Non-steroidal anti-inflammatory drugs

By

Dr. N. C. Baruah

Inflammation

• Inflame means to burn.

• Inflammation is a series of changes occurring in the tissues following an injury.

• Inflammation is associated with the classic inflammatory symptoms that include calor (warmth), dolor (pain), rubor (redness) and tumor (swelling) in the tissue because of injury or infection.

• When there is tissue damage the immune defense cells release histamine, prostaglandin, leukotrienes, serotonin and other substances.

• These chemical substances dilate the blood vessels and increase blood flow to the injury site.

• The blood capillaries become leaky and so the fluid oozes out into the tissue that causes swelling in the area. The site becomes red because more blood accumulates in the area.

• Pain is caused by the nerve endings stimulated by the chemicals released in the injury site.

• The WBCs move to the site to destroy the invading microorganisms and to take part in the repairing processes of damaged tissues.

• The anti-inflammatory drugs are the substances which inhibit the symptoms of inflammation.

• Inflammation can be treated with two major classes of anti-inflammatory drugs: the steroids and the non-steroidal anti-inflammatory drugs (NSAID).

• The steroids are compounds with glucocorticoids activity, and include the physiological glucocorticoids such as cortisol, and synthetic glucocorticoids analogs like dexamethasone, betamethasone, prednisone and prednisolone.

• The NSAIDs are used to treat in various painful conditions such as headaches, toothaches, sprains and strains, painful periods and in inflammation of joints.

• NSAIDs are classified on the basis of their basic chemical structures as –

• 1. Salicylic acid analogues: Aspirin, Salicylamide, Sodium salicylate, Diflunisal, Salsalate, Choline salicylate.

• 2. Aryl & Heteroarylpropanoic acid analogues: Ibuprofen, Fenoprofen, Flurbiprofen, Ketoprofen, Naproxen, Suprofen, Oxaprogin

• 3. Aryl & Heteroarylacetic acid analogues: Indomethacin, Sulindac, Tolmetin, Zomiperac, Ketorolac, Etodolac, Bromfenac, Nebumetone

• 4. Arylanthranilic acid analogues: Mafenamic acid, Flufenamic acid, Meclofenamic acid, Diclofenac,, Lumiracoxib

• 5. Oxicams : Piroxicam, Meloxicam,

• 6. Aryl sulfonamides: Nimesulide, Flosulide

• 7. Pyrazolone derivatives: phenylbutazone, oxyphenbutazone, azapropazone & dipyrone

• Selective COX-2 inhibitors:

• Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Flumizole

• The ω3 fatty acids like eicosapentanoic acid and docosahexanoic acid (DHA) are cox inhibitors.

Mechanisms of action of NSAIDs

• The NSAIDs are cyclooxygenase inhibitors. The conventional NSAIDs are nonselective anti-inflammatory agents. They block both constitutive and inductive synthesis of prostaglandins by inhibiting the functions of COX-1 and COX-2.

• Selective COX-2 inhibitors block only the COX-2 enzyme and not the COX-1 enzyme. The pain and inflammation are mainly associated with the prostaglandins synthesized through COX-2 enzyme. By blocking this enzyme they prevent the pain and inflammations.

• What are prostaglandins ?

• Prostaglandins and related molecules are known as eicosanoids. • The term eicosanoids means 20 carbons containing compounds. • They are used as signaling molecules. • They act locally on all cells that make them or nearby cells. They are hormones

like substances and have short half-lives; so called autocoids. • They play a vital role in many important physiological and patho-physiological

functions including pain, inflammation, gastric acid secretion, wound healing, and renal function.

• Most prostaglandins are synthesized from arachidonic acid (20:4 Δ5, 8, 11, 14).

• Arachidonic acid obtained from linolenic acid through catalytic reactions.

• Cells store arachidonic acid as membrane phospholipids such as phosphoinositol.

• Arachidonic acid is liberated at the damage site from phospholipids by an enzymatic reaction catalyzed by phospholipase-A2.

• The free arachidonic acid is then converted to prostaglandins by the tissue specific enzymes cyclooxygenase-1(cox1) or cyclooxygenase-2 (cox2).

• The prostaglandins are synthesized on need basis (constitutive) via cytosolic cox-1 isozyme (iso-enzyme);

• Found in gastrointestinal, cardiovascular, kidney and in reproductive organ systems.

• The syntheses of prostaglandins are over expressed as induced by an injury, inflammation, or infection via microsomal cox-2 isozyme.

Functions of prostaglandins: Prostaglandins in the system- 1.Induce inflammation 2. Mediates of pain signals Induce fever 3.Induce smooth muscle contraction (including uterus) 4.Induce smooth muscle relaxation -- especially PGE series 5.Protect stomach lining by maintaining alkalinity. 6.Simulate platelet aggregation (thromboxanes) Inhibit platelet aggregation (prostacyclin)

• The prostaglandins play a protective role in the gastrointestinal (GI) tract.

• The nonselective anti-inflammatory drugs by

• blocking the cox-1 enzyme reduce the synthesis of protective prostaglandins and

• causes stomach upset, ulceration and bleeding in the stomach and intestinal membranes.

• COX-2 inhibitors do not produce the risk of injury to the stomach or intestine.

• The drugs such as the glucocorticoids can prevent phospholipase-A2 and prevent arachidonic acid synthesis.

• But the steroids have many adverse effects.

Cell membrane phospholipids

Phospholipase A2

Arachidonic acid

Cyclooxygenase-1 & 2

PGG2 & PGH2

PGE2 synthase

PGE2

TXA2 synthase

PGI 2 synthase

PGF2α synthase

PGD 2 synthase

PGD2

PGF2α TXA2

PGI2

Synthesis of Prostaglandins

Phospholipids (Cell membrane)

• Phospholipase-A2

arachidonic acid Cyclooxygenase-1 & 2 5-lipoxygenase

HPETE

PGG2 Leukotrienes (LTB, LTC…)

TXA2 PGH2 PGF2α

PGE2 PGD2 PGI2 (Prostacyclin)

Salicylates • Salicylic acid is a monohydroxy benzoic acid and is a

non-steroidal anti-inflammatory drug. The analogues of salicylic acid also have good analgesic and anti-inflammatory activity.

• The main compounds of this group are aspirin, methyl salicylate, choline salicylate, Salicylamide, salsalate and diflunisal . They are well absorbed from the stomach, more from upper small intestine.

• All these salicylates are Non selective COX inhibitors

• Side effects: Gastric upset & Ulceration in GIT

Salicylic acid (2-hydroxybenzoic acid)

Aspirin (Acetylsalicylic acid )

Salicyliamide

Diflunisal Salsalate

Aryl & Heteroarylpropanoic acid analogues

• The active drugs from this group are Ibuprofen, Fenoprofen, Flurbiprofen, Ketoprofen, Naproxen, Suprofen, Oxaprogin.

• They are non-selective COX inhibitors.

• To stop pain & inflammation symptoms COX-2 inhibition is required.

• COX-2 is induced by inflammation and excess protaglandins are synthesized.

• COX-1 blockage inhibits the formation of protective prostaglandins such as in GIT.

• Side effects are Gastric upset & Ulceration in GIT

Ibuprofen (2-Isobutylphenylpropanoic acid)

Flurbiprofen Ketoprofen

Naproxen

Aryl & Heteroarylacetic acid analogues

• The active members of this class of drugs are Indomethacin, Sulindac, Tolmetin, Zomiperac, Ketorolac, Etodolac, Bromfenac, Nebumetone.

• This drugs are Ethanoic acid (acetic acid) derivatives.

• They are also non-selective COX inhibitors.

• Side effects: They produce gastric upset and ulceration of gastric and intestinal mucosa as they inhibit formation of protective prostaglandins in GIT.

Indomethacin

Ketorolac Sulindac

Tolmetin Zomepirac

Arylanthranilic acid analogues

• The drugs from this group are Mafenamic acid, Flufenamic acid, Meclofenamic acid, Diclofenac, Aceclofenac, Lumiracoxib

• This class has a characteristics in their structure is that they have a second aromatic ring attached through a secondary amine linkage.

• Mafenamic acid is the oldest of this group and is used in mild to moderate pain.

• Meclofenamic acid is used for the treatment of acute and chronic rheumatoid arthritis and osteoarthritis as well as in dysmenorrhea.

• Diclofenac is used for short- and long term treatment of rheumatoid, osteoarthritis and and in ankylosing spondylitis.

• The potassium salt of Diclofenac is faster acting, and is used for management of acute pain and primary dysmenorrhea.

• Lumiracoxib is a potent NSAID of COX-2 selective inhibitors used for rheumatoid and osteoarthritis and in acute pain.

Arylanthranilic acid analogues

Mafenamic acid Diclofenac

Oxicams : Piroxicam, Meloxicam

• The oxicams are the non-carboxylic acid group of NSAIDs.

• The two members of the group are Piroxicam and Meloxicam.

• Piroxicam has a plasma half life of 50 hours, thus required only 20 to 30 mg daily in oral dosage form.

• Side effects of piroxicam is causing GI irritation.

• Meloxicam is a selective COX-2 inhibitor.

• Meloxicam is used in rumatoidarthitis and in osteoarthritis.

• It has much lower GI side effects in comparison to the rest of the non-selective NSAIDs.

Piroxicam & Meloxiocam

Piroxicam Meloxicam

Aryl sulfonamides: Nimesulide, Flosulide

• Arylsulfonamides are also non-carboxylic acid derivatives.

• Nimesulide is non selective NSAID

• Flosulide is a selective COX-2 inhibitor.

Pyrazolone derivatives

• The pyrazolones are 3,5-pyrazolidinedione derivatives .

• The active drugs of this group are phenylbutazone, oxyphenbutazone.

• All are non selective NSAIDs

Pyrazolidinediones

Phenylbutazone Oxyphenbutazone

Antipyretic analgesic

• The antipyretic analgesics reduce elevated body temperature in fever and reduce pain. The drugs of this group are acetaminophen, acetanilide, phenacetin, antipyrine, aminopyrine.

• The antipyretic analgesics do not inhibit COX-1 and COX-2 enzymes.

Antipyretic analgesic

Antipyrine Aminopyrine Acetaminophen / paracetamol

Selective COX-2 inhibitors

• Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Flumizole are the drugs of selectively active COX-2 inhibitor.

• The selective COX-2 inhibitors are specific anti-inflammatory agents. The have less side effects in gastrointestinal tract.