University of duhok

college of veterinary medicine

Non-steroidal anti-inflammatory drugs

By
Jivan Q Ahmad
E-mail,jivan1425@hotmail.com

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs, usually abbreviated
to NSAIDs or NAIDs, are drugs with analgesic,
antipyretic and, in higher doses, with anti-inflammatory
effects . The term "non-steroidal" is used to distinguish
these drugs from steroids, which (among a broad range
of other effects) have a similar eicosanoid-depressing,
anti-inflammatory action. As analgesics, NSAIDs are
.unusual in that they are non-narcotic

NSAIDs are among the oldest and most widely used drugs in
human history. The ancient Greeks chewed the bark of willow
trees to alleviate pain and fever, but it was not until the 1800s
that the active ingredient in willow bark, salicin (which is
metabolized to salicylate), was isolated. At the end of the
nineteenth century, acetylsalicylic acid or aspirin was
synthesized and marketed for its anti-pyretic, antiinflammatory and analgesic properties. Soon after, compounds
with similar properties to aspirin were discovered and
collectively named non-steroidal anti-inflammatory drugs
(NSAIDs) to distinguish them from the anti-inflammatory
activity of glucocorticoids. The connection between NSAIDs
and the COX pathway was made in the early 1970s, when
John Vane proposed that NSAIDs mediate their antiinflammatory effects by inhibiting the enzymatic activity of
COX work for which he was subsequently awarded the Nobel
.Prize for physiology or medicine

: Mode of Action
Generally, the classification NSAID is applied to drugs that
inhibit one or more steps in the metabolism of arachidonic
acid (AA). NSAID act primarily to reduce the biosynthesis of
prostaglandins (PG) by inhibiting cyclooxygenase (COX). In
general, NSAID do not inhibit lipoxygenase (and hence
leukotriene) formation, or the formation of other inflammatory
mediators, although tepoxalin, a recently introduced NSAID
does inhibit lipoxygenase.

Traditional NSAIDs can be grouped into three classes

based on their inhibition of cox:

Class 1: simple, competitive reversible inhibitors that compete

with arachidonic acid for binding to the cox active
site.included in this class are ibuprofen, piroxican, sulindac
sulfide, flufenamate, mefenamic acid and naproxen.
Class 2: competitive, time dependent, reversible inhibitor that
bind to the cox active site in a first phase to form reversible
enzyme inhibitor complexthat if retained for sufficient time,
cause non covalent conformational changes in protein. This
class includes indumethacin, flubiprofen, meclofenamic acid
and diclofenac.
Class 3: competitive, time dependent, irreversible inhibitors
that form an enzyme inhibitor complex after a covalent
conformational change in the protein. Included in this class is
aspirin

Kinetics of NSAID (ADME)

Absorption: Since all NSAIDs are highly lipophilic substances,

Drug absorption after oral administration is generally rapid

and complete.
Distribution: The most significant aspect of NSAID distribution is
plasma protein binding.
Metabolism: Knowledge of the mechanism of action of NSAIDs, as
competitive inhibitors for arachidonic acid binding to COX, provides a
good tool to predict whether NSAID metabolites are active or not.

Metabolism and elimination is via hepatic conjugation with

glucoronic acid.
Excretion: small percentages of NSAIDs are excreted unchanged in urine. If
the drug is excreted unchanged, its rate of excretion is expected to increase
if the drug iscoadministered with agents that render the urine pH alkaline
such as the antacids aluminum hydroxide and milk of magnesia.

forms

By mouth, they come in tablets, capsules or medicines. This is

the most widely used form.
Some NSAIDs are available as injections. This form is used
for the pain after surgical operations and also is very effective
for the treatment of pain produced by kidney stones (renal
colic).
Suppositories are available. These are often used for post
operative pain and sometimes in chronic pain when the patient
is unable to take medication by mouth.
Creams, gels and foams to apply to the skin. These are not felt
to be as effective, but some people do get considerable relief
from their use.

Common types

Aspirin
carprofen
Diclofenac
Ketoprofen
Naproxen
Valdecoxib
Indomethacin
Ibuprofen

Aspirin
Acetylsalicylic Acid, Aspirin is a non-selective, irreversible COX
inhibitor.Aspirin was the first discovered member of the
non-steroidal anti-inflammatory drugs (NSAIDs) Often used as an
analgesic to relieve minor aches and pains, as an antipyretic to reduce fever
, and as an anti-inflammatory medication.

Mechanism of action/Effect:
The effectiveness of aspirin is largely due to its ability to inhibit
prostaglandin synthesis. This is done by irreversibly blocking
cyclooxygenase (prostaglandin synthase), which catalyzes the
conversion of arachidonic acid to endoperoxide compounds; at
appropriate doses, the drug decreases the formation of both the
prostaglandins and thromboxane A2 but not the leukotrienes.

Indications
There are three main indications:
Inflammation (treatment)1Dogs and cats: Aspirin
is used for the relief of inflammation associated with
arthritis and joint problems.
Pain (treatment)Cattle, dogs, pigs, and cats:
Aspirin is used for relief from mild to moderate
somatic pain, such as incisional pain following
surgery, pain following dental procedures, and
discomfort associated with cystitis.
Fever (treatment)Cattle, dogs, pigs, and cats:
Aspirin is used to reduce fever; however, the
treatment of fever with antipyretic medications is
controversial and specific therapy for the underlying
disease should be sought.

Drug Interactions
Drugs that alkalinize the urine (e.g., acetazolamide, sodium
bicarbonate) significantly increase the renal excretion of
salicylates. Because carbonic anhydrase inhibitors (e.g.,
acetazolamide, dichlorphenamide) may cause systemic
acidosis and increase CNS levels of salicylates, toxicity may
occur. Urinary acidifying drugs (methionine, ammonium
chloride, ascorbic acid) will decrease the urinary excretion of
salicylates. Furosemide may compete with the renal excretion
of aspirin and delay its excretion. This may cause symptoms of
toxicity in animals receiving high aspirin doses.

Side/Adverse Effects
The most common side effect of aspirin at therapeutic doses is
gastric or intestinal irritation with varying degrees of occult GI
blood loss occurring. The resultant irritation may lead to
vomiting and/or anorexia. Sever blood loss may result in
secondary anemia or hypoprotienemia.In dogs , plain un coated
aspirin may be more irritant to the gastric mucosa than either
enteric coated tablets or buffered aspirin. hypersensitivity
reaction have been reported in dogs, although they are thought
to occur rarely.
Salicylates are possible teratogenes and their use should be
avoided during pregnancy, particularly during later stages.
Vomiting and melena may be seen at higher doses. The PGE1
analog misoprostol may be effective in decreasing GI
ulceration associated with aspirin and other NSAID.
Aspirin overdose in any species can result in salicylate poisoning,
characterized by severe acid-base abnormalities, hemorrhage,
seizures, coma, and death.

Dosage
Recommended dosages
Dogs
For analgesia: 10-25 mg/kg PO Q8-12h
As anti-inflammatory/antirheumatic: 25 mg /kg PO q8h
For antipyrexia: 10 mg/kg PO bid
Cats
For analgesia and anti pyrexia: 10 mg/kg po q48h
For treatment of arthritis/antirheumatic/anti-inflammatory: 10-20 mg/kg po
q48h
Cattle
For analgesia/antipyrexia: 50-100 mg/kg po q12h
horses
For analgesia: 25 mg/kg po q12h initially then 10 mg/kg once daily
For laminitis: 5-10 mg/kg, PO q24-48h

CARPROFEN. 2
This NSAID of the arylpropionic acid class ,Carprofen
is approved to manage pain and inflammation
associated with osteoarthritis and acute pain
associated with soft-tissue and orthopedic surgery in
dogs.
In Europe and other countries, carprofen is also
registered for use in cattle and for short-term therapy
in cats. In dogs, oral bioavailability is high (90%) and
plasma concentrations peak ~2-3 hr after dosing. The
elimination half-life is ~8 hr. As with other NSAID,

mechanism of action
The exact mechanism of action of carprofen is unclear. Although
it has greater selectivity for COX-2 over COX-1, carprofen is
considered a weak COX inhibitor. In vitro canine cell line
assays indicate that it is 129-fold selective for COX-2,
whereas in vitro canine whole blood assays indicate it is 7- to
17-fold selective for COX-2, equine whole blood assays
indicate it is 1.6-fold selective for COX-2, and feline whole
blood assays indicate it is 5.5-fold selective for COX-2. Other
mechanisms of action, including inhibition of PA2 may be
responsible for its anti-inflammatory effects.

Indications
Carprofen has been used extensively in dogs since its introduction
nflammation (treatment); or Pain (treatment) Dogs:
Carprofen caplets, chewable tablets, and ELCANinjectionEL
are indicated in the control of inflammation and pain associated
with osteoarthritis.
Pain, postoperative (treatment)Dogs:chewable tabletsEL, and
injection are indicated in the control of postoperative pain
associated with soft tissue or orthopedic surgery.Preoperative
administration is recommended because it can be more effective
than postoperative administration alone in the
control of postoperative pain.
Inflammation (treatment); or Pain (treatment) Horses:
Although the safety and efficacy have not been established,
there is evidence to suggest that oral or parenteral carprofen can
be effective in the treatment of pain and inflammation in horses.

Side effects
Gastrointestinal effects (vomiting, diarrhea, constipation, inappetence,

melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding,

pancreatitis);
hepatic effects(inappetence, vomiting, jaundice, acute hepatic toxicity,
hepaticenzyme elevation, abnormal liver function tests,hyperbilirubinemia,
bilirubinuria, hypoalbuminemia);
neurologic effects(ataxia, paresis, paralysis, seizures, vestibular signs,
disorientation);
urinary effects (hematuria, polyuria, polydipsia, urinary incontinence,
urinary tract infection, azotemia, acute renal failure, tubular abnormalities,
including acute tubular necrosis, renal tubular necrosis, glucosuria,
glomerular disease, including glomerulonephritis);
behavioral effects(Sedation, lethargy, hyperactivity, restlessness,
aggressiveness);
hematologic effects(immune-mediated hemolytic anemia, immunemediated Thrombocytopenia, blood loss anemia, epistaxis);
dermatologic effects(pruritis, increased shedding, alopecia, pyotraumatic
moist dermatitis, necrotizing panniculitis/vasculitis, ventral ecchymosis);
immunologic effects or hypersensitivity (facial swelling, hives, erythema

Dosage
Dogs:
As anti-inflammatory/analgesic: 2.2mg/kg po twice
daily
For surgical pain: 4mg/kg iv once
Cats:
For surgical pain: 4mg/kg iv once
Horses:
As anti-inflammatory/analgesic: 0.7mg/kg iiv one
time

Diclofenac. 3
Diclofenac(voltaren)(2[(2,6-diclorophenyl)amino]phenylacetate)
is relatively non selective cox inhibitor. used to reduce
inflammation and as an analgesic reducing pain in conditions
such as arthritis or acute injury. It can also be used to reduce
menstrual pain, dysmenorrhea.
Mechanism of action
The exact mechanism of action is not entirely known, but it is
thought that the primary mechanism responsible for its
anti-inflammatory / antipyretic / analgesic action is inhibition
of prostaglandin synthesis by inhibition of cyclooxygenase
(COX).

Indications

musculoskeletal complaints, especially arthritis

gout attacks
pain management in case of kidney stones and gallstones.
acute migraines
menstrual pain
post-operative or post-traumatic pain
Dc liposomal cream is used safely and effectively for
symptomatic treatment of joint-associated lameness in horses
It's also found very effectively in the treatment of clinical
cases of myositis and arthritis in cattle and buffaloes.
Dc in rectal suppository form is a drug of choice for
preemptive analgesia.
Ophthalmic preparation of Dc is used for prevention of
postoperative ophthalmic inflammation

Side effects

in human include gastrointestinal distress, occult

gastrointestinal bleeding, and gastric ulceration. Dc at dosage
of l50mg\day appears to impair renal blood flow and
glomerular filtration rate.
In veterinary practice, Dc is reported to produce gastric ulcer
and mild nephropathy. Hypersensitivity to Dc was also
reported in calves .

Dipyrone
Dipyrone (metamizole). The mechanism of action of dipyrone is
thought to be similar to that of other NSAIDs: inhibition of
the production of prostaglandins. It is commonly used in the
horse as an antipyretic, analgesic, and anti-inflammatory.
Dipyrone is a very mild NSAID. Because of its very mild analgesic
properties it is unlikely to mask abdominal pain due to a surgical
problem. Traditionally, dipyrone has been thought to also have
anti-spasmodic properties on the smooth muscle of the gastrointestinal tract, which has been the basis for its common use in
cases of mild colic. Although research evidence does not
support any claim of anti-spasmodic activity, many clinicians
consider it a very useful drug precisely for this reason. Flunixin
meglumine is a NSAID with stronger analgesic properties that is
also used to treat GI pain.
Dipyrone may be used in foals and in adult horses to reduce fevers.
It is not commonly used for the treatment of musculoskeletal
pain. Dipyrone may be given IM, IV, or subcutaneously.

Side Effects
The most common side effect for dipyrone is injection site
reactions. These reactions usually respond to hot compresses
and NSAIDs.
Prolonged use of dipyrone may cause bone marrow suppression
(leukopenia, agranulocytosis). Animals receiving prolonged
courses of dipyrone should be followed with regular CBCs.

Ketoprofen
Ketoprofen is propionic acid derivative available as a 10%
injectable solution for horses, and as tablets and a 1%
injectable solution for dogs and cats.
Ketoprofen is a potent inhibitor of COX and bradykinin and may
also inhibit some lipoxygenases. Its efficacy is comparable to
that of opioids in the management of pain following
orthopedic and soft-tissue surgery in dogs. Following
administration PO, ketoprofen is rapidly absorbed and has a
terminal half-life in cats and dogs of 2-3 hr. As with other
NSAID, ketoprofen is metabolized in the liver to inactive
metabolites that are eliminated by renal excretion.
Ketoprofen is recommended for acute pain (up to 5 days) in both
dogs and cats. In horses, it is used for pain and inflammation
associated with osteoarthritis and for visceral pain associated
with colic.

Adverse effects
Adverse effects, including GI upset, are similar to those of other
NSAID. Other side effects, including hepatopathies and renal
disease, have been reported in animals. Due to potential
antiplatelet effects, care should be exercised when using
ketoprofen perioperatively

References

Dr. Miriam I. Yasin , The effectiveness of antibiotic, nsaids and glycerol

in reducing post operative complications of rumonatomy in sheep's,
Susan E. Aielo, B.S.,E.l.S ,The Merck Veterinary Manual .
Donald C. Plumb, Veterinary drug hand book,
Forth edition, 2002
Charles E.OPhardt ,Virtual chembook, Elmhurst college,, c.2003
(VeterinarySystemic), The United States Pharmacopeial Convention
Wedge wood Pharmacy
http://www.wedgewoodpharmacy.com/monographs/dipyrone.asp
Wikipedia, the free encyclopedia.
http://www.drugs.com/vet/dipyrone-50-can.html