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Autacoids Pharmacology

Autacoids are locally acting hormones that are produced in tissues rather than glands. Histamine is an important amine autacoid that is synthesized and stored in mast cells and basophils. It is released upon stimulation and acts through four types of histamine receptors (H1-H4) to produce various effects. Histamine's actions are terminated by enzymatic degradation or receptor desensitization within minutes. Antihistamines competitively inhibit histamine receptors to treat allergic disorders and histamine-mediated conditions.

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Autacoid • Autacoids are the local hormone produced in tissues rather than in glands. • Autacoids are locally acting hormone like substance, which originates from different tissue & produce intense biological activities near their site of synthesis or release. • Classification of autacoids A. Amine autacoids B. Peptide autocoids C. Eicosanoids
Amine autacoids • Histamine • Types of histamine receptor and their distribution 1. H1 receptor :Blood vessels, CNS, smooth muscles, Adrenal medulla, autonomic ganglia 2. H2 receptor: Blood vessels(smaller ), CNS, heart, parietal cell of stomach. 3. H3 receptor: Blood vessels( certain ), Brain(presynaptic), lungs, spleen, skin, ileum. 4. H4 receptor: Bone marrow, Basophils, thymus , small intestine, lungs, spleen & Colon. Synthesis of histamine: • L- Histidine decarboxylase converts L- Histidine into Histamine.
• Metabolism: • a. Diamine oxidase acts on histamine to form imidazole acetic acid • b. Histamine-N-methyl transferase acts on histamine to form N-methyl histamine and monoamine oxidase further converts N-methyl histamine into N-methyl imidazole acetic acid. • Storage: • mainly occurs in mast cells or basophils where it is held in intracellular storage granules in a complex form with an acidic protein & a heparin of high molecular weight. • Its content is approx.:0.1 to 0.2 pmol per mast cel & 0.01 pmol per basophil
• Release: from mast cell by secretory/degranulation process during physiological, mechanical or chemical insult. • initiated by a rise in intracellular ca2+ levels, which triggers extrusion of the contents of granules by exocytosis. • Stimuli • - interaction of antigen with cell fixed IgE antibodies. • - interaction of complement component C3a & C5a with specific receptors on cell surface. • Excretion: • Very little amount of unchanged histamine is excreted in urine & Imidazole acetic acids is excreted in urine in large amount. The activity of histamine is terminated within 5 to 15 minutes after it's synthesis or release.
Pharmacology Of Histamine& Analogue • Histamine: It has no therapeutic use because of its profound adverse effects. However, it is infrequently used as a diagnostic tool to test acid secreting capacity of stomach & to distinguish between pernicious anemia & other form of anemia. • → Loss of gastric parietal cells in pernicious anemia results in an inability to secrete gastric acid even in response to histamine but in other types of anemia, gastric acid secretion increases in response to histamine. • →Not given orally due to rapid inactivation in GI tract & liver. Administered by parenteral route –virtually complete absorption.
Betazole
Pentagastrin • It has been used as a diagnostic aid. It is more commonly used for gastric analysis because it is short acting& has minimal side effects. Dose:- Dogs-6μg/kg.sc It stimulates gastric acid secretion, pepsin & intrinsic factor secretion. It also stimulates pancreatic secretion, inhibits absorption of water & electrolyte & increases blood flow in the gastric mucosa.
Histamine blocking drugs
First generation antihistaminic drugs
• Antidote:- -There is no specific antidote of mepyramine. Intravenous (IV). Sodium bicarbonate improves wider of QRS that may result from antihistamines with sodium channel blocking properties (eg.pyrilamine ) • Clinical use:- - It is used occasionally to reduce or help prevent histamine mediated adverse effects. - It is also used topically as cream for the treatment of insect bites& stings nettle rash.
• Side/Adverse effects:- Sedation, diminished alertness, lethargy, somnolence& ataxia(Lack of coordinate in voluntary movement ) due to central depression &dry mouth, dysuria, constipation, increased heart rate & pupil dilation due to anticholinergic effects. • Antidote:- Overdose can be treated symptomatically & with decontamination therapy. Phenytoin IV is recommended in the treatment of seizures caused by diphendramine & other antihistamines over dosage.
• Phenytoin IV is recommended in the treatment of seizures caused by diphendramine & other antihistamines over dosage. Dose Rate:- In allergic disorder dogs and cats a) 2-4mg/kg IM or slow IV, 2 times diary or as needed. b) 2mg/kg IM or slow IV, 2 times dairy or as needed. For adjunctive therapy of anaphylaxis a) cattle: 0.5-1mg/kg IM or IV b) Horse 0.25-1mg/kg IV or IM Note: The Iv route shouldn’t be used routinely because it carries risk of cardiac arrest.
• Pharmacokinetics:- Hydroxyzine is rapidly absorbed after oral & intramuscular administration. It is distributed through the body & crosses blood brain barrier It is metabolized in liver and the main metabolites cetirizine Duration of action:- 6-8 hours in dogs and up to 12 hours in cat. Side effects:- Sedation and gastric disturbances inn dog it produces hyper excitability (tremors& rarely seizures) Antidote:- There is no specific antidote ECG monitoring is recommended in case of hydroxyzine. Drug rate:- a) Dogs: 1-2mg, PO or IM, 3-4 times daily b) horse: 0.5-1mg/kg, PO or IM, 2 times daily.
• Contraindication:- It is contradicted in early pregnancy. It is contradiction in patients with known hyperxyzine. Contradiction in patient with a prolonged QT interval. Clinical Use:- Hydroxyzine is used primarily as antihistamine for the treatment of itching, allergies, hyperalgesia, motion sickness, induced nausea& insomnia. It is also used for the treatment of mild anxiety. In veterinary medicine hydroxyzine is mainly for antihistaminic, antipruritic (anti itching) & sedative/tranquilizing properties, often in atopic patient (hereditary disease). Allergic airway disease & Rhinitis.
• Side effects:- Dry mouth constipation fatigue, drowsiness, sore throat hepatic toxicity Antidote:- There is no specific antidote to cetirizine, not effetely removed by dialysis. Treatment is symptomatic& supportive therapy. Clinical use:- Used in the treatment of pruritus& allergic conditions. It may help in the treatment of eosinophils. Dosage: Dogs& cats – 1mg/kg PO once daily. Horse- 10mg/kg PO once daily.
• Terfenadine& its metabolites are excreted in feces via biliary elimination& urine. • Pharmacological effects:- • It has rapid onset of action (1-2 hours& moderate duration of action 12-24 hours) • Side effects:- • Dizziness, weakness, or muscle cramps, nausea, diarrhea, upset stomach. • Antidote:- • It doesn’t have specific antidote.
• Drug interaction:- • Never take terfenadine with antifungal drugs such as ketaconazole, itraconazole . • Antibiotic such as erythromycin, azithromycin • ulcer drug such as cimetidine. • Clinical uses: • Dose:- 0.25-2.5mg/kg PO once daily.
• H2 receptor Antagonists • The H2 receptor antagonists are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. • The H2 receptor antagonist drugs are: • a) Cimetidine • Cimetidine was the first H2 receptor blocker to be introduced clinically and was described as the protype. • Cimetidine HCl occurs as white, crystalline powder and is soluble in water and alcohol. It should be stored & protected from light anf kept at room temperature. Cimetidine and other H2 receptor antagonists, so they reach the central nervous system only to a limited extent.
• Pharmacological effects • Cimetidine, like other H2 receptor antagonists, inhibits the interaction of histamine with H2 receptors present in numerous tissues, but its important action is observed on gastric parietal cells. At the H2 receptors of parietal cells, cimetidine competitively inhibits histamine, thereby reducing gastric acid output both during basal conditions and when stimulated by food, pentagastrin, histamine, insulin, fundic distension and to a lesser extent by muscarinic antagonists in a dose dependent and to a lesser extent by muscarinic agonists in a dose dependent manner. It reduces both the secretion as well as the amount of pepsin induced by a variety of secretogogues. Gastric emptying time, pancreatic or biliary secretion, and lower oesophageal pressure are not altered by cimetidine. Secretion of intrinsic factor is also reduced.
• Pharmacokinetics • Absorption: Cimetidine is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 95%. • Distribution: It is distributed throughout the body, crosses placenta and reaches in milk but penetration into the brain is poor due to it's hydrophilic nature . • Metabolism: It is metabolised in liver. • Excretion: excreted in urine in both unchanged and conjugated forms.
• Side effects • - Very rare in animal at the dosage generally used. • - Thrombocytopenia • - tachycardia and respiratory failure in lab animals at very high dose. • - prolonged use may produce gynaecomastia, loss of libido, impotence and temporary decrease in sperm count. • - Rebound hypersecretion and relapse gastroduodenal ulceration after the therapy is discontinued ( in human)
• Drug interaction • a. Cimetidine decreases the hepatic metabolism of numerous drugs including theophylline, phenobarbitol, warfarin, digitoxin, quinidine and phenytoin. Impaired metabolism of other drugs can leads to their accumulation to toxic levels in body. • b.It impairs oral absorption of a number of drugs due to alteration of GI pH and by binding to them. • c.Cimetidine reduces hepatic blood flow by about 20% and has shown to reduce the clearance of flow limited drugs such as propranolol and lidocaine. • d.Cimetidine can inhibit tubular secretion of procainamide, with increase in plasma concentrations of the drug and its cardioactive metabolite N-acetylprocainamide. • e.Antacids and metoclopramide reduce absorption of cimetidine and other H2- receptor antagonists. If used concurrently, a gap of 2 hours should be allowed between the dosing of two drugs.
• Dose: • For gastric ulceration, oesophagitis or gastric hyperacidity. • Dog & cats : 5-10 mg/kg, PO, SC, IM, or slow IV, 3 to 4 times daily • Cattle : 8-16 mg/kg, 3 times daily • Swine : 330 mg ( total ), 2 times daily • Foals : 20 mg/kg, PO, 2 times daily , • For uraemic gastritis • Dogs & cats : 2.5-5 mg/ kg, PO or slow IV, 2 to 3 times daily. • For equine melanoma • Horses : 2.5 mg/kg, PO, 3 times daily for 3 months. • Clinical uses: • cimetidine has been used for the treatment and prophylaxis of gastric, abomasal and duodenal ulcers and in uremic gastritis, stress related or drug induced erosive gastritis, duodenal gastric reflex and oesophageal reflux. • Cimetidinr is employed to treat hypersrcretory conditions associated with gasrinomas and systemic mastocytosis. • Cimetidine is used in the treatement of equine melanomas.
Rantidine • Pharmacological effects • Ranitidine is a H2 receptor antagonist that possess pharmacological properties similar to those of cimetidine. However, it is 5 to 12 times more potent as an inhibitor of gastric acid secretion than cimetidine and doesn't significantly inhibit hepatic metabolism of other drugs.unlike cimetidine Ranitidine lacks anti-androgenic effect and inhibit microsomal P450 enzymes.
• Pharmacokinetics • Absorption: well absorbed through the GI tract, bioavailability is approximately 80% . • Distribution: volume of distribution is 2.6 L/kg. • Metabolism: metabolised in liver • Excretion: excreted in urine and bile • Side effects • Side effects of ranitidine appear to be very rare in animals at the dosages generally used. Although some side effects like- confusion, headache, diarrhoea /constipation have been reported in human.
• Contraindications and precautions • Ranitidine should not be used in animals with known hypersensitivity or allergy to the drug. Ranitidine should be avoided in animals with liver or kidney disease. • Drug interactions • Unlike cimetidine, ranitidine appears to have only minimal effects on the hepatic metabolism of drugs and is unlikely to cause clinically relevant drug interaction via this metabolism. The relative bioavailability of ranitidine may be increased with high peak serum level when propantheline is administered concomitantly with ranitidine. Antacids may decrease absorption of ranitidine. • Dose: • Dogs & cats : 0.5 - 2 mg/kg, PO ,IV, IM, or SC, 2 to 3 times daily. • Horses : 4-6 mg/kg, PO, 2 times daily • : 1 mg/kg, IV, 3 times daily.
SEROTONIN AND ITS ANTAGONIST
SEROTONIN(5-HT)  Serotonin is a biogenic amine i.e monoamine neurotransmitter and an autacoides.  Primarily found in the GI tract mostly enterochromaffin cells,platelates and CNS.  These regulates sleep,body temperature & mood.  A hormone melatonin is derived from serotonin.
SYNTHESIS AND DEGRADATION L-TRYPTOPHAN T.Hydroxylase 5-HYDROXYTRYPTOPHAN Decarboxylase 5-HT(SEROTONIN) MAO Dehydrogenase 5-HIAA 5-Hydroxytryptophol
Storage and Release  After synthesis ,it is stored in storage vesicles mainly in enterochromaffin cells and often stored in neurons.  Platelets do not synthesis serotonin due to lack of decarboxylase enzyme.  But collect the autacoid from blood by an active transport mechanism.
PATHOPHYSIOLOGICAL ROLES  Neurotransmitter  Precursor for melatonin  Neuroendocrine Function  Nausea and Vomiting  Migraine  Haemostasis
MECHANISM OF ACTION  Action mediated through a variety of serotonin receptor called 5-HT receptors.  Receptors are classified into 5-HT1 to 5-HT7 receptor on the basis of pharmacological characteristics.  5-HT receptor induced membrane hyperpolarization and reduction in input resistance from an increase in k-ion conductance.  Slow depolarization induced by receptors activation in area such as the facial motor neuron involves a decrease in K-ion conductance.
A second distinct mechanism involving Ca-ion activated membrane current enhances neuronal excitability and potentiality the response to excitatory signals such as glutamate. The fast depolarization elicited by 5-HT receptors reflect direct gating of an ion channel instrinsic to the receptor structure itself. 5-HT receptors acts through the G-protein couple receptors which activates an intracellular second messenger or ionotropic receptors that directly regulates Na-K channels.
PHARMACOLOGICAL ACTIONS  Action on GIT 5-HT act as a local hormone & to regulate peristalsis movement.  Action on CNS It act as neurotransmitter in CNS.  Action on smooth muslcles It constricts the smooth muscle of bronchia and GIT.  Action on blood vessels 5-HT dilates the blood vessels of skeleton muscles,coronary arteries & capillary of skin.  Action on platelets It enhances the aggregation of platelates & haemostasis.  Depression Low brain cells production of serotonin, a lack of receptor sites able to receive the serotonin that is made inability of receptor to reach the receptoer site or shortage of tryptophan lead to depression.
SEROTONIN ANTAGONIST Non selective serotonin antagonist 1.Cyproheptadine • It is combine serotonin and cholinergic antagonist. • Its anti-serotonin activity utilized in intestinal manifestation of carcinoid. • It also has been used in the treatment of cyclical vomiting syndrome and stimulate appetite. • Side effects: drowsiness,dry mouth,ataxin confusion.
2.Ketanserin • Non selective 5HT receptor blocking property blocks 5HT2𝐴 and 5𝐻𝑇2𝐵.receptors. • It induced vasoconstriction, platelets aggregation & contraction of smooth muscles. • Ketanserin also lowers the blood pressure in hypertensive patients and its effects is likely related to the blockage of alpha-1 adrenergic receptors.
3. Ergot Alkaloides • it acts as patrtial agonist and antagonist at serotonin receptors at 5𝐻𝑇2𝐵. • Antagonist action of 5HT on smooth muscles including that of blood vessels. • Used for migraine prophylaxis.
Selective Serotonin Antagonists 1.Ritanserin • It is more selective 5𝐻𝑇2𝐴 and less 5𝐻𝑇2𝐶 receptor. • It posses low affinity for alpha-1 adrenergic receptor. • It is used together with typical antipsychotics in the treatment of schizophrenia.
2.Odansetron • Selectively 5𝐻𝑇3antagonist • Remarkable efficacy in controlling nausea & vomiting following administration of highly emetic anticancer drug and radiotherapy. 3.Agometaline • It is an antidepressant that acts as a melatonergic MT1 and MT2 receptor agonist and serotonin 5𝐻𝑇2𝐶 receptor antagonist. • Agomelatine is indicated for the treatment of major depressive disorder in human medicine.
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PROSTAGLANDINS
INTRODUCTION Prostaglandins and related compounds are collectively known as eicosanoids. Most are produced from arachidonic acid, a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid). The eicosanoids are considered "local hormones."  They have specific effects on target cells close to their site of formation.  They are rapidly degraded, so they are not transported to distal sites within the body. But in addition to participating in intercellular signaling, there is evidence for involvement of eicosanoids in intracellular signal cascades.
ROLE OF EICOSANOID – Inflammation – Fever – Regulation of blood pressure – Blood clotting – Immune system modulation – Control of reproductive processes & tissue growth – Regulation of sleep/wake cycle.
PGE2 (prostaglandin E2) It is an example of a prostaglandin, produced from arachidonic acid.
Prostaglandins all have a cyclopentane ring. A letter code is based on ring modifications (e.g., hydroxyl or keto groups). A subscript refers to the number of double bonds in the two side-chains. Thromboxanes are similar but have instead a 6-member ring. PGE2 (prostaglandin E2).
Prostaglandin receptors:  Prostaglandins & related compounds are transported out of the cells that synthesize them.  Most affect other cells by interacting with plasma membrane G-protein coupled receptors. ♦ Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP, or may activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release.
 Prostaglandin receptors are specified by the same letter code. E.g., receptors for E-class prostaglandins are EP. Thromboxane receptors are designated TP.  Multiple receptors for a prostaglandin are specified by subscripts (E.g., EP1, EP2, EP3, etc.). Different receptors for a particular prostaglandin may activate different signal cascades. Effects of a particular prostaglandin may vary in different tissues, depending on which receptors are expressed. E.g., in different cells PGE2 may activate either stimulatory or inhibitory or G-proteins, leading to either increase or decrease in cAMP formation
Prostaglandin H2 Synthase catalyzes the committed step in the “cyclic pathway” that leads to production of prostaglandins, prostacyclins, & thromboxanes. Different cell types convert PGH2 to different compounds. leukotrienes phospholipids arachidonate diacylglycerol prostaglandin H2 prostacyclins thromboxanes other prostaglandins Lipoxyganase PGH2 Synthase Prostacyclin Synthase Thromboxane Synthase Linear pathway Cyclic pathway Two major pathways of eicosanoid metabolism. Cyclic pathway:
Role of prostaglandin
Role of prostaglandin
Role of prostaglandin
Role of prostaglandin
Thromboxane A2 It stimulates blood platelet aggregation, essential to the role of platelets in blood clotting.  Many people take a daily aspirin for its anti- clotting effect, attributed to inhibition of thromboxane formation in blood platelets.  This effect of aspirin is long-lived because platelets lack a nucleus and do not make new enzyme.
Leukotrienes have roles in inflammation. They are produced in areas of inflammation in blood vessel walls as part of the pathology of atherosclerosis. Leukotrienes are also implicated in asthmatic constriction of the bronchioles. Some leukotrienes act via specific G-protein coupled receptors (GPCRs) in the plasma membrane. Anti-asthma medications include:  inhibitors of 5-Lipoxygenase, e.g., Zyflo (zileuton)  drugs that block leukotriene-receptor interactions. E.g., Singulair (montelukast) & Accolate (zafirlukast) block binding of leukotrienes to their receptors on the plasma membranes of airway smooth muscle cells.
1) Prostaglandins and analogues a) misoprostol: synthetic analogue of prostaglandin E1 Pharmacological effect: Cytoprotective and antiulcer effect on gastric mucosa. Inhibits gastric acid secretion by a direct action on gastric parietal cells. Increase production of gastric mucus and bicarbonate and enhances blood supply to gastric mucosal cells. Pharmacokinetics: Effectively absorbed from the GI tract Rapidly metabolized to misoprostol acid which is primary active metabolite. Further biotransformed to inactive metabolites
Side effects: Includes diarrhoe, nausea, vomiting, abdominal cramps Potentially uterine contractions and vaginal bleeding may occur In bithches Contraindications It is contraindicated during pregnancy due to its uterine stimulant activity. Should be used cautiously in patients sensitive to prostaglandins and in cerebral or coronary vascular disease Drug interaction: Non-systemic antacids reduce absorption of misoprostol . Dose: Dogs: 2-5 ug/, po,2-3 times daily
• Horses: 0.5ug/kg,po,4 times daily PROSTAGLANDINS E2 AND ANALOGUES Dinoprostone: Synthetic prostaglandin E2 Promotes ripening and dilation of cervix and causes contraction of uterus. Also stimulates osteoblasts to release factors which stimulate bone resorption Sulprostone: Selective agonist for EP3 receptors Potent stimulator of uterine smooth muscle contractions.
PROSTAGLANDIN F AND ANALOGUES Dinoprost Pharmacological effects: Causes stimulation of uterus , relaxation of cervix and regression of corpus luteum. Side effects: Transient sweating, decreased body temperature, tachycardia, abdominal pain, ataxia in horses Transient salivation, increased body temperaure , restlessness, tremor and mild diarrhoea in cattle Contraindication: Not to be used during pregnancy. Contraindicated in animals with bronchoconstrictive respiratory disease and disordersof vascular sytem
Drug interaction Should not be administered along with other oxytocic agents because of enhancement of pharmacological effects Inhibitors of eicosanoid synthesis 1) Glucocorticoids : important class of therapeutic agents which inhibit the release of arachidonic acid from membrane phospholipids, which in turn inhibits synthesis of all eicosanoids. Glucocorticoids are widely used in therapeutic for anti- inflammatory actions. 2) Non –steroidal anti-inflammatory drugs(NSAIDS) NSAIDS are important class of therapeutic agents which inhibits cyclooxygenase enzyme (COX) and blocks the synthesis of prostaglandins which in turn prevents the inhibition of gastric acid production.
• Others inhibitors includes • Zileuton: inhibits 5-lipoxygenase enzyme ,prevents generation of leukotrienes • Piriprost: also blocks synthesis of leukotrienes • Dazoxiben: selective thromboxane synthase inhibitor, hence prevents platelets aggregation 2) inhibitors of eicosanoids receptors: Montelukast : Leukotriene CysLT1 receptor antagonist. Reduces inflammatory conditions in respiratory tract and decreases bronchoconstriction. Has been indicated for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. Zafirlukast: Leukotriene CysLT1 receptor antagonist with pharmacological effects similar of montelukast Ramatroban : Thromboxane A2 receptor antagonist. Indicated for the treatment of coronary artery diseases and treatment of asthma
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PEPTIDE AUTACOIDES 77
PEPTIDE AUTACOIDES (Locally Acting hormone like peptides)Exert important effect on blood vessels and smooth muscles Some are involved in tissue damage , allergic reaction and other inflammatory condition 78 Peptide Autacoids Kinins Angiotensin Tachykinins Cytokines
A. KININS  Involve in vasodilation, increase vascular permeability , nociception and prostaglandins synthesis. BRADYKININ and KALLIDIN • Vasodilator peptide autacoids originated from kininogens have effect on vascular smooth muscles, capillary permeability and bronchioles and intestinal muscles. CHEMISTRY AND DISTRIBUTION: o Bradykinin is a nonapeptide and kallidin is decapeptide as lysine residue is at amino-terminal portion so sometimes called as Lysyl-bradykinin. o Widely distributed in human , animal’s body ,certain snake venoms , etc. Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg fig:Bradykinin 79
Synthesis and Metabolism  Synthesized from circulating alpha 2 globulins called kininogens of proteolytic enzyme, kallikreins.  Rapidly metabolized(t12=60sec) mainly in lungs but also in other tissues by enzyme called kininases (specially kininase II) splitting off 2aminoacid from carboxy terminal to form inactive kinin metabolite 80
Mechanism of action  Act through two types of kinin receptor B1 and B2. a) B1 receptors : major role at inflamed sites. b) B2 receptors: mediate majority effects in absence of inflammation. Bradykinin has more affinity to B2 than B1 but kinin is equipotent to both B1 and B2. B2 receptor is coupled to G-proteins and activates phospholipase C and A2 that leads to increase in inositol 1,4,5-triphosphate and diacylglycerol,which in turn increase cytosolic calcium ion and protein kinase activity ,respectively. 81
Pathophysiological Roles 1.Mediation of Inflammation: • Produce all signs of inflammation-redness,exudation,pain and leukocyte mobilization. • Activation of B2 receptors on macrophages inducesproduction of IL-1 and TNF-alpha and other inflammatory mediators. 2.Mediation of Pain: • Directly stimulating nerve ending and increasing PG production , substance P, kinins appear to serve as mediator of pain. • B2 antagonists block the acute pain produced by bradykinin but induced B1 receptors appear to mediate pain of chronic inflammation. 82
Continued… 3.Functional Hypermia : • Functional Hypermia in glands during secretion.  Regulation of micro circulation-especially in kidney may be occurring through local kinin production. 4.Other: • Vital role in Rhinitis, Angiodema,Asthma and Carcinoid Syndrome. • Blood Coagulation: Liberated Kalikrein activates Factor XII by positive feedback mechanism, independent of kinin production. 83
Kinin No therapeutic but some drugs that alter their activities are available. KININ AGONIST 1) RMP-7:  Bradykinin analogue resistant to kinin metabolizing enzyme.  Increases permeability of blood barrier to certain drugs.  In the treatment of primary brain tumours. 84
2. Angiotensin Converting enzymes inhibitors  Known as Kininase II Inhibitors.  Prevent the degradation of endogeneous kinins.  Prolong their duration of action.  Clinically not used to prolong kinin duration of action but their antihypertensive effects are mediated through vasodilation. 85
KININ ANTAGONIST 1. Aprotinin:  Polypeptide from bovine lungs. Inhibits kalikriens and blocks synthesis of kinin and factor XIIa. Hence,inhibition of intrinsic pathway of coagulation as well as fibrinolysis. Use in open heart surgery and hyperplasminaemia. Withdrawn worldwide from 2007 due to hypersensitivity. 86
B.ANGIOTENSIN Involve in electrolyte , blood volume and blood pressure homeostasis. Types: i. Angiotensin I ii. Angiotensin II (most active biologically commonly called angiotensins) iii. Angiotensin III Collectively are called Renin- Angiotensin System that serve as circulating link between kidney and systemic haemodynamic control system.
Synthesis and Metabolism Angiotensinogen (alpha 2 globulin) Renin Angiotensin I(NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His- Leu-COOH) ACE 1 2 3 4 5 6 7 8 9 10 Angiotensin II (NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe- COOH) Angiotensinase 1 2 3 4 5 6 7 8 Angiotensin III(NH2-Arg-Val-Tyr-Ile-His-Pro-Phe- COOH) + 1 2 3 4 5 6 7 Inactive fragment Fig: Biosynthesis and metabolism of Angiotensin(structure shown is in rat, pig,horse and human but bovine contains valine in position 5) 88
• Two main types of G protein coupled receptors: AT1 and AT2 . • They are important in the renin- angiotensin system: they are responsible for the signal transduction of the vasoconstriction stimulus of the main effector hormone, angiotensin II. Mechanism of action
PHYSIOLOGICAL AND PHARMACOLOGICAL EFFECTS: 1.Blood pressure homeostasis Long term and short term pressure regulation. Also has positive ionotropic and chronotopic effect on heart. 2. Electroyte and blood volume Increases Na⁺ and water reabsorption in kidney Plays imp role in electrolyte and ecf balance 3. Mineralocorticoid secretion Stimulate aldosterone secretion from adrenal cortex 4 . Cardiovascular disease Involve in development of congestive heart failure, left ventricular dysfunction following infarction 5 CNS Function as neurotransmitter or neuromodulator and regulation of thirst , release of hormones like ADH &ACTH Its most of functions is via renin angiotensin system
Renin-angiotensin system :
Pharmacology of angiotensin: ANGIOTENSIN AGONIST : 1. Angiotensin II is not commercially marketed as a drug and is not approved for veterinary use . 2.Angiotensin II amide is a synthetic compound that produce sustained rise in blood pressure when given IV. However , it cause vasoconstriction that may decrease tissue perfusion.
On the basis of action and chemical structures , inhibitors of renin – angiotensin are of four classes : I. Renin secretion inhibitor: • Antagonist of sympathetic nervous system. • Block renal sympathetic activity by beta adrenoceptor blocker e.g propanolol II . Renin inhibitors: • Interfere with the generation of angiotensin I from angiotensinogen • All the drugs , except inhibitors of renin , has low bioavailability and short duration of action . • They produce dose dependent reduction in plasma renin activity .So, used occasionally for reduction of elevated blood pressure. E.g Aliskiren, Remikerin Angiotensin antagonist:
ContinuED... III. Angiotensin converting enzyme inhibitor : ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure: a. Sulfhydryl-containing agents eg .Captopril Zofenopril b. dicarboxyl containing ACE inhibitors: eg Enalapril Ramipril Quinapril Perindopril Lisinopril Benazepril Imidapril Trandolapril Cilazapril
• IV. Angiotensin receptor antagonists : a.Peptide antagonists • e.g saralasin b.Non-peptide antagonists • e.g. losartan , irbesartan , candesartan , eprosartan, valsartan, olmesartan and telmisartan Contin ueD...
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