PLATELET ACTIVATING FACTOR (PAF) / platelet activating factor structure / Pharmacology Notes pdf / Bpharm notes

 PLATELET ACTIVATING FACTOR (PAF) :

Like eicosanoids, platelet activating factor (PAF) is a cell membrane derived polar lipid with intense biological activity. Discovered in 1970s PAF is active at subnanomolar concentration and is now recognized to be an important signal molecule. PAF is acetylglyceryl ether-phosphoryl choline. The etherlinked alkyl chain in human PAF is mostly 16 or 18 C long.

Synthesis and degradation :

PAF is synthesized from precursor phospholipids present in cell membrane by the following reactions:

The second step is rate limiting. Antigen-antibody reaction and a variety of mediators stimulate PAF synthesis in a Ca2+ dependent manner on demand. There are no preformed stores of PAF. In contrast to eicosanoids, the types of cells which synthesize PAF is quite limited—mainly WBC, platelets, vascular endothelium and kidney cells.

PAF is degraded in the following manner:

Actions :

PAF has potent actions on many tissues/organs..

Platelets :

PAF induces aggregation and release reaction; also releases TXA2 ; i.v. injection of PAF results in intravascular thrombosis.

WBC :

PAF is a potent chemotactic for neutrophils, eosinophils and monocytes. It stimulates neutrophils to aggregate, to stick to vascular endothelium and migrate across it to the site of infection. It also prompts release of lysosomal enzymes and LTs as well as generation of superoxide radical by the polymorphs. The chemotactic action may be mediated through release of LTB4 . It induces degranulation of eosinophils.

Blood vessels :

Vasodilatation mediated by release of EDRF occurs causing fall in BP on i.v. injection. Decreased coronary blood flow has been observed on intracoronary injection, probably due to formation of platelet aggregates and release of TXA2 .

PAF is the most potent agent known to increase vascular permeability. Wheal and flare occur at the site of intradermal injection.

Injected into the renal artery PAF reduces renal blood flow and Na+ excretion by direct vasoconstrictor action, but this is partly counteracted by local PG release. 

Visceral smooth muscle :

Contraction occurs by direct action as well as through release of LTC4 , TXA2 and PGs. Aerosolized PAF is a potent bronchoconstrictor. In addition, it produces mucosal edema, secretion and a delayed and long-lasting bronchial hyper-responsiveness. It also stimulates intestinal and uterine smooth muscle.

Stomach :

PAF is highly ulcerogenic: erosions and mucosal bleeding occur shortly after i.v. injection of PAF. The gastric smooth muscle contracts.

Mechanism of action :

Membrane bound specific PAF receptors have been identified. The PAF receptor is a G-protein coupled receptor which exerts most of the actions by coupling with Gq protein and generating intracellular messengers IP3 /DAG → Ca2+ release. It can also inhibit adenylyl cyclase by coupling with Gi protein.

As mentioned above, many actions of PAF are mediated/augmented by PGs, TXA2 and LTs which may be considered its extracellular messengers. PAF also acts intracellularly, especially in the endothelial cells. Rise in PAF concentration within the endothelial cells is associated with exposure of neutrophil binding sites on their surface. Similarly, its proaggregatory action involves unmasking of fibrinogen binding sites on the surface of platelets.

PAF antagonists :

A number of natural and synthetic PAF receptor antagonists have been investigated. Important among these are ginkgolide B (from a Chinese plant), and some structural analogues of PAF. The PAF antagonists have manyfold therapeutic potentials like treatment of stroke, intermittent claudication, sepsis, myocardial infarction, shock, g.i. ulceration, asthma and as contraceptive. Some of them have been tried clinically but none has been found worth marketing. Alprazolam and triazolam antagonize some actions of PAF.

Pathophysiological roles :

PAF has been implicated in many pathological states and some physiological processes by mediating cell-to-cell interaction. These are:

1.  Inflammation: Generated by leukocytes at the site of inflammation PAF appears to participate in the causation of vasodilatation, exudation, cellular infiltration and hyperalgesia. 

2.  Bronchial asthma: Along with LTC4 and LTD4 , PAF appears to play a major role by causing bronchoconstriction, mucosal edema, recruiting eosinophils and provoking secretions. It is unique in producing prolonged airway hyper-reactivity, so typical of human bronchial asthma. 

3.  Anaphylactic (and other) shock conditions: are associated with high circulating PAF levels. 

4.  Haemostasis and thrombosis: PAF may participate by promoting platelet aggregation. 

5. PAF may also play a role in implantation of fertilized ovum, ischaemic states of brain, heart and g.i.t., including g.i. ulceration.