ANTI-INFLAMMATORY DRUGS Chapter 13

Inflammation is a bodily process that occurs in response to injury of the tissues caused by trauma. The goal of this process is to remove/isolate the cause of the injury and to repair/replace the damaged tissue. Blood supply is increased to the affected area, leukocytes migrate, and phagocytic cells become more active.

Arachidonic Acid Pathway (pg 345) Cell membrane With phospholipids Arachadonic acid Prostaglandins Thromboxanes Leukotrienes phospholipase cyclooxygenase lipoxygenase

INFLAMMATION cont’d Signs that an animal is in pain: increased heart/respiratory rates, mydriasis, salivation, vocalization, facial expression, aggressiveness, guarding painful area, restlessness, unresponsiveness, failure to groom, abnormal gait/stance. CORTICOSTEROID DRUGS: -block phospholipase NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: -block cyclooxygenase

CORTICOSTEROID REVIEW Group of hormones produced by the cortex of the adrenal glands. Mineralocorticoids: affect the mineral (electrolytes) and water balance of the body Have little to no anti-inflammatory effect. Aldosterone is the main mineralocorticoid. Glucocorticoids: inhibit phospholipase in the arachidonic acid pathway, suppress the immune system, and influence metabolism. Cortisol is the main naturally occurring glucocorticoid.

GLUCOCORTICOID PRODUCTION Hypothalamus produces Corticotropin Releasing Hormone when blood levels of glucocorticoids are low. This signals the pituitary to secrete ACTH. ACTH signals the adrenals to produce glucocorticoids (Cortisol). If Cortisol levels are high, Negative Feedback will occur to inhibit the production of CRH and ACTH until Cortisol levels fall

Effects of Glucocorticoids Cause gluconeogenesis, decrease the ability of glucose to leave the blood and enter the cells, and glycogenesis. Increase gastric acid secretion and decrease mucus production. Stress leukogram: Neutrophilia, Lymphopenia (possible Eosinopenia and Monocytosis) Inhibition of fibroblasts, whose role is to help close wounds and form scar tissue.

Effects of Glucocorticoids Destroy malignant lymphocytes. Cause catabolism of protein during gluconeogenesis. When used in the presence of a corneal ulcer, the protein that forms the middle layers of the cornea can be catabolized which deepens the ulcer. Decreased fibroblast activity will also prolong corneal ulcer healing.

Effects of Glucocorticoids Myometrial contractions and cervical dilation. 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 agents so use in the presence of a fungal infection is contraindicated. High doses can also suppress humoral immunity (antibody production by B-lymphocytes) which can effect vaccine efficacy.

Cortisone, Hydrocortisone topical SHORT ACTING – less than 12 hours Cortisone, Hydrocortisone topical INTERMEDIATE ACTING - last 12-36 hours Prednisone, Prednisolone (Solu-Delta-Cortef), Methylprednisolone (Depo Medrol), Triamcinolone (Vetalog, Panalog) oral or injectable can be given every other day and still be effective LONG ACTING – last longer than 48 hours Dexamethazone, Betamethasone (Azium)

Injectable glucocorticoids Glucocorticoids in alcohol solutions Drug dissolves in alcohol without the addition of any substances to the drug (Ex: Dexamethasone) 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.

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: Dexamethasone acetate) Must be shaken Opaque appearance Do not give IV Once injected, the crystals slowly dissolve over several days, releasing small amounts of drug.

DVM Steroid Rules of Thumb: 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.

NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) Drugs that do not contain a cholesterol ring structure and have fewer side effects than glucocorticoids, while still decreasing inflammation. Most block cyclooxygenase in the arachidonic acid pathway (block the production of Prostaglandins and Thromboxanes), but some also block lipoxygenase (which 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.

A note about cyclooxygenase: -There is also Cyclooxygenase in the body that exists outside of the arachidonic acid pathway! COX 1 (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. COX 2 is the cyclooxygenase that is involved in the arachidonic acid pathway and causes inflammation.

Using NSAIDS that selectively inhibit COX 2 should be able to decrease inflammation without affecting kidney or stomach health. Newer NSAIDS are more COX 2 selective. 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.

NSAID SIDE EFFECTS -All NSAIDS are highly protein-bound. Use with caution in animals with hypoproteinemia or if giving with another protein- bound drug as toxic levels can occur. Blocking Prostaglandins E and I (Cox 1 inhibitors) can cause gastritis, ulcers, and signs of 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.

NSAID SIDE EFFECTS The body naturally constricts blood flow to the kidney when hypotension 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 hepatotoxicity. The cause is unknown and occurrence is unpredictable.

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!!!

COX 2 SELECTIVE NSAIDS (aka Cox 1-sparing) Meloxicam (METACAM) Approved for use in dogs and cats, however the manufacturer cautions using it often in cats. Oral (liquid) and injectable Robenacoxib (ONSIOR) Approved for use in cats, dog product exists for other countries Oral (tablet) and injectable

COX 2 SELECTIVE NSAIDS (aka Cox 1-sparing) Carprofen (RIMADYL) Approved for dogs Oral and injectable Deracoxib (DERAMAXX) Dogs, oral Firocoxib (PREVICOX)

NON-SELECTIVE NSAIDS Phenylbutazone (aka BUTE) 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

NON-SELECTIVE NSAIDS Fluninxin Meglumine (BANAMINE) Labeled for use in large animals Oral and injectable (ok to give IV or IM) fast acting- 15 minutes

MISCELLANEOUS NSAIDS Dimethyl Sulfoxide (DMSO) Does not inhibit prostaglandins, but instead inactivates free radicals that are produced by inflammation Label approval is for topical use in dogs and horses Smells like garlic and can cause the patient to taste garlic Wear gloves when applying as it can penetrate intact skin Bandaging over DMSO can cause skin irritation Teratogenic

MISCELLANEOUS NSAIDS Acetylsalicylic acid (ASPIRIN) 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 Often used in people to “thin the blood” as these drugs effectively inhibit thromboxanes from promoting platelet aggregation

MISCELLANEOUS Acetaminophen (TYLENOL) 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.

MISCELLANEOUS Acetaminophen (TYLENOL) Metabolism of Acetaminophen in cats forms a toxic metabolite within RBCs that converts hemoglobin to methemoglobin within, which cannot adequately carry oxygen. Hemolysis and Heinz bodies are seen on smears Blood, urine, and mucous membrane are “chocolate-colored” Acetylcysteine (Mucomyst), a mucolytic, converts the toxic metabolite to a nontoxic form

OTHER METHODS OF PAIN/INFLAMMATION REDUCTION: Cyclosporine – ATOPICA Anti-inflammatory, anti-pruriticthat is an immunosuppressant (T- lymphocytes) Used for skin conditions, cancer, and when other immunosuppression is necessary Oclacitinib- APOQUEL Newly released anti-inflammatory used to treat pruritis by inhibiting cytokines Currently only approved for dogs over 1 year of age. NARCOTICS - OPIODS