NSAIDs II

Dr.U.P.Rathnakar MD.DIH.PGDHM 1

ARACHIDONIC ACID

Cyclooxygenase-1

Cyclooxygenase-2

[Constitutive-Good???]

[Induced-Bad???]

ADEs

NSAIDs

Uses

PGs -Gastro protective -Platelet function -Renal function -Uterine contractions

-Inflammation -Fever -Pain 2

Classification-NSAIDs Nonselective Irreversible inhibitors of COX Aspirin Nonselective reversible inhibitors of COX Ibuprofen, Diclofenac, Indomethacin, Piroxicam Weak inhibitors of COX1 Nimesulide Preferential inhibitors of COX-2[>10times] Meloxicam,Nabumetone, Etodolac •

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

Inhibitors of COX-3[?] or hypothalaamic COX-1 inhibitors Paracetaamol, Analgin NSAIDs Not inhibitors of COX Nefopam, Diacerein 3 •

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NSAIDs-Common benefits and ADEs Beneficial effects

Toxicities

• Analgesic

• Gastric ulcer

• Anti-inflammatory

• GI bleed

• Antipyretic

• Nephropathy

• Antithrombotic

• Delay in labour

• Closure of D.A.-new born

• Hypersensitivity • Premature closure of D.A.

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“A

simple idea can change the World. Aspirin  – 110 years ”. ”.

Wright Brothers 

Albert Einstein, John Logie Baird 

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Aspirin [Acetylsalicylic acid] • The name aspirin is derived from “A” from Acetyl and “spirin” from old German name Spirsaure meaning salicylic acid. • Only drug which has lasted more than a century! 1899 2012

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Aspirin •

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Gut wall, liver, plasma

Chemically acetylsalicylic acid salicyclic acid Nonselective, irreversible irreversible inhibitor of COX Absorbed from stomach & small intestines Poorly water soluble Microfining drug particles & adding alkali absorption Small vol of distributi distribution; on; 80% plasma protein bound Metabolized in liver by glycine & glucuronic acid conjugation –

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Pharmacological actions Analgesic:

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Relieves inflammatory, tissue injury related, connective tissue & intugemental pain - Ineffective in severe visceral & ischemic pain

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Antipyretic:

- Resets hypothalamic thermostat And rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation) –

Antiinflammatory:

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Suppresses signs of inflammation: pain,

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Pharmacological Pharmacological actions

[Aspirin] –

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Metabolic effects[high doses]:

Cellular metabolism in skeletal muscles heat production Utilization of glucose blood sugar & liver glycogen is depleted Toxic doses: hyperglycemia •

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Central sympathetic stimulation corticosteroids

Chronic use

release of adrenaline &

negative nitrogen balance

protein

carbohydrate 9

Pharmacological Pharmacological actions [Aspirin] •

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Respiration:

Anti-inflammatory dose: Respiration stimulated

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Peripheral: CO2 production

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Central: sensitivity of respiratory centre to CO2

Toxic doses-respiratory depression due to respiratory failure

death 10

Pharmacological Pharmacological actions •

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Initially respiratory stimulation respiratory alkalosis •

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Acid base & electrolyte balance: wash out CO2

Compensated by renal excretion of HCO 3-(with accompanying Na, K & water)-Compensated water)-Compensated resp.alkalosis

Higher doses: respiratory depression with CO2 retention Excess CO2 production continues respiratory acidosis Addition of dissociated salicylic acid +metabolic Uncompensated acids- lactic, pyruvic acid + sulfuric & phosphoric metabolic acidosis acids retained due to 11 renal function

Pharmacological Pharmacological actions [Aspirin] •

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CVS:

Large doses: cardiac output to meet peripheral O2 demand & cause direct vasodilatation Toxic doses: vasomotor centre BP CHF may be precipitated •

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Cardiac work Retention of NA+ & water [Renal insufficiency-COX inhibition]

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Pharmacological Pharmacological actions [Aspirin]

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Urate excretion:

Dose related effect < 2g/day: urate retention[Opposes retention[O pposes uricosuric drugs] 2-5 g/day: variable effects > 5g/day: urate excretion –

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Pharmacological actions Pharmacological [Aspirin] •

GIT: Epigastric distress, nausea & vomiting-Irritant of mucosa

Acute ulcers, erosive gastritis, congestion microscopic hemorrhage

•Irritant •Ion trapping •Back diffusion of acid •Inhibition of COX

Aspirin [unionized]

Aspirin [ionized] Ion trapping 

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Pharmacological Pharmacological actions [Aspirin] •

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Blood:

Irreversible inhibition of Thromboxane (TXA2) synthesis by platelets Interferes with platelet aggregation Prolongs bleeding time; lasts for a week. WHY? 15

Pharmacological Pharmacological actions [Aspirin] •

Low aspirin dose (50-150mg/day) –

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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] But why administer low dose every day? New platelets are synthesized every day

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Pharmacological Pharmacological actions [Low dose Aspirin] •

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 NSAIDsthis activity is lost

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Adverse effects [Aspirin] •

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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

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Adverse effects [Aspirin] Higher doses: Salicylism-dizziness, tinnttus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion,hyperventilation and electrolyte imbalance. Dose gradually decreased till tolerated Hepatic damage 19

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Adverse effects [Aspirin] Higher doses: Metabolic toxicity 'Reye's syndrome', a rare form of hepatic encephalopathy Aspirin+ children having viral (varicella, influenza) infection

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Adverse effects [Aspirin] •

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Aspirin [Any NSAIDs] induced asthma Cross sensitivity-NSAIDs Nimuselide-may be safer Inhibition of PG synthesis → More LT synthesis COX pathway

LOX pathway

PG

LT

[Asthma]

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Adverse effects [Aspirin] •

Hypersensitivity reactions

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Precautions & Contraindications [Aspirin]

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C/I: Sensitive, peptic ulcer, bleeding tendencies, chicken pox or influenza suffering children Any chronic liver disease→Aspirin→ hepatic necrosis To be avoided in diabetics, low cardiac reserve or frank CHF, juvenile rheumatoid arthritis Should be stopped 1 week before surgery To be avoided in pregnant, lactating & G-6 G -6 PD deficiency 23

Drug interactions [Aspirin]

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Displacement reactions-Warfarin, sulfonylurea, phenytoin Antagonizes uricosuric action-probenecid Blunts the action diuretics[Furosomide,thiazides]

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Acute salicylate poisoning Treatment: •Symptomatic &

supportive •External cooling

[Hyperpyrexia!!!]; IV fluids with Na, K,HCO3 & glucose •Alkaline diuresis •Gastric lavage; •Haemodialysis •Blood transfusion & vitamin K 25

USES-ASPIRIN •

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Analgesic: headache, backache, myalgia, joint pain, toothache, neuralgia & dysmenorrhoea Antipyretic: fever of any origin Acute Rheumatic fever Rheumatoid arthritis Osteoarthritis Postmyocardial infarction, post stroke patients, TIA, DVT, Pulmonary embolism [Secondary prevention] For closure of patent ductus arteriosus …………………………. Contd….

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Uses Aspirin Other uses… •

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Mastocytosis

Familial Colonic polyposis [Prevention of recurrence] Prevention of colon & RECTAL cancer Alzheimer’s Preeclampsia

Niacin induced flushes

Counter irritant Keratolytic [Whitfield ointment] •

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•Analgesic: headache, backache, myalgia, joint

pain, toothache, neuralgia & dysmenorrhoe dysmenorrhoea a •Antipyretic: fever of any origin •Acute Rheumatic fever •Rheumatoid arthritis •Osteoarthritis •Postmyocardial infarction & post stroke patients

For closure of patent ductus arteriosus

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Other salicylates •

Methyl salicylate---Counter irritant

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Salicylic acid….Keratolytic

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Salfasalazine---U.colitis & Rheumatoid arthritis

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Sod. Salicylate-Anelgesic-not used

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osage [Aspirin] •

Lowdose- 50-150 mg

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Medium[anelgesic&anti-pyretic] 300 to 600mg 6-8 hourly

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Large[Antiinflammatory]

3-6 Grams/day

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