ANTI-INFLAMMATORY & PAIN-REDUCING DRUGS

Chapter 13-2

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

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

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 An example is tepoxalin tepoxalin

(Zubrin®)(Zubrin®), which is a rapidly

disintegrating tablet used for osteoarthritis in dogs

Selective COX-2 inhibitors

Selective COX-2 inhibitors

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.

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.)

Type of NSAIDs Indol acetic acid

derivatives Inhibit

cyclooxygenase (more selective for Cox-2)

Is an analgesic and anti-inflammatory

An example is etodolac etodolac (Etogesic(Etogesic®®)), which has the benefit of once-a-day dosing Labeled for K9 Evaluate liver

enzymes Deramax is more

cox 2 selective

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

Types of NSAIDs

Used in equine medicine for musculoskeletal pain

Phenylbutazone (“bute”): powder, Phenylbutazone (“bute”): powder, paste, injectablepaste, injectableFrequently used in equine Frequently used in equine medicine for musculoskeletal medicine for musculoskeletal pain.pain.

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

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

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

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)

NSAID - derivatives of propionic acid

ibuprofen

carprofen

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

Types of NSAIDs Fenamates

Inhibit cyclooxygenase antiinflammatory/ analgesic

meclofenamic acid meclofenamic acid (Arquel®)(Arquel®)

Equine osteoarthritisEquine 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 Tolfedine®: K9/ Feline Antithromboxane (caution)Antithromboxane (caution)

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

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

• Chondroprotective agents• Polysulfated

glycosaminoglycans• Hyaluronic acid• Glucosamine• Chondroitin sulfate

(Cosequin)• Slow the process of

arthritis by supporting the joint cartilage

Other Osteoarthritis Treatments Polysulfated glycosaminoglycans – PSGAGsPolysulfated glycosaminoglycans – PSGAGs

mimic the components of the normal joint mimic the components of the normal joint cartilagecartilage

large and complex molecules in cartilage large and complex molecules in cartilage trap molecules of water and give cartilage trap molecules of water and give cartilage its springy characteristic and ability to its springy characteristic and ability to tolerate stressful shockstolerate stressful shocks

may inhibit or reduce activity of enzymes may inhibit or reduce activity of enzymes in the joint fluid that degrade cartilagein the joint fluid that degrade cartilage

Used in injured joints (either from trauma or surgical intervention) or hip dysplasia INJECTABLE

Other Osteoarthritis Treatments Hyaluronic acidHyaluronic 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

Other Osteoarthritis Treatments Glucosamine and chondroitin sulfateGlucosamine 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)

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 catA single extra-strength acetaminophen tablet (500 mg) can kill an average-size catDogs: (above 150 mg/kg) hepatic necrosis, weight loss, and icterus (jaundice)TX: acetylcysteine (Mucomyst) also for resp. infections

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

Antihistamines

Antihistamines counteract the effect of histamine (histamine cause bronchoconstriction and inflammatory changes -> edema and pain)

Antihistamines compete with histamine for receptor sites (H1 receptors constrict smooth muscles and H2 receptors increase gastric secretions)

H1 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

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

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)

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

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)

NarcoticsChapter 8: pg 203 – 212 need to know in surgery

X30 potent than morphine

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)

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.

http://complementaryoncology.com/reports/breast-cancer/cox-2-expression-predicts-worse-breast-cancer-prognosis-and-does-not-modify-the-association-with-aspirin/