Cyanide Poisoning

GROUP 4 CYANIDE POISONING I. II. III. IV. V. VI. VII.

Define cyanide poisoning (acute and chronic exposure) Identify the sources characteristics, purposes of cyanide. Enumerate causes of cyanide poisoning. Discuss the normal metabolism of cyanide in the body. Illustrate how cyanide disrupts the electron transport chain Explain the molecular basis of the different clinical manifestations observed in cyanide poisoning. Discuss the management and rationale for treatment of cyanide poisoning.

CYANIDE - Cyanide is fast-acting, bitter-tasting and one of the deadliest known. Its compound has famously been utilized in suicide pills over the years. - Exists in gaseous, liquid, and solid forms. Hydrogen cyanide (HCN, also known as prussic acid) is a volatile liquid that boils at 25.6° C (78.1° F). Potassium and sodium cyanide salts are water soluble and gets converted to HCN by stomach acid. - Hydrogen cyanide is a colorless gas or liquid with a faint, bitter almond odor (odor threshold of 0.58 parts per million) - Sodium cyanide and potassium cyanide are both colorless solids that has a slight odor of bitter almonds - Uses: o Historically, they were used as a chemical weapon in World War I and II. o Used in pesticides and fumigants, plastics, electroplating, photodeveloping and mining o Also used by dye and drug companies [vasodilator nitroprusside sodium, which may produce iatrogenic cyanide poisoning during prolonged or high-dose intravenous (IV) therapy (>10 mcg/kg/min)] - Sources: o Combustion of rubber, plastic, wool, polyurethane, and silk produces cyanide fumes o Photography, chemical research, synthetic plastics, metal processing, and electroplating industries o Plant sources: apricot pits, cassava (104 mg CN/100g), almond (250 mg CN/100g), wild cherries (140-370 mg CN/ 100g), lima beans (100300 mg CN/ 100g) and sorghum (250 mg CN/100 g) o Laetrile, a compound that contains amygdalin (a chemical found in the pits of raw fruits, nuts, and plants) has been purported as a cancer treatment worldwide o Cigarette smoke (most common source of cyanide exposure) CYANIDE POISONING

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Rare form of poisoning, occurs relatively frequently in patients with smoke inhalation from residential or industrial fires. Results from inactivation of cytochrome oxidase (at cytochrome a3), thus uncoupling mitochondrial oxidative phosphorylation and inhibiting cellular respiration, even in the presence of adequate oxygen stores

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Causes: o Smoke inhalation during house or industrial fire: major source of cyanide poisoning in USA (blood cyanide concentrations >40 mmol/L or approx. 1 mg/L) o Intentional poisoning: uncommon, but effective means of suicide o Iatrogenic exposure: vasodilator sodium nitroprusside when used in high doses or over a period of days can produce toxic blood concentrations o Industrial exposure: metal trades, mining, jewelry manufacturing, dyeing, photography and agriculture, etc. o Ingestion of cyanide-containing supplements or plants: rare (Amygdalin or synthetic laetrile, also marketed as vitamin B-17 postulated to have anticancer properties contains cyanide)

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ACUTE CYANIDE POISONING  Short-term inhalation exposure to 100 milligrams per cubic meter or more of hydrogen cyanide will cause death in humans (fatal dose in humans of 1.5 mg/kg body weight)  At lower doses (6 to 49 mg/m3 ) will cause variety of effects in humans, such as weakness, headache, confusion, nausea, increased rate or respiration, and eye and skin irritation  May progress to deep coma and finally cardiac arrest CHRONIC CYANIDE POISONING  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  Exposure to very small concentration daily of pesticides, tobacco smoke, smoke, some foods like almonds, apricot kernel, cassava, etc  Non-carcinogenic even in chronic cyanide poisoning (classified by EPA as Group D, not classifiable as to human carcinogenicity).

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TOXIC DOSE Hydrogen Cyanide - Fatal: 150-200 ppm - Air level: 50 ppm - Permissible exposure limit: 10 ppm Sodium Cyanide/Potassium Cyanide

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Ingestion of Cyanide salts may be fatal with as little as 200 mg Solutions of Cyanide Salts can be absorbed through intact skin or through the conjunctiva of the eye

How is Cyanide normally metabolized in the body? -

Cyanide is normally metabolized in the body through the enzyme rhodanese (Thiosulfate cyanide sulfurtransferase). Rhodanese is an ubiquitous enzyme that is known to be responsible for the biotransformation of cyanide to a less toxic

thiocyanate.

cyanid

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thiosulfat

thiocyana

sulfite

This mechanism involves binding of thiosulfate to a metal ion in the enzyme. In this complex, there is election shift away from the planetary sulfur atom of the thiosulfate with resultant stretching and weakening of the S – S bond, making it more susceptible to attack by a strong enzymic nucleophile which affects the cleavage. The enzyme substrate complex, differing in reactivity depending on the nature of sulfur donor substrate, is formed by discharging sulfite ion from enzyme-thiosulfate complex. The acceptor substrate, cyanide ion then combines with the E– S intermediate to form the second product, thiocyanate ion, thereby regenerating the free enzyme.

How does cyanide disrupts the electron transport chain? - The primary effect of cyanide poisoning is the impairment of oxidative phosphorylation a process whereby oxygen is utilized for the production of essential cellular energy sources in the form of ATP (adenosine triphosphate). The cyanide ion can rapidly combine with iron in cytochrome a3 (a component of the cytochrome aa3 or cytochrome oxidase complex in mitochrondria) to inhibit this enzyme, thus preventing intracellular oxygen utilization.

What is the molecular basis of the different clinical manifestations found in cyanide poisoning? Why is a cyanide poisoned patient not cyanotic even if he is gasping for breath? Cyanide is known to bind and inactivate several enzymes, particularly those containing iron in the ferric (Fe3+) state and cobalt. It is thought to exert its ultimate lethal effect of histotoxic anoxia by binding to the active site of cytochrome c oxidase, the terminal protein in the electron transport chain located within mitochondrial membranes. By this means, cyanide prevents the transfer of electrons to molecular oxygen. Thus, despite the presence of oxygen in the blood, it cannot be utilized toward adenosine triphosphate (ATP) generation, thereby stopping aerobic cell metabolism. Initially cells attempt to replenish the ATP energy source through glycolysis, but the replenishment is short lived, particularly in the metabolically active heart and brain. Binding to the cytochrome oxidase can occur in minutes. A more rapid effect appears to occur on neuronal transmission. Cyanide is known to inhibit carbonic anhydrase and this enzyme interaction may prove to be an important contributor to the well-documented metabolic acidosis resulting from clinically significant cyanide intoxication. Patients do not appear cyanotic because of oxygenated venous blood. Symptoms of Cyanide Poisoning 

General weakness, confusion, bizarre behavior, excessive sleepiness, coma, shortness of breath, headache, dizziness. An acute ingestion will have a dramatic, rapid onset, immediately affecting the heart and causing sudden collapse. It can also immediately affect the brain and cause a seizure or coma. Chronic poisoning from ingestion or environmental poisoning will have a more gradual onset. The skin of a cyanide-poisoned person can sometimes be unusually pink or cherry-red because oxygen will stay in the blood and

not get into the cells. The person may also breathe very fast and have either a very fast or very slow heartbeat. Person's breath can smell like bitter almonds. What is the rationale for treatment and management of cyanide poisoning? What are the contents and mechanism of action of the Antidote kit? Is oxygen administration useful? The primary goal is to maintain cellular utilization of oxygen by interfering with cyanide to prevent its interaction with cytochrome oxidase. Since cyanide poisoning usually kills people in less than 15 minutes, immediate treatment is absolutely essential. First induce vomiting if possible, or wash the stomach with a saline solution. Then give amyl nitrite, sodium nitrite and sodium thiosulfate which are contained in a cyanide antidote kit. And based on the case, Activated charcoal suspension was administered because it acts as an adsorbent wherein it binds with the poison in the stomach to decrease absorption of the poison into the body. Contents of Antidote Kit • • • • • • • • • •

2 ampoules Sodium Nitrite Injection (300 mg in 10 ml of water/ a 3% solution) 2 vials Sodium Thiosulfate Injection (12.5 g in 50 ml of water/ a 25% solution) 12 ampoules Amyl Nitrite Inhalants Contents Also: 10 mL plastic disposable syringe with a 22 gauge needle 1 sterile 60 ml plastic disposable syringe 1 sterile 20 gauge needle 1 stomach tube 1 non-sterile 60 ml syringe 1 tourniquet 1 set of instructions 

Amyl Nitrite and Sodium Nitrite

The mechanism of action of amyl nitrite and sodium nitrite as antidotes for cyanide poisoning is to produce methemoglobinemia and vasodilation. Intravenous sodium nitrite produces significant methemoglobinemia. The cyanide bound to cytochrome oxidase is then preferentially bound to methemoglobin, forming cyanomethemoglobin. Rhodanese, an endogenous enzyme, then facilitates the formation of thiocyanate, a much less toxic metabolite, which is renally excreted. In the context of cyanide poisoning, the differences between nitrites lie in the route of administration and the degree of methemoglobinemia they produce. Amyl nitrite is inhaled, produces a minimal amount of methemoglobin, and is designed to be administered pending the establishment of i.v. access, as is often the case in the prehospital setting. Sodium nitrite is administered intravenously and results in a methemoglobin concentration of about 15% in healthy adults. In other scenarios of cyanide toxicity, particularly the intentional ingestion of cyanide salts, amyl nitrite

can be given to adults as one ampul (0.3 mL) inhaled until i.v. access is obtained, followed by 300 mg (10 mL of 3%) i.v. sodium nitrite over two to four minutes. Children should receive 6 mg/kg (0.2 mL/kg of 3%) sodium nitrite up to the adult dose, at the same rate. 

Sodium Thiosulfate

Cyanide is metabolized by the enzyme rhodanese to a less toxic metabolite, thiocyanate, which is renally eliminated. However, this metabolic pathway is capacity limited. Thiosulfate enhances the activity of rhodanese by donating a sulfur group, thereby increasing the amount of thiocyanate that rhodanese can produce. Sodium thiosulfate is relatively well tolerated, but there is a potential for nausea and vomiting, as well as rate-related hypotension. Because of its relatively favorable adverse-effect profile, sodium thiosulfate should be given to all patients with suspected cyanide toxicity, including those with smoke inhalation. The recommended dosage of sodium thiosulfate for adults is 12.5 g i.v. (50 mL of 25% solution); for pediatric patients, it is 0.5 g/kg i.v. (2 mL/kg of 25% solution) up to the adult dose.