Non-steroidal Anti-inflammatory Drugs

Dr.B.V.Venkataraman

Professor in Pharmacology

International Medical School

Faculti Perubatan, New BEL Rd

Bangalore - 560054

Venkataraman_bv@yahoo.com

COX

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

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

Classification of NSADs (contd)

COX-2 inhibitors (Coxibs)Valdecoxib, etorocoxibCOX-3 inhibitorsParacetamolMiscellaneous COX InhibitorsNimesulide, Meloxicam, Etodolac etcDrugs do not inhibit PGsNefopam

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.

SALICYLATES

LOCAL ACTIONS

• Irritants

• Salicylic acid: Keratolytic, used in ring worm infection

• Methyl salicylate: counter irritant in relieving joints and muscular pain

Aspirin: systemic effects

Analgesic

Aspirin

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

Systemic actions of aspirin

Antipyretic action: Inhibition of central PG

Antiplatelet action:

(Anti inflammatory action)

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)

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.

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.

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.

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.

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.

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.

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.