NSAIDs-II

Dr.U.P.Rathnakar
MD.DIH.PGDHM
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ARACHIDONIC ACID

Cyclooxygenase-1
[Constitutive-Good???]

Cyclooxygenase-2
[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 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 3 Nefopam, Diacerein

NSAIDs-Common benefits and ADEs

Beneficial effects Analgesic Anti-inflammatory Antipyretic Antithrombotic Closure of D.A.-new born Toxicities Gastric ulcer GI bleed Nephropathy Delay in labour Hypersensitivity Premature closure of D.A.

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

www.manipal.edu

Aspirin

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

Pharmacological actions
Analgesic:
Relieves inflammatory, tissue injury related,

connective tissue & intugemental pain

- Ineffective in severe visceral & ischemic pain

Antipyretic:

- Resets hypothalamic thermostat

And rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation)

Antiinflammatory:
Suppresses signs of inflammation: pain,

swelling,vasodilatation & leukocyte infiltration

Pharmacological actions

[Aspirin]
Metabolic effects[high doses]:
Cellular metabolism in skeletal muscles heat
production Utilization of glucose blood sugar & liver glycogen

is depleted
Toxic doses: hyperglycemia
Central sympathetic stimulation release of adrenaline & corticosteroids

Chronic use negative nitrogen balance protein

carbohydrate
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Pharmacological actions
[Aspirin]
Respiration:
Anti-inflammatory dose: Respiration stimulated
Peripheral: CO2 production Central: sensitivity of respiratory centre to CO2

Toxic doses-respiratory depression death due to respiratory failure

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Pharmacological actions
Acid base & electrolyte balance:
Initially respiratory stimulation wash out CO2 respiratory alkalosis
Compensated by renal excretion of HCO3-(with accompanying Na, K & 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 actions
[Aspirin] CVS:

Large doses: cardiac output to meet peripheral O2 demand & cause direct vasodilatation Toxic doses: vasomotor centre BP CHF may be precipitated
Cardiac work Retention of NA+ & water [Renal insufficiency-COX inhibition]

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Pharmacological actions
[Aspirin] Urate excretion:

Dose related effect < 2g/day: urate retention[Opposes uricosuric drugs] 2-5 g/day: variable effects > 5g/day: urate excretion
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Pharmacological actions [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 14

Pharmacological actions
[Aspirin]

Blood:
Irreversible inhibition of Thromboxane (TXA2) synthesis by platelets Interferes with platelet aggregation Prolongs bleeding time; lasts for a

week.
WHY?
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Pharmacological actions
[Aspirin]

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

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.
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 Higher doses:

Adverse effects [Aspirin]

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

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 Higher doses:

Adverse effects [Aspirin]

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]

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

LT

[Asthma]

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Adverse effects [Aspirin]

Hypersensitivity reactions

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Precautions & Contraindications [Aspirin]

C/I: Sensitive, peptic ulcer, bleeding tendencies, chicken pox or influenza suffering children Any chronic liver diseaseAspirin 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 PD deficiency 23

Drug interactions [Aspirin]

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
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USES-ASPIRIN
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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Other uses
Mastocytosis

Uses Aspirin

Familial Colonic polyposis [Prevention of recurrence]

Prevention of colon & RECTAL cancer
Alzheimers

Preeclampsia
Counter irritant Keratolytic
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 For closure of patent ductus arteriosus 27

Niacin induced flushes

[Whitfield ointment]

Other salicylates
Methyl salicylate---Counter irritant Salicylic acid.Keratolytic Salfasalazine---U.colitis & Rheumatoid arthritis Sod. Salicylate-Anelgesic-not used

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Dosage [Aspirin] Lowdose- 50-150 mg Medium[anelgesic&anti-pyretic] 300 to 600mg 6-8 hourly

Large[Antiinflammatory]
3-6 Grams/day

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