Plasma kinins

By
Dr. Fazlullah Khan
 Introduction
 The term plasma kinins was introduced in 1958.
 Poly peptides which have marked biological effects and are
derived from plasma.
 Liberated from protein precursors in plasma (kininogens) by
the action of kinnogenases.
 These enzymes are found in exocrine glands and their
secretions .
 Also in plasma and snake & wasp venoms and human urine.
 Plasma kinins

A). Bradykinin
B). Kallidin
They are potent vasodilator peptides.

Also called vasodilator peptides.

Renal autacoids
 Bradykinin

• Brady; Slow Kinin; Movement (Greek words)

• Triggered by: Tissue injury, Inflammation and
allergic action.
• Different pathogenic substances induces their
release.
• They are local hormones (autacoids).
• Locally synthesized, released and show their
effects….destroyed.
 Pharmacological actions

• Bradykinin and kallidin have similar actions.

1). Blood vessels:
 Kinin is potent vasodilator. It can dilate vessels
markedly.
 The research studies conducted on snake
venom showed hypotension hence it was
introduced as vasodilator.
 Compared to Ach and histamine…they are
potent dilator.
• They causes vasodilation through endothelial NO
and PGI2

• They can release histamine from mast cells.

• Binds with the epitope of the mast cell and

causes the release of histamine from the mast
cell.
2). Smooth muscles: Contraction of intestine, uterus
and airways.
 Hence can affect the bowel movement,
facilitating baby delivery.
 May cause complications for asthmatic patients.
 Causes bronchoconstriction in asthmatic patient.
3). Neurons: Strongly stimulates Nonciceptive
afferent neurons causing burning sensation
(pain).
 Used in pain induction in experimental
animals.
 Analgesic activity.
4). Kidneys:
 Increase renal blood flow
 Increase water and salt elimination.
(B2 receptor antagonist).
 Receptors

• Bradykinin receptor
• The B1 receptor (also called bradykinin
receptor B1) is expressed only as a result of
tissue injury, and is presumed to play a role in
chronic pain. This receptor has been also
described to play a role in inflammation. It
was shown that the kinin B1 receptor
recruits neutrophil via the
chemokine CXCL5 production.
• The B2 receptor is constitutively expressed and
participates in bradykinin's vasodilatory role.

• The kinin B1 and B2 receptors belong to G

protein coupled receptor (GPCR) family.

• Bradykinin and killadin are selective agonist

for B1 & B2 receptors.
 Pathophysiological actions ( Bradykinin)

1). Inflammation: Redness, Exudation, Pain,

Leukocytes mobilization…..these processes are
mediated by Bradykinin during inflammation.

• Activation of B1 receptor= Production of IL1

and TNF-α.
2). Mediation of pain:
a). Stimulation of nerve ending causing pain.
b). Increase PG synthesis (PG= Important
inflammatory mediator).
c). B2 receptor antagonist blocks acute pain
caused by Bradykinin.
3). Hereditary angioedema:
 Caused by malfunctioned deficiency of C1
esterase inhibitor ( Decrease kinogensis)
 This results into= Increase plasma Bradykinin
causing swelling of lips , tongue, face, hands
etc (Painless swelling= angioedema).
• Kinin inhibitor or B2 kinin receptor blocker
provides relief from angioedema.

• Oppose overactive RAS

 Bradykinin antagonist
Icatibant

B2 antagonist= Reverse swelling and angioedema

Uses: Angioedema, Burns and Pancreatitis

Icatibant, sold under the brand name Firazyr, is a

medication for the symptomatic treatment of acute attacks
of hereditary angioedema (HAE) in adults with C1-esterase-
inhibitor deficiency.
 Mechanism of action
• Icatibant acts as a bradykinin inhibitor by
blocking the binding of native bradykinin to
the bradykinin B2 receptor. Little is known
about the effects of icatibant on the
bradykinin B1 receptor.
 Legal status

• Icatibant received orphan drug status in Australia, the EU, Switzerland,

and the US for the treatment of hereditary angioedema (HAE).

• In the EU, the approval by the European Commission (July 2008)

allows Jerini to market Firazyr in the European Union's 27 member states,
as well as Switzerland, Liechtenstein and Iceland, making it the first
product to be approved in all EU countries for the treatment of HAE. In the
US, the drug was granted FDA approval on August 25, 2011.
 Safotibant

 Safotibant also known by the research code

LF22-0542 is a non-peptide bradykinin
B1 antagonist.
 Systemic administration of LF22-0542
inhibited acute pain induced by acetic
acid, formalin, and a hot plate.
 In a neuropathic pain model, LF22-0542
reversed the thermal hyperalgesia, but not the
mechanical hyperalgesia.