ANTI -INFLAMMATORY DRUGS

PRESENTED BY,MANJUNATH D

GUIDED BY,Prof. K. KEMPARAJU

Introduction Inflammation is a protective immunovascularresponse that involves immune cells, blood vessels, andmolecular mediators.

Can be CAUSED by numerous stimuli including:

•Antigen-antibody interaction

•Thermal and physical injury

•Microbial invasion

•Physical damage

•Immune reactions

Signs of inflammation

Redness –due to vasodilation of capillaries toincrease blood flow.

Heat - due to effect on thermoregulatory site ofthe brain.

Swelling – due to Increased vascular permeabilityand influx of plasma proteins and

phagocytic cells into the tissue spacesPain – due to

-Hyperalgesia, sensitization of nociceptors-local release of pain inducers and-increased tissue pressure

Inflammatory responses occur in

three distinct phases:1. An acute transient phase, characterized by:

– local vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor)

– Increased permeability of the blood vessels results in the leakage of plasma proteins and fluid into the tissue (edema), which manifests itself as swelling.

2. A delayed phase, most prominently characterized by:

– infiltration of leukocytes and phagocytic cells to the

injured /inflammed tissue

3. A chronic proliferative phase, in which:

– tissue degeneration and fibrosis occur

Mediators of the inflammatory response Histamine – Secreted from mast cell .Histamine causes dilation and increased permeability of capillaries.

ProstaglandinsPGE2 - promote Vasodilation,Directly Cause Pain and

Induces FeverPGI2 - increase vascular permeability, enhance pain

producing properties of bradykinin.

Plasma proteases (Bradykinin)- A vasoactive protein which is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain.

Bradykinin

(C5H9N3)

C50H73N15O11

Leukotrienes- increase vascular permeability and leakiness.- increase mobilization of endogenous mediators of inflammation

Thromboxane A2 (TXA2)- Thromboxane is a member of thefamily of lipids known as eicosanoids. The two major thromboxanesare thromboxane A2 and thromboxane B2.

cause platelets to aggregatecauses vasoconstrictioncauses smooth muscle contractionenhances function of inflammatory cells.

C20H32O5

Types of anti-inflammatory drugs

Steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drug

- Cortisone

- Hydrocortisone- Acetaminophen

- Aspirin

Steroidal anti-inflammatory drugs (SAIDs)

The steroids are compounds with glucocorticoid activity, and are more powerful drugs than NSAIDs.

- Containing steroid moiety in their structure.

Derived from cholesterol.

Glucocorticoids (GC)

CortisoneHydrocortisone C21H28O5C21H30O5

Glucocorticoids (GC)

Mechanism of Action :

They act by indirect inhibition of the enzyme phospholipase A2

which activate synthesis of arachidonic acid with subsequent

formation of prostaglandins.

They induce synthesis of a protein “lipocortin-1” which has

the inhibitory effect on phospholipase A2.

They enter in to the cell and reach nucleus.

phospholipase A2

GC inhibition

Hyperglycemia due to increased gluconeogensis, insulin resistance,

and impaired glucose tolerance ("steroid diabetes");

Redistribution of body fat: moon face, buffalo hump and truncal

obesity.

Muscle breakdown (proteolysis),weakness; reduced muscle mass.

Increased plasma amino acids, increased urea formation;

Growth failure,

Adrenal insufficiency.

Glaucoma due to increased cranial pressure.

Side Effects :

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that provide unmistakable and significant health benefits in the treatment of pain and inflammation.

The NSAIDs can be sub-classified on the basis of chemical structure as follows:

Salicylates Propionic Acids (Profens) Aryl and Heteroarylacetic AcidsOxicams (“Enol Acids”)Anilides

In general, NSAIDs structurally consist of an carboxylic acid, enols attached to a planar, aromatic functionality.

General Mechanism of NSAID Action

The primary action of NSAIDs is the inhibition of the COX enzyme, by inhibiting this enzyme the production of prostaglandins are also inhibited. The COX enzyme synthesised prostaglandins from fatty acids such as arachidonic acid.

Most NSAIDs inhibit both major forms of the COX enzyme, however all are still considered toxic. Newer drugs which are believed to be COX-2 specific are relatively safer in chronic use.

Besides from the inhibition of the COX enzyme, other actions include: Inhibit superoxides (toxic) and free radicals. Inhibit Bradykinin production (A Peptide which dilates blood vessels, lowering blood pressure) Inhibits metalloproteinases (Proteolytic enzymes whose catalytic mechanism involves a metal) Antagonises interleukin-1 and tumour necrosis factor.

Other Actions of NSAIDs

Commonly Used NSAIDs and their properties

Aspirin (Acetylsalicylic acid) Aspirin is a potent anti-inflammatory drug with mild central analgesic and antipyretic actions. It is readily absorbed from the stomach and small intestine, an acid drug is well absorbed in an acidic environment. It is metabolised by tissue /plasma esterases. Aspirin may also be used in low doses, daily to prevent platelet aggregation.

Aspirin

C9H8O4

Aspirin and nonselective NSAIDs produce inhibition of platelet function via their inhibition of COX1. In the case of aspirin, the inhibition is irreversible, so the effect on platelet function continues for the life of the affected platelet

Action of aspirin

Aspirin-like drugs act by inhibiting the activity of the cyclooxygenase(COX) enzyme.

COX-1 are implicated in the maintenance of normal physiological function and have a 'cytoprotective' action in the stomach. COX-2 expression is normally low but is induced by inflammatory stimuli and cytokines.

Mechanism

Phenylbutazone is the most widely used NSAID in equine medicine; however it is extremely toxic in humans. Due to the acidity of the drug, it is readily absorbed from the stomach or duodenum. Phenylbutazone metabolites are weak acids and therefore preferably excreted in alkaline urine.

Phenylbutazone

Meloxicam

Meloxicam is a similar drug, but with a shorter half-life (30-40 hours). It is thought to have greater potency for COX-2 than COX-1 therefore side-effects may be less. It is also thought to be chondroprotective (The slowing of degradation of articular cartilage)

Phenylbutazone

Meloxicam

C19H20N2O2

C14H13N3O4S2

Meclofenamic acid is a potent anti-inflammatory, anti-pyretic analgesic. It is more potent than aspirin but similar in effect. As well as inhibiting COX enzymes it has found to be a prostaglandin antagonist, interacting with prostaglandin receptors. It therefore prevents the action of prostaglandin already present possibly exerting a more rapid reduction of inflammation.

Meclofenamic Acid

Carprofen is a potent anti-inflammatory drug, but is a weak inhibitor of COX. Its mode of action is not yet known but it significantly inhibits neutrophil migration. Due to weak inhibition of COX, toxicity of Carprofen tends to be low.

Carprofen

All this anti-inflammatory drugs have similar mechanism as aspirin.

Meclofenamic Acid

Carprofen

C14H11Cl2NO2

C15H12ClNO2

Mild to moderate inflammatory lesions and associated pain Acute inflammation and pain Joint inflammation and pain Suppression of pulmonary oedema Endotoxaemia Anti-thrombic

When to Use NSAIDs

Gastric irritation and ulceration Vomiting and diarrhoea Hepatotoxicity Renal papillary necrosis, chronic nephritis Bone marrow disturbance Skin rashes Respiratory distress

Side Effects of NSAIDs

Conclusions

Anti inflammatory drugs plays pivotal role in preventing inflammation either by affecting inflammatory mediators or by modifying enzymes required for the synthesis of these mediators.

The understanding of the pivotal role of inflammation in seemingly unrelated diseases has resulted in the use and development of new anti-inflammatory agents.