LIPID DERIVED AUTOCOIDS AND PLATELET ACTIVATING FACTOR

Drug

HISTAMINE

Mechanism of action and

Pharmaco

dynamics

Histamine acts directly on the blood vessels to dilate arteries and capillaries;

this action is mediated by both H 1- and H 2-receptors. Capillary dilatation

may produce flushing of the face, a decrease in systemic blood pressure, and

gastric gland secretion, causing an increased secretion of gastric juice of high

acidity. Increased capillary permeability accompanies capillary dilatation,

producing an outward passage of plasma protein and fluid into the

extracellular spaces, an increase in lymph flow and protein content, and the

formation of edema. In addition, histamine has a direct stimulant action on

smooth muscle, producing contraction if H 1-receptors are activated, or

mostly relaxation if H 2-receptors are activated. Also in humans, the

stimulant effect of histamine may cause contraction of the intestinal muscle.

However, little effect is noticed on the uterus, bladder, or gallbladder.

Histamine has some stimulant effect on duodenal, salivary, pancreatic,

bronchial, and lacrimal glands. Histamine also can bind to H3 and H4

receptors which are involved in the CNS/PNS neurotransmitter release and

immune system chemotaxis, respectively.

Pharmacokinetics

Readily absorbed after parenteral administration. Metabolised in liver.

Adverse effects

Intense Headache, Fast Heartbeat, High blood pressure, Low blood pressure,

Amine

derived

• Histamine (amino acid: Histidine), Seratonin(Tryptophan))

Peptide

derived

• Angiotensin, Bradykinin

Lipid

derived

• Prostaglandins, Leukotrienes, Interleukins, Platelet Activating Factor

Nervouseness

Contraindications

Dose, Route of administration

and Therapeutic effect

Histamine phosphate is indicated as a diagnostic aid for the evaluation of

gastric acid secretory function.

Interactions

The risk or severity of adverse effects can be increased when Acyclovir is

combined with Histamine.

BRADYKININ

Kinin Receptors-

 There are two types of bradykinin receptor

 B1 receptor

 B2 receptor

B1 receptor

B2 receptor

Present in low levels

It strongly induced in inflamed or damaged

tissues by Cytokines line IL-1

It is expressed in most normal tissues

Respond to des-Arg9bradykinin&des-

Arg9kallidin but not to bradykinin itself

Selectively binds the bradykinin and kallidin

and mediates the majority of actions

Has a role in Inflammation and Hyperalgesia.

It activates PLA2 and PLC via interaction with

distinct G Protein

Actions of Kinin

 Smooth muscles:

Causes marked bronco constriction in guinea pig and in

asthmatic patients.

 Neurons:

Potent pain producing agent and its action is potentiated

by the prostaglandins.

 It produces pain by stimulating nociceptive afferents in the skin

and viscera.

Kidney:

 It facilitate salt and water excretion by action on tubules.

 Kinins increases renal blood flow.

Pathophysiological

actions

1. Mediation of

Inflammation

 Kinins produces all signs of inflammation-

Redness,exudation,pain and leukocytes mobilization.

 Tissue injury can causes local kinin production which then sets

in motion the above defensive and reparative process.

 Activation of B2 receptors on macrophages induces production

of IL-1 and TNF alpha (Tumor necrosis factor) and other

inflammatory mediators.

2. Mediation of

Pain

 Due to direct stimulating nerve endings and by increasing

prostaglandin production.

3. Functional

hyperemia

 Hyperemia is an increased amount of blood in the vessels of an

organ or tissue in the body.

Drugs Affecting Kallikarein Kinin System

 Competitive antagonists of both B1 and B2 receptors are available for research use.

 B1 receptor antagonist

 (Leu8des Arg9)bradykinin

 Lys(Leu8 desArg9)bradykinin

 B2 receptor antagonist

 Icatibant

PLATELET ACTIVATING FACTOR

Platelet-activating factor, also known as

PAF, PAF- acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a potent

phospholipid activator and mediator of many leukocyte functions, including platelet aggregation

and degranulation, inflammation, and anaphylaxis.

Physiological and

pathophysiological

effects of PAF

Explanation

Platelet

Aggregation

1. Platelet aggregate or clump together using fibrinogen of vWF as a

connecting agent.

2. The most abundant platelet aggregation receptor is glycoprotein

IIb/3A. Activated platelets will adhere, via glycoprotein Ia to the

collagen that is exposed by endothelial damage.

3. Aggregation and adhesion act together to form platelet plug.

Platelet aggregation is stimulated by ADP,Thromboxane and a2 receptor-

activation but inhibited by other inflammatory products like PGI2 and

PGD2. Platelet aggregation is enhanced by exogenous administration of

anabolic steroids.

Initially, PAF was found to effect aggregation of platelets at

concentrations as low as 10^-11 M, and it induced a hypertensive

response at very low levels also. More generally, it is now recognised

that its primary role is to mediate intercellular interactions.

For example, by binding to its specific receptor, PAF activates the

cytoplasmic phospholipase A2 and phospholipase C. The result of the

latter is an increase in intracellular Ca2+ downstream of the cell and

activation of protein kinase C.

It is now known to exert effects on many different types of non-

inflammatory biological events and functions, including glycogen

degradation, reproduction, brain function and blood circulation.

Thrombus

formation

The function of platelets is the maintainence of haemostasis,this is

achievd by the formation of thrombi when damage to endothelium of

blood vessels occurs.

Conversely ,thrombus formation must be inhibited at times when there is

no damage to the endothelium,

Activation-the inner surface of blood vessel is lined with a thin layer of

endothelial cells,that in normal haemostasis acts to inhibit platelet

activation by producing endothelial ADPase, nor-adrenaline and PGI2.

Endothelial ADPase clears away ADP,a platelet activator,from platelet

surface receptors.

Endothelial cells produce a protein called von Willebrand factor,a cell

adhesion ligand,which helps endothelial cells adhere to collagen in the

basement membrane. Under physiological condition collgen does not

pass into the bloodstream;however vWF is secreted constitutively into

the plasma by the Endothelial cells that Produce it or otherwise is stored

within the endothelial cells or in platelet s

When endothelial damage

occurs platelets comes into contact with exposed collagen and

vWF,causing a reduction in secretion of endothelium platelet inhibitors

the inner surface of blood vessels is lined with a thin layer of endothelial

cells. Under this is a layer of collagen. When the endothelial layer is

injured the collagen is exposed.

When platelets contact collagen they are activated.

Inflammatory and

allergic responses

1-The proinflammatory actions of PAF and its elaboration by

endothelial cells, leukocytes, and mast cells under inflammatory

conditions are well characterized.

2 PAF and PAF-like molecules are thought to contribute to the

pathophysiology of inflammatory disorders, including

anaphylaxis, bronchial asthma, endotoxic shock, and skin

diseases.

3 The plasma concentration of PAF is increased in experimental

anaphylactic shock, and the administration of PAF reproduces

many of its signs and symptoms, suggesting a role for the

autacoid in anaphylactic shock.

4 In addition, mice overexpressing the PAF receptor exhibit

bronchial hyperreactivity and increased lethality when treated

with endotoxin.

5 PAF receptor knockout mice display milder anaphylactic

responses to exogenous antigen challenge, including less cardiac

instability, airway constriction, and alveolar edema; they are,

however, still susceptible to endotoxic shock.

Pharmacological

actions

Explanation

CVS

1 PAF is a potent dilator in most vascular beds; when administered

intravenously, it causes hypotension in all species studied.

2 PAF-induced vasodilation is independent of effects on sympathetic

innervation, the renin–angiotensin system, or arachidonate

metabolism and likely results from a combination of direct and

indirect actions.

3 PAF induces vasoconstriction or vasodilation depending on the

concentration, vascular bed, and involvement of platelets or

leukocytes.

For example, the intracoronary administration of very low

concentrations of PAF increases coronary blood flow by a mechanism that

involves the release of a platelet- derived vasodilator.

4. Coronary blood flow is decreased at higher doses by the formation

of intravascular aggregates of platelets and/or the formation of

TXA

5. The pulmonary vasculature is also constricted by PAF and a similar

mechanism is thought to be involved.

6. Intradermal injection of PAF causes an initial vasoconstriction

followed by a typical wheal and flare.

7. PAF increases vascular permeability and edema in the same manner

as histamine and bradykinin. but PAF is more potent than

histamine or bradykinin by three orders of magnitude.

Smooth Muscle

1 PAF generally contracts gastrointestinal, uterine, and pulmonary

smooth muscle.

2 PAF enhances the amplitude of spontaneous uterine contractions;

quiescent muscle contracts rapidly in a phasic fashion.

3 These contractions are inhibited by inhibitors of PG synthesis.

4 PAF does not affect tracheal smooth muscle but contracts airway

smooth muscle. Most evidence suggests that another autacoid (e.g.,

LTC

or TxA

) mediates this effect of PAF.

5 When given by aerosol, PAF increases airway resistance as well as

the responsiveness to other bronchoconstrictors.

6 PAF also increases mucus secretion and the permeability of

pulmonary microvessels; this results in fluid accumulation in the

mucosal and submucosal regions of the bronchi and trachea.

Stomach

1 In addition to contracting the fundus of the stomach, PAF is the

most potent known ulcerogen.

2 When given intravenously, it causes hemorrhagic erosions of the

gastric mucosa that extend into the submucosa.

Kidney

1 When infused intrarenally in animals, PAF decreases renal blood

flow, glomerular filtration rate, urine volume, and excretion of Na

without changes in systemic hemodynamics

2 These effects are the result of a direct action on the renal

circulation.

3 PAF exerts a receptor-mediated biphasic effect on afferent

arterioles, dilating them at low concentrations and constricting

them at higher concentrations.

4 The vasoconstrictor effect appears to be mediated, at least in part,

by COX products, whereas vasodilation is a consequence of the

stimulation of NO production by endothelium.