Non Steroidal Anti-inflammatory Drugs (NSAIDs)

Patho-physioloogy of Inflammation
Acute Inflammation:
Cell damage due to injury or infection Release of lysosomal enzymes from leukocytes Release of precursors of autacoids and their synthesis Autacoids are histamine, serotonin, bradykinin, prostaglandins and leukotriens Vasodilatation, redness, edema, pain, fever Immune cells are activated by foreign or antigenic substances Beneficial & destroys invading organisms Or may lead to: Release of interleukines, TNF-a, interferons & PGs, etc. Pain, damage to surrounding tissues (e.g. bone & cartilage)
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Immune response:

Chronic Inflammation:

PGs & other Eicosanoids Synthesis

Phospholipids Phosphatidyl-inositides
Phospholipase-C (PLC) Phospholipase-A2 (PLA2)

Steeroids

Di-glyceride
DG-lipase

Arachidonic acid
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1 COOH

NSAIDs

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Cyclooxygenase Prostaglandins (PGs) Thromboxanes (TXs)

Lipooxygenase Epooxygenase
Leukotrienes (LTs) Lipoxins (LXs) Epoxides

Free radicals

Isoprostanes
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Non-Steroidal Anti-Inflammatory Drugs ( NSAIDS)

Aspirin & related drugs Mechanism of Action (All NSAIDs)
Cyclo-oxygenase enzyme COX-I Most cells in the body COX-II Inflammatory and immune cells COX-III Hypothalamic temperature control center NSAIDs that act on COX-I, COX-II & COX-III, more side effects Selective COX-II/COX-III NSAIDs, less side effects Lipo-oxygenase enzyme (some of them)

Additional effects:

Interleukin-I Leukocyte migration Release of lysosomal enzymes Platelet aggregation

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Aspirin (Actions & Uses)

Analgesic Peripheral & central effects; synth. of PGs & other mediators Use: Mild to moderate pain, like headache, musculoskeletal pain & arthritic pains Anti-inflammatory Synthesis and release of inflammatory mediators; Leukocyte migration & release of lysosomal enzymes Use: Rheumatic fever, rhematoid arthritis, osteoarthritis Antipyretic Pyrogen induced PGE2 synthesis, interleukin-I, Temp Use: Fever

Aspirin (Pharm. Actions & Uses Cont.)

Platelets: TX-A2 synthesis, platelet aggregation & thrombus formation Aspirin more than others (causes irreversible acetylation of COX) Use: Prophylaxis of angina & myocardial infarction (MI) GI: PGE2 synthesis in gastric mucosa mucin & HCO3- , HCl, peptic-ulcers
Myenteric M1 neuron M3 H2 G

PGE2 EP3 Superficial epithelial cell

HCO3 Mucus
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Parietal cell
K+

+
PP

H+ Cl-

EP3

Aspirin (Pharm. Actions & Uses Cont.)

CNS: Salicylism (Headache, tinnitis, vertigo, nausea & vomiting). Hyperventilation (resp. alkalosis) Kidneys: Low doses (up to 2g) uric acid excretion High dose (above 4g) uric acid excretion Toxic doses cause renal damage & acidosis Liver: (Rarely) can cause hepatitis Hypersensitivity: (rarely) urticaria, angiodema, asthma Cautions & Contraindications: Peptic ulcer. Renal, cardiac and hepatic disease Hypersensitivity to salicylates
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Metabolism of Aspirin & other Salicylates

Plasma salicylate levels and effects (mg/dl)

Effects 160 __ 110 __ __ 100 Lethal Sever Moderate Mild T O X I C I T Y Complications Renal & Resp failure Vasomotor collapse, coma Hypoprothombenemia Fever, dehydration Metabolic acidosis Central stimulation, tinnitis Hhyperventilatin (Resp.Alkalosis) uric acid excretion Gastric upset, peptic ulcer uric acid excretion Bleeding tendency Hypersensitivity
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80 __
50 __

20 __
10 __ 0

Anti-inflammatory
Analgesic, anti-pyretic Anti-platelet

NSAIDs (Cont.)
Salicylates:
Aspirin (acetyl salicylic acid) Diflunisol: More effective in pain of bone metastases Avoid in renal disease. Can cause porphyria Salicylic acid: Applied topically (lotion & ointment) Causes more gastric irritation, if given orally

Propionic Acids:
Ibuprofen: (oral tab & topical cream) Less GI ulcers and bleeding. Less effect on platelets Ketoprofen: Inhibit both COX & LOX Oxaprozin: Longer acting (t-1/2 50-60 hrs), OD, mild uricosuric Flurbiprofen (also TNF-a & NO synth), naproxen

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NSAIDs (Cont.)
Phenylacetic acids
Diclofenac: COX & LOX, accumulates in synovial fluid; available as Injection, tablets, ointment & ophthalmic solution

Indoles:
Indomethacin: COX & LOX; phopholipase A & C Also used in gout, patent ductus arteriosis

Fenamates:
Mefenemic acid & meclofenamic acid: more diarrhoea & abdominal pain, more bleeding, avoid in children

Oxicams:
Piroxicam & tenoxicam: longer acting OD; COX-II more than COX-I
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NSAIDs (Cont.)
More selective COX-II inhibitors
Celecoxib (least GI and platelet effects)

Less selective
(inhibit COX-II more than COX-I) Nabumetone (a pro-drug) & etodolac

Miscellaneous
Benorilate (aspirin & paracetamol ester) & sulindac (a pro-drug)

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Paracetamol (Acetoaminophen)
Analgesic, anti-pyretic, weak anti-inflammatory Least GI and platelet effects No effect on uric acid excretion Can be used for the control of pain & fever in patients of peptic ulcer, haemophilia, or gout Not much effective in rheumatoid arthritis Can cause hepatic damage in overdosage, due to accumulation of a toxic metabolite, N-acetyl-benzoquinone Acetylcysteine & methionine is given to provide SH-radicals (as specific antidote)

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