1. 1
INDIRA GANDHI NATIONAL TRIBAL UNIVERSITY
AMARKANTAK(M.P)
ASSIGNMENT
ON
BRADYKININ AND SUBSTANCE P
SUBMITTED BY: SUBMITTED TO:
Mary Melna Dr. Kunjbihari Sulakhiya Sir
ENROLL NO:
1801024022
B.PHARM VSem
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BRADYKININ
HISTORY
In the 1920s and 1930s, frey, kraut, and werle characterized a hypotensive
substance in urine and found a similar material in saliva, plasma, and a variety of
tissues.
The pancreas also was a rich source, so they named this material kallikrein after a
greek synonym for that organ, kallikreas.
By 1937, werle, gotze, and keppler had established that kallikreins generate a
pharmacologically active substance from an inactive precursor present in plasma.
In 1948, werle and berek named the active substance kallidin and showed it to be a
polypeptide cleaved from a plasma globulin that they termed kallidinogen.
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HISTORY
Interest in the field intensified when rocha e silva and associates reported that trypsin
and certain snake venoms acted on plasma globulin to produce a substance that
lowered blood pressure and caused a slowly developing contraction of the gut.
Because of this slow response, they named the substance bradykinin.
A term derived from the greek words bradys, meaning "slow," and kinein, meaning "to
move."
In 1960, the nonapeptide bradykinin was isolated by Elliott and coworkers and
synthesized by Boissonnas and associates.
Shortly thereafter, kallidin was found to be a decapeptidebradykinin with an additional
lysine residue at the amino terminus.
kallidin and bradykinin are referred to as plasma kinins.
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Generation And Metabolism
Plasma kinins are polypeptides split off from a plasma globulin kininogen by the
action of specific enzymes kallikreins.
Two important plasma kinins are :
-kallidin (decapeptide) and
-bradykinin(nonapeptide).
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KININOGENS
Two kininogens are known to be present in plasma: A low-molecular-weight form
(LMW kininogen) and a highmolecular-weight form (HMW kininogen).
Bradykinin is generated from high molecular weight (hmw) kininogen by the action of
plasma kallikrein.
On the other hand, kallidin can be produced from both (lmw) kininogen as well as
hmw-kininogen by action of tissue kallikreins.
Bradykinin can also be generated from kallidin on the removal of lysine residue by
amino peptidase.
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KALLIKREINS
Kallikreins are glycoprotein enzymes produced in the liver as prekallikreins and
present in plasma and in several tissues, including the kidneys, pancreas, intestine
etc.
Prekallikrein is activated by hageman factor (factor xii) which itself is activated by
tissue injury and contact with surfaces having negative charge. E.g.: collagen,
basement membrane, bacterial liposaccharides, urate crystals etc. Plasmin facilitates
contact activation of hagemen factor.
Kinins are also generated by trypsin, proteolytic enzymes in snake and wasp
venoms.
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Hageman factor, prekallikrein and the kininogens leak out of the vessels during
inflammation because of increased vascular permeability, and exposure to negatively
charged surfaces promotes the interaction of Hageman factor with prekallikrein. The
activated enzyme then 'clips' bradykinin from its kininogen precursor.
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METABOLISM OF KININS
Metabolized rapidly (half-life < 15 seconds).
By peptidases, commonly referred to as kininases.
Two plasma kininases have been well characterized.
I. Kininase I:- apparently synthesized in the liver, is a carboxypeptidase that releases the
carboxyl terminal arginine residue.
II. Kininase II :- present in plasma and vascular endothelial cell throughout the Body. It is
identical to angiotensin-converting enzyme (ace-peptidyl dipeptidase), inactivates
kinins by cleaving the carboxyl terminal dipeptide,Phenylalanyl-arginine.ss
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KININ RECEPTORS
Existence of two types bradykinin receptor has been established :
B1 and B2
Both are GPCR & mediate similar effects.
B1
normally expressed at very low levels
but are strongly induced in inflamed or
damaged tissues by cytokines such as
IL-1.
Respond to des-Arg9-bradykinin &des-
Arg9-kallidin but not to bradykinin
itself.
Likely that B1 receptors play a
significant role in inflammation and
hyperalgesia
B2
Constitutively expressed in most
normal tissues
Selectively binds bradykinin and
kallidin and mediates the majority of
their effects.
The B2 receptor activates PLA2 and
PLC via interaction with distinct G
proteins.
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PHARMACOLOGICALACTIONS OF KININS
Cardiovascular system
Kinins are more potent vasodilators than ACh and histamine.
Dilatation is mediated through endothelial NO & PGI2 generation and
involves mainly arterioles.
They markedly increase capillary permeability due to separation of
endothelial cell -exudation and inflammation occurs.
Larger arteries and most veins are constricted through direct action on
smooth muscle.
Can release histamine and other mediators from mast cells.
Injected I.V kinins cause flushing, throbbing headache and fall in Bp.
Kinins have no direct action on heart, reflex stimulation occur due to fall in
BP.
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PHARMACOLOGICALACTIONS OF KININS
Smooth muscle:
Kinin induced contraction of intestine is slow.
Cause marked bronchoconstriction in guineapig and in asthmatic patients.
Neurones:
potent pain-producing agent, and its action is potentiated by the
prostaglandins.
elicit pain by stimulating nociceptive afferents in the skin and viscera.
Kidney:
Kinins increase renal blood flow.
facilitate salt and water excretion by action on tubules.
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PATHOPHYSIOLOGICAL ROLES
1.Mediation of inflammation
Kinins produce all signs of inflammation-redness, exudation, pain and
leukocyte mobilization.
Tissue injury can cause 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-α and other inflammatory mediators.
2.Mediation of pain
By directly stimulating nerve endings and by increasing PG production
kinins appear to serve as mediators of pain.
B2 antagonist block the acute pain produced by bradykinin.
But induced B1 receptors appear to mediate pain of chronic inflammation.
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PATHOPHYSIOLOGICAL ROLES
3.Fuctional hypermia
Functional hypermia in glands during secretion
Regulation of microcirculation –especially in kidney may be occurring
through local kinin production.
4. Other roles
Kinins cause closure of ductus arteriosus, dilation of foetal pulmonary
artery and constriction of umblical vessels-they may be involved in
adjusting from foetal to neonatal circulation.
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DRUGS AFFECTING KALLIKRIEN-KININ SYSTEM
Drugs that modify the activity of the kallikrein-kinin system are available,
though none are in wide clinical use.
Competitive antagonists of both B1 and B2 receptors are available for
research use.
Examples of B1 receptor antagonists are the peptides
-[Leu8-des-Arg9]bradykinin and
- Lys[Leu8-desArg9]bradykinin.
Non-peptide B1 receptor antagonists are not yet available.
The first B2 receptor antagonists to be discovered were also peptide
derivatives of bradykinin.
These first-generation antagonists were used extensively in animal studies
of kinin receptor pharmacology.
However, their half-life is short, and they are almost inactive on the human
B2 receptor.
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ICATIBANT:
Second generation B2 receptor antagonist.
It is orally active, potent, and selective.
Has a long duration of action (> 60 minutes).
And displays high B2 receptor affinity in humans and all other species in
which it has been tested.
Has been used extensively in animal studies to block exogenous and
endogenous bradykinin and in human studies to evaluate the role of kinins
in inflammation, Pain and hyperalgesia.
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.
Recently, a 3rd generation of B2 receptor antagonists was developed
Examples are
- FR 173657
- FR 172357 and
- NPC 18884.
These antagonists block both human and animal B2 receptors and are
orally active.
They have been reported to inhibit bradykinin-induced bronchoconstriction
in guinea pigs, carrageenan-induced inflammatory responses in rats, and
capsaicininduced nociception in mice.
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The synthesis of kinins can be inhibited with the kallikrein inhibitor
Aprotinin
Actions of kinins mediated by prostaglandin generation can be blocked
nonspecifically with inhibitors of prostaglandin synthesis such as
aspirin.
Conversely, the actions of kinins can be enhanced with ace
inhibitors,Which block the degradation of the peptides.
Inhibition of bradykinin metabolism by ace-inhibitors contributes
significantly to their antihypertensive action.
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DEFINATION
Substance P is an undecapeptide(a peptide composed of a
chain of 11 amino acid residues) belongs to the tachykinin
family.
It is a neuropeptide,acting as a neurotransmitter and as a
neuromodulator.
It is closely related neurokinin A ,produced from a polyprotein
precursor.
It is widely distributed throughout the nervous sytem of
human and animal species.
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SYNTHESIS
Peptides are synthesized through translation and
transcription process.
Substance P is synthesised in the endoplasmic reticulum
then transferred to the Golgi apparatus for packaging and
finallly transported to the cell membrane for exocytic release.
It is present in high concentration in nerve endings in
selected region of the mammalian brain.
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DISTRIBUTION
Substance P stands for Preparation the neurokinin type 1
receptor is distributed over cytoplasmic and nuclear
membranes of many types of cells(neurons,glia,endothelia of
capillaries and lymphatics,fibroblasts,stem cells,white blood
cells)and many tissues and organs.
It excites more cellular processes.
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RECEPTORS
Tachykinin receptor TACR1
Neurokinin 1 receptor NK1R
Substance P receptor SPR
It is a G protein coupled receptor found in CNS and
peripheral nervous system.
Substance P is the Neurokinin neurotransmitter selectively
binds with the NK1 receptor
NK1 receptor is have some affinity for other tachykinins
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MECHANISM
Substance P is synthesises by neurons and transported to
synaptic vesicles.
These are released by the depolarizing action of calcium
dependent mechanisms.
When NK1 receptor is stimulated,they can generate various
second messengers,which triggers the various effector
mechanism that regulate cellular excitability and function.
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MECHANISM
The three well defined second messenger system is
stimulation:
1. Via phospholipase C of phosphatidyl inositol,turnover leading
to Calcium mobilization from intra and extracellular sources.
2. Arachidonic acid mobilization via phospholipase A2
3. cAMP accumulation via stimulation of adenylate cyclase
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FUNCTIONS
Substance P is a key first responder to most noxious/external
stimuli(stressors).
It is an immediate defence,stress,repair,survival system.
FUNCTIONS :
• Vasodilation
• Inflammation
• Pain
• Mood,anxiety,learning
• Vomiting
• Cell growth,proliferation,angiogenesis
• Migration
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FUNCTIONS
VASODILATION :
Substance P is a potent vasodilator.
It is dependent on nitric oxide release.
It also has broncho constrictive properties,administered
through the non adrenergic,non cholinergic nervous system.
INFLAMMATION:
Substance P and other sensory neuropeptides can be released
from the peripheral terminals of sensory nerve fibers in the
skin,muscle and joints.
This release is involved in neurogenic inflammation which is a
local inflammmatory response to certain types of infection or
injury
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FUNCTIONS
PAIN :
It is due to the transmission of pain information into the
central nervous system. Substance P coexists with the
excitatory neurotransmitter glutamate in primary affarents that
respond to pain stimulation.
MOOD,ANXIETY,LEARNING :
Substance P is associated with the regulation of mood
disorders,anxiety,stress,reinforcement,neuro
genesis,respiratory rhythm,neurotoxicity,pain and nociception.
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FUNCTIONS
VOMITING :
Vomiting center in the medulla called the area
postrema,contains high concentrations of substance P and its
receptors with other neurotransmitters such as
choline,histamine,dopamine,serotonin and opioids. Their
activationn stimulates the vomiting reflex.
CELL GROWTH,PROLIFERATION,ANGIOGENE SIS AND
MIGRATION:
Substance P stimulate cell growth in normal and cancer cell
line cultures. Substance P promote wound healing of non
healing ulcers in humans.
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CLINICAL SIGNIFICANCE
Quantification in disease
Blockade for diseases with a chronic immunological
component
Dermatological disorders: eczema/psoriasis, chronic pruritus:
High levels of BDNF and substance P have been found
associated with increased itching in eczema.
Mood disorders, major depressive disorder, anxiety disorders
Arthritis, Cancer,
Infections: HIV-AIDS, Measles, RSV, others, Inflammatory
bowel disease (IBD)/cystitis
Other findings like Denervation super sensitivity, Male
aggression
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Reference:
Goodman & Gilman's The Pharmacological Basis of
Therapeutics
Essentials of Medical Pharmacology byK.D.Tripathi
Bertram G Katzung -Basic and Clinical Pharmacology
9th ED
