1. ANTI-INFLAMMATORY & PAIN-REDUCING DRUGS Chapter 13-2

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. 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

5.  Dual-pathway NSAIDs - 2003  Block arachidonic acid cycle (both cyclooxygenase and lipoxygenase pathways)  Pain, inflammation and also resp. inflammation  COX-1 to COX-2 is 30:1  Are analgesics and anti- inflammatories tepoxalin (Zubrin®)  An example is tepoxalin (Zubrin®),  which is a rapidly disintegrating tablet used for osteoarthritis in dogs Selective COX-2 inhibitors

6.  Selective cox 2 inhibitor  Rimadyl (carprofen)  Deramxx (Deracoxib) Need bloodwork, give after meal, chewable tablet, liver function (ALKP, ALT, protein, bile acid)  PL -> Arachidonic acid -> PG: Cox 2 (pain, inflammation kidney function); Cox 2: stomach lining, kidney function, platelet fx.

7. Selective COX-2 inhibitors  Metacam: Meloxicam  Also inhibit Leukotriene production  Antipyretic  Injectable (Dog/ cat only once in cats) or oral suspension (Only dog)  Associated with ARF and death in cats  Warning: Oct 2010  Use of oral metacam in cats is associated with ARF in cats  Pre-emptive analgesia (only one in cats: before pain caused before orthopedic/ soft tissue sx.)

8. Type of NSAIDs  Indol acetic acid derivatives  Inhibit cyclooxygenase (more selective for Cox-2)  Is an analgesic and anti-inflammatory etodolac (Etogesic ® )  An example is etodolac (Etogesic ® ), which has the benefit of once-a-day dosing  Labeled for K9  Evaluate liver enzymes  Deramax is more cox 2 selective

9. NSAID - PHENYLBUTAZONE  Pyrazolone derivatives  Pharmokinetics:  metabolized by the liver  1 metabolite – oxyphenbutazone (antiinflammatory agent)  is highly protein bound  increased hepatic metabolism of phenylbutazone (less in body) w/ phenytoin, digitoxin, barbiturates and corticosteroids DA: GI ulceration; renal papillary necrosis if renal perfusion is decreased; and retention of water and sodium from decreased renal function, bone marrow suppression resulting in neutropenia

10. Types of NSAIDs  Used in equine medicine for musculoskeletal pain  Phenylbutazone (“bute”): powder, paste, injectable Frequently used in equine medicine for musculoskeletal pain. Frequently used in equine medicine for musculoskeletal pain.

11. NSAID – PHENYLBUTAZONE - DA  GI ulceration  renal papillary necrosis (renal perfusion is dec.) > retention of H20 and Na from dec. renal function  bone marrow suppression resulting in neutropenia more common in people and dogs (blood dyscrasias: abnormal blood cells) than horses  IM/SQ injections: thrombocytopenia, and anemia and tissue necrosis  Horses give should be given IV/PO Perivascular injection: inflammation and necrosis carotid artery can cause marked CNS stimulation: seizures and collapse

12. NSAID - Aspirin  Salicylates  Aspirin (acetylsalicylic acid)  bismuth subsalicylate - Pepto-Bismol and, since its new formulation released in 2003, Kaopectate  Aspirin  block the cyclooxygenase pathway  HCM: low dose aspirin (81 mg) thromboxane inhibition : blood thinner  caution in cats because they have low amounts of glucuronyl transferase which conjugates aspirin – glycine/ glucuronic acid  T ½: Half life: 1.5 hours - people, 8 hours in dogs, 30 hours in cats: q 2-3 days  If aspirin need to d/c before surgery

13. NSAID – Aspirin - CONS  Signs of salicylate toxicity include:  Gastrointestinal problems Anorexia, abdominal pain, vomiting, diarrhea  Respiratory problems Panting  Neurological problems Restlessness, anxiety, seizures  Bleeding problems  Kidney failure

14. NSAID - derivatives of propionic acid  Propionic acid derivatives: KNOW  Block both cyclooxygenase (non selective) and lipoxygenase  Examples include ibuprofen (c), ketoprofen (c and l), carprofen (c), and naproxen: alleve (the –fen drugs)  Side effects include gastrointestinal problems, renal papillary necrosis and possible liver toxicities (esp. Labrador type breeds)

15. NSAID - derivatives of propionic acid ibuprofen carprofen

16. NSAID – Flunixin meglumine  Flunixin meglumine  Inhibits cyclooxygenase  Used in cattle and horses for musculoskeletal and colic pain  Is a potent analgesic (than “bute”): hip dysplasia, arthritis, IVDD, and anterior uveitis also blocks the effects of endotoxins (gram – bacteria), and anti-inflammatory  analgesic in dogs ONLY NSAID approved for use in beef and dairy cattle HAS TO BE GIVEN IV IM and SQ: Illegal Cat use with caution and in dogs with parvo

17. Types of NSAIDs  Fenamates  Inhibit cyclooxygenase  antiinflammatory/ analgesic  meclofenamic acid (Arquel®)  Equine osteoarthritis  Dogs: chronic joint degenerative diseases e.g. hip dysplasia or chronic arthritis  SE:  SE: anorexia, diarrhea, or changes in stool color (melena)  Tolfedine®: K9/ Feline Antithromboxane (caution)

18. NSAID - DMSO  Dimethyl sulfoxide (DMSO)  industrial solvent - wood pulp > dissolve drugs that in water  Inactivates superoxide radicals (hydroxyl radicals and hydrogen peroxide) - inflammation  Topically or parenteral  Extra-label  swelling from CNS trauma,  Mastitis  mammary swelling associated with nursing  postoperative pain  burns, and other superficial trauma  acral lick granuloma: cocktail will include baytril and DMSO

19. NSAID – DMSO - CONS  Topical  wearing high-quality rubber gloves  thoroughly cleanse clean to avoid absorption of bacterial toxins or other chemicals such as oil, grease, and insecticides  applied topically, erythema (redness: histamine release), edema, and pruritus more severe reaction may occur if the animal has mast cell tumors  Horses: cause hemolysis > hemoglobinuria hence concentration below 20% for IV administration  May not be safe in pregnant animals smell of DMSO: garlic / raw oysters

20. Chondroprotective agents Polysulfated glycosaminoglycans Hyaluronic acid Glucosamine Chondroitin sulfate (Cosequin) Slow the process of arthritis by supporting the joint cartilage

21. Other Osteoarthritis Treatments  Polysulfated glycosaminoglycans – PSGAGs  mimic the components of the normal joint cartilage  large and complex molecules in cartilage trap molecules of water and give cartilage its springy characteristic and ability to tolerate stressful shocks  may inhibit or reduce activity of enzymes in the joint fluid that degrade cartilage  Used in injured joints (either from trauma or surgical intervention) or hip dysplasia INJECTABLE

22. Other Osteoarthritis Treatments  Hyaluronic acid  Hyaluronic acid :  part of joint synovial fluid  anti-inflammatory: suppression of PG and by scavenging free radicals  given intra-articularly, helps cushion degenerating joints  Local reactions may occur but usually resolve 24-48 hrs INJECTABLE

23. Other Osteoarthritis Treatments  Glucosamine and chondroitin sulfate  Glucosamine and chondroitin sulfate: believed to play a role in the maintenance of cartilage.  precursors for PSGAG formation by the chondrocytes (cartilage-forming cells) and for the proteoglycans that are found in cartilage  Mechanism of action  both chondroitin and glucosamine in the serum increases efficiency of the chondrocytes to repair cartilage  stimulates production of hyaluronic acid (glucosamine's action)  inhibits some of the destructive enzymes found in injured or diseased cartilage (chondroitin's action).  OTC: Neutraceutical Early on in DJD / Osteoarthritis challenge with these products is the variability in the amount of active product since some products are extracts from living organisms (mussel, sea cucumber, sea algae, shark cartilage) and others are purified extracts (more expensive)

24. NSAID - Acetominophen  Acetaminophen is another non-narcotic analgesic, which includes the drug Tylenol (Not NSAID)  Rarely used in veterinary medicine unless combined with codeine  Reduces fever and likely reduces the perception of pain (not inflammation)  Gastrointestinal side effects are rare but it can cause liver and kidney dysfunction in all animals  Poisonous in cats: liver damage, methemoglobin (chocolate-colored mucous membranes) and dark urine caused by methemoglobin in the blood and urine  50 mg/kg to 60 mg/kg can poison a cat  A single extra-strength acetaminophen tablet (500 mg) can kill an average-size cat  Dogs: (above 150 mg/kg) hepatic necrosis, weight loss, and icterus (jaundice)  TX: acetylcysteine (Mucomyst) also for resp. infections

25. OTHERS  Orgotein: Horses: joint and vertebral dz.  works as an enzyme, superoxide dismutase > convert superoxide radicals into oxygen and hydrogen peroxide > H2O and O2: preserves the integrity of hyaluronic acid  Gold salts: immune-mediated skin problems e.g. pemphigus  prevent release of lysosomal enzymes, dec. histamine release from mast cells and inhibit prostaglandin formation  Piroxicam (Feldene): some tumors not commonly used NSAID

26. Antihistamines  Antihistamines counteract the effect of histamine (histamine cause bronchoconstriction and inflammatory changes -> edema and pain)  Antihistamines compete with histamine for receptor sites (H 1 receptors constrict smooth muscles and H 2 receptors increase gastric secretions)  H 1 blockers are used to treat pruritus, laminitis, motion sickness, anaphylactic shock, and some upper respiratory conditions  Examples include diphenhydramine, dimenhydrinate, chlorpheniramine, pyrilamine maleate, tripelennamine, terfenadine, hydroxyzine, and meclizine

28. Immunomodulators  Immunomodulation is the adjustment of the immune system to a desired level.  Immunosuppression is reducing the immune response (also steroid)  Cyclosporine (Atopica®) is one of the most effective immunosuppressant agents available (not as dangerous as steroids)  Suppresses T-lymphocyte activity  Anti-inflammatory and anti-pruritic properties  Developed for atopic dermatitis in dogs  Must treat bacterial and fungal infections before use  Has to build up in body, can have GI upset (anorexia) once use to drug works well

29. PAIN The pain pathway A painful stimulus is converted into a depolarization wave by the pain receptor (transduction) sent along the sensory nerve to the spinal cord (transmission), where it may be modified in intensity (modulation): natural opioids such as enkephalins or endorphins before ascending the spinal cord and reaching the conscious areas of the brain (perception)

30. OPOIDS  Receptors  in the central nervous system (CNS) (both brain and spinal cord), gastrointestinal (GI) tract, urinary tract, and smooth muscle mu ( μ ) receptors: Nerves - brain and spinal cord: strong analgesia Antitussive SE: resp. depression, hypothermia kappa ( κ ) receptors: milder degree of analgesia than the μ stimulation has been suggested to partially inhibit some of the beneficial μ receptor effects, resulting in less analgesia delta ( δ ) receptors: not commonly used

31. OPIODS  most potent analgesics used in veterinary medicine  Pre/post surgery  Strong agonists: Morphine (standard: μ, κ, visceral and somatic pain), fentanyl ( μ ), hydromorphone ( μ, κ ): X5, meperidine ( μ )  Partial agonists: Butorphanol ( μ partial antagonist, κ agonist), buprenorphine ( μ partial agonist, κ antagonist)  Strong antagonists: Naloxone ( μ, κ )  Partial antagonists: Nalorphine ( μ partial antagonist, κ agonist)

32. Narcotics Chapter 8: pg 203 – 212 need to know in surgery X30 potent than morphine

33. OPOIDS - CONS  respiratory depression: breathe slow and accumulate CO2  Stronger μ receptor stimulating opioids (morphine, hydromorphone, fentanyl) > more profound resp. depression than the partial μ agonists (buprenorphine, butorphanol).  head trauma : vasodilator hence exceberates  Vomiting: CRTZ and emetic center  Bradycardia  Analgesia not anesthesia: sensitive to sound, light …  Cats: mydriasis (morphine mania: very sensitive to light)

34. References  Bill, R.L. Clinical Pharmacology and Therapeutics for the Veterinary Technician, 3 rd edition. 2006.  Romich, J.A. Pharmacology for Veterinary Technicians, 2 nd edition. 2010.  http://complementaryoncology.com/reports/breast -cancer/cox-2-expression-predicts-worse-breast- cancer-prognosis-and-does-not-modify-the- association-with-aspirin/