Leukotriens

 Leukotrienes

 PKGhatak,MD

 

In 1979 Mr. Samuelsson of Sweden discovered Leukotriene. As the name suggests, Leukotriene is a leukocyte product. It is an organic compound containing 3 separate carbon to carbon double bonds called triene. There are several Leukotrienes (LTs), and LTs are grouped as 1. Inflammatory Leukotrienes involving Neutrophil leukocytes and 2. Cysteinyl leukotrienes (CyLT) involving mast cells and Eosinophils. Cysteinyl-leukotrienes are designated as LTC4, LTE4, and LTF4.  Inflammatory-leukotrienes are designated by LTB4, LTD4, LTG4, LTB5. 

Leukotrienes are only active in and around the place of production.

Chemistry.

LTs are derivatives of Arachidonic acid, released from the cell wall by an enzyme Phospholipase, then converted to LTs by specific Lipoxygenase enzymes. LTs structurally resemble Prostaglandins and Thromboxane.

LTs receptors.

LTs act on G-protein receptors and Peroxisome receptors. These receptors are most abundant in the skin, lungs, uterus, GI tract, heart, and liver.

Physiological role of Leukotrienes.

LTs are intimately involved in the initiation and maintaining a healthy inflammatory response to injury or infection. And allergic response to noxious agents and in triggering an Asthma attack and prolonging the duration of asthma.

Specific actions by different LTs.

LTB4. Promotes the release of inflammatory cytokines, recruits neutrophils, increases neutrophil chemotaxis, causes degranulation of neutrophils, increases interaction between neutrophils and endothelial cells, stimulates the release of mediators, enzymes and superoxide, increases IL 6, increases pain perception by lowering pain receptors threshold.

LTB5. Potentiate bradykinin induced asthma.

LTD4. Produce smooth muscle contractions of bronchial tubes.

LTG4. Not much is known in humans.

LTC4. It binds with cysteinyl LT receptors R1 and R2 present in mast cells and Eosinophils. It initiates asthma and prolongs asthma duration. Promote binding of eosinophils to the bronchial epithelium and initiate an inflammatory response in bronchi. It causes constriction of bronchial smooth muscles. It causes allergic reactions to drugs and reactions to IV contrast medium. When produced in excess amounts it can trigger an anaphylactic shock.

Leukotriene Blocking drugs.

Like most biological molecules, drugs can block the action of LTs by neutralizing the LTs and an antibody that will bind to the specific receptors and prevent the LTs from bond with the receptors.

Montelukast. It is an LT receptor antagonist. It is approved for allergic rhinitis, allergic conjunctivitis, and allergic cough.

Zairlukast. Is also an LT receptor antagonist. Also approved for conditions mentioned under Montelukast.

Zileution. It inhibits the enzyme LT synthase and down the way stops LTs production.

Corticoids. Inhibit phospholipase and ultimately block the production of more LT. 

Monoclonal Antibodies.

Several monoclonal antibodies have been developed against LTC4 receptors R1 and R2. In experimental models, these are proven to be effective. It is expected one or two monoclonal antibodies will be approved soon.

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