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:snail: Bradykinins and tachykinins :rabbit: (Drugs affecting KKK system…
:snail: Bradykinins and tachykinins :rabbit:
Bradykinins
Kallikreins/kininogenases
Proteolytic enzymes
Convert kininogens into kinins
Found in
Plasma
Tissue
Pancreas
Intestine
Kidney
sweat & salivary glands
Kininogens
Precursors of kinins
Synthesised and secreted from liver
High MW kinins
15-20%
Remain in blood stream
Activated by plasma kallikreins
Low MW kinin
75-80%
Can diffuse out from capillary plasma
Metabolised by tissue kinins
Found in plasma, intestitial fluid, lymph
Kinins
Vasodilator peptides
Formed by proteolytic cleavage of kinins via protease cascade pathway
Three main types
Bradykinin
Lysyl-bradykinin
aka kallidin
Methionyllysyl-bradykinin
Released by pepsin, pepsin-like enzyme
Receptors
B1
Inflammatory response
Collagen synthesis
Cell multiplication
Limited distribution in mammalian tissue
B2
Highest affinity for bradykinin>kallidin>methionyllysl-bradykinin
Exception: in B2 contracting venous smooth muscle - kallidin highest sensitivity
GPCR - activates PLA, PKA, adenylate cyclase
Ca mobilisation
Chloride transport
Pharmacology
CVS
Arteriolar vasodilation, increase vascular permeability
Direct inhibitory effect of kinins
Release of NO, PGE2, PGI2 (vasodilator PG)
60x potency of histamine
Venoconstriction
Direct stimulation or mediation by PGI2
IV
Brief fall in BP due to arteriolar vasodilation
Compensated by venous constriction
Cannot be maintained, must increase infusion rate for continuous hypotension
Endocrine
Transported from organs into blood
Modulates blood flow
Regulates salivary and pancreatic secretions
Mediates transepithelial movement in GIT
Water
Amino acids
Glucose
Electrolytes
Activates
proinsulin
Prorenin
Inflammatory
Kinins are increased in inflammation
Redness
Swelling
Pain
Sensory
Generates pain-producing substance
Activates nociceptive afferent
Viscera
skin
Metabolism
Kininase I
Liver enzyme
Remove C-terminal Arg residue
Kininase II
ACE dipeptidyl peptidase
Found in plasma and vascular
Removes C-terminal Phe-Arg residue
Drugs affecting KKK system
2nd generation B2 antagonists
Icatibant
Orally active, potent, selective, long acting
Blocks exo and endogenous kinins in animal studies
Used to study the role of kinins
Pain
Hyperalgesia
Inflammation
Kallikrein inhibitor
Aprotinin
Inhibit kinin synthesis
Prostaglandin inhibitor
Block kinins mediated by PG secretion
ACE inhibitor
Potentiate kinin activity
prevent metabolism
B2 agonists
Cardioprotective effect
May be useful in hypertension and myocardial hypertrophy
Tachykinins
Substances
Substance P
Neurokinins
A
B
Main pharmacological action
Binds to mast cells
Releases inflammatory mediators
PNS
Hyppotension - potent arteriolar vasodilation
Natriuresis and diuresis
CNS
Affects behaviour
Anxiety
Depression
N and V
Contracts smooth muscle
Veins
Gi
Bronchial
Increase mucus secretion in GI
Acts by GPCR
Mainly on the NK1 receptor
Tachykinin has highest affinity
NK A and B are roughly similar affinity
Antagonists
Aprepitant
Used for CINV, PINV
Highly selective and potent
Enters CNS