NSAIDS

Dr.B.M.PUROHITAssistant Professor (Pharmacology)

P.D.U.MEDICAL COLLEGE,Rajkot (GUJARAT). 360001

purohitbhargav@rediffmail.com

INTRODUCTION• NSAIDs means.. “Non Steroidal Anti Inflammatory Drugs”• If you want to study ANTI INFLAMMATORY drugs , you should know ……• What is inflammation ?...

– “Response of the body to injurious stimuli”– So it is beneficial.

• Than why it is required to be suppressed ?– Because at times it can be in EXAGGERATED form and can be….– Harmful to body– Extremely disturbing to the patient

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Which are the features of inflammation… ?

1. Heat/fever 2. Swelling 3. Pain 4. Redness5. Loss of function

NSAIDS addresses mainly FEVER, PAIN AND SWELLING.Redness is not a problem from functional point of view.Loss of function is usually restored when FEVER , PAIN and SWELLING are

taken care of “if” it is due to those features..Loss of function because of permanent fibrosis can not be reversed.

IN ONE WAY, fever and pain are beneficial ….. HOW ?

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So both phenomenon are beneficial

• But when these reflexes are EXAGGERATED it is required to be suppressed because ……

• RAISED TEMPERATURE ….– May make a person incapable for doing his job.– May inactivate several enzymes required to

maintain normal metabolism.– In extreme cases…interfere with the state of

consciousness.

• EXCESSIVE PAIN …– May interfere with the quality of life.– May frighten the patient.– In extreme cases …may produce shock …

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• We will study both pathways…• Now get ready for a LONG CHAIN OF

CHEMICAL REACTIONS …• This chemical reactions are IMPORTANT..• Products of this pathway PRODUCE

NUMEROUS ACTIONS.• They are the sites of pharmacological

intervention.

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PGG2

MEMBRANE PHOSPHOLIPID

ARACHIDONIC ACID

12-HPETE

PHOSPHOLIPASE

CHEMICAL AND MECHANICAL

STIMULIE

5-HPETE

PGH2

ISOMERASE

PGD2 PGE2 PGF2α

THROMBOXANE SYNTHEASE

PROSTACYCLINE SYNTHEASE

TXA2

TXB2

PGI2

LTB4

LTA4

LTC4

LTD4

LTE4LTF4

CYCLOXYGENASE PATHWAY LIPOXYGENASE

PATHWAY

15-HPETE

• Was it frightening…. ?• DEFINATETLY NEED A REVISION…….. RIGHT ?

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PGG2

MEMBRANE PHOSPHOLIPID

ARACHIDONIC ACID

12-HPETE

PHOSPHOLIPASE

CHEMICAL AND MECHANICAL

STIMULIE

5-HPETE

PGH2

ISOMERASE

PGD2 PGE2 PGF2α

THROMBOXANE SYNTHEASE

PROSTACYCLINE SYNTHEASE

TXA2

TXB2

PGI2

LTB4

LTA4

LTC4

LTD4

LTE4LTF4

CYCLOXYGENASE PATHWAY LIPOXYGENASE

PATHWAY

15-HPETE

Summary of the chart…• Cycloxygenase pathway generates …

– TXA2.– PGD2– PGE2– PGF2α– PGI2.

• How to remember it ?• Alphabetical order is … DEFGH• Here first … G & H and then D E F.

• Lipoxygenase pathway generates – 12 HPETE through 12-lipoxygenase– 15 HPETE through 15-lipoxygenase– 5-HETE through 5-Lipoxygenase

• 5-HETE subsequently produces …– LTA4 LTB4– LTA4 LTC4 LTD4 LTE4

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• So that was CHEMISTRY part of inflammation…

• Now their FUNCTIONAL part….• There are so many mediators of

inflammation..• Which causes numerous effects….

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They are Opposite !!! Store it in your mind !!!

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It is not possible to remember

everything !! Don’t worry !!

• Its not possible to remember ALL THE EFFECTS of ALL THE MEDIATORS.

• Just try to remember the NAMES OF MEDIATORS and

• MAJOR EFFECT produced by it.

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PAIN

• Unpleasant experience• Protective reflex

– Warning bell of tissue damage !!

• Interferes with Quality Of Life.• Two components

– Sensations peripheral component– Perception central component

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CLASSIFICATION

• Superficial or cutaneus pain• Deep pain from muscle,joints,ligaments and

bones.• Visceral pain-(spasm,infla.,ischemia,stim. Of

nerve endings)• Deafferentiation pain /neuropathic pain-

(damage to axons or nerve membranes)• Psychological/Functional

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• Now move ahead for “PAIN PATHWAY”• 1ST Slide shows afferent pathway. ( periphery to

centre).• 2nd Slide shows efferent pathway.(centre to

periphery).• Again you are not expected to remember it, but you

should have an idea about nuts and bolts of pain circuits.

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SOMATIC SENSORY CORTEX

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Amygdala Hypothalamus

Midbrain periaqueductal gray matter

Parabrachialnucleus

Medullary Reticular formation

Locuscerulous

Raphe nuclei

Dorsal horn of the spinal cord

Anterolateral

System

• Prostaglandins (PGS) sensitize the nerve endings….

• To the nociceptive stimuli …….• Caused by …….• Histamine…… and• Bradykinin.

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Pharmacological/Physiological EffectsI. Cardiovascular System

II. PLATELETS

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NORMALLY IN GIT…

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NSAIDS blocks

this

So PGS have PROTECTIVE effect on GIT

RESPIRATORY SYSTEM

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GI TRACT

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V. Reproductive Organs

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VI. Pain and Inflammation1. PGE2, PGI2, LTB4: sensitize nerve endings to painful

stimuli.2. Hyperemia, Edema, Hotness due to increased

eicosanoids at inflammation sites.3. LTB4: chemotactic factor for neutrophils and

mononuclear cells. Promotes aggregation and degranulation of PMN’s, adhesion to vessel wall and migration

Pharmacological/Physiological Effects

PGS produce PAIN… how ?

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PGS produces FEVER….. How ?

• Hypothalamus contains thermoregulatory centre

• Maintains balance between heat production and heat loss

• It regulates heat dissipating mechanisms

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PGs PRODUCES INFLAMMATION … HOW ?

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INFLAMMATION

Mechanism Of Action : NSAIDS

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MOST IMPORTANT MECHANISM

Efficacy of these mechanisms is

doubtful..So you are not

required to remember

everything!! Just keep in mind that such mechanisms

exist !!

COX-1• Physiologically expressed• Maintains the normal

(house keeping) function.• Expressed in ..

– Platelets – GIT

COX-2• Induced in pathological

states (mostly)• Physiologically expressed in

kidney.

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So NON SPECIFIC NSAIDS

produces bleeding

tendency and peptiuc ulcer

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SALICYLATES

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Analgesic activity

• No impairment of mental activity. No hypnosis

• Major component peripheral action• Minor component central action

• Can be combined with opioids

• ONLY NSAID THAT BLOCKS THE COX ENZYME IRRERVERSIBLY

• NSAIDS suppresses the pain arising out of bones and joints exception DYSMENORRHEA 38

NSAIDS blocks..

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REDUCES THE INTENSITY OF

PAIN

ANTIPYRETIC ACTIVITY

• Hypothalamus contains thermoregulatory centre

• Maintains balance between heat production and heat loss

• It regulates heat dissipating mechanisms

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Reduces fever due to inflammation. But not due to…1.Heat stroke2.Exercise induced/Physiological diurnal variation in temperature

NSAIDS inhibits PGE2 synthesis and

reduces fever

GIT

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So Use aspirin with Plenty of water or after foodMilkAlkaliSoluble of buffered aspirin

ANTIINFLAMMATORY ACTIVITY

• Decrease PG in peripheral tissue• Reduce capillary permeability• Inhibition of neutrophil aggregation and

activation• Inhibition of activated kallikrein from inactive

plasma and leucocyte kallikrein.• Inhibite mucopolysaccheride biosynthesis

reduce edema.

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BLOOD AND PLATELETS

• Antiplatelet action• Irreversibe COX inhibition• 75-150 mg OD• Platelet activity starts after 7-10 days when

new platelets are synthesized.• IN RHEU. FEVER aspirin reduces WBC count

and ESR.• Decrease fibrinogen level

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URICOSURIC ACTION

• Urate present in glomerular filtrate is reabsorbed by proximal tubule

• Excretion occurs because of tubular secretion.

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PHARMACOKINETICS• ABSORPTION :

– Skin– GIT

• Particle size• pH• Solubility of salicylate preparation• Presence of food

• DISTRIBUTION:– 80% Albumin– Achieves significant concentration in saliva,milk,spinal,synovial fluid, peritoneal fluid

and in RBCs.– HIGH AMOUNT liver, heart and muscle– SMALL AMOUNT brain.

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So little central action.

• MetabolismAspirin

• 300-600 mg dose : 1st order kinetics• 1-2 gm dose : zero order kinetics toxicity

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SalicylateDeacetylation

Salicylic acid

PHARMACOKINETICS

• EXCRETION :

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Salicylate

Glycine conjugation

Glucuronic acid conjugation

Oxidized to Gentisic acid

PHARMACOKINETICS

• INTOLERANCE :» HS reaction.» Angioedema & anaphylactic symptoms adrenalin» G6PD deficiency hemolytic anaemia»

•

ADVERSE REACTION

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Cell Membrane Phospholipids

Arachidonic Acid

Prostaglandin H2

Phospholipase A2

Cyclooxygenase I&II

Leucotriens

Inflammation Bronchospasm

NSAIDS

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GIT

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KIDNEY

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REYE’S SYNDROME

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Aspirin Toxicity - Salicylism

MANAGEMENT OF SALICYLISM• Hospitalization• Gastric lavage• Rx of

– Hyperthermia– Dehydration– Hypokalamia– Acid base disturbances– Ketosis

• Alkalization• Vit,K, BLOOD TRANSFUSION

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USES

• LOCAL APPLICATION– Keratolytic– Fungistatic– Antiseptic– Counter irritant– IBS

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• ANALGESIC – Musculoskeletal pain– Dysmenorrhea

• ANTIPYRETIC– Remember, it reduces fever due to inflammation

but not due to ….?????

• ANTIINFLAMMATORY– Arthritis– Fibromyositis

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Antirheumatic action

ANTIRHEUMATIC

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ANTIPLATELET ACTION – Platelets aggregates and provides the nidus for thrombus formation.

– Platelet aggregation is prevented by PGI2 in circulation and

promoted by TXA2.

– Inhibition of TXA2 by Aspirin at LOWER DOSES (75-150 mg) reduce platelet aggregation.

– Platelet TXA2 remains irreversibly inhibited

– Only when new platelets are synthesized , platelet activity restarts (approx. 7-10 days)

– Stop aspirin one week prior to surgery.– Useful in …..thromboembolic disorders ( MI, TIA, Ischemic stroke, atherosclerotic PVDs)– Avoid aspirin in …..Liver damage Hypo prothombinemia Vit. K deficiency Haemophilia

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• PDA :– PG mediadted– IV administration of 0.1 to 0.2 mg/kg every 12 hours for three doses. – 70% success..– Primarily in premature infants who weigh between 500 and 1750 g, – Who have a hemodynamically significant patent ductus arteriosus, and– In whom other supportive maneuvers have been attempted.

• Several food allergy– PG mediadted

• Radiation induced diarrhoea– PGmediadted

• Local application in sunburn PG mediadted

• Systemic mastocytosis– Use with antihistaminics

• C0lon carcinoma – Familial adenomatous polyposis (fap)– Pgs involved in carcinogenesis– Inhibits angiogenesis

• Dysmenorrhoea :– Increase d PG in menstrual blood uterine cramps. 60

NOW IT’S TIME TO REVISE• What is inflammation ?• Why it is required to be suppressed >?• How PAIN and FEVER and beneficial and how they are harmful ?• Following injury which chemical reactions are set off ?• What are the effects of PGD2,PGE2,PGF2α, PGI2, TXA2, LTA4 ?• How will you classify pain ?• Do your remember pain pathway ? If yes … good …if no … it’s ok.• What is the effect of different mediators on I.blood vessels, II. platelets, III. GIT, IV. respiratory

system and V. reproductive system ?• How PGS produces PAIN, FEVER and INFLAMMATION ?• Which are the mechanisms of action of NSAIDS ?• Which are the local actions of NSAIDS ?• How NSAIDS produces ANALGESIC, ANTIPYRETIC and ANTIINFLAMMATORY actions ?• How it produces anti platelet action ?• What is the effect of aspirin on urate levels ?• Which are the main ADRs of NSAIDS ? What are the pharmacological basis of the same ?• How they produces reye’ s syndrome ?• What is salicylism ? How will you treat it ?• Which are the uses of aspirin ? Which are the pharmacological basis of the same ?

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Diflunisal

• Cancer pain with bone metastases • For pain control in dental (third molar)

surgery. • 2% diflunisal oral ointment is a clinically useful

analgesic for painful oral lesions.

PARACETAMOL• Analgesic • Antipyretic• Central action> Peripheral action• 10–15 mg/kg every 4 hours (maximum of 5 doses/24 hours)• NO

– GI disturbances Acid-base imbalance Electrolyte imbalance Impairment of clotting

• ADR :– Extremely safe drug. But rarely produces …. Hepatic toxicity

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Paracetamol overdose• Ingestion of >10g of paracetamol may be fatal• May be lower in chronic alcoholics or subjects with

underlying liver disease. Clinical featuresIn severe poisoning • Up to 24 hours - none or nausea and vomiting• > 24 hours - nausea and vomiting, right

upper quadrant pain, jaundice, encephalopathy

NAC SUPPLIES GLUTATHIONES

so detoxifies toxic

metabolites !!

NAC “MAY”directly conjugates with

quinones/epoxide.

MAY BE… NAC has additional

antioxidant and antiinflammato

ry activity

Management • Repeat blood paracetamol estimatations.

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PARACETAMOL (acetaminophen)

• Now we will discuss all the remaining NSAIDs..• Their

– MOA, – ADR, – USES

are more or less same.So we will only discuss differentiating points.Or something UNIQUE about that particular drug.You are not required to remember ALL THE DETAILS of ALL THE DRUGS.This list has been added only so that …. Presentation does not look

incomplete !!!! ????

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• PHENYLBUTAZONE & OXYPHENBUTAZONE– Now almost obsolated

• ANALGIN :– Fatal blood dyscrasias

• DICLOFENAC SODIUM:• Neutrophil chomotaxis and superoxide production is reduced• Hepatotoxicity more common than other NSAIDS.• Eye drops/Gel for solar keratosis (3%)/Rectal suppository for post op.

analgesia/Oral mouthwash/IM injection• ACECLOFENAC• More GI friendly• Some what selective on COX-2.• Enhancement of glycosaminoglycan synthesis chondroprotective

property.• MELOXICAM• Preferential COX-2 inhibitor

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• ETODOLAC • Postoperative pain relief after coronary artery bypass operations• IBUPROFEN • Oral • Topical cream preparation -primary knee osteoarthritis • Patent ductus arteriosus in preterm infants • FENOPROFEN• The NSAID most closely associated with interstitial nephritis • FLURBIPROFEN• Also affect TNF-a and nitric oxide synthesis?? • 200-400 mg/d • Ophthalmic formulation for inhibition of intraoperative miosis • Flurbiprofen intravenously has been found to be effective for perioperative

analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat.

• Rarely with cogwheel rigidity, ataxia, tremor, and myoclonus

• PIROXICAM • A nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear

leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. • Decreases the production of IgM rheumatoid factor.• USES :

– Same • TENOXICAM

– SAME ….• INDOMETHACIN

• PDA – 0.1-0.2 mg/kg /12 hr X 3 times. • Ophthalmic preparation -- conjunctival inflammation reduce pain after traumatic

corneal abrasion • Gingival inflammation is reduced after administration of indomethacin oral rinse. • Malignancy induced fever.• frontal headache & other CNS side effects. C/I in psychiatric illness or epilepsy.• HYPERKALAMIA

• KETOROLAC • Replace morphine in some situations involving mild to moderate postsurgical pain. • ORAL/IM/IV/EYE DROP

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• NABUMETONE– Pseudoporphyria and photosensitivity

• NAPROXEN – Oral suspension/SR preperation/Eye drops

• SULINDAC :– Suppresses familial intestinal polyposis – It may inhibit the development of colon, breast, and prostate cancer – Sulfa like reaction

• NIMESULIDE• Weak PG synthesis inhibitor. Relative COX-2 inhibitor• Other mechanisms like …

– inhibition of neutrophil activation– Reduced generation of superoxide– Inhibition of PAF synthesis & TNF α release.– Free radicle scavanging– Inhibition of metalloproteinase activity.– possibly activation of glucocorticoid receptors???

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SELECTIVE COX-2 INHIBITORS

• CELECOXIB• ROFECOXIB• VALDECOXIB• ETOROCOXIB• LUMERACOXIB• PARACOXIB– only selective COX-2 inhibitor for

parental use.

BANNED BECAUSE OF CARDIOVASCULAR MORATLITY

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Advantages• No ADR like

– GI ulceration– Bleeding tendency

Disadvantage– Increases cardio vascular

mortality because of inhibition of endothelial PGI2 production without effect on platelet TXA2 synthesis.

– ??Incomplete suppression of inflammation.

– COX-2 is constitutively expressed in kidney so nephrotoxicity can not be avoided. Na+ and Water retention,edema,HT,CHF may be ppted.

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• CELECOXIB– GI friendly– Sulfalike reaction– Edema and HT

• ETOROCOXIB– Maximum COX2: COX 1 activity ration– OA – 60 mg OD– RA - 90 mg OD– Acute gouty arthritis 120 mg OD– Acute musculoskeletal pain- 60 mg OD– ADR :

• Dry mouth• Aphthous ulcer• Taste disturbnaces• Paraesthesia

• Lumiracoxib :– Its acidic nature allows it to penetrate well into areas of inflammation– The half-life in synovial fluid is considerably longer than in plasma.– Once-daily dosing.– 900-mg dose.– Cardiovascular safety questionable….– Gi safety promised…

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TOPICAL NSAIDS• Used for RA,OA,musculoskeletal pain,Soft Tissue Injury etc.• Advantage (???):

– ??? High local levels????? may be better therapeutic efficacy.– Low systemic levels GI safety.

• DILEMMA , whether the effect is ….– Due to drug ?– Due to placebo ?– Due to irritant present in ointments ?– Due to concomitant oral NSAID?

• EVIDENCES AVAILABLE SO FAR ….– Slow topical absorption (~10 times than oral)– Highest blood levels remains 15% below the same dose given orally.– Upto 4-6 mm( Dermis) high concentraion.– At 25 mm (muscle ) concentration is low and same as blood.

• MARKED INTERINDIVIDUAL VARIATION( 18-92%) 76

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Selection of NSAID

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