Anti-inflammatory

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Anti-inflammatory Pain-reducing drugs

• Chapter 13-2

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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

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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

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Selective COX-2 inhibitors

• 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 301
• Are analgesics and anti-inflammatories
• An example is tepoxalin (Zubrin),
• which is a rapidly disintegrating tablet used for
  osteoarthritis in dogs

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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 -gt Arachidonic acid -gt PG Cox 2 (pain,
  inflammation kidney function) Cox 2 stomach
  lining, kidney function, platelet fx.

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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.)

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Type of NSAIDs

• Indol acetic acid derivatives
• Inhibit cyclooxygenase (more selective for Cox-2)
• Is an analgesic and anti-inflammatory
• 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

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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
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Types of NSAIDs

• Used in equine medicine for musculoskeletal pain
• Phenylbutazone (bute) powder, paste,
  injectable
• Frequently used in equine medicine for
  musculoskeletal pain.

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NSAID PHENYLBUTAZONE - DA

• GI ulceration
• renal papillary necrosis (renal perfusion is
  dec.) gt 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

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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

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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

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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)

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NSAID - derivatives of propionic acid
carprofen
ibuprofen
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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
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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 anorexia, diarrhea, or changes in stool color
  (melena)
• Tolfedine K9/ Feline Antithromboxane (caution)

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NSAID - DMSO

• Dimethyl sulfoxide (DMSO)
• industrial solvent - wood pulp gt 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

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NSAID DMSO - CONS
smell of DMSO garlic / raw oysters

• 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 gt hemoglobinuria hence
  concentration below 20 for IV administration
• May not be safe in pregnant animals

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

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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
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Other Osteoarthritis Treatments

• 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
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Other Osteoarthritis Treatments

• 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)

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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

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OTHERS

• Orgotein Horses joint and vertebral dz.
• works as an enzyme, superoxide dismutase gt
  convert superoxide radicals into oxygen and
  hydrogen peroxide gt 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

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Antihistamines

• Antihistamines counteract the effect of histamine
  (histamine cause bronchoconstriction and
  inflammatory changes -gt 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

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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

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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)

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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 (?) 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 (d) receptors not commonly used

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OPIODS

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

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Narcotics Chapter 8 pg 203 212 need to know
in surgery
X30 potent than morphine
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OPOIDS - CONS

• respiratory depression breathe slow and
  accumulate CO2
• Stronger µ receptor stimulating opioids
  (morphine, hydromorphone, fentanyl) gt 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)

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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-ca
  ncer/cox-2-expression-predicts-worse-breast-cancer
  -prognosis-and-does-not-modify-the-association-wit
  h-aspirin/