# Cyanide question



## NYMedic828

So I was bored reviewing the mechanisms of cyanide/cyanokit meds and the question came to mind,

Cyanide, hydrogen sulfide and hydrogen cyanide all bind to hemoglobin and cytocrome c oxidase resulting in histotoxic hypoxia but what is the primary action of cyanide?

CO I believe the primary issue is the massive displacement of oxygen from hemoglobin and less inhibition of cytocrome oxidase.

Are the problems the opposite in the case of cyanide/hydrogen sulfide? By that I mean do they primarily inhibit cytocrome c oxidase or do they displace oxygen from hemoglobin?

Or are all 3 vastly different in their mechanism of achieving the above?


Sorry I lied, guess my question wasn't just cyanide


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## Handsome Robb

NYMedic828 said:


> So I was bored reviewing the mechanisms of cyanide/cyanokit meds and the question came to mind,
> 
> Cyanide, hydrogen sulfide and hydrogen cyanide all bind to hemoglobin and cytocrome c oxidase resulting in histotoxic hypoxia but what is the primary action of cyanide?
> 
> CO I believe the primary issue is the massive displacement of oxygen from hemoglobin and less inhibition of cytocrome oxidase.
> 
> Are the problems the opposite in the case of cyanide/hydrogen sulfide? By that I mean do they primarily inhibit cytocrome c oxidase or do they displace oxygen from hemoglobin?
> 
> Or are all 3 vastly different in their mechanism of achieving the above?
> 
> 
> Sorry I lied, guess my question wasn't just cyanide



Ooh good question!

My understanding is the cyanide/hydrogen sulfide inhibits c oxidase which disrupts the cell's ability to function in an aerobic metabolism and produce ATP. It's disrupting the electron transport chain in the mitochondria. It's not actually displacing oxygen but rather interfering with the cell's ability to use the oxygen whereas, like you stated, CO has a greater affinity for hemoglobin and thus grossly displaces oxygen. 

I don't know if that answers your question?


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## NYMedic828

Well that part I know.

From the many resources I've searched, all 3 ultimately both bind to hemoglobin displacing oxygen AND inhibit cytocrome c oxidase.

My question is, where does the primary damage from each come from.

I think I'm right in saying CO mainly from displacing oxygen and the latter two primarily inhibit the ETC

Just wanted to be certain.


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## bigbaldguy

My head just exploded a little bit. You guys are wayyyy to smart.


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## Handsome Robb

NYMedic828 said:


> Well that part I know.
> 
> From the many resources I've searched, all 3 ultimately both bind to hemoglobin displacing oxygen AND inhibit cytocrome c oxidase.
> 
> My question is, where does the primary damage from each come from.
> 
> I think I'm right in saying CO mainly from displacing oxygen and the latter two primarily inhibit the ETC
> 
> Just wanted to be certain.



Yea I can't answer that one for you. I was under the impression Cyanide binds with the iron and cytochrome c oxidase not the hemoglobin itself but I've been wrong before. 

Alright now you've got me interested as well as distracted from studying for the NREMT. Thanks! :rofl:


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## NYMedic828

The iron in hemoglobin is what I believe ALL the above bind to.

Oxygen, cyanide, carbon monoxide, sulfide all bind to the iron aspect of hemoglobin.



Where you at Ven we need your infinite wisdom -.-


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## Handsome Robb

NYMedic828 said:


> The iron in hemoglobin is what I believe ALL the above bind to.
> 
> Oxygen, cyanide, carbon monoxide, sulfide all bind to the iron aspect of hemoglobin.
> 
> 
> 
> Where you at Ven we need your infinite wisdom -.-



You sir are correct. I'm not sure how I spaced that :blink: Technically they bind to heme which is made up up iron among other things. 

I do know that cyanide changes the chemical compound and can't be "forced" off the heme like CO can be. That's where the treatment you posted about earlier comes into play. 

Alright I'm all sorts of turned around, I'm going to second the call for vene or usalsfyre or anyone else that knows the answer and can explain it.


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## Dwindlin

From _Goldfrank's Toxicologic Emergencies_:

"Cyanide is an inhibitor of multiple enzymes, including succinic acid dehydrogenase, superoxide dismutase, carbonic anhydrase, and cytochrome oxidase.130 Cytochrome oxidase is an iron-containing metalloenzyme essential for oxidative phosphorylation and hence aerobic energy production. It functions in the electron transport chain within mitochondria, converting catabolic products of glucose into adenosine triphosphate (ATP). Cyanide induces cellular hypoxia by inhibiting cytochrome oxidase at the cytochrome a3 portion of the electron transport chain (Fig. 126–2).93,130 Hydrogen ions that normally would have combined with oxygen at the terminal end of the chain are no longer incorporated. Thus, despite sufficient oxygen supply, oxygen cannot be used, and ATP molecules are no longer formed.72 Unincorporated hydrogen ions accumulate, contributing to acidemia."

Hydrogen sulfide works in much the same way, and this little quote is also from _Goldfrank's_:

"Sulfhemoglobin is not found in significant concentrations in the blood of animals or fatally poisoned humans."


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## NYMedic828

So it would seem the answer is, they bind to iron so it can bind to hemoglobin, but in reality the primary problem with cyanide/sulfide is the result of inhibition of the electron transport chain, not so much displacement of oxygen.


I need to get this textbook. Sounds like a great resource.


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## NYMedic828

Found a LONG extensive study.

The once again is the fact that it can bind to hemoglobin competitively with oxygen is not as relevant because its highest affinity is for cytochrome oxidase.

However, all of the above (CO, H2S, HCN) have an even higher affinity for methemoglobin. (i think CO does anyway, H2S and HCN definitely)

http://www.epa.gov/IRIS/toxreviews/0060tr.pdf
*
4.5.2. Acute Neurotoxicity*
The mode of action for the acute toxicity of cyanide is well understood (Klaassen, 2001; Hall and Rumack, 1990). Cyanide is considered a chemical asphyxiant because it impairs aerobic metabolism without affecting oxygen delivery to the tissues. It has a high affinity for iron in the ferric state, resulting in binding to and inactivation of tissue cytochrome c oxidase. Since cytochrome c oxidase normally accepts oxygen from the blood and functions as an electron acceptor in cellular energy production, this inactivation inhibits cellular respiration. As anaerobic metabolism proceeds, blood levels of pyruvic acid, lactic acid, and NADPH rise; the ATP/adenosine diphosphate (ADP) ratio decreases. The earliest effects of acute cyanide toxicity occur in organs with high aerobic energy demands, particularly the brain and heart. The inhibition of oxygen use by cells causes oxygen tension to rise in the peripheral tissues, which results in a decrease in the unloading gradient for oxyhemoglobin. Thus, oxyhemoglobin is present in the venous blood. In addition to cytochrome c oxidase, cyanide binds to other metalloproteins and other cellular molecules, including catalase, peroxidase, methemoglobin, and hydroxycobalamin; this binding also contributes to the symptoms of acute cyanide toxicity.
Cyanide also stimulates the release of secondary neurotransmitters and catecholamines from the adrenal glands and adrenergic nerves (Kiuchi et al., 1992; Kanthasamy et al., 1991). Thus, the cardiac effects and the peripheral autonomic responses observed following cyanide exposure appear to be due to the increase of plasma catecholamine levels. CNS necrosis and demyelination caused by cyanide may be due to vasoconstriction and low blood flow in the brain, resulting from low carbon dioxide levels (Brierley et al., 1976). Alternatively, the decreased ATP/ADP ratio may alter energy-dependent calcium homeostasis in nerve cells (Johnson et al., 1986). Thus, the acute effects of cyanide result primarily from the interruption of aerobic metabolism and from the release of secondary neurotransmitters and catecholamines; these effects include altered respiration, vomiting, nausea, and weakness and ultimately convulsions, coma, and death.


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## Veneficus

NYMedic828 said:


> So it would seem the answer is, they bind to iron so it can bind to hemoglobin, but in reality the primary problem with cyanide/sulfide is the result of inhibition of the electron transport chain, not so much displacement of oxygen.
> 
> 
> I need to get this textbook. Sounds like a great resource.



the best explanation of this is found in this book:

Which as far as medical texts go, is easy to read and inexpensive.

http://www.amazon.com/Rapid-Review-...972844&sr=8-1&keywords=rapid+review+pathology


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## NYMedic828

There he is 


I'll have to pick it up. I need something to do in the ambulance anyway I ran out of movies to watch. 

Thanks as always.


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## Melclin

While you're all at it, being smart and all, can anyone shed any light on why cyanide related illness seems to get a lot exposure in american EMS but we people who stand on our heads and ride kangaroos don't ever mention it. 

I don't think the word cyanide was mentioned once in the whole of uni and certainly never since. Why is that do you reckon?


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## Veneficus

Melclin said:


> While you're all at it, being smart and all, can anyone shed any light on why cyanide related illness seems to get a lot exposure in american EMS but we people who stand on our heads and ride kangaroos don't ever mention it.
> 
> I don't think the word cyanide was mentioned once in the whole of uni and certainly never since. Why is that do you reckon?



probably because it is used in heavy industry, building materials, and other forms of manufacturing. 

It is also found in the pest control industry as well in pest control products sold in stores for regular home use.

The most common place to find hydrogen cyanide is from microwaving styrofoam and certain types of plastics.


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## Aidey

Simpler answer. Terrorism. The government gave out tons of grants for chemical warfare training and all that jazz. Cyanide comes up commonly in classes like that as a potential terrorist agent.


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## NYMedic828

The reason here in NYC is due to terrorism and the byproducts of smoke inhalation these days.

Years ago most things were made out of metal and wood now they are made out of hydrocarbon containing products like plastics that release a cornucopia of toxic chemicals when they burn.

Cyanide is an abundant byproduct of burning plastic/styrofoam and fossil fuels.

From what I was told, which im sure someone actually in the field in the UK such as Ven can maybe shed light on, is that hydroxocobalamin (cyanokit) has been proven overseas to reverse the acute effects of cyanide with early administration. The issue that while it has a fairly normal shelf life of 3 years, it almost never gets used and it comes at a price of $800 a kit. (kit includes 5g of hydroxocobalamin and 12.5g of sodium thiosulfate, with some fancy plastic tubes and spikes to utilize it)

Cyanide is nowhere near the level of todays nerve agents but a high enough concentration via inhalation will kill you within seconds/minutes. It also can be absorbed dermally regardless of breathing apparatus or not. The haz-mat approach to cyanide requires a breathing apparatus and level A protective suit.


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## Veneficus

NYMedic828 said:


> The reason here in NYC is due to terrorism and the byproducts of smoke inhalation these days.
> 
> Years ago most things were made out of metal and wood now they are made out of hydrocarbon containing products like plastics that release a cornucopia of toxic chemicals when they burn.
> 
> Cyanide is an abundant byproduct of burning plastic/styrofoam and fossil fuels.
> 
> From what I was told, which im sure someone actually in the field in the UK such as Ven can maybe shed light on, is that hydroxocobalamin (cyanokit) has been proven overseas to reverse the acute effects of cyanide with early administration. The issue that while it has a fairly normal shelf life of 3 years, it almost never gets used and it comes at a price of $800 a kit. (kit includes 5g of hydroxocobalamin and 12.5g of sodium thiosulfate, with some fancy plastic tubes and spikes to utilize it)
> 
> Cyanide is nowhere near the level of todays nerve agents but a high enough concentration via inhalation will kill you within seconds/minutes. It also can be absorbed dermally regardless of breathing apparatus or not. The haz-mat approach to cyanide requires a breathing apparatus and level A protective suit.



I am not in the UK 

But perhaps the most major scientific study that identified the need for cyanide treatment was done by a french physician who is credited with proving that toxic gases of combustion cause more fatalities from structure fires than smoke inhalation. 

Sorry, I don't have a link, but it was in the 90s and when it came out everyone working in the fire service felt vindicated for professing that anecdotally for decades.

The kits were originally designed to be used for firefighters rescuing people from structure fires and used by medically untrained staff in the field.


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## NYMedic828

I haven't actually administered one to a real patient but fro playing with expired ones you need a GOOD IV line to infuse the hydroxocobalamin. It is very thick.


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## Melclin

Well we have all those things...except terrorism (although it could be argued that we are risk as well).

Perhaps we should be considering it.


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## NYMedic828

As a volunteer medic/ff and a paid medic for FDNY, I think it is insane not to spend $1600 for a 3 year supply of atleast two kits. If I go down in a fire atleast someone may be able to provide the answer.

We spend countless dollars and crazy rescue equipment to potentially save someone else, the potential to save one of our own is priceless.


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## mycrofft

NYMedic828 said:


> Well that part I know.
> 
> From the many resources I've searched, all 3 ultimately both bind to hemoglobin displacing oxygen AND inhibit cytocrome c oxidase.
> 
> My question is, where does the primary damage from each come from.
> 
> I think I'm right in saying CO mainly from displacing oxygen and the latter two primarily inhibit the ETC
> 
> Just wanted to be certain.



Cellular hypoxia then? Kind of like if you had a competitive antagonist (like antibodies) against insulin, with lots of sugar around but the cell can't accept or utilize it?


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## NYMedic828

mycrofft said:


> Cellular hypoxia then? Kind of like if you had a competitive antagonist (like antibodies) against insulin, with lots of sugar around but the cell can't accept or utilize it?



All 3 cause hypoxia regardless of stable PaO2/SpO2.

All 3 are histotoxins that cause histotoxic hypoxia.

The simple answer from what I've been reading is

Carbon Monoxide binds to hemoglobin 200-250x more readily than oxygen. It also binds to cytochrome c oxidase but it more readily stays at the hemoglobin level. The primary action is displacement of oxygen though.

Hydrogen Cyanide and sulfide are truer histotoxins in that they bind to hemoglobin as well but they more ready bind directly to cytochrome c oxidase ultimately preventing production of ATP, asphyxiating the cells.

All of the above will also bind to methemoglobin more readily than hemoglobin making therapeutic metehemoglobinemia the potential cure.

CO poisoning can usually be handled via hyperbaric therapies.

H2S depending on the degree may require sodium nitrite and hyperbaric therapies.

HCN requires hydroxocobalamin as well as sodium thiosulfate.

In theory cyanide is easier to fix than sulfide but cyanide is such a lethal substance the opportunity to fix it usually passes by too quickly.


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## mycrofft

If you think about it:
1. Anoxia without cellular blockade takes a bit to kill or injure organs because of residual oxygen (and maybe someone regularly and briskly pressing and releasing your sternum).
2. If the cells CAN'T accept O2, use O2, or cast off CO2, then the damage starts as quickly as each cell need more oxygen. Which could be immediately.


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## Handsome Robb

Melclin said:


> While you're all at it, being smart and all, can anyone shed any light on why cyanide related illness seems to get a lot exposure in american EMS but we people who stand on our heads and ride kangaroos don't ever mention it.
> 
> I don't think the word cyanide was mentioned once in the whole of uni and certainly never since. Why is that do you reckon?



I'm hesitant to say it but we spent a decent amount of time on it in class. All the mining in Nevada uses cyanide and it's almost a daily occurrence for a train car with tons of compressed cyanide to roll through our cities in NV as well as having even larger storage tanks out on the refinery grounds full of the stuff sitting around. 

You should see the train cars they use to transport it. Same color scheme as a candy cane. They can have either the vertical stripe like in the picture below or a horizontal red strip.


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## bigbaldguy

NVRob said:


> I'm hesitant to say it but we spent a decent amount of time on it in class. All the mining in Nevada uses cyanide and it's almost a daily occurrence for a train car with tons of compressed cyanide to roll through our cities in NV as well as having even larger storage tanks out on the refinery grounds full of the stuff sitting around.
> 
> You should see the train cars they use to transport it. Same color scheme as a candy cane. They can have either the vertical stripe like in the picture below or a horizontal red strip.



Good info. I've seen those tanks but didn't know about the color coding.


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## AnthonyM83

My understanding is it inhibits the final electron acceptance in the electron transport chain.


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## Melclin

NVRob said:


> I'm hesitant to say it but we spent a decent amount of time on it in class. All the mining in Nevada uses cyanide and it's almost a daily occurrence for a train car with tons of compressed cyanide to roll through our cities in NV as well as having even larger storage tanks out on the refinery grounds full of the stuff sitting around.
> 
> You should see the train cars they use to transport it. Same color scheme as a candy cane. They can have either the vertical stripe like in the picture below or a horizontal red strip.



One supposes we must use it for something as well, but I know almost nothing about the stuff. Perhaps I'd better get a googlin'.


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## mycrofft

In many biochemical compounds. 
Also a product of combustion of many man-made materials


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## NYMedic828

Cyanide is a very abundant byproduct of the burning of hydrocarbons.

Plastic/styrofoam + fire = cyanide + CO


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