rumman15
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I've been asked:
'The half-life of paracetamol in water at pH 6 and 25 °C is 22 years, while the half-life of aspirin in water at pH 7.5 and 25 °C is 52 hours. How can these observations be explained?'

This was an assignment for a module on Carbonyl carbons and how they can be converted to amides/esters/acid chlorides/acid anhydrides.

Any help would be appreciated - it might have something to do with the molecules relative stability, maybe it's conversion into a salt increasing half life -but I'm not at all sure.
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macpatgh-Sheldon
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@rumman15

Hi this is my cup of tea (partly: only the pharmacokinetics - not the high power chemistry ).

As you will know the cell membrane of all cells (including the membranes internally lining the mitochondria, nucleus, etc.) is a phospholipid bilayer with the lipophilic heads pointing to each other in the middle and the hydrophilic tails in contact with the intracellular and extracellular aqueous material. The membr
ane being lipophilic in the main, lipid-soluble substances (including in this context drugs) pass through the membrane more easily.

As regards half-life, the excretion rate in the kidneys, subsequent to the metabolism of the drug (if any) in the liver, determines the rate of excretion and therefore the half-life i.e. the time it takes for half the drug initially present to be excreted/retained.

Ioninzed drugs are generally less able to pass through the lipid membrane, including the filtration equivalent (which is the glomerular basement membrane in the nephron [functional unit of the kidney], of which there are about 1.3 million in each kidney).

You will know better than I that the amount of a weak acid or base that is ionized is determined by the pH of the medium and the pKa of the drug, based on the Hederson-Hasselbalch equation: The result is that, in general, acidic drugs are excreted more efficiently in an alkaline situation, and vice versa for alkaline drugs.

log [protonated form]/[unprotonated form] = pKa - pH

Aspirin (salicylic acid) is a weak acid [look up its pKa] and will be mostly unionised at pH 7.5, so will be excreted v quickly = short half-life.

In contrast, there will be an extreme excess of the ionised form of paracetamol (para-aminophenol derivative) [your chemistry knowledge, no doubt superior to mine, will help you work this out based on the structural formula of paracetamol and its resultant pKa) at pH 6, which will not cross the glomerular basement membrane easily; therefore it is excreted v v slowly = v long half-life (magnified tremendously by the log in the equation).

In fact, the antidote used to treat paracetamol overdose (cysteamine) works by changing this balance and making paracetamol less ionised so that the kidneys can get rid of the excess toxic amount quickly (only effective if administered within a certain time after the ingestion of the overdose, otherwise often fatal, depending on the magnitude of the intake).

Hope this helps.

M (clinical pharmacologist)
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bethbarwell
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Hey @rumman15,

I don't have the answer to your question... I am, however, looking for the answer to the exact same question. Are you doing your degree through the University of Kent?

P.S. thank you for the explaination macpatelgh!!
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nexttime
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(Original post by macpatelgh)
@rumman15

Hi this is my cup of tea (partly: only the pharmacokinetics - not the high power chemistry ).
I'm pretty sure this is an in-virto, chemistry-based question, and not in-vivo. Either that or the answer is simply: 'It takes 22 years for my patient to metabolise the paracetamol because with a pH of 6.0 and temperature of 25 degrees they are clearly already dead'.

In fact, the antidote used to treat paracetamol overdose (cysteamine)
Maybe if you found yourself time-jumped back to the 70s :p:

N-acetylcysteine is much more effective. So much so, in fact, that in the US some paracetamol tablets contain NAC and its impossible to overdose on it!
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macpatgh-Sheldon
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(Original post by nexttime)
I'm pretty sure this is an in-virto, chemistry-based question, and not in-vivo. Either that or the answer is simply: 'It takes 22 years for my patient to metabolise the paracetamol because with a pH of 6.0 and temperature of 25 degrees they are clearly already dead'.



Maybe if you found yourself time-jumped back to the 70s :p:

N-acetylcysteine is much more effective. So much so, in fact, that in the US some paracetamol tablets contain NAC and its impossible to overdose on it!
Thank you nexttime (btw, are you a Cliff Richard fan? [https://www.youtube.com/watch?v=11XUGdBB8Ns]) for pointing out these facts that are blaring us in the face - I trained in medicine just a little before you obviously (NOT quite 70s haha!) which also explains my absent-mindedness (my advice to ALL you spring chickens: don't get middle-aged in other words, get cracking on anti-ageing research!
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macpatgh-Sheldon
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(Original post by bethbarwell)
Hey @rumman15,

I don't have the answer to your question... I am, however, looking for the answer to the exact same question. Are you doing your degree through the University of Kent?

P.S. thank you for the explaination macpatelgh!!
My pleasure, BethBarwell!
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