ANTI-INFLAMMATORY DRUGS Chapter 13

1. ANTI-INFLAMMATORY DRUGSChapter 13

2. Inflammation is a protective mechanism that occurs in response to injury of the tissues. • The goal of this process is to protect and stabilize the affected area and improve the healing process. • If inflammation interferes with the animal’s function or if it is autoimmune in nature, it should be suppressed to avoid damaging the healthy surrounding tissues. • Two categories of drugs reduce inflammation: _______________ and __________________anti-inflammatory drugs

4. Arachidonic Acid Cascade (pg 297) A pathway that generates inflammatory mediators called ______________________. • 1st: The cell membrane’s PHOSPHOLIPID BILAYER is traumatized. • 2nd:Phospholipase is activated and converts the phospholipids to ARACHIDONIC ACID. • 3rd: Either Cyclooxygenase and Lipoxygenase break down ARACHIDONIC ACID. • 4th : Cyclooxygenase produces PROSTAGLANDINS and THROMBOXANES. Lipoxygenase produces LEUKOTRIENES. • PROSTAGLANDINS, THROMBOXANES, AND LEUKOTRIENES produce the 5 signs of inflammation Steroids block the action of Phospholipase and Cyclooxygenase, NSAIDS block the action of Cyclooxygenase and Lipoxygenase.

5. CORTICOSTEROID REVIEW • Group of hormones produced by the adrenal cortex. • Mineralocorticoids: affect the mineral (electrolytes) and water balance of the body at the kidney. • Have little to no anti-inflammatory effect. • __________________ is the main mineralocorticoid. __ Na, __ K. Addison’s disease occurs when Aldosterone is not adequately produced. • Glucocorticoids: inhibit the arachidonic acid cascade, suppress the immune system, and influence metabolism. • _______________ is the main naturally occurring glucocorticoid. All body cells have glucocorticoid receptors (which is why these drugs have so many side effects).

6. GLUCOCORTICOID PRODUCTION • Hypothalamus produces Corticotropin Releasing Hormone when blood levels of glucocorticoids are low. • This signals the pituitary to secrete Adrenocorticotropic Hormone. • ACTH signals the adrenal glands to produce Cortisol. • If Cortisol levels are high, NEGATIVE FEEDBACK will occur to inhibit the production of CRH and ACTH until Cortisol levels fall below normal.

7. SHORT ACTING – last less than 12 hours • hydrocortisone • Topical for skin inflammation INTERMEDIATE ACTING - last 12-36 hours • prednisone, prednisolone (______-______-_______), methylprednisolone (______ ________), triamcinolone (_________,___________) • oral or injectable • can be given every other day and still be effective LONG ACTING – last longer than 48 hours • dexamethazone, betamethasone (________), flumethasone, isoflupredone (___________) • oral or injectable

8. Injectable glucocorticoids • Glucocorticoids in aqueous solutions • Drug is combined with a salt to make the drug dissolvable in water (Ex: dexamethasone sodium phosphate). • Can be given in large amounts IV, so are often used in emergency situations. • Glucocorticoids in alcohol solutions • Drug dissolves in alcohol without the addition of any substances to the drug (Ex: dexamethasone) • Can also be given IV

9. Injectable Glucocorticoids • Glucocorticoids in suspensions • Drug is not dissolved in liquid and exists as large crystals. Follow label instructions for storage info. Extreme temps can cause the crystals to change size/shape. • Name has acetate, diacetate, pivalate, or valerate added to it (Ex: triamcinolone acetonide) • Must be shaken • Opaque appearance • Do not give IV • Once injected, the crystals slowly dissolve over several days, releasing small amounts of drug.

10. Effects of Glucocorticoids Doses of glucocorticoids are low (_______________), medium (______________________), and high (________________________). Doses above physiologic can cause the following side effects: • 1) Cause gluconeogenesis while simultaneously decreasing the body’s response to insulin. • Proteins go through catabolism during gluconeogenesis. The sources of these proteins are skeletal muscle and collagen in skin/wounds. Hence, gluconeogenesis also causes thin skin, pot belly, and prolonged healing.

11. Effects of Glucocorticoids • 2) Decrease autoimmune response. • Suppress T-lymphocytes which provide cell-mediated immunity (encourages phagocytic cells to engulf foreign materials and/or invaders). Cell-mediated immunity is the main defense against fungal and bacterial agents so use in the presence of them is contraindicated. • Very high doses can also suppress humoral immunity (antibody production by B-lymphocytes) which can effect vaccine efficacy. • 3) Stress leukogram: neutrophilia, lymphopenia, eosinopenia • 4) Destroy malignant lymphocytes (often used with lymphoma treatment).

12. Effects of Glucocorticoids • 5) Increase gastric acid secretion and decrease mucus production (ulcer risk). • 6) Suppression of Antidiuretic Hormone, so PU/PD is noted. • 7) When used in the presence of a corneal ulcer, collagen that forms the middle layers of the cornea can be degraded, which deepens the ulcer. Decreased fibroblast activity will also prolong corneal ulcer healing. (Note: horses on ophthalmic steroid medication are more prone to ocular fungal infections due to their environment.) • 8) Myometrial contractions and cervical dilation.

13. Hyperadrenocorticism (Cushing’s) Review • Iatrogenic Cushing’s is caused by glucocorticoid administration to an animal. • Clinical signs: poor hair coat, thin skin, muscle atrophy, alopecia, pot-belly, polyuria, polyphagia, polydipsia • Steroids should always be tapered to slowly stimulate the atrophied adrenal glands and avoid an Addisonian crisis.

14. DVM Steroid Rules of Thumb: • The animal should ideally have a diagnosis before the start of steroid therapy as it is usually aimed at decreasing the signs of inflammation, not the cause of the disease. • If an NSAID or a glucocorticoid can be used to treat an animal, choose the NSAID. • If extended glucocorticoid use is required, choose an intermediate-acting drug instead of long-acting to decrease adrenal atrophy. • Use the smallest dose that provides a response and alternate day therapy if possible. • Taper an animal off of steroids by gradually reducing the dose and frequency.

15. NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) • Drugs that do not contain a _______________ ring structure and have fewer side effects than glucocorticoids, while still decreasing inflammation. • Block cyclooxygenase in the Arachidonic Acid Cascade (block the production of Prostaglandins and Thromboxanes), but some also block lipoxygenase(blocks the production of Leukotrienes). • Because glucocorticoids work higher up in the pathway (by blocking phospholipase), they are said to be more effective anti-inflammatory medications than NSAIDS, however they have more side effects.

16. A note about cyclooxygenase: • -There is also Cyclooxygenase in the body that exists outside of the arachidonic acid pathway! • __________ (the good one), plays a major role in the health of the stomach and kidneys by providing prostaglandins that aid in their function. • Prostaglandins in the stomach provide a balance between mucus production and HCl secretion. • Prostaglandins in the kidney counteract vasoconstriction to allow for adequate blood supply to the kidney. • __________ (will inflame you) is the cyclooxygenase that is involved in the arachidonic acid pathway and causes inflammation.

17. Newer NSAIDS are more selective about inhibiting COX 2. • Using NSAIDS that selectively inhibit COX 2 should be able to decrease inflammation without damaging the kidney or stomach. • The catch is that research has shown that COX 2 has been found to also play a role in gastric and renal health and COX 1 can produce some prostaglandins that encourage an inflammatory response. Also, when higher doses of COX 2- selective NSAIDS are used, the selectivity for COX 2 decreases. • Still, COX 2 selective NSAIDS generally have fewer gastric and renal side effects that non-selective NSAIDS.

18. NSAID SIDE EFFECTS • -All NSAIDS are highly protein-bound. Use with caution in animals with __________________ or if giving with another protein-bound drug as toxic levels can occur. • Cox 1 inhibitors reduce the production of Prostaglandin E. This can cause gastritis, ulcers, and GI upset. Animals on NSAIDS long-term or that have received an overdose can be treated with H2 antagonists, proton pump inhibitors, misoprostol, and/or sucralfate.

19. NSAID SIDE EFFECTS • The body naturally constricts blood flow to the kidney when _________________ occurs. PGE is released by the kidney to counteract this and maintain perfusion of the nephron. By inhibiting COX 1, PGE cannot enhance renal blood flow during times of hypotension and parts of the kidney can become necrotic due to lack of oxygen. • All NSAIDS (whether selective or not), have the potential to produce __________toxicity. The cause is unknown and occurrence is unpredictable.

20. NSAID SIDE EFFECTS • By decreasing the activity of Thromboxane, NSAIDS may cause the patient to bleed due to reduced platelet aggregation. • Monitoring bloodwork is important for patients with NSAIDS. Kidney and liver values should be assessed. • DO NOT USE MULTIPLE NSAIDS OR AN NSAID + CORTICOSTEROID SIMULTANEOUSLY!!!

21. NON SELECTIVE NSAIDS • acetylsalicylic acid (_____________) • Same family as salicylates • Cats cannot metabolize salicylates rapidly due to low levels of the liver enzyme needed for metabolism, so they are highly susceptible to overdose. (NOTE: aspirin is used for saddle thrombus tx in cats and uveitis tx in horses) • Often used in people to “thin the blood” as these drugs effectively inhibit thromboxanes from promoting platelet aggregation • Other non selective common NSAIDS that humans use are ibuprofen (__________ & __________) and naproxen (___________). These should not be used in animals due to severe side effects!

22. NON-SELECTIVE NSAIDS • phenylbutazone(aka __________) • Commonly used in large animals. Approved, but not commonly used in dogs • Oral (tablet, bolus, paste, gel, powder) and injectable • Injectable should be given by IV only! IM or SQ can cause tissue necrosis/sloughing • Can cause bone marrow suppression with long-term use

23. NON-SELECTIVE NSAIDS • fluninxinmeglumine (______________) • Labeled for use in large animals • Oral and injectable (ok to give IV or IM) • fast acting- 15 minutes

24. NON-SELECTIVE NSAIDS • diclofenac sodium (______________) • Topical NSAID that treats lameness in horses • Can have some systemic absorption so care must be taken to not “over apply”. • Wear gloves to avoid human absorption • Ophthalmic formulation available

25. COX 2 SELECTIVE NSAIDS (aka Cox 1-sparing) • carprofen (____________) • 1st veterinary-approved COX2 selective inhihibitor • Approved for dogs (more species in other countries) • Oral and injectable • deracoxib (_____________) • Dogs, oral • firocoxib (___________, ___________) • Dogs, oral; horses, oral and inject.

26. COX 2 SELECTIVE NSAIDS (aka Cox 1-sparing) • meloxicam (_____________) • Approved for use in dogs and single use in cats. • Oral (liquid) and injectable • robenacoxib (_______________) • Approved for use in cats and now, dogs too • Oral (tablet) and injectable • Labeled for 3 day use Onsior Pain Drug Approved for Dogs Medication may be used to counter postoperative pain and inflammation. BY VETERINARY PRACTICE NEWS EDITORS Published: 2016.12.08 09:22 AM

27. MISCELLANEOUS NSAIDS • dimethyl sulfoxide (________) • Compound derived from wood pulp • Does not inhibit prostaglandins, but instead inactivates free radicals that are produced by inflammation • Can penetrate the skin and is used as a vehicle for dissolved drugs. • Clean the skin before applying! • Label approval is for topical use in dogs and horses • Smells like garlic and can cause the patient to taste garlic. Apply in ventilated area. • Wear gloves when applying • Bandaging over DMSO can cause skin irritation • Teratogenic

28. MISCELLANEOUS • acetaminophen (________________) • Technically not an NSAID, but it is often grouped with NSAIDS. It decreases pain perception and decreases the effects of pyrogens (fever-producing agents) in the body. • Because it does not inhibit prostaglandins or thromboxanes, it will not directly lead to ulcers or interfere with platelet clumping. • CATS SHOULD NEVER BE GIVEN ACETAMINOPHEN as one dose can kill them.

29. MISCELLANEOUS • Metabolism of acetaminophen in cats forms a toxic metabolite within RBCs that converts hemoglobin to methemoglobin, which cannot adequately carry oxygen. The metabolite also accumulates in the liver, causing damage. • Hemolysis and Heinz bodies are seen on smears • Blood, urine, and mucous membranes are “chocolate-colored” • acetylcysteine (Mucomyst), a mucolytic, converts the toxic metabolite to a nontoxic form

30. OTHER METHODS OF PAIN/INFLAMMATION REDUCTION: • cyclosporine (_____________) • Anti-inflammatory, anti-pruritic that is an immunosuppressant (T- lymphocytes) • Used for skin conditions, cancer, and when other immunosuppression is necessary • oclacitinib (_____________) • Newly released anti-inflammatory used to treat pruritis by inhibiting cytokines • Currently only approved for dogs over 1 year of age. • NARCOTICS - OPIODS