Acetaminophen overdose coma help.

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coreytayloris

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Hey,

One of our learning objectives this week in class was

''account for Early and late loss of consciousness with acetaminophen overdose and explain the mechanisms involved''

so this is the answer for the above that i found, however i'm confused on some parts....

Lactic acidosis is usually associated with coma....

Acetaminophen poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning (before the onset of hepatotoxicity); a lactic acidosis is usually associated with coma. The toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, (NAPQI) inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours.

The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. Lactate is elevated primarily because of reduced hepatic clearance.

My questions are:

1. How does reduced hepatic clearance cause lactate levels to increase.

and,

2. How does Lactic acidosis itself then bring about coma/ how would increased lactate levels bring about coma?

if someone could explain please, i asked in my pbl group but no one could come up with an answer.

Thanks

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Hey,

One of our learning objectives this week in class was

''account for Early and late loss of consciousness with acetaminophen overdose and explain the mechanisms involved''

so this is the answer for the above that i found, however i'm confused on some parts....

Lactic acidosis is usually associated with coma....

Acetaminophen poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning (before the onset of hepatotoxicity); a lactic acidosis is usually associated with coma. The toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, (NAPQI) inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours.

The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. Lactate is elevated primarily because of reduced hepatic clearance.

My questions are:

1. How does reduced hepatic clearance cause lactate levels to increase.

and,

2. How does Lactic acidosis itself then bring about coma/ how would increased lactate levels bring about coma?

if someone could explain please, i asked in my pbl group but no one could come up with an answer.

Thanks

1) I'd assume in liver failure, you have decreased ability to convert lactate into glucose for peripheral tissues, ie muscle (cori cycle) --> elevated lactic acid levels. I think that's what they mean by hepatic clearance?

2) not sure about #2. maybe something to do with pH? or anion-gap metabolic acidosis?
 
Read about hepatic encephalopathy.
 
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Hey,

One of our learning objectives this week in class was

''account for Early and late loss of consciousness with acetaminophen overdose and explain the mechanisms involved''

so this is the answer for the above that i found, however i'm confused on some parts....

Lactic acidosis is usually associated with coma....

Acetaminophen poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning (before the onset of hepatotoxicity); a lactic acidosis is usually associated with coma. The toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, (NAPQI) inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours.

The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. Lactate is elevated primarily because of reduced hepatic clearance.

My questions are:

1. How does reduced hepatic clearance cause lactate levels to increase.

and,

2. How does Lactic acidosis itself then bring about coma/ how would increased lactate levels bring about coma?

if someone could explain please, i asked in my pbl group but no one could come up with an answer.

Thanks

Interestingly, I found an article entitled "Metabolic acidosis and coma following a severe acetaminophen overdose":

http://www.theannals.com/cgi/reprint/33/11/1191

[FONT=verdana,arial,helvetica,sans-serif][SIZE=-1]Ann Pharmacother Koulouris et al. 33 (11): 1191.[/SIZE].

To quote: "The mechanism by which acetaminophen causes CNS depression at very large doses is unknown." :cool: Basically, this is in reference to coma that occurs BEFORE onset of hepatotoxicity, and in association w/ lactic acidosis.

Summary at the end (for those reading this too lazy to get the article):

"Acetaminophen, in a severe overdose, can independently cause lactic acidosis in the absence of hepatotoxicity. Additionally, coma has been reported in some patients, although the mechanism is unclear and appears unrelated to the acidosis.

These clinical findings are either briefly touched on or not mentioned in the major emergency medicine and critical care texts. The equivalently rare acute renal failure, myocarditis, and pancreatitis are also rarely mentioned.

The basic mechanisms of these manifestations are obscure, but we speculate that mitochondrial inhibition could underlie all of these events and may result in the initial hyperglycemia that was manifested by our patient. Practitioners should be aware of these unusual manifestations of severe acetaminophen overdose."

Edit: Makes me curious that #2 is a PBL group Q... if the above is indeed true, and basically the mech is unknown (?!). So, if you get a different explanation, I'd be curious to hear it ;)
 
one of the top dogs in my class provided me with this answer:


1) How does reduced hepatic clearance cause lactate levels to increase.

Ans: I kind of thought there were 2 things going on here. We know that more lactate is being produced because of the inhibition of oxidative respiration.

First, less lactate is going to be able to leave the liver due to impaired hepatic clearance (NAPQI has covalently bonded to thiol groups in hepatocytes & damaged them). Thus, local lactate concentration in the liver will increase.

Second, the blood concentration of lactate will also increase. If the liver is making so much lactate, it only makes sense that some of this will end up in the circulation, no matter how damaged the liver is. In a normal, healthy individual, our kidneys are responsible for prevention of metabolic acidosis (i.e. preventing lactic acidosis in this case). However, recall that hepatorenal failure is associated with acute liver failure. Thus, Michelle Ryan's kidneys aren't working properly -> less lactate clearance = increased lactate in blood = metabolic acidosis.

2) With respect to the coma, I thought it was a hepatic coma induced by increased levels of ammonia in the blood (azotaemia). Hepatic failure causes toxic metabolites to be released in the blood (ammonia, increased mercaptans, etc.) that will damage your brain (I think it's specifically the astrocytes that get screwed over)

I'm not too sure about how lactate itself brings about a coma. I would think it is the acidosis itself (a general lowering of pH) that causes the neuronal activity to be decreased, thus causing coma. - i.e. if you mess with the brain's super-sensitive balance of ions, metabolites, neurotransmitters, etc. you're screwed (I'm pretty sure lactate can cross the blood-brain barrier)

"Conversely, acidosis greatly depresses neuronal activity;
a fall in pH from 7.4 to below 7.0 usually causes a
comatose state. For instance, in very severe diabetic or
uremic acidosis, coma virtually always develops." - Guyton p. 570
 
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