1. CYANIDE

2. OBJECTIVES  Recognize the physical and chemical properties  Describe the mechanism of action  Identify routes of exposure  Describe the clinical presentation  Discuss proper treatment modalities

3. CYANIDE  Rapidly acting chemical poison  CW agents  Hydrogen cyanide (AC)  Cyanogen chloride (CK)  Naturally occurring chemical  Found in most living organisms  Man: < 0. 3 mcg / mL in blood CN -

4. OTHER CYANIDE SOURCES  Foods and other plants  Lima beans, cassava root, peach pits  Combustion  Plastics, synthetic fibers  Nitriles (acrylic and nylon manufacture)  Cigarette smoke  Fumigant / pest killer

5. NONMILITARY USES  Poisonings  Terrorists, Executions, Homicides, Suicides  Industry  Electroplating  Plastics processing  Gold and Silver extraction  Fumigation  Photography  Metallurgy

6. HISTORY AND MILITARY USE  Scheele: Isolated in (1782)  Napoleon: Troops dipped bayonets  WW I: French  Nazi Germany: Zyklon B  Japan: Against the Chinese in WW II  Stockpiled by U.S. in WW II  Chemical agent identification kits

7. CYANIDE CHARACTERISTICS  Liquid, gas, or salt  Volatile: boiling point 60-80 0 F  Non-persistent  Bitter almond to biting, pungent odor  Cyanogen chloride (CK) Chlorine smell  Strong affinity for metals, especially ferric iron (Fe 3+ )  Cytochrome oxidase (Fe 3+ )  Methemoglobin (Fe 3+ )

8. DOSE: Toxicity Relationship General Principle Bigger exposure Means Worse injury and sooner onset

9. SITE OF ACTION  Primary site of action: Cells rather than blood  Organelles affected: Mitochondria

10. CLASSICAL MECHANISM OF ACTION  Cyanide binds to hemoprotein in mitochondria  Cytochrome oxidase hemoprotein (cyt a 3 ) has Fe 3+ (Cell energy producer)  Stable but reversible binding  CN - has higher affinity for Fe 3+ in cyt a 3 than Fe 2+ in hemoglobin  Cyanide interrupts oxidative phosphorylation …

11. HOW CYANIDE INTERFERES WITH OXIDATIVE PHOSPHORYLATION

12. EFFECTS OF CYANIDE IN THE CELLS AND BLOOD  No aerobic generation of adenosine triphosphate (ATP). This blocks cell’s ability to use oxygen (aerobic metabolism) causing cell death  Aerobic metabolism stops and shifts to anaerobic metabolism, causing rapid lactic acidosis  No extraction of Oxygen from blood; venous blood oxygen increases to near arterial levels

13. MANIFESTATIONS OF TOXICITY  Rapid onset (inhalation)  Brief period of tachypnea  Loss of consciousness  Convulsions  Apnea without cyanosis  Asystole  Death

14. HIGH DOSE INHALATIONAL CYANIDE TIMELINE Convulsions Inhalation Hyperpnea LOC Apnea Heart stops Death 15 sec 30 sec 3-5 mins 5-8 mins 60 sec

15. HIGH DOSE INGESTION CYANIDE TIMELINE Ingestion Hyperpnea Anxiety Convulsions Heart stops Death 7 min 10 min 20 min 30 min LOC 15 min Weakness Apnea 25 min

16. DIAGNOSIS  History of exposure  Rapid onset of symptoms  “Cherry red” skin; odor of bitter almonds  Respiratory depression  Laboratory  Methemoglobin level  Whole blood or tissue cyanide or thiocyanate level  Metabolic acidosis

17. THE BOTTOM LINE  Cyanide blocks aerobic metabolism and energy production causing cellular hypoxia  Normally body metabolizes cyanide by enzymatic reaction mediated by mitochondrial enzyme rhodanese in the liver. This reaction forms thiocyanate which is excreted in the urine  Toxic dose overwhelms the normal metabolic processes  Treat cyanide overdose by enhancing normal metabolic mechanisms

18. MEDICAL MANAGEMENT  Protect yourself!  Eliminate further exposure  General supportive therapy  Specific antidotal therapy

19. GENERAL SUPPORTIVE THERAPY  Termination of exposure  Removal of patient: Physical removal, masking  Removal of agent  Decontamination (soap and water)  Gastric lavage with activated charcoal, 5% sodium thiosulfate, 0.1% potassium permanganate, or 1.5% hydrogen peroxide (ingestion)  Airway, Breathing, and Circulation (but beware unprotected mouth-to-mouth respiration)  100% oxygen  Correct metabolic acidosis / manage seizures  Observation for at least 24 to 48 hours

20. GOALS OF SPECIFIC ANTIDOTAL THERAPY  Displace cyanide from cytochrome a 3  Use Nitrites to form methemoglobin, Ferric iron (Fe 3+ )  Eliminate cyanide from the body  Administer sulfane (e.g., sodium thiosulfate) as a sulfur donor  Convert cyanide to thiocyanate nitrite thiosulfate metHb (Fe 3+ ) HbO 2 (Fe 2+ )

21. ANTIDOTE THERAPY  Cyanide Antidote Kit  Methemoglobin Formers  Amyl Nitrite  Sodium Nitrite  Sulfur Donor  Sodium Thiosulfate

22. AMYL NITRITE: (C 5 H 11 NO 2 )  Therapeutic effect noted as early as 1888  Generates methemoglobin (variable levels)  Casualty must inhale - give by ambu bag  Causes marked vasodilation, orthostatic hypotension, dizziness, and headache  Use your judgment if casualty is conscious and able to stand

23. CYANIDE IS IN THE BODY: Where Will it Bind? HbO 2 (Fe 2+ ) CN - (Fe 3+ ) cyt a 3

24. BOUND CYANIDE INACTIVATES CYTOCHROME OXIDASE CN - cyt a 3 (Fe 3+ ) cyt a 3 HbO 2 (Fe 2+ )

25. NITRITE PRODUCES METHEMOGLOBIN: What Will Cyanide Do? HbO 2 (Fe 2+ ) metHb (Fe 3+ ) nitrite ? ? ? CN - cyt a 3 (Fe 3+ )

26. CYANIDE RELEASES CYTOCHROME OXIDASE … CN - metHb (Fe 3+ ) cyt a 3 (Fe 3+ )

27. AND FORMS CYANOMETHEMOGLOBIN CN - metHb (Fe 3+ ) A stable, but reversible, bond cyt a 3 (Fe 3+ )

28. OVER TIME CYANIDE WILL MOVE OUT OF THE BOND WITH METHEMOGLOBIN … metHb (Fe 3+ ) CN - cyt a 3 (Fe 3+ )

29. SODIUM NITRITE (NaNO 2 )  Forms methemoglobin  Beneficial effects rapid  Single dose raises metHb level to 20%  Adverse effects  Headache  Nausea  Orthostatic hypotension  Methemoglobinemia (maintain less than 40% metHb)

30. SODIUM NITRITE: Administration  10 mL IV of a 3% soln (30 mg / mL) = 300 mg  Administer over a 5 to 15 minute period  Vasodilatory affects STOP if systolic BP drops below 80  Give half original dose if signs recur

31. SODIUM NITRITE: CAUTION!  In children – USE CAUTION!  0.33 mL per kilogram of body weight 10% solution  Fire victims – USE CAUTION!  Should not be given methemoglobin-inducing substances  Alternative therapy  administer oxygen, thiosulfate, hydroxicobalamin, or other supportive measures

32. SODIUM THIOSULFATE (Na 2 S 2 O 3 )  Normally rhodanese enzyme (primarily in liver) metabolizes sulfur and cyanide to produce thiocyanate  Thiosulfate is the sulfur donor to help rhodanese enzymatic reactions that form thiocyanate (SCN - ) and sulfite (SO 3 2- )  Irreversible reaction; thiocyanate excreted by kidney  Adverse effects few and usually not serious  Nausea, vomiting, arthralgias, psychosis only with levels greater than 10 mg / dL

33. SODIUM THIOSULFATE: Administration  50 mL IV of a 25% soln (250 mg / mL) = 12.5 g  Administer over a 10- minute period beginning immediately after nitrite administration  Give half original dose if signs recur  Pediatric Dose:  1.65 mL / kg

34. IN THE LIVER, FREE CYANIDE IS TRANSFORMED INTO THIOCYANATE WHICH IS THEN EXCRETED IN THE URINE metHb (Fe 3+ ) CN - thiosulfate rhodanese urine Liver thiocyanate

35. REVIEW OF THE ANTIDOTE STEPS thiocyanate CN - thiosulfate rhodanese urine Liver CN - metHb (Fe 3+ ) HbO 2 (Fe 2+ ) metHb (Fe 3+ ) nitrite1.2. cyt a 3 (Fe 3+ )

36. OTHER METHEMOGLOBIN FORMERS  4-Dimethylaminophenol (4-DMAP)  Forms metHb more rapidly than do nitrites  No hypotension, but metHb levels often too high  Local necrosis may occur after IM injection (give IV only)  Used in Germany

37. COBALT COMPOUNDS  Dicobalt edetate (Co 2 EDTA, Kelocyanor)  Chelates CN -  Adverse effects  Angina pectoris, ventricular dysrhythmias, periorbital and laryngeal edema, convulsions  Used in the U.K., France, and the Netherlands

38. COBALT COMPOUNDS  Hydroxocobalamin (vitamin B 12a )  Reacts with CN - to form cyanocobalamin (vitamin B 12 )  Difficult to administer adequate amounts  Used in France

39. SUMMARY  Killed millions throughout history. Top terrorist consideration  Battlefield or terrorist use probably as a vapor (enclosed area)  Variable potency (LCt 50 ) because of body’s natural metabolism, but rapidly acting in high concentrations  Cellular poison, NOT a “blood” agent  Nitrites generate metHb, which “pulls” cyanide from cyt a 3 temporarily  Thiosulfate provides sulfides to help liver enzyme rhodanese form thiocyanate which is excreted in the urine CN -