Tag Archives: glucuronic acid

overdose and grapefruit

Sarah was hiding under her bedclothes. She is 24, and has had a really miserable time recently. Last week she was sacked from her underpaid job, which she hated anyway. Her Mother and Ken (her Mother’s new partner) have been putting pressure on her to “get her life sorted out”.

She had seen her GP, who thought she was depressed and organised some group cognitive behaviour therapy. Sarah did not like the group leader, he was too much like Ken. Her GP then gave her some sertraline tablets – she was told they would not work straight away but might take two weeks – that was last week.

She was planning to move into a flat with her new boyfriend, but yesterday found out he was seeing someone else. Life seemed totally hopeless and she drank half a bottle of vodka and took thirty paracetamol tablets.

paracetamol is sold in boxes of only 16 in the UK to reduce the likelihood of overdose
paracetamol is sold in boxes of only 16 in the UK to reduce the likelihood of overdose

She left the empty packets on the kitchen table – she admitted that she wanted her Mother to find them when she returned from the pub with Ken. They found her in her room, semi-conscious from the vodka, and rang for an ambulance.

In the emergency department she had blood taken, and the paracetamol level was high enough to need treatment. She was started on a drip containing acetylcysteine (Parvolex), about five hours after taking the overdose, and sent to our assessment ward.

December is always a popular month for deliberate self-harm. It might be the “dark days before Christmas”, with insufficient sunshine to activate the pineal gland. It also seems that Christmas puts a lot of tension on families, and makes some people very miserable, rather than happy. My Mother-in-Law remembers Christmas as a child:

“the smell of sprouts and the sound of weeping from the kitchen”

We have medical students on the ward, who have all recently spent time in primary care. I ask

“Do you see a lot of depression in GPs surgeries?”

They smile as they recount the very large numbers of patients who attend their family doctors because they are unhappy and seem unable to cope with their lives.

We look after a lot of people who have taken a deliberate overdose of drugs. Many are young and female, and when we go to see them in the morning, they are often hiding under the bedclothes – reluctant to talk. Sarah was not keen to talk to begin with, but soon told us the whole story. She said she felt really stupid now, and felt she had wasted everyone’s time. She was glad she had not managed to kill herself. We told her that she would soon be seen by our psychiatry colleagues. They sent her home later that day, after we had checked her blood results and were sure she had not done any serious damage to her liver. She has an outpatient appointment with the psychiatric team next week.

Overdose of paracetamol, or acetaminophen as it is called in the US, is the commonest reason for acute liver failure needing liver transplant in the UK and US in young people. Why is it so toxic in overdose?

Paracetamol is metabolised by our liver. Normally, about 90% is conjugated with glucuronic acid or sulphate. Glucuronic acid is like glucose, with an extra COOH attached.

liver metabolic pathways for paracetamol
liver metabolic pathways for paracetamol – Fvasconcellos  wikicommons

Once conjugated paracetamol is much more soluble in water, and is excreted in the kidneys. But about 10% is metabolised by liver cytochrome enzymes. They are called cytochromes because they make the liver cells coloured – a brownish red colour. Cytochromes enzymes contain haem, but mostly with the iron in the Fe3+ form. This makes them brownish rather than the bright red in haemoglobin and myoglobin, where the iron is in the Fe2+ oxidation state. That is why liver is a different colour from ordinary meat. These cytochrome enzymes are also known as p450 enzymes. This is because if a pure solution of the enzyme in a test tube is bubbled with carbon monoxide, the enzyme absorbs light with a peak at 450nm – purplish blue. Absorbing blue light means that it looks reddish – the colour which is not absorbed. There are a whole range of cytochrome p450 enzymes in the liver – to deal with the vast number of chemicals which our bodies need to deal with. Their job is to oxidise the variety of chemicals in our diet and render them soluble and make it easier for them to be excreted by our kidneys.

The small proportion of paracetamol which is oxidised by p450 enzymes is turned into a toxic chemical – NApQI – this stands for N-acetyl-p-quinone-imine. This molecule is only very slightly different from the parent paracetamol molecule, but contains a C=O group on the benzene ring, making it a quinone. Quinones are often reactive chemicals.  They are used industrially to generate hydrogen peroxide. NApQI will rapidly damage the liver cells that make it from paracetamol. But this damage does not happen when we take the normal dose. Fortunately all of the NApQI is rapidly detoxified by reaction with glutathione, a substance normally present in the liver cells, to produce a non-toxic conjugate which is excreted in the urine.

The problem comes when paracetamol is taken in overdose. The glucuronic acid and sulphate conjugation pathways are overwhelmed, and more of the paracetamol is turned into NApQI by cytochrome p450 enzymes. After a short time the glutathione runs out and NApQI cannot be detoxified and causes liver damage. The acetylcysteine we gave to Sarah as soon as she came in is used by liver cells to replenish glutathione and prevent any more liver damage. We give a lot of acetylcysteine – about 25 grammes in total – about an ounce, over a period of 21 hours. After this time all of the paracetamol should be eliminated as non-toxic substances. Chemicals that cause induction of p450 enzymes, such as alcohol and anticonvulsant drugs, can make paracetamol toxicity more likely. Malnutrition, which can deplete glutathione reserves, can also increase the risk of liver damage.

 

The second question I will ask, but not give a satisfactory answer to, is why does it take a long time for antidepressant drugs like sertraline to work? This drug, like Prozac, or fluoxetine, is thought to increase the amount of serotonin available in the brain. Serotonin is a small molecule, made from the amino acid tryptophan. There is a lot of tryptophan in certain foods such as soyabeans and cheese, but smaller amounts in all protein sources. Sertraline is an SSRI – a selective serotonin reuptake inhibitor. Serotonin is released from one nerve and travels across a synapse to cause an effect of the next nerve. Following release serotonin is taken back up into the cell that released it, causing the effect to terminate. Blockade of this uptake will mean that there is more serotonin available to have its effect. Drugs such as ecstasy (MDMA) are thought to have their euphoric effect by increasing serotonin levels, but they work more or less straight away.

I think we have an awful lot to learn about how the brain works. In fact I’m sure that we have very little idea. We don’t even seem to understand the basic operating system.

The information for this red apple is coded in the silicon chips of your computer as 0s and 1s, in a particular sequence to allow the screen to form this image. How does it work in your brain?
The information for this red apple is coded in the silicon chips of your computer as 0s and 1s, in a particular sequence to allow the screen to form this image. How does it work in your brain?

If I ask you to close your eyes and think of an apple, a nice red one, that is easy to do. But what is that thought? The thought – the image of an apple in your mind is certainly a thing – a physical thing. Although you think you are only imagining the picture of the apple – the picture must be there – somewhere. The thought must be made of something – even if it is a perturbation of electrical charge or change in chemicals. And it is certainly in your brain. But if I ask you exactly what the thought is made of, and where in your brain it is, we have no idea. No idea at all. Is the thought of an apple in the shape of an apple? – probably not, but of course it might be.

I have an analogy for how much we understand how the brain works. Let us imagine that you find an Amazonian tribe which has had very little contact with industrialised  society. You take them a plasma-screen television, a large solar panel to recharge the batteries, and a satellite dish. You put them together in a clearing in the forest, charge up the battery and turn the television on. Adjustment of the satellite dish results in the face of Simon Cowell presenting the X-Factor appearing on the television.

Simon Cowell photo courtesy Alison Martin of SimonCowellOnline.com.
Simon Cowell photo courtesy Alison Martin of SimonCowellOnline.com.

The tribespeople are intrigued. You leave them with the whole kit. They start experimenting with it – they realise that moving the satellite dish changes the clarity of the image, they realise that they can change the picture or increase the sound volume by pressing various buttons. One enterprising young man has even unscrewed the back of the television and discovered that some components are removable, and taking them out does all sorts of interesting things to the picture and sound. They feel that after a few months they have a pretty good idea about how the television works. That is about the level of understanding we have of how our brains work – we can give people chemicals which change conscious level and behaviour, we can operate and stimulate certain parts of the brain to see what happens, and can use functional MRI to see what part lights up when we do, or think about certain things. But we don’t know how it works. Not a clue.

Now for the food link – grapefruit.Slide6 We have known for some time that drinking grapefruit juice can cause potentially serious interactions with certain drugs which are metabolized by liver p450 enzymes. This was discovered when researchers, who were looking for an effect of alcohol on the blood pressure drug felodipine, mixed the alcohol with grapefruit juice to disguise the taste. They found that the grapefruit juice, rather than the alcohol, had a huge effect on the rate at which felodipine was metabolized by the liver. This is because it contains a substance which binds to and inhibits certain cytochrome p450 enzymes.  Grapefruit also affects the metabolism of many other drugs, such as statins and oral contraceptives – for more information see: http://www.healthcentral.com/peoplespharmacy/pp_guides/pdf/gfruit02.pdf