1. CYANIDE ANTIDOTE FOR MASS CASUALTIES Present by RAHUL B S M. Pharm Part II Pharmaceutical Chemistry

2. CONTENTS INTRODUCTION CYANIDE POISONING TREATMENT OF POISONING AND ANTIDOTES ADVERSE EFFECTS OF EXISTING THERAPY CYANIDE ANTIDOTES FOR MASS CASUALTIES CONCLUSION REFERENCES 3. INTRODUCTION A cyanide is any chemical compound that contains cyano group(-CN), consisting of a carbon atom, triple-bonded to a nitrogen atom. 4. CLASSIFICATION Inorganic cyanide and cyanide salts (HCN, KCN,NaCN) Organic cyanides(CH3CN, acrylonitrile) Cyanogenic glycosides ( Amygdalin, linamarin) Cyanogens and its halides {(CN)2,CClN,CBrN} 5. Inorganic cyanides (NaCN), -CN group is present as the negatively charged polyatomic cyanide ion Organic cyanides the -CN group is linked by a covalent bond to a carbon-containing group -CN ions have high nucleophilicity, so cyano groups are readily introduced into organic molecules by displacement of a halide group (e.g., the chloride on methyl chloride). RX + CN RCN + X (nucleophilic substitution) 6. INDUSTRIAL SOURCES Insecticides, Photographic solutions, Metal polishing materials, Jewellery cleaners etc NATURAL SOURCES Seeds of Prunus species, cherry and apricot, apple etc. ENVIRONMENTAL SOURCES Smoke, volcanoes, and natural biogenic processes from higher plants etc SOURCES OF CYANIDE 7. CYANIDE POISONING Cyanide poisoning occurs when a living organism is exposed to a compound that produces cyanide ions (CN) Common poisonous cyanide compounds include hydrogen cyanide gas and the crystalline solids- potassium cyanide and sodium cyanide Types of cyanide poisoning Acute poisoning Chronic poisoning 8. ACUTE POISONING Acute cyanide poisoning may results from inhalation of liquid or gaseous HCN/-CN salts. The toxicity depends on dose and route of exposure. At lower doses, loss of consciousness preceded by general weakness, headache, vertigo, confusion, difficulty in breathing may progress to deep coma and finally cardiac arrest A fatal dose for humans can be as low as 1.5 mg/kg body weight 9. CHRONIC POISONING Cyanide is entering to the body daily in very small concentration through pesticide, insecticide, tobacco smoke, smoke, some foods like almonds, apricot kernel, apple seeds, cassava etc Exposure to lower levels of cyanide over a long period results in increased blood cyanide levels, which can result in weakness and a variety of symptoms, including permanent paralysis, nervous lesions, hypothyroidism, and miscarriages. 10. MECHANISM OF CYANIDE POISONING Cyanide is highly lethal because it diffuses into tissues and binds to target sites within seconds. Intravenous and inhaled exposures produce more rapid onset of signs and symptoms than does oral ingestion Oral or transdermal ingestion may produce a delay in signs and symptoms as concentrations increase in the bloodstream 11. cyanide anion inhibits the enzyme cytochrome c oxidase (aa3) in the fourth complex of the electron transport chain. prevents transport of electrons from cytochrome c to oxygen. No aerobic production of ATP for energy Tissues that depend highly on aerobic respiration, such as the CNS and the heart, are particularly affected. This is an example of histotoxic hypoxia 12. Cyanide reversibly binds to the ferric ion in cytochrome oxidase a3 within the mitochondria. 13. Cyanide prevents cellular use of oxygen, and for ATP production cells switch from aerobic to anaerobic metabolism. In anaerobic metabolism large amounts of lactic acid will release into the muscle tissue (Lactic acidosis), characterized by low pH in body tissues and blood. At first rapid, deep breathing and shortness of breath, followed by convulsions and loss of consciousness. If an average men inhaled HCN in Moderate concentration the symptoms will appear with in 15 seconds and with 4 to 8 mins death will occur. CLINICAL MANIFESTATIONS 14. TREATMENT OF POISONING AND ANTIDOTES A fatal dose of Cyanide for humans is 1.5 mg/kg body weight. People who breathed 546 ppm of hydrogen cyanide will die within 8-10minutes. 110 ppm of hydrogen cyanide was life-threatening after a 1- hour exposure. 20 ppm of HCN will produce symptoms after several hours. There are several agents that are used against cyanide poisoning. 15. Nitrites oxidizes ferrous state to the ferric state Cyanide binds to methemoglobin, forming cyanomethemoglobin, thus releasing cyanide from cytochrome oxidase. Thiosulfate By the mitochondrial enzyme rhodanese (thiosulfate cyanide sulfurtransferase) Thiosulfate must therefore be used in combination with nitrites. Hydroxocobal amin It is a form of vitamin B12 , is used to bind cyanide to form the harmless cyanocobalamin form of vitamin B12 Cyanocobalamin is then eliminated through the urine. 16. Dicobalt edetate Cobalt ions, being chemically similar to ferric ions, can also bind cyanide. This agent chelates cyanide as the cobalticyanide cobalt-based antidote available in Europe (dicobalt edetate or, (Kelocyanor). Glucose The coadministration of glucose protects against cobalt toxicity associated with the antidote agent dicobalt edetate 17. Treatment of poisoning and antidotes 18. CYANIDE ANTIDOTES Currently, 2 antidotes for acute cyanide poisoning are available This kit consists of 3 medications Amyl nitrite Administered via inhalation Sodium nitrite Administered intravenously Sodiumthiosulfate Intravenous 19. Cyanide binds to the ferric ion of methemoglobin rather than to the ferric ion of the cytochrome oxidase a3 in the mitochondria. Methemoglobin draws cyanide away from the mitochondria Mitochondria will returns to aerobic cellular respiration Cells are able to generate ATP, and the production of lactic acid ceases Extracellular cyanide binds with sulphur of thiosulfate to form the renally excreted thiocyanate 20. Hydroxocobalamin (Cyanokit) approved by FDA for the treatment of acute cyanide poisoning. Administered via IM 21. Cyanide antidote kit Vasodilatation, leads to Hypotension Methemoglobinemia IMPORTANT ADVERSE EFFECTS OF EXISTING THERAPY 22. Bright pink discolouration of the Epicardium Bright pink to reddish discolouration of the biological fluids. 23. Mass Casualties in cyanide poisoning Cyanide is a poison used in mass homicides, suicides, and as a weapon of war. Cyanide disaster occurs usually by a major chemical accident or a terrorist-caused incident. In industries, Cyanide can be liberated during the combustion of products containing both carbon and nitrogen. Occupational exposures are reported in Metal extraction in mining, electroplating in jewellery production, photography, plastics and rubber manufacturing, and pesticide. Workers in Cassava processing units Animals also face accidental poisoning through cyanogenic plants (Prunus species, Sorghum species). 24. Example for a cyanide accident The Baia Mare cyanide spill (January 30, 2000 ) Mass Casualties may be of 2 types. With low concentration With high concentration 25. CYANIDE ANTIDOTES FOR MASS CASUALTIES There are two mammalian enzymes that sequester cyanide as thiocyanate Rhodanese and 3- Mercaptopyruvate sulfurtransferase. Rhodanese - mitochondria, 3-MPST both in cytoplasm and mitochondria of all organs including brain and heart. 26. 3-MST substrate/enzyme system is difficult to exploit for use in cyanide antidote therapy 3-mercaptopyruvate (3-MP) is unstable in blood Transamination product of L cysteine, and cysteine catabolite may utilizes the enzyme. 27. For mass casualties, With low concentration of cyanide - Prodrugs of 3-MP. Orally effective anticyanide agents are previously unknown. 3-MP produgs are orally bioavailable. Can be use for chronic poisoning. 28. 3-MP prodrugs are useful for subjects exposed to cyanide. For comatose victims the only option is IV antidote therapy. O O CH3 O O CH3 H S O CH3 N H S O OH O O CH3 SH ethyl (2E)-2-(acetyloxy)-3-(acetylsulfanyl)prop-2-enoate 2-(ethoxycarbonyl)-2-(sulfanylmethyl)-1,3-thiazolidine-5-carboxylic acid Prodrugs of 3-mercaptopyruvate 29. Need for rapid drug delivery methods For mass casualties with high cyanide concentration IV antidote therapy, a relatively slow and elaborate procedure requiring highly trained paramedical personnel. There is chance for large numbers of cyanide-exposed victims untreated. 30. Rapid delivery methods are needed for the treatment of mass casualties The choices are to administer the antidote by 1. Intramuscular (IM), 2. Intraosseous (IO), 3. Intranasal/intratracheal routes 31. Sublingual and transdermal delivery are possibilities, the absorption rates of the antidotes via such routes are too slow for the treatment of a rapid acting poison like cyanide. Among these methods IM administration is more efficient to treat mass casualties 32. TECHNICAL CHALLENGE IM MODE FOR CYANIDE ANTIDOTE ADMINISTRATION (a) large doses must be administered within a short time for maximal efficacy, (b) Inflammatory responses must be minimal at the IM injection site (c) The antidote must be highly water-soluble If an anticyanide agent over comes the above challenges, it would be beneficial for the treatment of cyanide victims. 33. First approach It is based of the preparation of sodium salt of the dimeric, Dithiane (sulfanegen) form of 3-mercaptopyruvate S S O OH O OH OH OH 34. Sodium salt of dithiane shows high potency as antidote for cyanide. But salt could not fulfill the above role because its aqueous solubility was not greater than 128 mg/mL (0.35 M). Dose calculations demands, a minimum water solubility of 1.05 M, for antidotal efficacy by the IM route for 60 kg human with a maximum injectable volume of 5 mL. 35. The second approach It is based of the preparation of salt forms of sulfanegen with biocompatible organic amines. N + OH OH OH H N + OH OH H H NH3 + OH triethanolamine diethanolamine ethanolamine Solubility 1.58 M Solubility 2.25M Solubility 1.05M The Salts of ethanolamine, diethanolamine (DEA),and triethanolamine (TEA) shows superior efficacy relative to the sodium salt and aqueous solubility is optimum for activity. 36. Synthesis of Sulfanegen salts Br O OH O S S O O Na O O Na OH OH S S O O H O O H OH OH S S O O - O O - OH OH +M 2 mol equiv NaHS H+ amines 3-bromo-2-oxopropanoic acid disodium 2,5-dihydroxy-1,4-dithiane-2,5-dicarboxylate 2,5-dihydroxy-1,4-dithiane-2,5-dicarboxylic acid M = amines 37. Sulfanegen salts were tested individually in mouse model for assessing antidotal efficacy using sublethal doses of cyanide. Recovery times of the antidote treated vs untreated mice were compared. The antidotal efficacy were measured by reduction in time required for the mouse to recover neuromuscular coordination. Shorter time of recovery indicates greater antidotal efficacy. 38. CONCLUSION Both the cyanide antidote kit and hydroxocobalamin are considered acceptable for treatment of cyanide poisoning in uncomplicated exposures, but in case of mass casualties highly water-soluble IM injectable antidotes are needed. Sulfanegen salts (Amide Salts) are promising lead for development as an IM injectable cyanide antidote for the treatment of cyanide victims in a mass casualty setting. 39. REFERENCES Steven E. Patterson Cyanide Antidotes for Mass Casualties: Water-Soluble Salts of the Dithiane (Sulfanegen) from 3-Mercaptopyruvate for Intramuscular Administration . J. Med. Chem. 2013, 56, 13461349 Text book of Medical Toxicology edited by R.C Dart 3rd edition page No. 1155- 66 Toxicological Review Of Hydrogen Cyanide And Cyanide Salts by U.S. Environmental Protection Agency Washington, DC C. Brunel, C. Widmer, M. Augsburger, F. Dussy, T. Fracasso. Antidote treatment for cyanide poisoning with hydroxocobalamin causes bright pink discolouration and chemicalanalytical interferences. Forensic Science International 223 (2012) e10e12. 40. Jillian Hamel. A Review of Acute Cyanide Poisoning With a Treatment Update. CriticalCareNurse Vol 31, No. 1, (FEB) 2011 73-81. Robert J. Geller, MDa,b, Claudia Barthold, MDa,b, Jane A. Saiers, PhDc, Alan H. Hall. Pediatric Cyanide Poisoning: Causes, Manifestations,Management, and Unmet Needs. PEDIATRICS Volume 118, Number 5, November 2006 2146-58 Toxicological Profile For Cyanide by U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service. Herbert T. Nagasawa, Steven E. Patterson. Novel, Orally Effective Cyanide Antidotes. J. Med. Chem. 2007, 50, 64626464. All the information was collected from various sources, for education purpose only