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
1
.
7
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 reninangiotensin 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
2
.
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
4
or TxA
2
) 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.