ANTI INLAMMATORY AGENTS(NSAID)

ANTI INFLAMMATORY AGENTS
Inflammation may be defined as the series of changes that occur in living tissues following injury.
The injury which is responsible for inflammation may be variety of conditions such as

1. Physical agents like UV radiation, heat, mechanical trauma.
2. Chemical agents like organic and inorganic compounds.
3. Toxins of various bacteria, intracellular replication of virus.

In old days some steroids like prednisolone, dexamethasone, betamethasone, triamcinalone and hydrocartisone were used as anti inflammatory agents. But these drugs produce some adverse effects. But nowadays much safer and better tolerated Non Steroidal Anti Inflammatory Drugs (NSAID) are used.
The non narcotic analgesics are having the following groups.

1. Analgesics which relieve the pain without interacting the opioid receptors.


2. NSAID which possess anti inflammatory property.


3. Anti pyretic which reduce the elevated body temperature.

CLASSIFICATION
1. Salicylic acid derivatives :
Sodium salicylate, Sodium thio salicylate, Magnesium salicylate, Choline salicylate, Carb ethyl salicylate, Phenyl salicylate, Salicylamide, Aspirin, Aluminium aspirin, Calcium acetyl salicylate, Salsalate.
2. N-Anthranilic acid Derivatives:
Mefenamic acid, Meclofenamate sodium
3. Aryl acetic acid Derivatives:
Indomethacin, Sulindac, Tolmetin sodium, Zomepriac sodium, Ibuprofen, Naproxan, Fenoprofen calcium, Ketoprofen, Flurbiprofen, Diclofenac sodium and potassium, Ketorolac tromethamin, Piroxicam.
4. Aniline and Para Amino Phenol Derivatives:
Acetanilide, Phenacetin, Acetaminophen(Paracetamol).
5. Pyrazolone and Pyrazolidine dione Derivatives:
Anti pyrin, Aminopyrin, Dipyrone, Phenyl Butazone, Oxyphen Butazone.

I. Salicylic acid Derivatives

SAR of Salicylic acid Derivatives

1. Various substitution on the carboxyl or hydroxyl group result in to change in potency as well as toxicity.


2. The hydroxy group in ortho position is very important for activity.


3. Salt of salicylic acid with choline and magnesium possess longer duration of action and lesser gastro intestinal irritation tha aspirin.


4. Salsalate is an ester of two salicylic acid molecules. Since it is insoluble in stomach and is not absorbed until it reaches the small intestine. So it cause less gastric irritation.


5. Introduction of hydrophobic group(F) at 51 positionof flufenasil is more potent, longer acting and with less gastric irritation.

Mechanism of action

The antipyretic and Anti inflammatory actions of salicylates and other acidic drugs are probably due to their inhibitory effect on prostaglandin synthesis by inhibiting prostaglandin synthetase enzyme.
Salicylates exert their antipyretic action by increasing heat elimination of the body through the mobilization of water and consequent dilution of the blood.

II. Aryl acetic acid Derivatives

Synthesis of Indomethacin SAR for Aryl acetic acid Derivatives

I.For Indole acetic acid derivatives

1. N-substitution of indole derivative increase Anti inflammatory activity in the order of benzyl > alkyl > H
2. The methyl group at 2nd position of indole increase the activity.
3. The substitution at 5th position increase the activity in the order of OCH3 > (CH3)2 N >CH3 > H.
4. The carboxyl group is necessory for good Anti inflammatory activity.
5. The N-Benzoyl group of indolehave halogen, CF3 or SCH3 at para position provides the greatest Anti inflammatory activity.

II.For Phenyl propionic acid derivatives

1. The maximum activity is obtained for the substitution at R1 is isobutyl group. The smaller substituents (Methyl, Ethyl) reduces the activity.
2. Maximal activity is found with R2 is methyl group. Smaller and larger groups diminish the activity.
3. Replacement of carboxyl group by an ester, alcoholic, amide, Hydroxamic acid(NHOH) or tetrazole(CHN4) generally produce less active compounds.
4. The anti inflammatory activity resides in the S(+) isomer.

III.For Naphthyl propionic acid derivatives

1. The anti inflammatory activity is reduced when R1 is larger than OCH3 or SCH3 group.
2. The activity may be reduced when the carboxyl group is replaced with alcohol or aldehyde.
3. Dextro rotatory isomer is 11 times more active than phenyl butazone.

IV.For Oxicams

1. The nitrogen of benzothiazine ring have the substituent CH3 and other electron withdrawing groups on the anilide phenyl groups such as Cl, CF3, have good anti inflammatory activity.
2. The introduction of a heterocyclic ring in the amide oxide chain significantly increase the activity. (Sudoxicam is more potent than indomethacin).
3. The benzothiazine have pKa range of 6 to 8 have more activity.

III. Aniline and P-Aminophenol Derivatives

IV. Pyrazolone and Pyrazolidine dione Derivatives:

SAR for Pyrazolidine diones

1. The butyl group of carbon 4 may be replaced by propyl or allyl are less active.
2. The meta substitution of the aryl ring are inactive but para substitution such as CH3, Cl, NO2 or OH retains activity.
3. Replacement of nitrogen in pyrazolidines with oxygen yield isoxazole analog which is as active as pyrazolidine derivatives.
4. Decreasing pKa values of phenyl butazone analogs have shorter half lives.
5. Substitution at C-4 by methyl group destroys anti inflammatory activity.
6. The most active compound have the log P value is 0.7.

Mechanism of actions for NSAIDs

1. The prostaglandins are the mediation of inflammation. The NSAIDs are mainly prevent the formation of unstable proataglandin endoperoxide synthetase enzyme.
2. Most of the drugs are irreversible inhibitors of cyclo oxygenase activity, thus they prevent the formation of prostaglandins and consequently reducing the signs and symptoms of inflammation.
3. Besides inhibiting prostaglandin bio synthesis, the NSAIDs also inhibit the synthesis of leucotrienes, histamine and some biological process such as phagocytosis and platelet aggregation.
4. Other possible mechanisms of NSAIDs are kinin antagonism, prevention of leucocyte accumulation, stabilization of lysosome membranes, uncoupling of oxidative phosphorylation and oxygen radical scavenger action.
5. The inhibition of cyclo oxygenase can occur either by irreversible inactivation of enzyme(Eg-Aspirin) or rapid reversible non competitive inhibition involves anti oxidant or free radical trapping properties.
6. Some NSAIDs (Ibuprofen) reversible competitive inhibit by the propionic acid, which binds reversibly to the enzyme cyclo-oxygenase competing with arachidonic acid.