AUTACOIDS :AUTACOIDS Dr. P. K. Verma Division of Pharmacology And Toxicology Faculty of Veterinary Sciences and Animal Husbandry R. S. Pura Jammu


AUTACOIDS :AUTACOIDS Greek word autos- self; akos- remedy (healing substance) Naturally occurring substances Localized in tissues and normally do not circulate Differ from hormones and neurotransmitters Short duration of action Usually involved in response to injury Sites of action restricted to the synthesis area


Slide 3:The autacoids are also called as local hormone. (Hormone release by the specific cells whereas act upon distant target tissue). They are not stored and released from glands, nor do they need to circulate to the site of action like "classical" hormones. These are substances produced by wide variety of cells in the body having intense biological activity but generally act locally at the site of synthesis & release.


Classification of autacoids :Classification of autacoids Basis of chemical nature autacoids are classified into following group Decarboxylated amino acid (amine autacoids) Histamine , Serotonin Polypeptides autacoids Angiotensins, Kinins, VIP, Substance P, CGRP Endothelium-derived autacoids Nitric oxide (NO), Endothelins (peptide) Lipid derived autacoids – Prostaglandins, Leukotrines, Platelet activating factor.


Modulation in the activity…. :Modulation in the activity…. Autacoids are involved in a number of physiological & pathological processes & even serve as transmitters or modulators in the nervous system. Know the physiologic effects of the selected autacoids on organ systems where we can pharmacologically modulate their action. Modulation of activities either decrease/increase in activity of these autacoids help in maintaining normal homeostasis. A no. of useful drugs acts by modifying their action or metabolism.


Histamine :Histamine Greek word – histos – tissue – amine Distributed throughout body of mammals, venoms (snakes, bee, etc) & food stuffs (pine apple). Mammalian tissues concentration ranging between 1- 100 μg/gm of tissue. Concentration of histamine in different tissue varies with different species Circulating histamine is high in case of goat & rabbit while low in horse dog, cat & humans.


Slide 7:Formed from basic amino acid Histidine Extracted from putrefying mixtures by Ackerman 1910. Assumed to be responsible for anaphylaxis by Dale and Laidlaw (1911, 1960) as synthetic material had the same effects. Eppinger (1913) demonstrated that histamine produced a reaction in human skin similar to that seen with insect bites. Chemically β-Imidazolyl ethylamine is first isolated from living tissue by Best & coworkers in 1927. Synthesis of Histamine


Slide 8:It is stored in intra-cytosolic granules with acidic protein (heparin, ATP, protease) in mast & basophill cells. Histamine is release from mast cells during inflammation or allergic condition by exocytosis. Mechanical stimulation like tissue damage, cold, heat, and ultra violet rays also causes degranulation of mast cells. Tissue rich in histamine are skin, gastric mucosa, lung, brain, liver & placenta.


Exocytosis :Exocytosis Large number of therapeutic agents (basic drugs) release histamine by non receptor mediated action quaternary ammonium compounds (Tubocurorine, succinyl-choline) Antibiotics (Polymixin B) Alkaloids (Morphine) Radio-contrast media, Carbohydrate plasma expander (dextran) Proteolytic enzymes Large protein molecules (egg white, toxins) Polypeptides (substance P, Bradykinin) releases during the injury are also histamine from mast cells to produce inflammatory effects. Non-mast cell histamine occurs in histaminocytes in the stomach & histaminergic neurons in brain.


Slide 10:Metabolism and excretion of Histamine


Mechanism of action :Mechanism of action Histaminergic receptors H1 receptors H2 receptors H3 receptors Organ function is controlled by Type and density of receptors and Compound affinity to the receptors


Histaminergic receptors :Histaminergic receptors


Slide 13:Pharmacological effect on different system


Cardiovascular system :Cardiovascular system Histamine produces positive ionotropic (by promoting Ca++ flux) & positive chronotropic effect (increase diastolic depolarization of the SA node) on the heart primarily through H2 receptors. Histamine causes increase in capillary permeability & capillaries vasodilatation due to stimulation of H1 receptors in capillary bed. Histamine can produce shock through hypotension, reduced blood volume by increased vascular permeability of capillaries (H1recetors), and decreased venous return.


Slide 15:In large blood vessels constrictor effect is seen (H2 receptors) which varies between species to species. Increasing in geological scale Rabbit > rodent > cat > humans Vasoconstriction vasodilatation (High density of H2 receptors) (High density of H1 receptors)


Triple response :Triple response If histamine is administered intra-dermal, it elicits a characteristic phenomenon consists of Initial red spot (flush) with in few seconds at the site of injection due to intense capillary dilation Wheal appears with in 1-2min. At the same area due to diffusion of histamine in surrounding (3-6mm dia.) Bright red flare (1-5cm) surrounding the wheal develop slowly due to exudation of fluid from capillaries & venues (localized edema)


Extra-vascular smooth muscle :Extra-vascular smooth muscle Histamine, acting on H1 receptors causes contractions of the smooth muscle of GIT, bronchi & the uterus. Except rat uterus is relax (H2 receptors). Effect of H1receptor is rapid and transient whereas H2 receptors response is slow onset and more sustained. H1 receptors are more sensitive to lower histamine concentration then H2 receptors.


Slide 18:Glands: Histamine causes increase in gastric acid secretion by directly acting on parietal cells through H2 receptors. Activation of H2 receptors increases cytosolic concentration of cAMP resulting into phosphorylation of membrane protein i.e. proton pump protein (H+K+ATPase). Sensory nerve ending: Itching & pain sensation occurs when histamine is injected subcutaneous due to stimulation of H1receptors on the free nerve ending.


Central Nervous System :Central Nervous System H1, H2 & H3 receptors are distributed throughout brain & are densely concentrated in the hypothalamus. Histamine increases wakefulness via H1 receptors & also regulates water intake, body temp, ADH secretion & perception of pain. Histamine doesn’t cross blood brain barrier, no central effects are seen on i/v administration. Intracranial administration produces behavioral arousal, hypothermia, vomiting & ADH release.


Histamine concentration in brain :Histamine concentration in brain Released by some neurons in the hypothalamus Important nt in regulation of sleep and wakefulness Otherwise not a common nt in vertebrates


Clinical uses of agonists :Clinical uses of agonists H2 receptor agonists used for diagnostic procedures in assessing gastric secretary response i.e. achlorhydria. Betazole has some residual H1 activity and Impromidine -10,000 fold greater selectivity for H2 receptors. In dogs Betazole is used dose rate of 0.5mg/kg b.wt oral, im, iv. For achlorhydria testing Diagnosis of pheochromocytoma, and to verify integrity of axon reflexes.


Anti-histaminics :Anti-histaminics The agents antagonizing the effect of histamine are termed as anti-histaminics. All available histaminergic receptor antagonists are reversible, competitive inhibitors of the interaction of histamine with H1 receptors. H1 receptor antagonists H2 receptor antagonists H3 receptor antagonists


H1 Receptor antagonists :H1 Receptor antagonists Indicated in: All type allergic & anaphylactic reaction, Inflammatory condition, like laminitis, bloat, acetonemia mastitis, matritis, dermatitis, pruritis, eczema, itching common cold, Pre-anesthetics & motion sickness hay fever, bronchial asthma, insect bites H1 Receptor antagonists are divided into two groups


Conventional / classical / first generation antihistaminics :Conventional / classical / first generation antihistaminics Competitive antagonism (do not prevent release or do not cause physiological antagonism). Do not prevent histamine release Diphenhydramine, Pheniramine maleate, Chlorpheniramine, Promethazine and Mepyramine


Conventional anti-histaminics :Conventional anti-histaminics Dose of the most of the compounds in this groups ranges in small animals @ 1-2mg/kg b. wt and in large animals @ 0.5-1 mg/ kg for parenteral administration.


Side effects :Side effects Do not block gastric acid production (blocked by H2) CNS depression, (sedative activity) Anti-cholinergic side effects (dry mouth, motion sickness) (inhibit release of ACh from nerve terminals). Local anesthetic effect Some drugs of this group (meclizine, buclizine & cyclizine) are having teratogenic effects in animals (structural abnormality in developing Fetus).


Second generation anti-histaminics :Second generation anti-histaminics To avoid side effects of first generation anti-histaminics some selective compounds have develop, these compounds have High selectivity to H1 receptors Have longer durations of action; Least of CNS depressant activity b/c can’t cross blood brain barrier Less anti-cholinergic side effects. E.g. Fexofenadine, cetirizine, astemizole, terfenadine, loatadine etc


2nd Generation Antihistamines :2nd Generation Antihistamines


H2 receptor antagonists :H2 receptor antagonists Used in: Duodenal & gastric ulcer Hyperacidity- excessive production of gastric acids secretion due to histamine Stress related gastritis & peptic ulcer Zollinger Ellison syndrome - a tumor of the pancreas producing excessive quantities of gastrin; beneficial response from high doses of H2 antagonists


H2 Antagonists :Cimetidine-inhibits cytochrome P450 enzyme activity & thereby effect metabolism of other drugs e.g. Phenytoin, phenobarbitone, warfarin, digitoxin and diazepam. Famotidine & ranitidine 4-12 times more potent then Cimetidine Famotidine & Ranitidine Dog – 2mg/kg BID orally, i/m H2 Antagonists


H3 receptor antagonists :H3 receptor antagonists Thioperamide, Burimamide Brain (pre-synaptically) regulate release of NE, ACh, 5-HT GABA, dopamine, glutamate Clinical phase in development of antipsychotic drugs


Inhibitors of mast cell degranulation :Inhibitors of mast cell degranulation Some agents inhibit the release of histamine from mast cell by stabilizing the cell membrane thus prevent degranulation. Nedocromil Cromolyn sodium Lodoxamide tromethamide


Cromolyn sodium :Cromolyn sodium Prophylaxis for asthma and treatment of allergic rhinitis Cromolyn sodium is administered by inhalation due to poor oral absorption and believed to inhibit calcium influx thus prevents exocytosis of histamine and leukotrines granules from mast cell.


Nedocromil :Nedocromil Mechanism similar to cromolyn also stabilizes other inflammatory cells such as eosinophils, macrophages, neutrophils, platelets. Administered by inhalation for prophylaxis of asthma. Also act by reducing intracellular calcium by acting at channels (Ca2+‑) resulting in decreased histamine release.


Lodoxamide tromethamide :Lodoxamide tromethamide Prevents antigen-induced calcium influx into mast cells that causes histamine release; may also interfere in leukotrines production. Used topically for inflammatory diseases of the eye (e.g. conjunctivitis)


Slide 37:THANK YOU…