Plasma kininsPlasma kinins

Plasma kininsPlasma kinins- Kallidin and BradykininKallidin and Bradykinin- Involved in edema, pain, erythema and Involved in edema, pain, erythema and

fever of inflammationfever of inflammation- Highest levels in many clinical Highest levels in many clinical

situations e.g traumatic shock, situations e.g traumatic shock, pancreatitis, peritonitis, Carcinoid pancreatitis, peritonitis, Carcinoid syndrome…etcsyndrome…etc

- Low levels in certain patients with Low levels in certain patients with essential hypertensionessential hypertension

Synthesis and catabolism of plasma kinins:Synthesis and catabolism of plasma kinins: Kallikrein (plasma)Kallikrein (plasma)

HMW kininogen bradykinin HMW kininogen bradykinin

aminopeptidaseaminopeptidase kininases I & II*kininases I & II* inactiveinactive

metabolitesmetabolites

LMW kininogen kallidinLMW kininogen kallidin

KallikreinKallikrein (tissues, glands, kidney)(tissues, glands, kidney)

*kininase II is*kininase II is identical with identical with

ACEACE

Renin-angiotensin-aldosterone axisRenin-angiotensin-aldosterone axis

AngiotensinogenAngiotensinogen ReninRenin

Angiotensin IAngiotensin I ACEACE

Angiotensin IIAngiotensin II

Aldosterone Aldosterone

Pharmacological and physiological Pharmacological and physiological effects to kinins:effects to kinins:

Mediated through interaction with at Mediated through interaction with at least 2 different types of receptorsleast 2 different types of receptors

Mechanisms involved:Mechanisms involved:

- ↑ Prostaglandin production- ↑ Prostaglandin production

- - ↑↑ NO production NO production

- ↑ cAMP, cGMP, IP- ↑ cAMP, cGMP, IP33, DAG, DAG

Effects of kinins :Effects of kinins :

- B.V’s: Relaxation → dilatation → ↓ S & - B.V’s: Relaxation → dilatation → ↓ S & D B.PD B.P

↑ ↑ permeability → edemapermeability → edema

- Heart: Reflex ↑ H.R & CO- Heart: Reflex ↑ H.R & CO

- Stimulation of sensory nerve endings - Stimulation of sensory nerve endings → initiation of pain signals→ initiation of pain signals

- Bronchi: Constriction → distress in- Bronchi: Constriction → distress in

asthmatics, dry cough asthmatics, dry cough

Therapeutic considerations:Therapeutic considerations:A. Conditions associated with low kinin A. Conditions associated with low kinin

levels e.g essential hypertensionlevels e.g essential hypertension - Synthetic kinin analogs - Synthetic kinin analogs Not available (under evaluation)Not available (under evaluation) - Inhibition of metabolism ACE - Inhibition of metabolism ACE

inhibitorsinhibitors - Kallikrein synthetic analogs Padutin - Kallikrein synthetic analogs Padutin ( pancreatic kallikrein ) orally effective ( pancreatic kallikrein ) orally effective Use in high B.P, ♂ Use in high B.P, ♂

infertilityinfertility

B. Conditions associated with high kinin B. Conditions associated with high kinin levels e.g septic, anaphylactic, levels e.g septic, anaphylactic, traumatic and hemorrhagic shock, traumatic and hemorrhagic shock, pancreatitis, peritonitis, fat embolism pancreatitis, peritonitis, fat embolism syndrome, hyperfibrinolytic syndrome, hyperfibrinolytic hemorrhage, inflammations…hemorrhage, inflammations…

- Kinin antagonists- Kinin antagonists Not available (under evaluation)Not available (under evaluation) - Kallikrein inhibitors- Kallikrein inhibitors Aprotinin Given I.VAprotinin Given I.V Plasmin inhibitor frequently used Plasmin inhibitor frequently used

to stop pre- or postoperative bleedingto stop pre- or postoperative bleeding