Analgesics

• Analgesics-Selectively relieves pain

Two Types:

• Narcotics /Opioid analgesics: Act on CNS &

cause drowsiness

• Non narcotics/NSAIDs: Act peripherally

Non steroidal anti-inflammatory Drugs

Non Selective Cox Inhibitor

• Salicylates

• Paracetamol

• Diclofenac

• Ibuprofen

• Mephenamic acid

• Indomethacin

• Piroxicam

• Preferential COX-2 inhibitors

• Nimesulide, Meloxicam

Selective COX-2 inhibitors

• Selecoxib, Etoricoxib

• Parecoxib( Valdecoxib)

COX= Cyclo-oxygenase (enzyme)

Mechanism of ActionPhospholipids (Cell Membrane)

Phospholipase A2

(Inhibited by Lipocortin-1)

Arachidonic Acid

Prostaglandin G/H Synthase Lipoxygenase

(Cyclo-oxygenase) Inhibited by NSAIDs

Hydroperoxy acids

Prostaglandins

Prostocyclin Thromboxane A2 Others PGS

PGI2 TXA2 PGE2

PGF2α Leukotrienes

Aspirin Mechanism of Action

• Inhibit cyclooxygenase - Enzyme

responsible for synthesis of:

Prostaglandins

–Pain response

–Suppression of gastric acid secretion

–Promote secretion of gastric mucus

and bicarbonate

–Mediation of inflammatory response

–Production of fever

–Promote renal vasodilation ( blood flow)

–Promote uterine contraction

Thromboxane A2

–Involved in platelet

–aggregation

• Cyclo-oxygenase (Cox) - 2 types

Cox 1 – Non inducible – present in

stomach, Kidney, blood vessels and

platelets

Cox 2 – inducible in activated

leucocytes and other inflammatory

cells

Acetyl salicylic acid (Aspirin)

• Pharmacological action

Local

salicylic acid and methyl salicylate –

irritant

salicylic acid – keratolytic, antiseptic

and antifungal

Analgesia

• Inhibits Cox irreversible

• Others NSAIDs – reversible inhibition

• Antipyretic – salicylate reset thermostatic

mechanism at the normal level – bring down

the temperature to the normal (does not

reduce heat production)

Action on GIT

• Dyspepsia, nausea, vomiting – gastric irritation

• Peptic ulceration which upper GI bleeding –haematemesis / melaena

• Anti-inflammatory and antirheumatic

-Inhibiting PG synthesis

-reducing capillary permeability

-inhibition of neutrophil aggregation and activation

Anti Platelet Activity

• Suppress thromboxane A2 (TX-A2) –

inhibits platelet aggregation

Pharmacokinetics

• Absorbed orally from stomach and intestine

• Poor water solubility – limiting factor

• Particle size, pH of GIT, presence of food –

affect of absorption

• Metabolism and excretion

Adverse effects

• Intolerance – skin rashes, urticaria, angioedema and bronchospasm

• GIT – nausea, vomiting and ulceration

• Reye’s syndrome – in viral infection in children below 12 yrs of age (serious and fatal)

• Pregnancy and infants – delay labour at term and cause blood loss at delivery

• Cause closure of the ductus arteriosis – serious pulmonary HTN in new born

Therapeutic Uses

• Local

• Systemic

–Analgesic, antipyretic,

antiinflammatory (4 to 6 gm / day)

–Antiplatelet in IHD

Other NSAIDs

• Diclofenac, aceclofenac- More cox-2

selective-incidence of ADRs less

Ketorolac-potent as morphine

Dose-10-30mg 6hrly p o/im/ iv

Nimesulide-

Selective Cox 2 Inhibitors

• Selectivity varies 6 to 375 folds

• Gastrointestinal mucosa not affected

• Platelet aggregation not affected (TX – A2) not reduced

Celecoxib

Pharmacokinetic

–Absorption po., slowly

–Metabolism and excretion

Adverse Drug Reaction

• Dyspepsia and mild diarrhoea

Uses

–Osteoarthritis and rheumatoid arthritis

(100 – 200 mg BD)

Etoricoxib

Highest cox-2 selectivity

60-120mg/day-once daily