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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/