CYANIDE

• deriva'ves: hydrogen cyanide, sodium or potassium cyanide, prussic acid, hydrocyanic acid, or cyanogen chloride.
• classified as a supertoxic substance that can exist as a gas or solid or in solu'on.
• hydrogen cyanide was first isolated from Prussian blue dye in 1786.
• first extracted from almonds around 1800
• it is used in many industrial processes and a component of some insec'cides and roden'cides
• can be produced by certain types of bacteria, fungi, and algae and found in several types of plants, seeds, and fruit
stones, including bamboo, cassava, biCer almonds, apples, and peaches.
• also produced as a pyrolysis product from the burning of some plas'cs, including urea foams used as insula'on in
homes.
• used as a poison in mass homicides and suicides. During World War II, the Nazis used cyanide as an agent of genocide
in gas chambers. à Zyklon B
• in medicine, cyanide can be found in the widely used an'hypertensive sodium nitroprusside.

Exposure
Exposure can occur by inhala'on, inges'on, intravenous, and transdermal absorp'on. Intravenous and inhala'on of
cyanide produce a more rapid onset of signs and symptoms than exposure via the oral or transdermal route. This is due to the
first two routes providing fast diffusion into the bloodstream.

Mode of Ac/on
The cyanide anion binds avidly to iron in the ferric or trivalent state. Because cyanide forms a rela'vely stable
cyanoferric complex, it is able to inac'vate iron-containing enzymes that cycle between the ferrous and ferric states in
oxida'on–reduc'on reac'ons. Cyanide produces 'ssue and cellular hypoxia primarily by reversibly binding to cytochrome A3
and by inhibi'ng its reoxida'on.
Cyanide primarily inhibits cytochrome A3, which is a component of cytochrome c oxidase (Complex IV) in the electron
transport chain. Cytochrome A3 contains a heme group with an iron ion (Fe) that is crucial for the reduc'on of oxygen to water
during aerobic respira'on. Cyanide binds to the ferric (Fe3+) heme iron center of cytochrome A3, blocking its ability to accept
electrons and par'cipate in the electron transport chain. This inhibi'on of cytochrome A3 prevents the final step of electron
transfer to oxygen, leading to a halt in aerobic respira'on. Without sufficient ATP produc'on, cells cannot func'on properly,
leading to cellular dysfunc'on and 'ssue damage.
In the absence of aerobic respira'on due to cyanide poisoning, cells resort to anaerobic metabolism to generate ATP.
This leads to the accumula'on of lactate and hydrogen ions, resul'ng in lac4c acidosis. Lac'c acidosis can lead to metabolic
acidosis, which further impairs cellular func'on and contributes to organ dysfunc'on.
Cyanide not only disrupts cellular respira'on but also induces cellular damage directly. Cyanide can cross cell
membranes and affect various organs, including the brain and heart. The central nervous system is par'cularly sensi've to
cyanide toxicity due to its high energy demands and reliance on aerobic respira'on for ATP produc'on.

Symptoms and Diagnosis

The principal symptoms of cyanide overdose are tachypnea (ini'ally), followed by respiratory depression and cyanosis,
hypotension, convulsions, and coma. Death may occur in a maCer of minutes because cyanide is a fast-ac'ng toxin. Clues
include the odor of bi6er almonds, the occurrence of an altered mental status and tachypnea in the absence of cyanosis, and
an unexplained metabolic acidosis (with an increased anion gap). The biCer almond odor is discernible by approximately 60%
of the popula'on.
Cyanide intoxica'on is largely a clinical diagnosis; however, several laboratory features are sugges've:
• Metabolic acidosis (increased anion gap)
• Elevated lac'c acid
• Venous oxygen satura'on > 90%

Evalua'on of cyanide exposure requires a rapid turn-around 'me. There are several methods available. Ion-selec4ve
electrode methods and photometric analysis following two-well microdiffusion separa4on are those most common. Chronic
low-level exposure can be evaluated by the determina'on of urinary thiocyanate concentra4on.

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Treatment and Management
The provider must prepare to stabilize the pa'ent's airway, breathing, and circula'on. Of note, mouth-to-mouth
resuscita4on is contraindicated in cyanide poisoning because of the risk to the provider of CPR. Decontamina'on is a vital part
of the management of a pa'ent with cyanide exposure through topical and inhala'on routes. They must be removed from the
source and have their clothing removed and discarded appropriately. Although lab studies have demonstrated that ac'vated
charcoal binds poorly to cyanide, animal studies report decreased mortality when subjects were given ac'vated charcoal. It is
suggested that a single dose of ac'vated charcoal of 50g in adults and 1 g/kg, up to a maximum of 50 g in children, be given.

Management of cyanide toxicity is based on the principle of reversing and/or displacing cyanide binding to
cytochrome a3. There are two major modali'es of treatment: hydroxocobalamin and the cyanide an'dote kit containing
sodium nitrite and sodium thiosulfate.

• Hydroxocobalamin (Cyanokit, King Pharmaceu'cals, Bristol, Tenn): The preferred an'dote, based on a 2018 US Food and
Drug Administra'on (FDA) expert consensus panel, is the Cyanokit, containing lyophilized hydroxocobalamin and other
products used for intravenous infusion. Hydroxocobalamin contains cobalt, to which cyanide has a strong binding affinity. The
reac'on of hydroxocobalamin with cyanide produces cyanocobalamin (vitamin B12) that is then excreted in the urine. Be
aware that this an'dote turns urine dark red; the dark red colora'on is not due to myoglobinuria.

• Cyanide An4dote Kit (Eli Lilly and Company): The primary components of these kits include sodium nitrite and sodium
thiosulfate. When administered intravenously, sodium nitrite and sodium thiosulfate release cyanide from cytochrome a3 by
providing a target for which cyanide has a higher aCrac'on. IV sodium nitrite reacts with hemoglobin to cause the forma'on of
methemoglobin, for which cyanide has a high binding affinity. Sodium thiosulfate provides a source of sulfur that the enzyme
rhodanese(thiosulfate sulfurtransferase)—the major pathway for metabolism of cyanide—u'lizes to detoxify cyanide.

àIn vivo, cyanide metabolism and neutraliza'on involve a number of mechanisms. The most important of these is the
detoxifica'on of cyanide via rhodanese, an enzyme found abundantly in many 'ssues but in the liver and muscle par'cularly.
Thiosulfate serves as a sulfur donor in the reac'on catalyzed by rhodanese that converts cyanide to thiocyanate, a water-
soluble molecule excreted in the urine.

àRemember that cyanide has high affinity to iron in the ferric state or trivalent state. Remember also that methemoglobin is a
dysfunc'onal form of hemoglobin in which the iron is in the ferric state and therefore cannot bind to oxygen. That is why in
the cyanide an'dote kit, the nitrite converts the hemoglobin to methemoglobin so that the cyanide would bind to the
methemoglobin rather than the cytochrome oxidase complex.

Recovery
Although recovery from a chemical aCack is rare, vic'ms may survive sub-lethal exposures, whether from inges'on,
smoke inhala'on, or exposure to cyanide-containing industrial products. Pa'ents who are treated successfully for cyanide
poisoning should be observed for development of long-term neuropsychiatric symptoms that are similar to symptoms
experienced by survivors of cardiac arrest or carbon monoxide poisoning. In acute type of poisoning, survival for 4 hours is
usually followed by recovery.

Laboratory Ac'vity.
Schonbein’s Test
1. Make a solu'on of the alcoholic 10% solu'on of Guaiac and 0.1% Copper sulfate.
2. Impregnate the strips of filter paper on this solu'on.
3. Then, immerse the strip of filter paper into the specimen.
4. This is a very sensi've test (0.005mg/100g). Observe for the color produced.
Note: False posi've result can be obtained with hydrogen peroxide, oxone, chlorine, and oxides of nitrogen.

Interpreta'on of Results:
Nega've: no color change or late forma'on of color
Posi've: dis'nct color forma'on

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