CYANIDE

OBJECTIVES

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

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-

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

NONMILITARY USES

Poisonings Terrorists, Executions,

Homicides, Suicides Industry

Electroplating Plastics processing Gold and Silver

extraction Fumigation Photography Metallurgy

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

CYANIDE CHARACTERISTICS

Liquid, gas, or salt Volatile: boiling point 60-800 F Non-persistent Bitter almond to biting, pungent odor Cyanogen chloride (CK) Chlorine

smell Strong affinity for metals, especially

ferric iron (Fe3+) Cytochrome oxidase (Fe3+) Methemoglobin (Fe3+)

DOSE: Toxicity Relationship

General Principle

Bigger exposure

Means

Worse injury and sooner onset

SITE OF ACTION

Primary site of action: Cells rather than blood

Organelles affected: Mitochondria

CLASSICAL MECHANISM OF ACTION

Cyanide binds to hemoprotein in mitochondria Cytochrome oxidase hemoprotein (cyt a3) has Fe3+

(Cell energy producer) Stable but reversible binding

CN- has higher affinity for Fe3+ in cyt a3 than Fe2+ in hemoglobin

Cyanide interrupts oxidative phosphorylation …

HOW CYANIDE INTERFERES WITH OXIDATIVE PHOSPHORYLATION

EFFECTS OF CYANIDE IN THECELLS 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

MANIFESTATIONS OF TOXICITY

Rapid onset (inhalation) Brief period of tachypnea Loss of consciousness Convulsions Apnea without cyanosis Asystole Death

HIGH DOSE INHALATIONALCYANIDE TIMELINE

Convu

lsio

ns

Inha

latio

nH

yper

pnea

LO

C

Apn

ea

Heart

stop

sD

eath

15 s

ec30

sec

3-5

min

s

5-8

min

s

60 s

ec

HIGH DOSE INGESTIONCYANIDE TIMELINE

Inge

stio

nH

yper

pnea

A

nxie

ty

Con

vuls

ions

Heart

stop

sD

eath

7 m

in10

min

20 m

in

30 m

in

LOC

15 m

inW

eakn

ess

Apn

ea

25 m

in

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

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

MEDICAL MANAGEMENT

Protect yourself! Eliminate further

exposure General supportive

therapy Specific antidotal

therapy

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

GOALS OF SPECIFICANTIDOTAL THERAPY

Displace cyanide from cytochrome a3

Use Nitrites to form methemoglobin, Ferric iron (Fe3+)

Eliminate cyanide from the body Administer sulfane (e.g., sodium

thiosulfate) as a sulfur donor Convert cyanide to thiocyanate

nitrite

thiosulfate

metHb

(Fe3+)

HbO2

(Fe2+)

ANTIDOTE THERAPY

Cyanide Antidote Kit Methemoglobin Formers

Amyl Nitrite Sodium Nitrite

Sulfur Donor Sodium Thiosulfate

AMYL NITRITE: (C5H11NO2)

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

CYANIDE IS IN THE BODY: Where Will it Bind?

HbO2

(Fe2+)

CN-

CN-

(Fe3+)

cyt a3

BOUND CYANIDE INACTIVATES CYTOCHROME OXIDASE

CN- cyt a3

(Fe3+)

cyt a3

HbO2

(Fe2+)

NITRITE PRODUCES METHEMOGLOBIN: What Will Cyanide Do?

HbO2

(Fe2+)

metHb

(Fe3+)

nitrite

?

?

?

CN- cyt a3

(Fe3+)

CYANIDE RELEASESCYTOCHROME OXIDASE …

CN-metHb

(Fe3+)

cyt a3cyt a3

(Fe3+)

AND FORMS CYANOMETHEMOGLOBIN

CN-metHb

(Fe3+)

A stable, but reversible, bondcyt a3

(Fe3+)

OVER TIME CYANIDE WILL MOVE OUTOF THE BOND WITH METHEMOGLOBIN …

metHb

(Fe3+) CN-

cyt a3

(Fe3+)

SODIUM NITRITE (NaNO2)

Forms methemoglobin Beneficial effects rapid Single dose raises metHb level

to 20% Adverse effects

Headache Nausea Orthostatic hypotension Methemoglobinemia (maintain

less than 40% metHb)

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

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

SODIUM THIOSULFATE (Na2S2O3)

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 (SO3

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

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

IN THE LIVER, FREE CYANIDE ISTRANSFORMED INTO THIOCYANATE

WHICH IS THEN EXCRETED IN THE URINE

metHb

(Fe3+)

CN-

thiosulfate

rhodanese

urine

Liverthiocyanate

REVIEW OF THE ANTIDOTE STEPS

thiocyanate

CN-

thiosulfate

rhodanese

urine

Liver

CN-metHb

(Fe3+)

HbO2

(Fe2+)

metHb

(Fe3+)

nitrite1.1.

2.2.

cyt a3

(Fe3+)

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

COBALT COMPOUNDS

Dicobalt edetate (Co2 EDTA, Kelocyanor) Chelates CN-

Adverse effects Angina pectoris, ventricular

dysrhythmias,periorbital and laryngeal edema, convulsions

Used in the U.K., France, and the Netherlands

COBALT COMPOUNDS

Hydroxocobalamin (vitamin B12a)

Reacts with CN- to form cyanocobalamin (vitamin B12)

Difficult to administer adequate amounts

Used in France

SUMMARY

Killed millions throughout history. Top terrorist consideration

Battlefield or terrorist use probably as a vapor (enclosed area)

Variable potency (LCt50) 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 a3 temporarily

Thiosulfate provides sulfides to help liver enzyme rhodanese form thiocyanate which is excreted in the urine

CN-