non-steroidal anti-inflammatory drugs dr.b.v.venkataraman professor in pharmacology international...
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Non-steroidal Anti-inflammatory Drugs
Dr.B.V.Venkataraman
Professor in Pharmacology
International Medical School
Faculti Perubatan, New BEL Rd
Bangalore - 560054
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COX
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Physiological stimulus Inflammatory stimulus
COX-1Constitutive
Macrophages/other cells
Cox-2Induced
TXA2Platelets
PGI2, endothelium
Stomach mucosa etc
PGE2, Kidney etc
PGsProteases
Other inflammatory
mediators
INFLAMMATION
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Classification of NSAID
COX-1 and COX-2 inhibitors
1. Salicylates: Aspirin
2. Para-aminophenols: Phenacetin, Paracetamol.
3. Pyrazolons: Phenylbutazone
4. Indoles: Indomethacin, Sulindac, Tolmetin, Ketorolac.
5. Phenylacetates: Diclofenac
6. Propionates: Ibuprofen, Ketoprofen,
7. Fenamates: Flufenamic acid and Mefenamic acid.
8. Oxicams: Piroxicam
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Classification of NSADs (contd)
COX-2 inhibitors (Coxibs)Valdecoxib, etorocoxibCOX-3 inhibitorsParacetamolMiscellaneous COX InhibitorsNimesulide, Meloxicam, Etodolac etcDrugs do not inhibit PGsNefopam
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SALYCILATES
Source: bark of willow (used in malaria)
Now it is commercially synthesised.
Salicylic acid
Sodium salicylate
Acetyl salicylic acid (aspirin)
Methyl salicylic acid (oil of winter green)
Diflunisal is a derivative of aspirin.
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SALICYLATES
LOCAL ACTIONS
• Irritants
• Salicylic acid: Keratolytic, used in ring worm infection
• Methyl salicylate: counter irritant in relieving joints and muscular pain
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Aspirin: systemic effects
Analgesic
Aspirin
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Types of Analgesis
Two types
1. Narcotic analgesics
Relieve pain and produce sedative/hypnotic effect e.g. morlphine, pethidine
2. Non-narcotic analgesics
Relieve pain with out affecting the consciousness e.g. aspirin, paracetamol
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Systemic actions of aspirin
Antipyretic action: Inhibition of central PG
Antiplatelet action:
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(Anti inflammatory action)
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Systemic actions of aspirin
TxA2 is present in platelets
At any dose anti-platelet aggregation (inhibiting TXA2)
At low dose PGI2 not inhibited
At high dose PGI2 is inhibited.
PGI2 : vasodilator and anti-platelet aggregation.
Action is irreversible.
Duration 8-10 days (life of platelet)
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Systemic actions of Salicylates
Renal effect: PGE2 (vasodilator) coordinate with angiotensin-II. Chronic NSAIDs leads to inhibition of PGE2 and vasoconstriction.
Respiration: directly and indirectly. O2 leads to CO2 which stimulates respiratory centre. These events leads to hyper ventilation.
Low dose decrease the uric acid level. High dose uricosuric effect.
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Pharmacokinetics
Well absorbed from stomach and small intestine
Empty stomach and acid medium helps absorption
Deacetylation in gut wall, liver, plasma & other tissues after absorption.
Protein binding 80%
Conjugated with glycine.
1/10 is excreted in active form which can be enhanced with alkalinisation.
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Side effects of aspirin
Intolerance (rare): rashes, urticaria, asthma etc.
Gastric irritation
Hypoprothrombinemia: Vit K is antidoteReye’s syndrome: Children prescribed for viral fever. Syndrome consists of liver dysfunction (fatal)
Salicylism: headache, dizziness, vertigo, difficulty in hearing and dimness of vision. The symptoms are reversible once the drug is withdrawn.
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Treatment of acute salicylate poisoning
Symptomatic treatment
Patent airway
Hyperthermia: reduced by external cooling.
Dehydration should be corrected.
Vitamin K should be administered.
Metabolic acidosis is corrected by NaHCO3 which also promotes renal excretion of salicylates.
Forced diuresis is done by administration of furosemide (40 mg) in the infusion fluid.
Dialysis is done in renal failure.
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Clinical uses of Salicylates
Keratolytic and antifungal : salicylic acidCounter irritant: Methyl salicylic acidAcute rheumatic fever: Streptococcal infection induces antibodies reacting with lymphocytes. These antibodies react with heart valves and myocardium. Treatment: a. Penicillin for the streptococcal infection. b. Aspirin (5-8 g in divided doses) for the inflammation. c.corticosteroids can also be given.
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Clinical uses of aspirin
Arthritis and fibromyositis: In rheumatoid arthritis, aspirin at 5-6 g in divided doses is advised.
Ischaemic heart disease: In low doses (100 mg daily) aspirin is given to prevent platelet aggregation.
Pain: headache, fever, dysmenorrhoea etc.
For closure of patent ductus arteriosus.
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Drug interaction
Aspirin displaces oral anticoagulants, oral antidiabetics etc.
Interfers with uric acid excretion (analgesic dose inhibit)
Decreases the diuretic actions (thiazides and furosemide)
Reduces the K+ sparing action of spiranolactone.