Good Morning

BY TABISH AHMED

BRADYKININ

1ST M-PHARM

GCP

Contents

1. History.

2. Generation and metabolism.

3. Receptors ( B1 and B2).

4. Pharmacological actions.

5. Pathophysiological roles.

6. Drugs affecting the bradykinin system.

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.

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."

History.

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 decapeptide-bradykinin with an additional lysine residue at the amino terminus.

kallidin and bradykinin are referred to as plasma kinins.

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).

Two kininogens are known to be present in plasma:A low-molecular-weight form (LMW kininogen) and a high-molecular-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.

Kininogens.

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.

Kallikreins.

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.

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.

arg pro pro Gly phe Ser Pro Phe arg

Kininase II

Kininase Ibradykinin

BRADYKININ

KALLIDIN

Des-arg bradykinin

Des-arg kallidin

aminopeptidaseKininase ICP M/N

Kininase II

Inactive fragments

CP M: Carboxypeptidase MCP N : Carboxypeptidase N

Kinin receptors.

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

Existence of two types bradykinin receptor has been established : B1 and B2 Both are GPCR & mediate similar effects.

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

B

Gq

PLC PIP2

IP3 DAGCalciummobilization

Vascular endothelium

NO Generation &Release Smooth

Muscle Vasodilation Increased permeability Contraction

G

PLA2 Arachidonic acid PG I

ACTIONS OF KININSCardiovascular 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.

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.

PATHOPHYSIOLOGICAL ROLES

1.Mediation of inflammationKinins 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 painBy 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.

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.

Drugs affec t ing kal l ikr ien-kin in sys tem

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.

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.

Recently, a 3rd generation of B2 receptor antagonists was developedExamples 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 capsaicin-induced nociception in mice.

The synthesis of kinins can be inhibited with the kallikrein inhibitor Aprotinin

Actions of kinins mediated by prostaglandin generation can be blocked non-specifically 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.

THANK YOU

ReferenceGoodman & Gilman's The Pharmacological Basis of TherapeuticsEssentials of Medical Pharmacology byK.D.TripathiBertram G Katzung -Basic and Clinical Pharmacology 9th ED