Unconscious Uncoupling And Salicylate Overdose - Aspirin

Pdohlen

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What do you all think of this article?

Tox and Hound - Unconscious Uncoupling - Managing pH in Salicylate Overdoses

From the article you get the impresiion that overdosing is somewhat common.

"So, what do uncouplers do? They uncouple electron flow from ATP formation. Salicylate is a great example of an uncoupler. It works by grabbing protons and shuttling them back across the inner mitochondrial membrane. It can also open up pores in the membrane but the effect is the same, it shorts out the battery. This causes less ATP formation. Now the body doesn’t take kindly to having less ATP. In response, it revs up the engine sending more and more electrons through the system. This results in big increases in metabolism, glycolysis, the TCA cycle, and all those processes that feed into this. So, what happens clinically when you rev up a system without producing more work? You get heat. This is why patients who overdose on uncouplers can get profoundly hyperthermic.5 This is akin to what happens if you sit in your car and floor the gas while the engine is in neutral. Lots of energy is consumed, but no work is produced – the engine overheats. Clinically this is also one of the ways that aspirin contributes to death. The lack of ATP targets the brain and the heart (they are so needy) causing the famous life-threatening dyad of a really bad aspirin overdose – cerebral and pulmonary edema."

The author describes the uncoupling from aspirin as a depletion of atp, and thus a needed upregulating of metabolism in order to restore balance. It seems to me that this could be a dangerous game of balancing?

I would be grateful if someone could help with an explanation to why and at what doses this could be a problem.

"
  1. At high concentrations salicylate uncouples oxidative phosphorylation
  2. Uncoupling decreases ATP formation
  3. ATP consumption > ATP production
  4. ATP imbalance causes hypermetabolism and metabolic acidosis
  5. Hypermetabolism stimulates ventilation
  6. Metabolic acidosis is balanced by respiratory alkalosis
  7. The patient is sedated and paralyzed, stops ventilating
  8. Acidosis worsens, pH goes down
  9. Salicylate rapidly moves into the brain and heart
  10. You fill out another death report "

Sodium bicarbonate to the rescue?
 

Hans

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Uncoupling increase CO2 production which is acidic, so yes bicarbonate can increase pH again, but CO2 can also be converted to bicarbonate.
Aspirin has been used in doses of 8-9g per day for a couple of weeks by type I diabetic and no one died or suffer hyperthermia. High dose aspirin can damage the liver though, so such high doses are not advised long term. Regular intake of aspirin around 100mg to 2g would not nearly cause death by loss of ATP. Actually a good uncoupling dose for aspirin is at 1g.
 

Frankdee20

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Uncoupling increase CO2 production which is acidic, so yes bicarbonate can increase pH again, but CO2 can also be converted to bicarbonate.
Aspirin has been used in doses of 8-9g per day for a couple of weeks by type I diabetic and no one died or suffer hyperthermia. High dose aspirin can damage the liver though, so such high doses are not advised long term. Regular intake of aspirin around 100mg to 2g would not nearly cause death by loss of ATP. Actually a good uncoupling dose for aspirin is at 1g.

Liver damage, what are the doses generally to be avoided long term ? I only mess with like one or two tabs a day, and a few days off....
 
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I have never been able to make my mind around drugs overdoses. I don't understand how is it even possible to overdose on something. Probably IQ issues. Inability to make some math.
 

Frankdee20

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I have never been able to make my mind around drugs overdoses. I don't understand how is it even possible to overdose on something. Probably IQ issues. Inability to make some math.

Are yyou talking about illegal drugs or supplements ?
 

Hans

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Liver damage, what are the doses generally to be avoided long term ? I only mess with like one or two tabs a day, and a few days off....
Aspirin - LiverTox - NCBI Bookshelf
"The more dramatic examples of aspirin hepatotoxicity usually occur with doses of 1,800 to 3,200 mg daily (>100 mg/kg) and with salicylate levels of greater than 25 mg/dL, but mild-to-moderate ALT elevations occur with even lower doses and lower serum levels. These abnormalities resolve rapidly with discontinuation of aspirin, but instances of resolution despite continuation of aspirin in the same or lower doses (adaptation) have also been described."

Europe PMC
"Aspirin use is associated with improved liver function test results and survival after TAE for HCC. It is not associated with differences in response or time to progression."

Error - Cookies Turned Off
"There are several proposed molecular mechanisms underlying the possible effectiveness of aspirin against NAFLD. First, aspirin can stimulate the expression of endothelial nitric oxide synthase and vascular endothelial growth factor, which induce nitric oxide and prostacyclin, resulting in antioxidant activity.24 Second, aspirin inhibits the expression of inducible nitric oxide synthase and the production of tumour necrosis factor‐α, which causes liver inflammation and fibrosis.25 Third, aspirin reduces the expression of platelet‐derived growth factor (PDGF)‐C, leading to inhibition of profibrotic pathways and transforming growth factor‐β expression, which also cause liver inflammation, steatosis and fibrosis"

Efficacy between low and high dose aspirin for the initial treatment of Kawasaki disease: Current evidence based on a meta-analysis
"One study [22] reported three cases of epistaxis, rectal bleeding, and abdominal pain attributed to aspirin in the high-dose group, but there was no mention of the low-dose group (there were 358 people total in the study). Another trial [25] reported that digestive symptoms were the most common side effects, and approximately 0.9% of patients had severe liver function damage, but there was no indication as to which group this occurred."

So I think 1-2 tablets should be pretty safe unless you're just really sensitive to aspirin.
 
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Are yyou talking about illegal drugs or supplements ?
Both.

By the way I don't support dividing drugs into legal/illegal categories as I believe any chemical substance should be available for personal use, excluding highly letal toxins.
 

tankasnowgod

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I have never been able to make my mind around drugs overdoses. I don't understand how is it even possible to overdose on something.

Don't understand how its possible? Guessing you never drank too much and had a hangover, huh?

Do you not understand the concept of doses? Would you think 10 milligrams and 10 kilograms of a substance would have the exact same effect on a subject?
 

Frankdee20

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Both.

By the way I don't support dividing drugs into legal/illegal categories as I believe any chemical substance should be available for personal use, excluding highly letal toxins.


If someone on the street thinks they’re buying heroin, but instead gets fentanyl with 100 times the potency, can you understand why that would lead to an overdose ?
 
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Don't understand how its possible? Guessing you never drank too much and had a hangover, huh?

Do you not understand the concept of doses? Would you think 10 milligrams and 10 kilograms of a substance would have the exact same effect on a subject?

There is a dose suggestion for every chemical compound and there is a warning e.g. do not take more than X mcg-mg-gr. Inability to follow simple instructions is what I can't understand.

If someone on the street thinks they’re buying heroin, but instead gets fentanyl with 100 times the potency, can you understand why that would lead to an overdose ?
Consumption of unknown substance is what I don't understand too.
 

tankasnowgod

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There is a dose suggestion for every chemical compound and there is a warning e.g. do not take more than X mcg-mg-gr. Inability to follow simple instructions is what I can't understand

So it's not the mechanism you don't understand, but more the why. Got it.

To that end, sometimes directions themselves aren't safe. And it can often happen to kids. Kids overdosing on iron pills is very common, and as few as ten pills can potentially be lethal.

Something like manufacturing errors can happen, too.
 
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Something like manufacturing errors can happen, too.

This type of cases is excluded. There was a big scandal with highly preached on this forum drug Mildronate. They have messed something and got another chemical in vials if Mildronate. Some dead people as the result.

To that end, sometimes directions themselves aren't safe. And it can often happen to kids. Kids overdosing on iron pills is very common, and as few as ten pills can potentially be lethal.

It's a natural selection. I don't understand how is it even possible to have a kid overdosed on something. It's says keep any medication/supps away from kids where they can't reach it. And stupid parents are not capable to teach their stupid kids not to touch any medication.
 
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Pdohlen

Pdohlen

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Thank you for valuable inputs. I'll cycle aspirin, not more than 1g per day, maybe not more than three days in a row, with at least a week off.
 

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