Anti-inflammatory & Pain-reducing drugs

1. Anti-inflammatory & Pain-reducing drugs Chapter 13 -1

2. OBJECTIVES • Terminology used to describe anti-inflammatory drugs • MOA by which inflammation occurs • MOA which glucocorticoids and NSAIDs work • Comparisons of glucocorticoids and NSAIDs in their effects and side effects • Precautions that apply to glucocorticoids, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitor drugs

3. Terminology • Anti-inflammatories: Drugs that relieve pain or discomfort by blocking or reducing the inflammatory process • Steroidal anti-inflammatory drugs (corticosteroids) • Nonsteroidal anti-inflammatory drugs (NSAIDs) • not considered to be true analgesics • Opoids work on CNS and reduce perception of pain

4. MOA - Inflammation EICOSANOIDS

5. ARACHIDONIC PATHWAY Phospholipids: cell membrane • EICOSANOIDS • GOOD PG: PgE and PgI2. normally decrease the volume, acidity, and pepsin content of gastric secretions released during normal digestion

6. Anti-inflammatory Drugs • Two main groups of anti-inflammatory drugs • Steroidal anti-inflammatory drugs block the action of phospholipase (lipoxygenase) • Nonsteroidal anti-inflammatory drugs block the action of cyclooxygenase (thromboxane)

7. Steroidal Anti-inflammatories • Corticosteroids /adrenocorticosteroids • hormones produced by the cortex (the outer layer) of the adrenal gland. • mineralocorticoids • water and electrolyte balance (sodium, potassium, and other electrolytes), aldosterone • Hypoadrenocorticism/ Addison’s: • hyperkalemia, hyponatremia because of a lack of aldosterone production • TX: desoxycorticosterone pivalate (Percorten-V • glucocorticoids

8. Glucocorticoids-Antiinflammatories • Inhibit phospholipase, and to a lesser degree cyclooxygenase • Decreasing the production of prostaglandins and leukotrienes • Every corticosteroid drug has both mineralocorticoid (sodium retention) and glucocorticoid (anti-inflammatory effects to some degree • Are regulated by negative feedback

9. Glucocorticoids are natural hormones • adrenocorticotropic hormone (ACTH) • corticotropin-releasing factor (CRF)

10. Glucocorticoid - Pros • decrease inflammation • relieve pruritus • help maintain the integrity of the capillaries - decreases swelling • inhibit fibroblasts: reduce scarring by delaying wound healing normal therapeutic doses of glucocorticoid does not affect humoral immunity so ok to vaccinate animals on these drugs

11. Glucocorticoid - Cons • Dec. fibroblast activity delay wound healing • Suppress T-lymphocytes (normal therapy dose): • Protects fungal agents (e.g., histoplasmosis…) • Horses: fungal eye infections • Inc. gastric acid secretion and decrease mucus production: hyperacidity and GI ulceration • catabolize protein in the cornea > deepening ulcer, Desmetocele: poor prognosis • +/- induce abortion: cattle and mares , bitches • Stress leukogram: lymphopenia, monocytopenia, eosinopenia, neutrophilia: sequestered - lungs, spleen

12. Cushing’s Disease (hyperadrenocorticism) • Corticosteroids: catabolic – breakdown of protein > provide amino acids for gluconeogenesis • hyperglycemia • muscle wasting atrophy, alopecia, and decreased bone density. • “pot-bellied” appearance of dogs after long term glucocorticoid treatment PU/PD/PP, risk to infections iatrogenic Cushing's : DON’T GIVE TOO MUCH: EOD

13. Addison’s Disease (hypoadrenocorticism) • extended use of glucocorticoid: lack of CRF and ACTH • adrenal cortex begins to atrophy > natural cortisol is diminished. weakness, lethargy, vomiting, and/or diarrhea Taper off slowly

14. Uses for Glucocorticoid Drugs • Overreaction of the immune system: Autoimmune reactions such as lupus, Autoimmune hemolytic anemia, Hypersensitivity reactions such as allergic reactions • Shock • Systemic disease (Addison’s) OR iatrogenic cushion’s disease  • Cancer: Lymphosarcoma: lymphocytosis • glucocorticoids are part of the treatment protocol for this cancer • Inflammatory conditions: Ocular inflammation, MSK inflammation, IVD • Lameness (horses) • Pregnancy termination (Don’t use in pregnant animals)

15. Topical steroids almost always effect systematically so don’t give to immunocompromised/ pregnant animals CORTICOSTEROIDS (ADRENOCORTICOSTEROIDS) GLUCOCORTICOIDS • Short-acting: < 12 hrs • Hydrocortisone: topical • Cortisone • Intermediate-acting: 12 to 36 hrs; EOD; allergies/ inflammation • Prednisone • Prednisolone • Triamcinolone • Methylprednisolone (depomedrol) • Isoflupredone • Long-acting:12 to 36 hours • Dexamethasone • Betamethasone • Flumethasone

16. Glucocorticoids - Formulations • Aqueous solutions • combined with a salt: Na-phosphate or Na-succinate to make them soluble (dissolvable) in water. • E.g. dexamethasone sodium phosphate and prednisolone sodium succinate (Solu-Delta-Cortef) • Adv: can be given in large doses intravenously with less risk of an adverse reaction; shock or CNS trauma • DA: pain, irritation, or inflammation at the site of injection in hot/cold climate • Alcohol solutions • Suspensions: acetate-glucocorticoid lipid soluble: topical ophthalmic medications • acetate, diacetate, pivalate, acetonide, or valerate appended to the glucocorticoid drug name • Opaque

17. Safe Use of Glucocorticioid • •Use NSAID rather than a glucocorticoid (as long as no contraindications exist for NSAID use). • •Avoid continuous use of glucocorticoids: it is preferable to use an intermediate-acting glucocorticoid such as prednisolone rather LA-glucocorticoids: systemic administration (versus topical administration • •Use the smallest dose of glucocorticoids that provides a clinical response. EOD • Tapering: to avoid Addison’s • Cat’s not really affected

18. NSAID • COX-2 inhibitors: Carprofen (Rimadyl), Etodolac (EtoGesic), Deracoxib (Deramaxx), Meloxicam (Metacam), Firocoxib (Previcox) • Tepoxalin (Zubrin) • Phenylbutazone • Aspirin (salicylates) • Propionic acid derivatives: Ibuprofen (Advil, Motrin), Ketoprofen (Ketofen), Naproxen (Aleve) • Flunixin meglumine (Banamine) • Meclofenamic acid (Arquel) • Dimethyl sulfoxide (DMSO) • Chondroprotective agents Polysulfated glycosaminoglycans • Hyaluronic acid • Glucosamine • Chondroitin sulfate (Cosequin) • Acetaminophen • Orgotein (superoxide dismutase) • Gold salts • Piroxicam

19. IDEAL DRUG: COX 2 INHIBITOR: Newer NSAID: Deramaxx, Rimadyl, etogesic Non-Steroidal Anti-inflammatory Drugs • NSAIDs work by blocking the activity of cyclooxygenase > inhibit prostaglandins. • Few NSAIDs such as ketoprofen, ibuprofen, and tepoxalin (Zubrin) > inhibit lipoxygenase • Cyclooxygenase has two forms • Cox-1: in stomach: secretion of stomach-protective mucus, decrease acid; kidney: vasodilation of the renal blood supply and other organs • Cox-2: prostaglandins – inflammation • They can be used for analgesia • Post operative analgesia

20. NSAID - CON Cox -2 inhibitors: Flavorful hence put away from animals to avoid toxicities • NSAID overdose/ nonselective NSAIDs extended period : anorexia, diarrhea, ulcerations of the stomach or duodenum • sucralfate, histamine 2 (H2) blockers (e.g., cimetidine or ranitidine), and omeprazole are used to treat the open ulcer and reduce the acidity of the stomach, misoprostol: like PG-E • Protein bound hence toxic in hypoalbuminemia • Block good PG (PgE and PgI2): • Hypotension > prostaglandin E2 is released by the kidney to dilate vessels • renal papillary necrosis • Seen also in cox -2!! • Hepatotoxicity • GI SE is reported much more frequently in dogs than horses • E.g phenylbutazone (old NSAID) toxic in dogs: gastritis/ melena • Cats: poorly tolerant of NSAIDs • Low dose aspirin every 2 days can be tolerable

21. References • Bill, R.L. Clinical Pharmacology and Therapeutics for the Veterinary Technician, 3rd edition. 2006. • Romich, J.A. Pharmacology for Veterinary Technicians, 2nd edition. 2010.