Non-steroid anti-inflammatory drugs (NSAIDs)

Non-steroid anti-inflammatory drugs 
(NSAIDs)

Inflammation

Inflammation (I) is a protection reaction of the body, its organs and tissues to the disturbing factors. The main point of inflammation – a limitation and removal of the disturbing factors as well as regeneration of the disturbed tissues.    
Inflammation is a complex process regulated by numerous endogenous substances which are produced by various cell elements participating in inflammation: mast cells, monocytes, polymorphonuclear leucocytes, macrophages, thrombocytes, endotheliocytes. 

They secret bioactive substances (BAS): prostanoids, leukotrienes, NO, platelet-activating factor (PAF), histamine etc. Pharmacological regulation of inflammation is usually carried out by the depression of production and release of substances stimulating the inflammation process.

The main ones are the drugs affecting the formation of BAS out of phospholipids in cell membranes participating in the inflammation process.

Action of drugs at inflammation 

- Inhibition of phospholipase А2, in the synthesis of prostanoids (prostaglandins, thromboxane), leukotrienes and PAF. The action of glucocorticoids.
- Inhibition of COX in the synthesis of prostaglandins (NSAIDs).
- The block of prostanoid receptors (thromboxane  antagonist – сулотробан).
- The block of 5-lipoxydenase in the synthesis of leukotrienes (zileuton).
- The block of leukotriene receptors (LTD4 Zafirlukast).
- The block of the receptors for PAF (analogs of PAF, Alprazolam).

Non-steroid anti-inflammatory drugs

NSAIDs inhibit COX and decrease the synthesis of prostanoids. There are 2 enzymes: COX-1 and COX-2. 
COX–1 is produced in typical conditions and regulates the formation of prostanoids. The formation of COX-2 is induced by the inflammation process. 
Under the influence of COX-1 prostaglandins are constantly synthesizing in the body. They regulate the functions of organs and tissues (secretion of the protective mucus in stomach, aggregation of platelets, tone of vessels, renal blood circulation, tone and contractile activity of myometrium etc.). 

Normally, the activity of COX-2 is not great. However, the inflammation process induces the synthesis of this enzyme. The excess of prostaglandins Е2 and 12 causes vasodilation in the place of inflammation, increase of vascular wall penetrability, sensibilizes nociceptors to bradykinin and histamine.  
Under the influence of the factors inducing inflammation BAS are released. They stimulate phospholipase А2 — enzyme splitting phospholipids with the formation of arachidonic acid. Under the influence of COX prostaglandins are synthesized out of arachidonic acid, while under the influence of 5-lipoxygenase – leukotrienes.

Classification of anti-inflammatory drugs

A.teroid anti-inflammatory drugs

• Glucocorticoids; 

B. Non-steroid anti-inflammatory drugs 
C.Slow action antirheumatic drugs

• Gold drugs: aurothiomalate sodium, auranofin, D- Penicillamine;
• 4-aminocholines: Chloroquine (Chingaminum), Hydroxychloroquine (Plaquenil).

Classification of NSAIDs

NSAIDs:
1)Nonselective COX-1 and COX-2 inhibitors:
а)irreversible COX inhibitors
 acetylsalicylic acid (Aspirin);
б)reversible COX inhibitors
Ibuprofen (Brufen), diclofenac sodium (Ortophen, Voltaren), Indometacin (Metindol), Naproxen, Piroxicam (Felden), Lornoxicam.
2)Selective reversible COX-2 inhibitors
Meloxicam (Movalis), Nimesulide (Nimulid), Celecoxib (Celebrex), Rofecoxibe (Vioxx).

Pharmacodynamics of NSAIDs
The mechanism of action of NSAIDs is associated with the competing inhibition of COX. The block of COX by NSAIDs leads to the disturbances in the synthesis of prostaglandins Е2 and 12 and to the development of 3 basic effects:

• Anti-inflammatory;
• Analgesic;
• Antipyretic.

Anti-inflammatory action of NSAIDs is mainly caused by the block of COX and the subsequent  inhibition of synthesis of prostaglandins Е2 and 12 in the inflammation focus.

Analgesic effect of NSAIDs is conditioned by the peripheral action associated with the block of synthesis of prostaglandins  Е2 and 12 and the decrease of bradykinin action on nociceptors (prostaglandins Е2 and 12 sensibilize the nerve endings to the action of bradykinin). NSAIDs are most effective in case of pains of an inflammatory nature.

Antipyretic effect. At inflammation interleukin-1 stimulates the production of prostaglandin Е2 in hypothalamus that causes fever. Any disturbance in the synthesis of prostaglandin Е2 in CNS leads to the t0 fall. Antipyretic effect on non-narcotic analgesics is used for the diseases with body t0  above 38 °С, as well as in case of less intense hyperthermia if it is accompanied by the risk of convulsing syndrome (small children) or not tolerated.

Non-selective NSAIDs inhibit both isoforms of COX, increase the risk of side effects connected with the inhibition of COX-1. Often it is ulcerations of mucous tunic of stomach that is connected with the inhibition of synthesis of prostaglandins of group E possessing gastroprotecting properties (increase mucus and hydrocarbonate ion secretion, decrease the secretion of HCL, improve the blood circulation in the mucous tunic of stomach). NSAIDs reduce platelet aggregation due to their block by COX-1 and decrease the synthesis of thromboxane А2.
In therapeutic doses selective inhibitors of COX-2 mainly inhibit the form of COX-2, induced by inflammation, and side effects associated with the inhibition of COX-1 (noticeable in 8—15%, and if the drugs are used for a long period of time). The long period of selective NSAIDs intake leads to the induction of COX-2 gene expression. It decreases their potency and conditions the increase of their daily dose. In large doses the selectivity of NSAIDs is lost.    

1. Acetylsalicylic acid
2. Ibuprofen
3. Indometacin
4. Ortophen
5. Celecoxib
6. Meloxicam
7. Lornoxicam
8. Nimesulid