NSAIDs II

(1)

Dr.U.P.Rathnakar

MD.DIH.PGDHM MD.DIH.PGDHM 1 1

NSAIDs-II

(2)

ARACHIDONIC ACID

PGs

Cyclooxygenase-1

[Constitutive-Good???] [Constitutive-Good???]

Cyclooxygenase-2

[Induced-Bad???] [Induced-Bad???]

NSAIDs

ADEs Uses ADEs Uses -Gastro protective -Gastro protective -Platelet function -Platelet function -Renal function -Renal function -Uterine contractions -Uterine contractions -Inflammation -Inflammation -Fever -Fever -Pain -Pain 2 2

(3)

Classification-NSAIDs

•

• Nonselective IrreversibleNonselective Irreversible

inhibitors of COX inhibitors of COX Aspirin

Aspirin

•

• Nonselective reversibleNonselective reversible

inhibitors of COX inhibitors of COX Ibuprofen, Diclofenac, Ibuprofen, Diclofenac, Indomethacin, Piroxicam Indomethacin, Piroxicam •

• Weak Weak inhibitors inhibitors of of COX1COX1

Nimesulide Nimesulide

•

• Preferential inhibitors ofPreferential inhibitors of

COX-2[>10times] COX-2[>10times] Meloxicam,Nabumetone, Meloxicam,Nabumetone, Etodolac Etodolac •

• Selective reversibleSelective reversible

inhibitors of COX-2[>50 inhibitors of COX-2[>50 times] times] Rofecoxib, Celecoxib, Rofecoxib, Celecoxib, Valdecoxib, Etoricoxib, Valdecoxib, Etoricoxib, Parecoxib Parecoxib •

• Inhibitors of COX-3[?]Inhibitors of COX-3[?]

or hypothalaamic COX-1 or hypothalaamic COX-1 inhibitors inhibitors Paracetaamol, Analgin Paracetaamol, Analgin •

• NSAIDsNSAIDs ––Not inhibitorsNot inhibitors

of COX of COX

Nefopam, Diacerein

(4)

NSAIDs-Common benefits and

ADEs

Beneficial effects Beneficial effects •• AnalgesicAnalgesic •• Anti-inflammatoryAnti-inflammatory •• AntipyreticAntipyretic •• AntithromboticAntithrombotic

•• Closure of D.A.-new bornClosure of D.A.-new born

Toxicities

•• Gastric ulcerGastric ulcer

•• GI bleedGI bleed

•• NephropathyNephropathy

•• Delay in labourDelay in labour

•• HypersensitivityHypersensitivity

•• Premature closure of D.A.Premature closure of D.A.

4 4

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www.manipal.edu www.manipal.edu Albert Einstein, Albert Einstein, Wright Brothers Wright Brothers

John Logie Baird

“

(6)

A

spirin

[Acetylsalicylic acid]

•• The name aspirin is derived fromThe name aspirin is derived from “A”“A” fromfrom A

Acetyl andcetyl and “spirin”“spirin” from old German namefrom old German name Spirsaure

Spirsaure meaning salicylic acid.meaning salicylic acid.

•• Only drug which has lasted more than aOnly drug which has lasted more than a century! century! www.manipal.edu www.manipal.edu 1899 1899 2012 2012

(7)

Aspirin

•

• Chemically acetylsalicylic acidChemically acetylsalicylic acid •

• salicyclic acidsalicyclic acid •

• Nonselective, irreversiNonselective, irreversible inhibitor of ble inhibitor of COXCOX •

• Absorbed from stomach & Absorbed from stomach & small intestinessmall intestines •

• Poorly water solublePoorly water soluble –

– Microfining drug particles & adding alkaliMicrofining drug particles & adding alkali •

• Small vol of Small vol of distributidistribution; 80% on; 80% plasma proteinplasma protein

bound

bound •

• Metabolized in liver by glycine & glucuronic acidMetabolized in liver by glycine & glucuronic acid

conjugation conjugation Gut Gut wall, wall, liver, liver, plasma plasma 7 7 ⇛⇧ ⇛⇧absorptionabsorption

(8)

Pharmacological actions

•

Analgesic:

Relieves inflammatory, tissue injury related,

connective tissue & intugemental pain

-- Ineffective in severe visceral & ischemic painIneffective in severe visceral & ischemic pain

--

Antipyretic:

-- Resets hypothalamic thermostatResets hypothalamic thermostat

And rapidly reduces fever by promoting heat

loss

loss (sweating, (sweating, cutaneous cutaneous vasodilatation)vasodilatation)

–

Antiinflammatory:

–

– Suppresses signs of inflammation: pain,Suppresses signs of inflammation: pain,

8 8

(9)

Pharmacologic

Pharmacological

al actions

actions

[Aspirin]

–

Metabolic effects[high doses]:

–

– Cellular metabolism in skeletal musclesCellular metabolism in skeletal muscles heatheat production

production

–

– Utilization of glucoseUtilization of glucose blood sugar & liver glycogenblood sugar & liver glycogen is depleted

is depleted

•

• Toxic doses: hyperglycemiaToxic doses: hyperglycemia

–

– Central sympathetic stimulationCentral sympathetic stimulation

corticosteroids

–

– Chronic useChronic use proteinprotein

9 9 ⇧⇛ ⇧⇛ ⇛⇩ ⇛⇩

release of adrenaline &

release of adrenaline & negative nitrogen balance

negative nitrogen balance⇛⇧⇛⇧

carbohydrate

(10)

•

Respiration:

–

– Anti-inflammatory dose: RespirationAnti-inflammatory dose: Respiration

stimulated

•

• Peripheral:Peripheral: productionproduction

•

• Central:Central:

–

– Toxic doses-respiratory depressionToxic doses-respiratory depression

due to respiratory failure

Pharmacologic

Pharmacological

al actions

actions

[Aspirin]

10 10 CO CO₂₂

sensitivity of respiratory centre to CO

sensitivity of respiratory centre to CO₂₂

death

(11)

•

• Acid base & electrolyte balance:Acid base & electrolyte balance:

–

– Initially respiratory stimulationInitially respiratory stimulation wash out COwash out CO22

•

• Compensated by renal excretion of HCOCompensated by renal excretion of HCO33--(with accompanying(with accompanying

Na, K &

water)-Na, K & water)-Compensated resp.alkalosisCompensated resp.alkalosis

–

– Higher doses: respiratory depression with COHigher doses: respiratory depression with CO22 retention

retention

–

– Excess COExcess CO22 production continuesproduction continues acidosis

acidosis

Pharmacologic

Pharmacological

al actions

actions

Addition of dissociated Addition of dissociated salicylic acid +metabolic salicylic acid +metabolic acids- lactic, pyruvic acid acids- lactic, pyruvic acid

+ sulfuric & phosphoric + sulfuric & phosphoric

acids retained due to acids retained due to

Uncompensated Uncompensated metabolic acidosis metabolic acidosis 1 111 respiratory alkalosis respiratory alkalosis respiratory respiratory renal function renal function

(12)

Pharmacologic

Pharmacological

al actions

actions

[Aspirin]

•

CVS:

–

Large doses:

meet

₂₂

demand &

cause direct vasodilatation

–

Toxic doses:

BP

–

CHF may be precipitated

•

Retention of NA

++

& water [Renal

insufficiency-COX inhibition]

1212

cardiac output to

peripheral O

vasomotor centre

⇛⇩⇛⇩

Cardiac work

(13)

Pharmacologic

Pharmacological

al actions

actions

[Aspirin]

•

Urate excretion:

•

Dose related effect

–

< 2g/day: urate

retention[O

pposes

uricosuric

drugs]

–

2-5 g/day: variable effects

–

> 5g/day: urate excretion

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•

GIT: Epigastric distress, nausea &

vomiting-Irritant of mucosa

Pharmacologi

Pharmacological cal actionsactions [Aspirin] [Aspirin] 14 14 Aspirin Aspirin [unionized] [unionized] Aspirin Aspirin [ionized] [ionized] Ion trapping Ion trapping

Acute ulcers, erosive gastritis, congestion microscopic hemorrhage Acute ulcers, erosive gastritis, congestion microscopic hemorrhage

••IrritantIrritant

••Ion trappingIon trapping

••Back diffusionBack diffusion of acid

of acid

••Inhibition ofInhibition of COX

(15)

•

Blood:

–

Irreversible inhibition of Thromboxane

(TXA

₂₂

) synthesis by platelets

–

Interferes with platelet aggregation

–

Prolongs bleeding time; lasts for a

week.

– –

WHY?

15 15

Pharmacologic

Pharmacological

al actions

actions

[Aspirin]

(16)

•

Low

aspirin

dose

(50-150mg/day)

–

Platelets are exposed to aspirin in portal

circulation before it undergoes first pass

metabolism in liver

–

TXA2 irreversibly acetylated

–

Platelets cannot synthesize fresh

enzyme-No nucleus

–

Inhibited for the life

of platelets[7 days]of platelets[7 days]

–

– But why administer low dose every day?But why administer low dose every day?

–

– New platelets are synthesized every dayNew platelets are synthesized every day

16 16

Pharmacologic

Pharmacological

al actions

actions

[Aspirin]

(17)

•

At higher doses antiplatelet activity

is lost

–

At this dose aspirin also inhibits

prostacyclins[

PGI2

] in the vessel wall

which are potent antiplatelet agents

–

Co-administration of other NSAIDs-

Co-administration of other

NSAIDs-this activity is lost

this activity is lost

1717

Pharmacologic

Pharmacological

al actions

actions

[Low dose Aspirin]

(18)

Adverse effects

[Aspirin]

•

• Lower doses:Lower doses:

•

Nausea, vomiting, epigastric

distress, increased occult

blood loss in stools.

•

Most important adverse

effect of aspirin is gastric

mucosal damage and peptic

ulceration.

18 18

(19)

Adverse effects

[Aspirin]

•

• Higher doses:Higher doses: •

• Salicylism-dizziness, tinnttus,Salicylism-dizziness, tinnttus, •

• vertigo, reversible impairment ofvertigo, reversible impairment of

hearing and vision, excitement and

mental confusion,hyperventilation

and electrolyte imbalance.

•

• Dose gradually decreased tillDose gradually decreased till

tolerated

•

• Hepatic damageHepatic damage

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(20)

Adverse effects

[Aspirin]

•

• Higher doses:Higher doses: •

• Metabolic toxicityMetabolic toxicity •

• 'Reye's syndrome', a rare form of'Reye's syndrome', a rare form of

hepatic encephalopathy

•

• Aspirin+ children having viralAspirin+ children having viral

(varicella, influenza) infection

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(21)

Adverse effects

[Aspirin]

•

• Aspirin [Any NSAIDs] inducedAspirin [Any NSAIDs] induced

asthma

•

• Cross sensitivity-NSAIDsCross sensitivity-NSAIDs •

• Nimuselide-may be saferNimuselide-may be safer •

• Inhibition of PG synthesisInhibition of PG synthesis → More LT→ More LT

synthesis synthesis 21 21 PG PG

L

T

[Asthma][Asthma] COX pathway

(22)

Adverse effects

[Aspirin]

•

• Hypersensitivity reactionsHypersensitivity reactions

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Precautions & Contraindications

[Aspirin]

•

• C/I: Sensitive, peptic ulcer, bleedingC/I: Sensitive, peptic ulcer, bleeding

tendencies, chicken pox or influenza suffering

children

•

• Any chronic liver diseaseAny chronic liver disease→Aspirin→→Aspirin→ hepatichepatic

necrosis

•

• To be avoided in diabetics, low cardiac reserveTo be avoided in diabetics, low cardiac reserve

or frank CHF, juvenile rheumatoid arthritis

•

• Should be stopped 1 week before surgeryShould be stopped 1 week before surgery •

• To be avoided in pregnant, lactating & GTo be avoided in pregnant, lactating & G-6 PD-6 PD

deficiency

(24)

Drug interactions

[Aspirin]

•

• Displacement reactions-Warfarin, sulfonylurea,Displacement reactions-Warfarin, sulfonylurea,

phenytoin

•

• Antagonizes uricosuric action-probenecidAntagonizes uricosuric action-probenecid •

• Blunts the action diuretics[Furosomide,thiazides]Blunts the action diuretics[Furosomide,thiazides]

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Acute salicylate poisoning

Treatment:

•

•Symptomatic &Symptomatic &

supportive

•

•_{External cooling}_{External cooling}

[Hyperpyrexia!!!]; IV fluids

with Na, K,HCO

with Na, K,HCO₃₃ &&

glucose

•

•_{Alkaline diuresis}_{Alkaline diuresis}

•

•Gastric lavage;Gastric lavage;

•

•HaemodialysisHaemodialysis

•

•Blood transfusion &Blood transfusion & vitamin K

vitamin K

25 25

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USES-ASPIRIN

•

• Analgesic: headache, backache, myalgia, joint pain,Analgesic: headache, backache, myalgia, joint pain,

toothache, neuralgia & dysmenorrhoea toothache, neuralgia & dysmenorrhoea

•

• Antipyretic: fever of any originAntipyretic: fever of any origin

•

• Acute Rheumatic feverAcute Rheumatic fever

•

• Rheumatoid arthritisRheumatoid arthritis

•

• OsteoarthritisOsteoarthritis

•

• Postmyocardial infarction, post stroke patients,Postmyocardial infarction, post stroke patients,

TIA, DVT, Pulmonary embolism [Secondary

prevention]

•

• For closure of patent ductus arteriosusFor closure of patent ductus arteriosus

•

• ……….……….ContdContd….….

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(27)

Uses

Aspirin

Other uses…

• • MastocytosisMastocytosis •

• Familial Colonic polyposis [Prevention of recurrence]Familial Colonic polyposis [Prevention of recurrence]

•

• Prevention of colon & RECTAL cancerPrevention of colon & RECTAL cancer •

• Alzheimer’sAlzheimer’s

•

• PreeclampsiaPreeclampsia

•

• Niacin induced flushesNiacin induced flushes •

• Counter irritantCounter irritant

• • KeratolyticKeratolytic [Whitfield ointment] [Whitfield ointment] 27 27 •

•Analgesic: headache, backache, myalgia, jointAnalgesic: headache, backache, myalgia, joint

pain, toothache, neuralgia &

pain, toothache, neuralgia & dysmenorrhoedysmenorrhoeaa

•

•Antipyretic: fever of any originAntipyretic: fever of any origin

•

•Acute Rheumatic feverAcute Rheumatic fever

•

•_{Rheumatoid arthritis}_{Rheumatoid arthritis}

•

•OsteoarthritisOsteoarthritis

•

•Postmyocardial infarction & post Postmyocardial infarction & post stroke patientsstroke patients

For closure of patent

(28)

Other salicylates

•

• Methyl salicylate---Counter irritantMethyl salicylate---Counter irritant

•

• Salicylic acid….KeratolyticSalicylic acid….Keratolytic

•

• Salfasalazine---U.colitis & Rheumatoid arthritisSalfasalazine---U.colitis & Rheumatoid arthritis

•

• Sod. Salicylate-Anelgesic-not usedSod. Salicylate-Anelgesic-not used

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osage osage [Aspirin] [Aspirin] • •

Lowdose- 50-150 mg

• •

Medium[anelgesic&anti-pyretic] 300 to

600mg 6-8 hourly

• •

Large[Antiinflammatory]

3-6 Grams/day

29 29

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