NONSTEROIDAL ANTINFLAMMATORY DRUGS

(NSAIDS)

AND

OTHER ANTINFLAMMATORY AGENTS

IN

VETERINARY PRACTICE

Introduction

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.

Introduction

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

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

OPIOIDS

Morphine

Oxymorphone

Diamorphine[heroin]

Codeine

Nalorphine

Levallorphan

Pethidine (meperidine)

Fentanyl

Methadone

Nalbuphine

hydromorphone

Dextropropoxyphene

Pentazocine

Cyclazocine

Etorphine

Buprenorphine

Sufentanil,

Methadone

Butorphanol

Alfentanil

Carfentanil

Remifenatnil

Tramadol hydrochloride

Pharmacological effects

Central effects

Analgesia, reduced nociception , euphoria

Elevated mood, relief of the anxiety

Respiratory depression, antitussive

Bradycardia,hypotension

Nausea, vomition, pica and pupilllary constriction

Panting with large doses of morphine or

pethidine reflect stimulation of the

thermoregulatory center.

Pharmacological effects…contd

Peripheral effects

Reduced propulsive motility of the GIT

Resulting in constipation (hence given in

combination with laxative)

Urinary retention

Histamine release (anaphylactoid reaction

causing itching or more severe allergic reactions

including bronchoconstriction)

Indications

Acute/chronic moderate to severe visceral pain

In horses for various ailments, particularly to relieveacute pain of spasmodic colic.

Combined with suitable tranquilliser as part ofof neurolept analgesia for the restraint of animals(wild)

To provide analgesia as part of a balanced anaesthetictechnique

Pentazocine as preanaesthetic in SA and horses

Some opiates are also used for the antitussive (eg:codeine, hydrocodeine, hydrocodone, morphine)proeperty and antidiarrhoeal (eg: loperamide,diphenoxylate, difenoxin) action.

Side effects

Severe respiratory depression

Excitement (Transient, overstimulation of theCNS) In animals such as. cats, horses, cattle,sheep, goats, pigs

Irregular effects in horses and ox, requiringhigher analgesic dosage

Nausea and vomition, constipation, sedation,allergy , respiratory depression

Reversed by specific opioid antagonists suchas Naloxone or Naltrexone together with thesuitable symptomatic therapeutic agents likeantiemetics, respiratory stimulants etc.

Tramadol hydrochloride

Centrally acting analgesic with opioid, monoaminergic, (monoamine reuptake inhibitor) and local anesthetic effects.

Approved for acute or chronic mild to moderate pain relief in dogs and cats.

Can be combined with other classes of analgesics including steroids, NSAIDs, NMDA antagonists, and gabapentin to allow a lower dose of both drugs

Should not be combined with tricyclic antidepressants (TCA; eg: clomipramine), selective serotonin reuptake inhibitors ( SSRIs; eg: fluoxetine) or monoamine oxidase inhibitors (MAOI; eg: selegiline ) due to the risk of serotonin syndrome.

NON-STEROIDAL ANTI-INFLAMMATORY

DRUGS (NSAIDs)

Most widely prescribed drugs in the treatment of pain and inflammation in many conditions.

The advantages over opioids

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

NSAIDS.. contd

Drawbacks

Potencywise : lesser than opioids

.with their effect on visceral pain

considered to be poor.

Other potential adverse effcets:

gastric, hepatic and renal

Mechanism of action

Inhibition of cyclo-oxygenase (COX) enzyme(s) which

leads to a decrease in the synthesis of various

prostaglandins and thromboxanes

May also inhibit phospholipase A enzyme; major

mechanism for effects of glucocorticoids on

prostaglandin production.

Few agents like ketoprofen and tepoxalin inhibit

lipooxygenase enzyme involved in leukotrienes

synthesis, in addition to cyclooxygenase inhibition

NSAIDS.. contd

COX-1

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

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

NSAIDS.. contd

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

Pharmacological Effects

Antipyretic, analgesic, and anti-inflammatory properties. ( acetaminophen: no antiinflammatory)

Less potent analgesics than opioids

Potent antithrombotic 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 bl;ood 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

NSAIDS.. contd

inhibits platelet aggregation by inhibiting thromboxanessynthesis; 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

Anti-inflammatory effects may inhibit antibody production.

potential to cause gastric ulceration.

NSAIDS.. contd

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 glucuronyltransferases that are important for glucuronidation.

As a result, drugs that are excreted as glucuronideconjugates such as aspirin, paracetamol (acetaminophen) may have a prolonged half-life in cats, increasing the risk of toxicity due to drug accumulation

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

Side /Adverse effects

Cellulitis, thrombophlebitis and tissue necrosis

Gastric ulceration

Renal toxicity

Haematological effects : Bleeding,

thrombocytopenia, haemolytic anaemia and

agranulocytosis

Hepatotoxicity

CNS (behavioural disturbances, seizure

precipitaion)

Skin (rashes, pruritus) manifestations

NSAIDS.. contd

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

Effective and well- tolerated analgesics in cats

Meloxicam, ketoprofen, carprofen, flunixin,

piroxicam and tepoxalin for short-term treatment

(five days)

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

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 pregnanat 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 effcets

H2 receptor antagonists (eg: ranitidine)

Proton pump inhibitors (eg: omeprazole)

Cytoprotective drugs (eg: misoprostol,

suclralfate)

NSAIDS.. contd

Aspirin

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

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.

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

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

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.

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

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.

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

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.

Adjuvant analgesic drugs…contd

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

administered orally a

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 is uncertain.

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

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