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Bradykinin
Dr.Jibachha Sah
M.V.Sc( Pharmacology)
College of Veterinary Science,NPI,
Bhojard,Chitwan
History
The first total syntheses of prostaglandin F2α and prostaglandin E2 were reported
by E. J. Corey in 1969
Introduction
The prostaglandins (PG) are a group of physiologically active lipid compounds
called eicosanoids having diverse hormone-like effects in animals.
Prostaglandins have been found in almost every tissue in humans and other
animals.
They are derived enzymatically from the fatty acid arachidonic acid.
Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring.
They are a subclass of eicosanoids and of the prostanoid class of fatty acid
derivatives.
There are various prostaglandin namely PGA, PGB, PGE, and PGF. They are found
in many mammalian tissues.
The unsaturated fatty acidarachidonic acid is the precursor for the synthesis of the
major classes of prostaglandins and leukotrienes, collectively known as
eicosanoids.
(i)Cyclooxygenase pathway
(ii)Lipoxygenase pathway
(iii)Isoprostane pathway
(iv)P-450 epoxygenase pathway
General mechanism of action
vasodilation
inhibit platelet aggregation
IP Gs
bronchodilation
•bronchoconstriction
EP1 Gq
•GI tract smooth muscle contraction
•bronchodilation
EP2 Gs •GI tract smooth muscle relaxation
•vasodilation
•↓ gastric acid secretion
•↑ gastric mucus secretion
•uterus contraction (when pregnant)
EP3 Gi •GI tract smooth muscle contraction
•lipolysis inhibition
•↑ autonomic neurotransmitters ↑ platelet response to their
agonists and ↑ atherothrombosis in vivo
Release of prostaglandins from the cell
Cyclooxygenases
However, while COX-1 and COX-2 are both located in the blood vessels, stomach and
the kidneys, prostaglandin levels are increased by COX-2 in scenarios
of inflammation and growth.
Functions of prostaglandin
●cause constriction or dilation in vascular smooth muscle cells
There are two COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that
promote inflammation, pain, and fever.
However, only COX-1 produces prostaglandins that support platelets and protect the
stomach.
Nonsteroidal anti-inflammatory drugs (NSAIDs) block the COX enzymes and reduce
prostaglandins throughout the body. As a consequence, ongoing inflammation, pain, and
fever are reduced.
Diclofenac ketoprofen
Ibuprofen Nimusulaide
Meloxicam Flunixin
Phenybutazone Carprofen
Mechanism of Action NSAID
NSAIDs are defined as "agents which inhibit the formation of eicosanoids from arachidonic
acid".
Prostaglandins (PGs), thromboxanes (TXs) and leukotrienes (LTs) are all eicosanoids which
have an inflammatory-mediating action.
Among the varied roles of prostaglandins and thromboxanes are the control
of vascular tone, hemostasis, cytoprotection, regulation of fetal sleep/wake states,
kidney function, thermoregulation, inflammation, cell proliferation, and many
others.
Indications and clinical uses
In dogs, dinoprost has been used to treat open pyometra. In cattle, dinoprost has been
used for treatment of chronic endometritis.
In large animals, dinoprost is used to induce abortion in the first 100 days of gestation, but
use for inducing abortion in small animals has been questioned.
The recommended dose of cloprostenol is 250 μg per 1000 lb/454 kg horse (0.55
μg/kg).
Adverse effect
Fever
Low Amount Of Calcium In The Blood
Short Periods Of Not Breathing
Temporary Redness Of Face And Neck
Angiotensin also stimulates the release of aldosterone from the adrenal cortex to
promote sodium retention by the kidneys.
This lowers the blood pressure and reduces the amount of work the heart has to
do.
In one study 72 dogs the efficacy and safety of quinapril and captopril in the
treatment of canine heart failure were found to be comparable. Differences exist
between the dosage schedules of both ACE inhibitors.
The recommended dosage schedule for the short acting captopril is three times
daily 0.5 mg/kg bodyweight. Quinapril belongs to a newer generation of ACE
inhibitors with a longer half life. Therefore a dosage of 0.5 mg/kg KGW once daily
was in most cases sufficient for a successful therapy. Morisse .B, Kersten .U. Tierarztl Prax. 1995
Oct;23(5):489-96.
Captopril may result in these side effects:
Antacids
Diuretics
Rimadyl (and other non-steroidal anti-inflammatory drugs)
Potassium sparing diuretics
Vasodilators
Cimetidine
Digoxin
Potassium chloride or gluconate
Direct renin inhibitors can also be used for hypertension. The drugs that
inhibit renin are aliskiren and the investigational remikiren.
These drugs inhibit the first and rate-limiting step of the renin–angiotensin–
aldosterone system (RAAS), namely the conversion
of angiotensinogen to angiotensin I.
Angiotensin I is produced by the action of renin (an enzyme produced by the
kidneys) on a protein called angiotensinogen, which is formed by the liver.
An allowance of up to 160 mmHg systolic is often used since many of patients are
quite anxious in the hospital setting (“white coat effect”).
Bradykinin
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to
dilate (enlarge) via the release of prostacyclin, nitric oxide, and Endothelium-
Derived Hyperpolarizing Factor.
ACE inhibitors are FDA approved for the treatment of hypertension and heart
failure.
Bradykinin receptor
The bradykinin receptor family is a group of G-protein coupled receptors whose
principal ligand is the protein bradykinin.
There are two Bradykinin receptors: the B1 receptor and the B2 receptor.
Receptors
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
The cardinal signs of inflammation include: pain, heat, redness, swelling, and loss of function.
Role of bradykinin
ACE, also referred to as kininase II, is the principal enzyme responsible for the
metabolism of bradykinin (a potent endothelium-dependent vasodilator).
Icatibant (Firazyr):
Recently, numerous BK receptor antagonists have been synthesized with prime aim
to treat diseases caused by excessive kinin production.
These diseases are rheumatoid arthritis (RA), inflammatory diseases of the bowel,
asthma, rhinitis and sore throat, allergic reactions, pain, inflammatory skin
disorders, endotoxic and anaphylactic shock and coronary heart diseases.