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Uploaded byDr. Jibachha Sah
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Prostaglandins,Angiotensin,Bradykinin-Dr.Jibachha Sah,M.V.Sc,Lecturer

The document discusses the roles and mechanisms of prostaglandins, angiotensin, and bradykinin in veterinary pharmacology. Prostaglandins are lipid compounds with diverse physiological effects, synthesized from arachidonic acid, and play a critical role in inflammation, pain, and reproductive processes. Angiotensin serves as a vasoconstrictor in blood pressure regulation, while bradykinin acts as a vasodilator; both have clinical significance in treating hypertension and related conditions.

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Prostaglandins, Aangiotensin, Bradykinin Dr.Jibachha Sah M.V.Sc( Pharmacology) College of Veterinary Science,NPI, Bhojard,Chitwan
The name prostaglandin derives from the prostate gland, chosen when prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler, and independently by M.W. Goldblatt. 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 four principal bioactive prostaglandins generated in vivo: prostaglandin(PG) E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2) and prostaglandinF2α (PGF2α). There are various prostaglandin namely PGA, PGB, PGE, and PGF. They are found in many mammalian tissues.
Biosynthesis Prostaglandins (PGs) are a family of fatty acid ecosanoids synthesized from arachidonic acid via cyclooxgenase, an enzyme involved in the synthesis of PGs, prostacyclin, and thromboxane, and the target of anti-inflammatory agents such as ibuprofen. The unsaturated fatty acidarachidonic acid is the precursor for the synthesis of the major classes of prostaglandins and leukotrienes, collectively known as eicosanoids. The four metabolic pathways are (i)Cyclooxygenase pathway (ii)Lipoxygenase pathway (iii)Isoprostane pathway (iv)P-450 epoxygenase pathway
General mechanism of action Cyclic adenosine monophosphate (cAMP)
Receptor Receptor type IP Gs vasodilation inhibit platelet aggregation bronchodilation EP1 Gq •bronchoconstriction •GI tract smooth muscle contraction EP2 Gs •bronchodilation •GI tract smooth muscle relaxation •vasodilation EP3 Gi •↓ gastric acid secretion •↑ gastric mucus secretion •uterus contraction (when pregnant) •GI tract smooth muscle contraction •lipolysis inhibition •↑ autonomic neurotransmitters ↑ platelet response to their agonists and ↑ atherothrombosis in vivo Prostaglandin receptor The following is a comparison of different types of prostaglandin, including prostaglandin I2 (prostacyclin; PGI2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α
Release of prostaglandins from the cell Cyclooxygenases Prostaglandins are produced following the sequential oxygenation of arachidonic acid, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows: COX-1 is responsible for the baseline levels of prostaglandins. COX-2 produces prostaglandins through stimulation. 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.
●cause constriction or dilation in vascular smooth muscle cells ● cause aggregation or disaggregation of platelets ● sensitize spinal neurons to pain ● induce labor ● decrease intraocular pressure ● regulate inflammation ● regulate calcium movement ● regulate hormones ● control cell growth ● acts on thermoregulatory center of hypothalamus to produce fever Functions of prostaglandin
Role in pharmacology Inhibition Examples of prostaglandin antagonists are: NSAIDs (inhibit cyclooxygenase) Corticosteroids (inhibit phospholipase A2 production) COX-2 selective inhibitors or coxibs Cyclopentenone prostaglandins may play a role in inhibiting inflammation
Prostaglandins are produced within the body's cells by the enzyme cyclooxygenase (COX). 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. The following veterinary is an example of NSAIDs available: 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. Chemical or physical injury to cells causes induction of the enzyme phospholipase-A2 (PLA2), which converts phospholipids to arachidonate. This newly-formed arachidonic acid is converted by the action of cyclo-oxgygenase (COX) enzymes to cyclic endoperoxidases, which can form inflammatory mediators including PGI2, PGD2, PGE2 and TXA2. Arachidonte may also be converted to 5-HPETE to eventually form leukotrienes, and some newer NSAIDs target this branch of the pathway
Bone cells produce PGE2, PGF2α, prostacyclin, and lipoxygenase products (e.g., leukotriene B4), which may also stimulate bone resorption. 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 Dinoprost is used for estrus synchronization in cattle and horses by causing luteolysis. To treat egg binding in small birds In pigs, dinoprost is used to induce parturition when given within 3 days of farrowing. 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.
Prostaglandin F2α (PGF2α) is used to terminate the luteal phase by causing lysis of the corpus luteum (CL), thereby allowing the return to estrus. most common prostaglandins used are dinoprost (Lutalyse, Pfizer, New York) and cloprostenol (Estrumate, Schering-Plough Animal Health Corporation, Union, N.J.). Dinoprost is a naturally occurring PGF2α, and cloprostenol is a synthetic prostaglandin analogue. For prostaglandins to effectively terminate the luteal phase a mature CL must be present that is responsive to prostaglandin.
Dose The standard recommended dose of dinoprost is 9 μg/kg (5 to 10 mg per 1000 lb/454 kg horse). The recommended dose of cloprostenol is 250 μg per 1000 lb/454 kg horse (0.55 μg/kg).
Abnormally Low Blood Pressure Diarrhea Fast Heartbeat Seizures Slow Heartbeat Adverse effect Fever Low Amount Of Calcium In The Blood Short Periods Of Not Breathing Temporary Redness Of Face And Neck
Angiotensin, Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys. 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. Angiotensin I is transformed into angiotensin II in the blood by the action of angiotensin-converting enzyme (ACE).
Clinical significance An angiotensin-converting-enzyme inhibitor (ACE) is a pharmaceutical drug used primarily for the treatment of hypertension and congestive heart failure. Captopril is an example of an ACE inhibitor. Drug Name: Captopril Common Name: Capoten® Drug Type: ACE inhibitor Used For: Heart failure, High blood pressure Species: Dogs, Cats Administered: Tablets Available Forms: Capoten® 12.5mg, 25mg, 50mg, and 100mg tablets
Mechanism of action Captopril inhibits the angiotensin converting enzyme (ACE), an enzyme that converts angiotensin I to angiotensin II. Angiotensin II acts as a potent vasoconstrictor, meaning it narrows the blood vessels. By inhibiting this enzyme, it prevents the angiotensin II from ever being created and relaxes the blood vessels. 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: Low blood pressure Loss of appetite Vomiting Diarrhea Rash High blood pressure if medication is halted abruptly Captopril may react with these drugs: 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. Remikiren is a renin inhibitor under development for the treatment of hypertension (high blood pressure). It was first developed by Hoffmann–La Roche in 1996. Renin inhibitors are a group of pharmaceutical drugs used primarily in treatment of essential hypertension (high blood pressure). 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. Angiotensin I is transformed into angiotensin II in the blood by the action of angiotensin-converting enzyme (ACE). 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. Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids. A class of drugs called angiotensin converting enzyme (ACE) inhibitors increase bradykinin levels by inhibiting its degradation, thereby increasing its blood pressure lowering effect. 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. How is bradykinin produced? Bradykinin is the major functional vasodilator produced by the kallikrein-kinin system. Bradykinin exerts its effects via B1 and B2 receptors. The bradykinin-synthesizing enzyme, kininase II, is identical to angiotensin- converting enzyme, which produces angiotensin II.
Function Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. Receptors Effect 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). Bradykinin induces vasodilation by stimulating production of nitric oxide, the arachidonic acid metabolites prostacyclin (PGI-2) and PGE-2, and endothelium-derived hyperpolarizing factor.
Clinical use Icatibant (Firazyr): Bradykinin B2 receptor antagonist indicated for acute attacks of hereditary angioedema (HAE). 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.