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PHARMACOLOGY OF

NONSTEROIDAL ANTINFLAMMATORY DRUGS (NSAIDS)

ANALGESICS

• Newer drugs being introduced and the development of new modalities of pain control particularly in companion animal species

• Analgesic therapy is best initiated before surgery or as soon as possible in the case of trauma or postoperatively.

Analgesics: Pharmacological agents

• OPIOIDS • NON STEROIDAL ANTI-INFLAMMATORY DRUGS

(NSAIDS) • CORTICOSTEROIDS( STEROIDAL ANTIINFLAMMATORY) • LOCAL ANAESTHETICS • Αlpha 2-AGONISTS • KETAMINE, GABAPENTIN ETC.

Pharmacological agents

Different sites of action

Combined therapy

Dose of each individual drug to be reduced.

The most commonly used class of analgesics in domestic animals are opioids (narcotic analgesics) and NSAIDs (non narcotic analgesics)

NSAIDS INTRODUCTION

Over The Counter (OTC) Analgesics/ Pain Killers

Aspirin-like drugs/ Non narcotic analgesics

provide symptomatic relief from pain and swelling in chronic joint disease such as occurs in osteo- and rheumatoid arthritis, and in more acute inflammatory conditions such as sports injuries, fractures, sprains and other soft tissue injuries

Virtually all NSAIDs, particularly the 'classic' NSAIDs, can have significant unwanted effects

Newer agents have fewer adverse actions ???

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

• Most widely prescribed /OTC drugs in the treatment of pain and inflammation in many conditions(musculoskeletal).

THE ADVANTAGES OVER OPIOIDS/DIFFERENCES

OTC Drugs

No immunosuppressive and metabolic side effects associated with corticosteroids.

Devoid of sedation, hypotension, bradycardia and respiratory depression

Long acting analgesia for mild to moderately painful conditions,

Analgesic, Antipyretic and Antiinflammatory actions

Not controlled substances / schedule drugs DRAWBACKS

Potencywise : lesser than opioids .with their effect on visceral pain considered to be poor.

Other potential adverse effcets: gastric, hepatic and renal

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MECHANISM OF ACTION

• Inhibition of cyclo-oxygenase (COX) enzyme(s) which leads to a decrease in the synthesis of various prostaglandins and thromboxanes (COX inhibitor- Non Selective and Selective/Preferential COX2 inhibitor)

• May also inhibit phospholipase A enzyme; major mechanism for effects of glucocorticoids on prostaglandin production.

• Few agents like ketoprofen, tepoxalin, licofelone inhibit lipooxygenase enzyme involved in leukotrienes synthesis, in addition to cyclooxygenase inhibition (DUAL COX-LOX inhibitor)

NSAIDS.. contd

Tissue membrane injury Pathway

COX-3 Arachadonic Acid

COX-1 COX-2

Prostaglandins

PGE2,PGI2,TXA2

GI Protection

Renal Blood Flow

Platelet Function

Prostaglandins

PGD2,E2,F2

Inflammation & Pain

Renal Blood Flow

GI Protection

LOX

Leukotrienes

LTB4,C4,D4

Inflammation

GI Ulceration

Prostacyclin

s

Vasodilation

Platelet Autonomy

Membrane Phospholipid

Phospholipase A2

GLUCOCORTICODS

NSAIDS

MOA

• The principal therapeutic effects of NSAIDs derive from their ability to inhibit prostaglandin production.

• The first enzyme in the prostaglandin synthetic pathway is prostaglandin G/H synthase, also known as cyclooxygenase or COX.

• This enzyme converts arachidonic acid (AA) to the unstable intermediates PGG2 and PGH2 and leads to the production of thromboxane A2 (TXA2) and a variety of

prostaglandins

• There are two forms of cyclooxygenase, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).

• "COX-3.“ is a Splice variants of COX 1

• COX-1 is a primarily constitutive isoform found in most normal cells and tissues

• Cytokines and inflammatory mediators that accompany inflammation induce COX-2 production

• However, COX-2 also is constitutively expressed in certain areas of kidney and brain and is induced in endothelial cells by laminar shear forces

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MOA

• Importantly, COX-1, is expressed as the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation

• Inhibition of COX-1 at this site is thought to account largely for the gastric adverse events that complicate therapy with NSAIDs

• Aspirin and NSAIDs inhibit the COX enzymes and prostaglandin production; they do not inhibit the lipoxygenase pathways of AA metabolism and hence do not suppress LT formation

COX-1 (Constitutive)

Virtually all tissues of the body

Catalyzes the formation of constitutive PG, which mediate a variety of normal physiologic effects including hemostasis, GI mucosal protection, and protection of the kidney from hypotensive insult.

COX-2 (Inducible)

Activated in damaged and inflamed tissues and catalyzes the formation of inducible PG, including PGE2, associated with intensifying the inflammatory response

Involved in thermoregulation and the pain response to injury.

COX-3

In brain, involved with central pain relief and thermoregulation

NSAIDS.. contd

Classification

• NONSELECTIVE COX INHIBITORS • inhibit both COX isoforms- COX 1 and COX 2

• SELECTIVE (COXIBS) /PREFERENTIAL COX 2 inhibitors

– inhibit COX 2 selectively/preferantially

• COX 3 INHIBITOR

– inhibit COX 3 isoform in brain

COX-2

inhibitors • Selective (coxibs)

• Preferential

COX-3

inhibitors •Antipyretic

analgesics

Nonselective

COX-1/COX-2

inhibitors NSAIDs

COX inhibitors Salicylic acid derivaties

o Aspirin ( Acetyl salicylic acid)-Prototype

o Sodium salicylate

oCholine megnesium trisalicylate

Diflunisal

Sulfasalazine

Olsalazine

Choline

Indole and indene acetic acid

Sulindac, indomethacin, etodolac

Arylpropionic acid derivatives/

Propionates

Ibuprofen, Naproxen

Flurbiprofen, Ketoprofenn,

Fenoprofen, Oxaprofen

Vedaprofen (COX 2)

Heteroaryl acetic acids

Tolmetin, Diclofenac

Ketorolac, eltenac

Anthranilic acids(fenamates)

.Mefenamic acid. Tolfenamic acid

.Meclofenamic acid, flufenamic

Enolicacid / Enolates (Oxicams)

Piroxicam, Piroxicam beta-cyclodextrin

(prodrug), Lornoxicam, Tenoxicam

Meloxicam (COX 2 inhibitor)

Alkanones

Nabumetone (COX 2 inhibtr)

Phenylacetates: Acelcofenac, Diclofenac

Pyrazolones: Phenazone, metamizole

(Analgin) Propyphenazone, etc.

Pyrazolidinediones: Oxyphenbutazone,

Phenylbutazone

NONSELECTIVE COX INHIBITORS

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Structurally

Diaryl-substitited furonones

Rofecoxib (COX 2 inhibitor)

Diaryl-substituted pyrazoles

Celecoxib (COX 2 inhibitor)

Indole acetic acids

Etodolac (COX 2 inhibitor)

Sulfonalides

Nimesulide (COX 2 inhibitor)

SELECTIVE COX-2 inhibitors

Selective COX-2 inhibitors (COXIBS)

• Celecoxib, firacoxib

• Etoricoxib, deracoxib, lumiracoxib

• Parecoxib, rofecoxib, valdecoxib

PREFERENTIAL COX-2 INHIBITORS • Meloxicam, vedaprofen

• Nimesulide, Aceclofenac

• Nabumetone, Etodolac

COX 3 INHIBITOR

• Paracetamol, phenacetin

• Acetanilid

DUAL COX-LOX inhibitor • ketoprofen, tepoxalin, licofelone

Agents with poor Anti inflammatory activity (Primarily only Antipyretic and Analgesic)

• Paracetamol

• Phenacetin

• Acetanilid

• Metamizole(analgin)

• Nefopam

• Most are nonselective COX inhibitors, with COX 1 inhibition ratio being highest

• Meloxicam, nimesulide, etodolac and aceclofenac are considered as preferential COX-2 inhibitors.

• The newer ‘Coxib’ class of selective COX-2 inhibitors includes rofecoxib, celecoxib, valdecoxib, parecoxib, deracoxicb, etoricoxib, firocoxib, lumiracoxib

• Paracetamol (acetaminophen) is a selective COX-3 inhibitor with only analgesic and antipyretic actions, devoid of anti-inflammatory action

NSAIDS.. contd

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General characteristics of NSAIDS

• weak organic acids

• AI, AP, Analgesic primarily + antiplatelet, uricosuric-difference in activities

• Symptomatic relief only

• effective in pain of low to moderate intensity - musculoskeletal

• interspecies differences in dosage and effects

• Except salicylates, many show PPB – drug interactions

• Metablism in liver

• Penetrate BBB

• No tolereance, dependance, respiratory, CNS depression unlike opioids

PHARMACOLOGICAL EFFECTS

• All the NSAIDs have actions very similar to those of ASPIRIN

• Three main therapeutic effects are:

• AN ANTI-INFLAMMATORY EFFECT: modification of the inflammatory reaction ;

• AN ANALGESIC EFFECT: reduction of certain types of (especially inflammatory) pain and

• AN ANTIPYRETIC effect: lowering of body temperature when this is raised in disease (i.e. fever).

• Antiplatelet and uricosuric action

All the NSAIDs share, to a greater or lesser degree, the same types of mechanism-based SIDE EFFECTS.

• GASTRIC IRRITATION, which may range from simple discomfort to ulcer formation

• An effect on RENAL BLOOD FLOW in the compromised kidney

• A tendency TO PROLONG BLEEDING through inhibition of platelet function

• Controversially, it is argued that they may also all-but especially COX-2 selective drugs-increase the likelihood of thrombotic events such as myocardial infarction by inhibiting prostaglandin (PG) I2 synthesis.

PAIN

• NSAIDs are particularly effective when inflammation has caused sensitization of

pain receptors to normally painless mechanical or chemical stimuli

• Pain that accompanies inflammation and tissue injury probably results from local

stimulation of pain fibers and enhanced pain sensitivity (hyperalgesia), in part a

consequence of increased excitability of central neurons in the spinal cord

• Bradykinin, released from plasma kininogen, and cytokines, such as TNF-a, IL-1,

and IL-8, appear to be particularly important in eliciting the pain of inflammation

• These agents liberate prostaglandins and probably other mediators that promote

hyperalgesia

• Neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP),

also may be involved in eliciting pain

Analgesic.. • these drugs usually are effective only against pain of low-to-

moderate intensity

• Although their maximal efficacy is generally much less than the opioids, NSAIDs lack the unwanted adverse effects of opiates in the CNS, including respiratory depression and the development of physical dependence

• NSAIDs do not change the perception of sensory modalities other than pain

• Chronic postoperative pain or pain arising from inflammation is controlled particularly well by NSAIDs, whereas pain arising from the hollow viscera usually is not relieved

• Regulation of body temperature requires a delicate balance

between the production and loss of heat

• Hypothalamus – Thermoregulatory Centre- regulates the set point

at which body temperature is maintained

• This set point is elevated in fever, and NSAIDs promote its return

to normal

• These drugs do not influence body temperature when it is

elevated by factors such as exercise or in response to ambient

temperature

FEVER • Fever may reflect infection or result from tissue damage,

inflammation, graft rejection, or malignancy

These conditions all enhance formation of cytokines such as IL-

1b, IL-6, interferons, and TNF-a(Pyrogens)

The cytokines increase synthesis of PGE2 in circumventricular

organs in and adjacent to the preoptic hypothalamic area

PGE2, in turn, increases cyclic AMP and triggers the

hypothalamus to elevate body temperature by promoting an

increase in heat generation and a decrease in heat loss

NSAIDS inhibit fever caused by agents that enhance the

synthesis of IL-1 and other cytokines, which presumably cause

fever, at least in part, by inducing the endogenous synthesis of

prostaglandins

FEVER

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Antipyretic..

• NSAIDs reduce fever in most situations, but not the circadian variation in temperature or the rise in response to exercise or increased ambient temperature

• Comparative analysis of the impact of NSAIDs and selective COX-2 inhibitors suggests that COX-2 is the dominant source of prostaglandins that mediate the rise in temperature evoked by bacterial LPS administration

• This is consistent with the antipyretic clinical efficacy of both subclasses of NSAIDs

Anti-inflammatory.. Mainly in the treatment of musculoskeletal disorders, such as

rheumatoid arthritis and osteoarthritis

• The NSAIDs reduce mainly those components of the inflammatory and immune response in which prostaglandins, mainly derived from COX-2, play a significant part.

• These include: vasodilatation, oedema (by an indirect action: the vasodilatation facilitates and potentiates the action of mediators such as histamine that increase the permeability of postcapillary venules, pain , again potentiating other mediators, such as bradykinin.

Antiinflammatory … • The NSAIDs suppress the pain, swelling and increased blood flow

associated with inflammation but have little or no action on the actual progress of the underlying chronic disease itself

• As a class, they are generally without effect on other aspects of inflammation, such as leucocyte migration, lysosomal enzyme release and toxic oxygen radical production, that contribute to tissue damage in chronic inflammatory conditions such as rheumatoid arthritis, vasculitis and nephritis. – Anti-inflammatory effects may inhibit antibody production. – potential to cause gastric ulceration.

In general, NSAIDs provide only symptomatic relief from pain and inflammation associated with the disease, do not arrest the progression of pathological injury to tissue

Pharmacological Effects – Antipyretic, analgesic, and anti-inflammatory properties.

( acetaminophen: no antiinflammatory) – Less potent analgesics than opioids – Potent antithrombotic / antiplatelet( by TXA2 inhibition) and

antiendotoxic poroprties (few)

– Reduce the effect of endotoxaemia by inhibiting the production of eicosanoids and thromboxanes, which are responsible for many of the clinical manifestations of endotoxaemia such as changes in cardiovascular output (vasoconstriction, followed by vasodilation), and renal blood flow, fever, ileus, leucopenia and a tendency to develop coagulaopathies.

– It is most common secondary to ischemic gastrointestinal injury or metritis.

– Flunixin, phenyl butazone, ketoprofen and meloxicam are the most effective in endotoxaemia

NSAIDS.. contd

– inhibits platelet aggregation by inhibiting thromboxanes

synthesis

– Has been prophylactically used for prevention or reoccurrence

of heart attack (leading to myocardial infarction) or stroke in

humans resulting from thrombosis.

– Chondrotoxic as they inhibit the synthesis of cartilage

proteoglycans (aspirin, naproxen, and ibuprofen)

– Carprofen and meloxicam, are considered chondroneutral, or

depending on dose, actually stimulate the production of

cartilage matrix

NSAIDS.. contd

Haematological - ANTIPLATELET EFFECTS (WITH ASPIRIN)

• Aspirin irreversibly inhibits platelet COX, so that aspirin's antiplatelet effect lasts 8–10 days (the life of the platelet)

• prolonged clotting time, increased tendency for bleeding

• Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting

Effect on Respiration: triphasic

1. Low doses: uncoupling phosphorylation → ↑ CO2 → stimulates respiration.

2. Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal compensation

3. Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also

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Metabolic (Mostly with Aspirin)

1. Uncoupling of Oxid. Phosphorylation

2. Hyperglycemia, glycosuria, and depletion of muscle and hepatic glycogen

3. enhanced protein catabolism

4. increase urate excretion at normal doses, butt reduce at lower doses

5. reduces plasma free fattya cid and cholesterol levels

• Renal effects

• PGE2 and PGI2- involved in maintaining renal blood flow

• Inhibition of synthesis leads to- sodium and water retention, oedema, hyperkalemia

Endocrine:

• Release epinephrine from adr. Medulla

• stimulate ACTH secretion from ant. pituitary

COX-2 SELECTIVE INHIBITORS (COXIBS) EFFECTS

• Developed in an attempt to inhibit prostaglandin synthesis by

the COX-2 isoenzyme induced at sites of inflammation

without affecting the action of the constitutively active

"housekeeping" COX-1 isoenzyme found in the

gastrointestinal tract, kidneys, and platelets.

• COXibs selectively bind to and block the active site of the COX-

2 enzyme much more effectively than that of COX-1.

• COX-2 inhibitors have analgesic, antipyretic, and anti-

inflammatory effects similar to those of nonselective NSAIDs

but with an approximate halving of gastrointestinal adverse

effects.

COX 2 inhibitors(COXIBS)

• COX-2 inhibitors at usual doses have been shown to have no impact on platelet aggregation, which is mediated by the COX-1 isoenzyme.

• As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs, which has resulted in some patients taking low-dose aspirin in addition to a coxib regimen to maintain this effect.

• COX-2 is constitutively active within the kidney, recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs.

• Clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in their withdrawal from the market

PHARMACOKINETICS

• Food impair the oral absorption of NSAID in horses and ruminants.

• Formulations cause tissue necrosis if injected perivascularly.

• Biotransformed in the liver to inactive metabolites that are excreted by

the kidney

• Half-lives vary significantly by species (and in some cases by breed)

• Cats tend to be deficient in certain families of glucuronyl transferases

that are important for glucuronidation.

• As a result, drugs that are excreted as glucuronide conjugates such as

aspirin, paracetamol (acetaminophen) may have a prolonged half-

life in cats, increasing the risk of toxicity due to drug accumulation

Pharmacokinetics and Pharmacodynamics

• Most of the NSAIDs are rapidly and completely absorbed from the gastrointestinal tract

• peak concentrations occurring within 1 to 4 hours.

• Aspirin begins to acetylate platelets within minutes of reaching the presystemic circulation

• The presence of food tends to delay absorption without affecting peak concentration

• Most NSAIDs are extensively protein-bound (95% to 99%)

• Undergo hepatic metabolism and renal excretion

• In general, NSAIDs are not recommended in the setting of advanced hepatic or renal disease due to their adverse pharmacodynamic effects

Comparative action between

COX inhibitors

COX-1/COX-2

inhibitors

COX-2

Inhibitors

1. Analgesic action + + +

2. Antipyretic action + +

3. Antiinflammatory action + + +

4. Antiplatelet aggregatory + ----

5. Gastric mucosal damage + + + +

6. Renal salt / water retention + +

7. Delay/prolongation of labor

8. Infertility

+ +

----

+

+ +

9. Ductus arteriosus closure + ?

10. Aspirin-like asthma

11. Cardiotoxicity

+

----

?

+ +

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Indications

• Pain resulting from musculoskeletal injury either due to trauma or surgery

• As adjunctive therapy to antimicrobial treatment in acute respiratory diseases in cattle.

• Antiendotoxic to reduce endotoxaemia( eg: flunixin, phenyl butazone)

• Antithrombotic (eg: aspirin) to prevent thrombosis.

NSAIDS.. contd

Effective and well- tolerated analgesics in cats

Meloxicam, ketoprofen, carprofen, flunixin, piroxicam and tepoxalin for short-term treatment (five days)

Drug Interactions

• Combination therapy- either tNSAIDs or COX-2 inhibitors with "cardioprotective" low-dose aspirin- increases significantly the gastrointestinal adverse events over either class of NSAID alone

• NSAIDs might attenuate the effectiveness of ACE inhibitors

• NSAIDs may increase the frequency or severity of gastrointestinal ulceration when combined with corticosteroids

• Augment the risk of bleeding in patients receiving warfarin

• Many NSAIDs are highly bound to plasma proteins and thus may displace other drugs from their binding sites

Drugs Result

Diuretics Decrease diuresis

Beta-blockers Decrease antihypertensive effect

ACE inhibitors Decrease antihypertensive effect

Anticoagulants Increase of GI bleeding

Sulfonylurea Increase hypoglycemic risk

Cyclosporine Increase nephrotoxicity

GCS Increase of GI bleeding

Alcohol Increase of GI bleeding

Drug interactions with NSAIDs

SIDE /ADVERSE EFFECTS

• Injections- Cellulitis, thrombophlebitis and tissue necrosis

• Gastric irritation, ulceration, erosion, perforation and bleeding

• Renal toxicity – ARF and CRF

• Haematological effects : Bleeding, thrombocytopenia, haemolytic anaemia and agranulocytosis

• Hepatotoxicity- Liver damage

• CNS (behavioural disturbances, seizure precipitaion)

• Skin (rashes, pruritus) manifestations

NSAIDS.. contd

Mechanisms by which NSAIDs may induce mucosal injury

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Cardiovascular

• Selective inhibitors of COX-2 depress PGI2 formation by endothelial cells without concomitant inhibition of platelet thromboxane

• PGI2 restrains the cardiovascular effects of TXA2, affording a mechanism by which selective inhibitors might increase the risk of thrombosis

• Placebo-controlled trials have now revealed an increased incidence of myocardial infarction and stroke in patients treated with rofecoxib, valdecoxib and celecoxib consistent with a mechanism-based cardiovascular hazard for the class

• Patients at increased risk of cardiovascular disease or thrombosis are particularly prone to cardiovascular adverse events on these agents

Blood Pressure, Renal, and Renovascular

Adverse Events

• NSAIDs have little effect on renal function or blood pressure

in normal human subjects

• However, in patients with congestive heart failure, hepatic

cirrhosis, chronic kidney disease, hypovolemia, and other

states of activation of the sympathoadrenal or renin-

angiotensin systems, prostaglandin formation becomes crucial

in model systems and in humans

• NSAIDs are associated with loss of the prostaglandin-induced

inhibition of both the reabsorption of Cl- and the action of

antidiuretic hormone, leading to the retention of salt and water

•CONTD..

•NSAIDs promote reabsorption of K+ as a result of decreased

availability of Na+ at distal tubular sites and suppression of the

prostaglandin-induced secretion of renin

•Deletion of receptors for both PGI2 and PGE2 elevate blood

pressure , mechanistically integrating hypertension with a

predisposition to thrombosis

•Although this hypothesis has never been addressed directly,

epidemiological studies suggest hypertensive complications

occur more commonly in patients treated with coxibs than with

tNSAIDs

Analgesic Nephropathy

Analgesic nephropathy is a condition of slowly progressive renal failure, decreased concentrating capacity of the renal tubule, and sterile pyuria

Risk factors are the chronic use of high doses of combinations of NSAIDs and frequent urinary tract infections

If recognized early, discontinuation of NSAIDs permits recovery of renal function

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Pregnancy and Lactation

•In the hours before parturition, there is induction of

myometrial COX-2 expression, and levels of prostaglandin E2

and F2a increase markedly in the myometrium during labor

•Prolongation of gestation by NSAIDs has been demonstrated

in model systems and in humans

•Some NSAIDs, particularly indomethacin, have been used off-

label to terminate preterm labor

•However, this use is associated with closure of the ductus

arteriosus and impaired fetal circulation in utero, particularly in

fetuses older than 32 weeks' gestation

• COX-2-selective inhibitors have been used as tocolytic agents;

this use has been associated with stenosis of the ductus

arteriosus and oligohydramnios

• Finally, the use of NSAIDs and aspirin late in pregnancy may

increase the risk of postpartum hemorrhage

• Therefore pregnancy, especially close to term, is a relative

contraindication to the use of all NSAIDs, and their use must

be weighed against potential fetal risk, even in cases of

premature labor, and especially in cases of pregnancy-induced

hypertension, where they have been used with questionable

effect

Hypersensitivity.

• vasomotor rhinitis

• angioedema

• generalized urticaria

• bronchial asthma

• laryngeal edema

• bronchoconstriction

• flushing

• hypotension

• shock

Treatment of aspirin hypersensitivity is similar to that of other

severe hypersensitivity reactions, with support of vital organ

function and administration of epinephrine

Aspirin Resistance

• All forms of treatment failure with aspirin have been

collectively called "aspirin resistance"

• Although this has attracted much attention, there is little

information concerning the prevalence of a stable, aspirin-

specific resistance or the precise mechanisms that might

convey this "resistance"

• Genetic variants of COX-1 that cosegregate with

resistance have been described, but the relation to clinical

outcome is not clear

PREDISPOSING FACTORS FOR ADVERSE EFFECTS

• Concurrent corticosteroid treatment

• Dehydration

• Hypovolaemic/post traumatic shock

• Disruption to normal gut blood flow

• Empty stomch

• Pre-existing renal insufficiency

• Aged animals pose additional risk

NSAIDS.. contd

Discontinue NSAID therapy if

• Decrease or increase in appetite or thirst

• Vomiting

• diarrhea or black, tarry or bloody stools

• Lethargy

• Seizure

• Aggression or confusion

• Jaundice (yellowing of skin, gums or eyes)

• Change in urinary habits (frequency, color or smell), red, itchy skin

NSAIDS.. contd

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CONTRAINDICATIONS

• In animals suffering from gastrointestinal ulceration or

bleeding

• Blood dyscrasia.

• Cardiac, hepatic or renal impairment (insufficiency)

• Dehydraion,, hypovolaemia or hypotension

• Concurrent use of potentially nephrotoxic drugs (eg:

aminoglycosides, diuretics, )

• Not advisable in in pregnant animals and animals nearing the

oestrus as COX-2 induction is necessary for ovulation and

implanation of the embryo.

• Found to delay the parturition, if used nearing term.

• The dose or the duration not to be exceeded longer

NSAIDS.. contd

Agents used for preventing/healing the gastric ulceration effects due to NSAID use(chronic/high

dose)

• H2 receptor antagonists (eg: ranitidine)

• Proton pump inhibitors (eg: omeprazole)

• Cytoprotective drugs (eg: PGE1 anlog-misoprostol)

• Ulcer healing drug- suclralfate

NSAIDS.. contd

Pathophysiologic events in a gouty joint Synoviocytes phagocytose urate crystals and then secrete

inflammatory mediators, which attract and activate polymor-

phonuclear leukocytes (PMN) and mononuclear phagocytes

(MNP) (macrophages). Drugs active in gout inhibit crystal

phagocytosis and polymorphonuclear leukocyte and macro-

phage release of inflammatory mediators.

(PG – prostaglandin; IL-1 – interleukin-1; LTB4 – leukotriene B4)

GOUT

DRUGS IN GOUT

(1) Acute goat Colchicine

Diclofenac, Indometacin,

Naproxen, Phenylbutazone, Piroxiam

(2) Chronic gout Uricostatics (xantine oxidase inhibitors)

Allopurinol, Febuxostat

Uricosurics

Benzbromarone, Probenecide

Sulfinpyrazone

Uricolytics: Uricase, Rasburicase

Drug combinations

(allopurinol & benzbromarone)

INDIVIDUAL NSAIDS

NONSELECTIVE COX-INHIBITORS

AGENTS WITH ANALGESIC AND MARKED ANTI-INFLAMMATORY ACTIVITY

1.Salicylic Acid Derivatives/Salicylates

Aspirin(Acetylsalicylic acid; ASA)

one of the most extensively used over-the-counter drugs

first developed in 1899

occurs as a white crystalline substance

stable in dry air but hydrolyses to salicylic acid and acetic acid in moist air.

slightly soluble in water and freely soluble in alcohol

Salicylism- overdose/toxicity

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ASPIRIN (Acetyl Salicylic acid )

• Relief of mild to moderate pain associated with musculoskeletal inflammation or osteoarthritis.

• No definitive efficacy studies in animals

• In cats, used for its anti-platelet effects in thromboembolic disease, every 48 hr, to allow for prolonged metabolism.

• May induce mucosal erosion and ulceration in dogs

• Vomiting and melena may be seen at higher doses

• Overdose can result in salicylate poisoning, characterized by severe acid-base abnormalities, hemorrhage, seizures, coma, and death

TREATMENT:

• Treatment of aspirin over dosage is symptomatic and

supportive

• Acidosis,! treatment and forced alkaline diuresis with sodium

bicarbonate should be performed for serious ingestion.

• Most important part of treatment is external cooling and IV

fluids with Na+, K+, HC03" and glucose

• Treatment of aspirin induced GI lesions includes the H2-

receptor antagonists (e.g., ranitidine), the PGE1 analogues

(e.g., misoprostol) or the proton Bump inhibitor omeprazole

Sodium Salicylate

• Used mainly as analgesic, antipyretic and antirheumatic drug

• Occasionally, it is used as a uricosuric drug.

• Dose

• Dogs: 10 mg/kg, IV, 2 times daily.

• Horses: 35 mg/kg, iv; 4 times daily

Salicylic Acid

• It is used externally mainly in combination with benzoic acid

in ointments and alcoholic solutions for their antifungal action

Other Salicylic Acid Derivatives

•Sodium thiosalicylate

•Choline salicylate

•Magnesium salicylate

•Methyl salicylate (oil of wintergreen)

•Calcium carbaspirin

•Salsalate (salicylsalicylic acid)

•Salol (phenyl salicylate)

•Benorylate (ester of aspirin and paracetamol) •Salicylamide

Metabolism of Aspirin

ACETANILIDE AND PHENACETIN

• (acetophenetidin) are aniline (a dye) derivatives and

chemically related to paracetamol

• Acetanilide in addition forms aniline as a metabolite, which

is highly toxic and readily converts haemoglobin into

methaemoglobin

• Phenacetin, once incorporated in the well-known APC

(aspirin, phenacetin and caffeine) tablet, has been associated

with high incidence of necrosis of renal papilla in man and is,

therefore, not freely available

• Both acetanilide and phenacetin are now banned in many

countries including India and are not used in therapeutics

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Paracetamol (ACETAMINOPHEN)

• Little ulcerogenic potential • No effect on platelets or bleeding time. • More effective in inhibiting COX-3, in the

brain rather than in the periphery. • Dose-dependent adverse effects include

depression, vomiting, and methemoglobinemia

• Use in cats is contraindicated due to a lack of glucuronosyl transferase and the potential for hemolytic anemia and centrilobular hepatic necrosis.

• N-acetyl cysteine- antidote

Paracetamol (ACETAMINOPHEN)

• Present in many OTC pain and cold remedies • Although equivalent to Aspirin as an effective analgesic and

antipyretic agent, paracetamol differs in that it lacks antiinflam- matory properties.

• It does not affect uric acid levels and lacks platelet-inhibiting properties.

• Useful in mild to moderate pain: headache, myalgia, postpartum pain.

• Alone is inadequate therapy for inflammatory conditions such as rheumatoid arthritis, although it may be used as an analgesic adjunct to antiinflammatory therapy.

• For mild analgesia, paracetamol is the preferred drug in patients allergic to Aspirin or when salicylates are poorly tolerated.

• It is preferable to Aspirin in patients with hemophilia or a history of peptic ulcer and bronchospasm.

• Preferred to Aspirin in children with viral infections.

Paracetamol (ACETAMINOPHEN)

Acute paracetamol poisoning

• in small children and felines- who have low

hepatic glucuronide conjugating ability.

• N-acetyl-p-benzoquinoneimine (NABQI) is a

highly reactive arylating metabolite of paracetamol

which detoxicated by conjugation with glutathione.

• When a very large doses of paracetamol are taken,

the glucuroconjugation capacity is saturated, more

NABQI is formed, hepatic glutathione is depleted

and NABQI binds covalently to proteins in liver

cells (and renal tubules) causing necrosis.

NABQI

Heinz Body Anemia vs. Methemoglobinemia

Reactive Chemical + Oxyhemoglobin

Iron Oxidation

Methemoglobinemia

Cyanosis

Reaction with Globin

Globin Precipitation

Heinz Body Formation

Hemolysis

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Cats and Hemoglobin

• The major form of hemoglobin in the cat has more reactive –SH groups (8) than any other animal; makes it prone to denaturing

• The cat spleen does not effectively remove abnormal red cells

• Moist cat food contains propylene glycol; cats on this food are more susceptible to Heinz Body formation

Signs of Toxicity

• Methemoglobinemia, Heinz body formation in cats

• Cyanosis, dyspnea

• Facial and paw edema

• Anorexia, vomiting

• Delayed liver injury

• Humans and dogs develop hepatic necrosis in overdoses

Facial Edema

Treatment of Toxicity

• GI decontamination, Activated charcoal, given orally or through the tube to prevent GI absorption,

• N-acetylcysteine to replenish and substitute for GSH (140 mg/kg loading dose; 70 mg/kg 6 x 6 hrs maintenance dose) – When given orally don’t mix w/ act. Charcoal

• Sodium sulfate is alternative to NAC (50 mg/kg q 4 hrs)

• Ascorbic acid (200 mg/kg q 8 hrs) used to treat methemoglobinemia in cats, methylene blue (4 mg/kg in dogs; 15 mg/kg in cattle; 1.5 mg/kg in cats) in other animals

Pyrazolone Derivatives

PHENYLBUTAZONE

• for the treatment of rheumatoid arthritis and other

musculoskeletal disorders

• for use in horses and dogs

• affinity for plasma proteins can displace other highly bound

drugs like warfarin

• Phenylbutazone is biotransformed primarily in liver to active

metabolites oxyphenbutazone and y-hydroxyphenylbutazone

OXYPHENBUTAZONE

• one of the active metabolites of phenylbutazone

• a lesser gastric irritant action than phenylbutazone but is

not superior to the parent drug

AZAPROPAZONE

• a weak inhibitor of cyclooxygenase

• potent uricosuric agent, particularly useful for the

treatment of acute gout

• also for the treatment of rheumatic arthritis and

osteoarthritis

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Indole and Indene Acetic Acid Derivatives

ETODOLAC

• In dogs for the management of pain and inflammation

associated with osteoarthritis

• Mechanism of action

• Like other NSAIDs, etodolac is an inhibitor of cyclooxygenase

enzyme

• Also thought to inhibit macrophage chemotaxis, which may

explain some of the antiinflammatory activity

• Wide safety margin, preferred eye drops for conjuctivitis

• Dose

• Dogs: 10 - 15 mg/kg, PO, once daily. For long-term therapy,

the dose should be reduced to minimum effective level

INDOMETHACIN

• Indomethacin is a methylated indole derivative

• not used in dogs because it is more ulcerogenic than other

NSAIDs in this species

• It is mainly used in human medicine and has limited use in

veterinary practice

SULINDAC

•Sulindac is closely related to indomethacin

•pro-drug that metabolises to its active sulphide metabolite

•for treatment of rheumatoid arthritis, osteoarthritis and

ankylosing spondylitis in man

•Not approved for use in animals

DICLOFENAC

• sodium and potassium (more safer) salts

• GI bleeding(>2 -3days), nephro, hepatotoxic

• Short lasting antiplatelet action

• reduces also neutrophil chemotaxis and superoxide production at

the inflammatory site

• Toxic in elephants

• highly toxic to vultures- which feed on carcasses, tretaed with diclofenac

• veterinary use banned due to drastic reduction in vulture population due to kidney damage- Gout

• Vulture death-???? Diclofenac or else??? Debatable now

• Meloxicam , tolfenamic acid, ketoprofen nimesulide have replaced this largely

PIROXICAM

• Treatment of some cancers in dogs and cats

• Pain due to osteoarthritis.

• Many types of tumors, including nasal epithelial tumors, mammary tumors, colorectal tumors, oral squamous cell carcinoma, oral melanoma, prostatic carcinoma, transitional cell carcinoma (TCC) of the urinary bladder , osteosarcoma. and some rectal neoplasms.

• Methotrexate should not be combined with piroxicam due to potential severe toxicity

MELOXICAM

recently developed congener of piroxicam

• the anti-inflammatory efficacy similar to piroxicam

• GI and renal side effects are significantly less in dogs for

relieving pain and inflammation associated with osteoarthritis

and synovitis

• It is given by oral, sc, im,IV routes

• Antiexudative action- in respiratory conditions- pneumonia, endotoxaemia

• Antisecretory actions- in secertory diarrhoea

• Dose

• Dogs: 0.2 mg/kg, PO, as a single dose for 1 day, then 0.1

mg/kg, once daily

• Cats: 0.2 - 0.3 mg/kg, SC or PO as a single dose for 1 day,

then 0.1 mg/kg, PO, 2 times weekly

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FLUNIXIN

• Flunixin meglumine is a nicotinic acid used mainly in horses and also other species like cattle and swine

• alleviates pain arising from spasms (colic) of the GI tract and is particularly useful for control of severe visceral pain

• does not appreciably alter GI motility in horses and may improve haemodynamic in animals with septic shock

• Flunixin should not be used in animals with a history of hypersensitivity reaction to it or aspirin

• Flunixin is usually considered to be contraindicated in cats

Dose • For anti-inflammatory and analgesic effects

(muscuio-skeletal disorders)

• Dogs: 1 mg/kg, PO, once daily for up to 3 days. Three-days

course may be repeated once weekly for chronic conditions

• Cats: 0.25 mg/kg, SC or IM, once only. May be repeated in

12-24 hours, if needed

• Horses: 1.1 mg/kg, PO, IM or IV, once daily for up to 5 days

• Cattle: 2.2 mg/kg, slow IV, once daily for up to 5 days

• Swine: 1.1-2.2 mg/kg, IV, IM, PO, 1 to 2 times daily or as

needed based on clinical response

• Birds: 1-10 mg/kg, IM

AGENTS WITH ANALGESIC AND MILD TO

MODERATE ANTIINFLAMMATORY ACTIVITY

Propionic Acid Derivatives/Aryl Propionic Acid Derivatives

• NAPROXEN • suppression of prostaglandins synthesis. Additionally, naproxen inhibits

leucocytes migration

• Bioavailability after oral administration is about 50% in horses and 70-100% in dogs

• long half-life is likely due to enterohepatic cycling in the dogs

• naproxen is used primarily in horses

• Dose

• Horses: 10 mg/kg, PO, 2 times daily for up to 14 days

• : 5 mg/kg, slow IV, followed by 10 mg/ kg, PO 2 times daily for up to 14 days

• Dogs: 1.1 mg/kg, PO, 2 times daily

Anthranilic Acid Derivatives/ Fenamates

• MECLOFENAMIC ACID

• In high concentrations, it may have, antagonistic effects on

histamine and kinins

• In horses, meclofenamic acid can be detected in urine for at

least 4 days following the final dose

• should be avoided during the last stages of pregnancy

• Dose

• Horses: 2.2 mg/kg, PO, once daily for 5 to 7 days best in feed

If treatment is required past 7 days, dosage may be reduced

and interval may be increased to lowest effective level

• Dogs: 1.1 mg/kg, PO, once daily for 5 to 7 days. Dosage may

be reduced, if required past 7 days

• MEFENAMIC ACID

• Mefenamic acid is another anthranilic acid derivative that

possesses analgesic, antipyretic and anti-inflammatory

activities

• Has lower efficacy

• TOLFENAMIC ACID

• Tolfenamic acid is similar in activity to meclofenamic acid and

is used mainly in veterinary medicine

• Dose

• Dogs & cats: 4 mg/kg, PO, once daily for 3 days given with

food. May be repeated after 4 days

• : 4 mg/kg, SC or IM. May be repeated once after 24 hours, if

required

• Cattle: 2 mg/kg, IM, once daily

NIMESULIDE

relatively weak inhibitor of COX-1, but has significant inhibitory effect on the COX-2

exert its effects by inhibition of histamine release, reduced generation of superoxide by neutrophils, inhibition of platelet activating factor and free radical scavenging

There is evidence that nimesulide inhibits also release of tumour necrosis factor-alpha(TNF a) and, thus, reduces the formation of cytokines

It also blocks the metalloproteinase activity of articular chondrocytes

Useful for patients that have allergic hypersensitivity to aspirin and other NSAIDs

Sulphonanilide Derivatives

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Nimesulide

Contraindications

• Animals suffering from gastrointestinal ulceration or bleeding.

• Hypersensitivity to the product.

• Animals suffering from cardiac, hepatic or renal impairment.

• Evidence of a blood dyscrasia.

• Puppies younger than 4 months and in dogs under 3,5 kg.

• Not for use in cats, pregnant animals

NABUMETONE

• Recently developed prodrug

• Nabumetone itself is a weak inhibitor of cyclooxygenase

enzyme

• main active metabolite 6-methoxy-2-naphthylacetic acid (6-

MNA) which is a potent inhibitor of cyclooxygenase, in

particular COX-2

Alkalones

METAMIZOLE (DIPYRONE, ANALGIN)

• is a pyrazoline derivative that continues to be used as an analgesic and antipyretic agent in spite of its ban in some

countries Analgin can be given orally, i.m. as well as i.v. (very slowly).

• Pain at the i.m. injection site and rarely abscess can occur. Occasionally an i.v. injection produces fall in BP.

• Long-term use of metamizole should be avoided as it may result in agranulocytosis and neutropenia It also has a tendency to increase bleeding as a result Of suppression of formation of prothrombin

• Dose Horses: 5 -10 g (total dose) IV, SC or IM. Dose may be repeated 1 or 2 times at 8 hour intervals

Pyrazolone Derivatives

Benzoxazocine Derivatives

NEFOPAM

• Nefopam is a recently introduced NSAID for use in

human medicine, which does not inhibit prostaglandins

synthesis

• It acts rapidly with an efficacy approaching morphine,

yet it has no opioid actions

• Favourable results hare been obtained in short lasting

musculo-skeletal pain not responding to other NSAIDs

CARPROFEN

• Approved to manage pain and inflammation associated with osteoarthritis and acute pain associated with soft-tissue and orthopedic surgery in dogs.

• The exact mechanism unclear. has greater selectivity for COX-2 over COX-1

• Labrador Retrievers more prone for toxicity

PHENYLBUTAZONE

• Generally a safe and effective drug in the horse

• Lameness, resulting from from soft tissue injury, muscle soreness, bone and joint problems, and laminitis

• Avoided or used with caution in pregnant or nursing animals.

• May affect blood levels and duration of action of phentoin, valproic acid, sulfonamides, sulfonylurea antidiabetic agents, barbiturates, promethazine, rifampin, chlorpheniramine, diphenhydramine, penicillin G.

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NIMESULIDE

• In dogs for relief of pain associated with musculo-skeletal inflammation

• Not indicated for use in puppies younger than 4 months/ dogs under 5kg. and in cats

• Contraindicated in pregnant and lactating bitches.

• No studies with regard to use in cattle.

KETOPROFEN

• Most commonly prescribed for musculoskeletal pain from soft tissue injury, osteoarthritis or other bone and joint problems.

• Potent inhibitor of COX and bradykinin and may also inhibit some lipoxygenases.

• Efficacy is comparable to that of opioids in the management of pain following orthopedic and soft-tissue surgery in dogs.

• Used to reduce or control fevers due to viral or bacterial infections.

• Used in the management of colic for protection from bacterial toxins (endotoxemia).

ACECLOFENAC

• Faster, more potent analgesic, antipyretic and anti-inflammatory activities

• Superior form other NSAIDs as it has selectivity for COX-2, and is well tolerated, with better GI tolerability and improved cardiovascular safety when compared to other selective COX-2 inhibitors.

• It also shows Increased matrix component synthesis and protection of chondrocytes against apoptosis.

• Efficiently interferes with neutrophils adhesion to endothelium and this effect may represent an additional relevant mechanism in its anti-inflammatory activity DOSAGE

10 mg/kg (4.5 mg/lb) on initial day of treatment followed by a daily maintenance dose of

10 mg/kg. Dogs with severe arthritic pain may be given an initial dose of 20 mg/kg

(9.1 mg/lb) to increase the likelihood of reaching minimum effective concentration after

the first dose.

Guidelines for minimising the damage from NSAID therapy

• Combining analgesic drugs allows for reduction in the dose of any one analgesic????

• Aggressive analgesic therapy of several days’ duration should be tapered rather than stopped abruptly.

• Many animals benefit from combined or multimodal therapy (eg, combining an α2-agonist and an opioid, also administering an NSAID).

• Many of the commercially available NSAIDs in combination with other suitable agents for their synergestic action in pain relieving:

• muscle relaxants like chlorzoxazone, carisoprodol, chlomezanone, methocarbamol, tizanidine and anti-inflammatory enzymes like serratiopeptidase.

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NSAID Doses in Small Animals

NSAID Canine

(mg/kg)

Feline

(mg/kg)

Etodolac 10-15 PO QD Not Recommended

Carprofen 4.4 PO, IV, SQ

QD

1-3 SQ ONCE

Deracoxib 1-2 PO QD Not Recommended

NSAID Doses in Dogs and Cats

NSAID Canine

(mg/kg)

Feline

(mg/kg)

Tepoxalin 10 PO QD 5 PO BID

Meloxicam 0.1 SQ ONCE

0.1 PO QD

0.3 SQ ONCE,

0.1 SC then

0.05 PO QD x

5 days

Firocoxib 5 PO QD Not Recommended

NSAID Doses in Small Animals

NSAID Canine

(mg/kg)

Feline

(mg/kg)

Ketoprofen 2 IV, IM, SC

q12-24h

1-2 IV, IM, SC

q12-24h

Phenylbutazone 10-15 PO

q8-12h max

4 days

Not Recommended

NSAID Doses in Small Animals

NSAID Canine

(mg/kg)

Feline

(mg/kg)

Flunixin 1.0 IV, SC

ONCE

1.0 POMax 3

days

Not Recommended

Aspirin 10-25 PO q8-

12h

10 q2-3 days

NSAID Doses in Horses & Cattle

NSAID Horses

(mg/kg)

Cattle (mg/kg)

Ketoprofen 1-2.2 IV, SC

q12-24h

1-2 IM, SQ

q12-24h

Phenylbutazone 2-4 IV, PO

q12-24h

Unclear

Flunixin 1.1 IV, IM

QD

1.1 - 2.2 IV QD

NSAID Doses in Swine & Small Ruminants

NSAID Swine

(mg/kg)

Sheep

(mg/kg)

Goats

(mg/kg)

Ketoprofen 1-3 IV,

IM, SC

PO QD

3 IV,IM QD 3 IV,IM QD

Phenylbutazone 4-8 PO

BID

2-8 IV

QD

2-4 IV,PO

QD

2-4 IV,PO

QD

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NSAID Doses in Swine & Small Ruminants

NSAID Swine

(mg/kg)

Sheep

(mg/kg)

Goats

(mg/kg)

Flunixin 0.5-2.2

IV,SQ QD

Max 3

days

0.5 - 2.2

IV, IM,PO

QD- TID

Max 3

days

0.5 - 2.2

IV, IM,PO

QD- TID

Max 3

days

Carprofen 2-4 IV, SC,

PO BID

4 SQ QD 4 SQ QD

Adjuvant analgesic drugs

• Generally not considered to be primary first choice analgesics

• Used in combination with other analgesic drugs in acute pain states to manage severe pain, so as to reduce the dose of the primary analgesic

Adjuvant analgesic drugs…contd

Methocarbamol

– Muscle relaxant that exerts its effect by acting on the CNS ,relieve muscle tension associated with arthritis in pets.

– Weak sedative properties and may make the urine appear darker.

Alpha-2 agonists

Xylazine and Medetomidine hydrochloride

NMDA Receptor Antagonists

Ketamine, dextromethorphan, memantine, and amantadine

Adjuvant analgesic drugs…contd

Gabapentin

– A newer anticonvulsant

– Used in dogs and cats for the treatment of chronic pain, particularly of neuropathic origin and also used in chronic arthritic pain and pain associated with malignancy.

– Most effective when combined with other types of analgesic agents, NSAIDs, permitting the use of lower doses.

– Side effects are mild sedation and ataxia.

– Care to be taken in animals with decreased liver or renal function.

– It should not be discontinued abruptly because withdrawal may precipitate seizures or rebound pain.

– The dosage should be decreased over the course of two to three weeks.

– The commercially available human liquid-product contains xylitol, which can be hepatotoxic in dogs.

Adjuvant analgesic drugs…contd

Local anaesthetics Long acting agent bupiavcaine is used along with lidocaine for

long acting pain relief.

A single dose of bupivacaine injected at a local site will provide local analgesia for 6-10 hours.

Lidocaine is administetred as an intravenous constant rate infusion(50-70µg/kg/minute in dogs, 10µg/kg/min in cats) is effective in the treatment of neuropathic pain, periosteal and peritoneal pain.

It may also reduce the opioid requirement after surgery when administered as constant rate infusion.

Corticosteroids – Major side effects when given over extended periods of time.

– Given in the minimal amount that will control and inflammation and should not be given more than two or three times a week.

Adjuvant analgesic drugs…contd

Other adjunctive drugs chondroprotectives, anxiolytics and sedatives like

benzodiazepines (eg: diazepam, midozolam), tricyclic antidepressants( eg: amitryptilline, imipramine),doxycycline, omega-3 fatty acids, magnesium, immunonutritional modifiers and bioflavinoids.

Non-pharmacologic therapies include acupuncture, electroacupuncture and various electrical nerve stimulation procedures, laser therapy and pulsed magnetic field therapy.

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Other Antiinflammatories

CHRONDROPROTECTIVE COMPOUNDS

• Heparinoids: Polysulfated glycosaminoglycan and Pentosan polysulfate sodium

• improve clinical outcome in animals with osteoarthritis.

• Heparin-like’ in structure and high dosages may inhibit clotting mechanisms.

• Indicated in Non-infectious and non-immune arthritis

• Contraindicated in advanced hepatic or renal impairment,uncontrolled bleeding, trauma, infection, neoplasia,concurrent treatment or within 24 hours of Cstds

SODIUM HYALURONATE:

• is the sodium salt of hyaluronic acid

• a constituent of the high molecular weight cartilage matrix molecules, aggregated proteoglycans, and is also present in synovial fluid.

• Administered by intra-articular or IV route for joint diseases in the horse

• Arthritis associated with synovitis; navicular disease

CHONDROITIN AND GLUCOSAMINE

• Assist the repair of cartilage by providing the ‘building blocks’ for new proteoglycan formation.

• A proportion of these ingested macromolecules may be absorbed intact, and some components penetrate the joint.

• dogs with osteoarthritis

DIMETHYL SULFOXIDE (DIMETHYL SULPHOXIDE, DMSO):

• is a solvent that readily dissolves both water-soluble and lipid-soluble drugs

• used to transport drugs through skin.

• It also possesses some anti-inflammatory activity and causes dissolution of collagen