce dose but maintain frequency when titrating down
- Intermittent therapy i.e. 2-3 times a week rather than daily better than nothing
- Liquids more easily measured


Describe the screening recommended prior to commencing treatment with NSAIDs in cats

- Thorough history and physical examintion esp. looking at conditions that may impact on NSAID therapy e.g. blood pressure
- Blood biochem to asses renal and hepatic function
- Plasma proteins and haematocrit may be markers of GI bleeding and/or mucosal damage
- Abnormalities may not preclude NSAID use but must be evaluated and discussed with owner


List the NSAIDs licensed for systemic use in cats

- Caprofen (once only)
- Ketoprofen
- Meloxicam
- Robenacoxib
- Tolfenamic acid
- Acetylsalicyclic acid


Describe the suggested minimum monitoring parameters for long term NSAID use in cats

- History
- Full clinical exam
- Haematocri
- Urea, creatinine, ALT, ALP
- Specific gravity
- Dipstick biochem


Out;line guidelines for the safe use of NSAIDs in chronic MSK disease

- Ensure no hypovolaemia
- No concurrent administration of another NSAID or steroid
- No hepatic or renal insufficiency
- Regular (every 3-6 months) monitoring with serum biochem and haematology


Explain the risk of paracetamol use in cats

- OD and toxicity common
- Low feline capacity for glucoronidation of paracetamol, rely on sulfation
- When saturated, switches to P450 door detox, creates highly reactive metabolite NAPQI
- overwhelms glutathione availability and result is oxidative injury


For which species is paracetamol particularly useful?

- Dogs: adjunct in refractory long term arthritis
- Rodents/rabbits
- Pigs


Discuss the use of Mavacoxib

- 1 month duration in dogs
- Good for some owners
- No additional risk of problems in surgery over other NSAIDs
- May need to consider addition of gastroprotectants


Outline a therapeutic plan for the use of NSAIDs

- Initial course of NSAIDs, re-check 4 weeks later
- Improvement: continue and reassess q1-2 months
- Little or no improvement: check owner compliance
- Poor compliance: consider reason, consider different formulation
- Good compliance: switch to another NSAID while observing wash out period
- Improvement after switch: continue and reassess q1-2 months
- No/little improvement after switch: reassess diagnosis, consider individual variation, re-evaluate complementary techniques, consider additional of adjunct, seek referral


Outline other therapies other than NSAIDs used in the treatment of OA

- Exerise management
- Weight control and diet
- Modification to lifestyle e.g. ramps
- Hydrotherapy and physio
- Chrondroprotectives
- Joint replacement
- IRap (interleukin-1 receptor antagonist protein)
- Stem cell therapies
- Other "drugs": isoxsuprine hydrochloride, vegetable tablets, PLT
- Neutraceuticals