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Codeine – Chemistry Behind the Headlines 4

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This video explains some of the chemistry behind codeine – which is an over-the-counter pain medication here in the UK. Recently, media attention has questioned whether codeine should be banned. As usual, this video tries to address the chemistry behind the story, discussing the mode of action of codeine, and how it relies on metabolic activation, which can vary between individuals. I reflect on how the benefits and risks of codeine may be balanced. There is a tutorial to support this video available on my YouTube channel. Music by Marillion (Happiness is the Road).

Good morning so i picked up my newspaper on the weekend and they’re on the front cover was a story that caught my attention so if you read the headline warning over britain’s addiction to codeine and the subheadings dangerous drug withdrawn from children’s cough medicines and demands grow ban to be extended to adult painkillers so i thought codeine would be a very

Interesting drug for us to take a look at going to have a look at the history the structure the chemistry what’s known how dangerous is it and why is it sold over the counter here in the uk codeine is effective for two things it’s an anti pain medication and it also helps suppress your coughing reflux so it helps with coughing it’s been used for very many years

In pharmaceutical practice than you’re looking here at a picture of one of the original pharmaceutical preparations of codeine and codeine is available over-the-counter in pharmacies here in the uk with advice from the pharmacist you can’t just pick it off the shelf and buy it but it’s very often added in two formulations with other common painkillers such as

Paracetamol or ibuprofen in relatively small amounts to give extra activity so codeine is a naturally occurring component of the opium poppy in fact it’s more commonly found in iranian opium poppies than afghani open pockets of higher levels in the iranian opium poppy and it was first isolated by a french chemist in 1832 now morphine had previously been isolated

From the opium poppy in 1800 and then codeine the knowledge of codeine was added to that in 1832 and codeine rather like morphine is an active opiate type drug here we’re looking at the structure of codeine and we’re comparing it to the structure of morphine and as you can see there’s just a single difference in terms of the chemical structure one of the alcohol

Groups on morphine specifically the phenol that’s attached to the benzene ring at the top of the structure has been methylated it’s been converted to a methoxy group and ch3 functional group now interestingly codeine itself is not an active compound it needs activation inside your body this is what we refer to as being a prodrug where you take a substance in tablet

Form and then your body converts it into the active drug and it’s an interesting story because what happens with codeine is a prodrug is you take the tablet the tablet goes through your stomach into the intestine where it gets absorbed into your body and the first thing that happens is the codeine gets into your liver now the liver as we’ve said in some previous

Videos in this series plays a key role in protecting your body against any drug that you take in and ingest and the way it does that is it tries to turn a compound into a more soluble form so you can excrete it in your urine through the kidneys now one of the things that makes codeine less soluble is that ch3 group and so what your liver does is it unmasks the ch3

Group and turns the methoxy group into a phenol and alcohol so in other words your liver in trying to protect your body from this unknown compound codeine takes off the methyl group and terms codeine into morphine which is then capable of having a pain killing effect and this is one of the reasons why codeine is an effective painkiller now what i want to do is go

Back and think about that liver metabolism of codeine in a little bit more detail because it’s where some of the problems with the drug potentially arise from and so what you’re looking at here is a reaction scheme with codeine on the left and the things it’s converted to on the right one of the things it’s converted to is morphine by loss of that methyl ether as

We’ve already said another of the things that happens is a glucuronic acid a sugar unit can get attached to the structure of codeine and the reason that the body does that is that sugars are highly water soluble and that helps the codeine to dissolve in the or in get removed by the kidneys and get passed out of the body in that manner the other thing that happens

To codeine metabolically within the liver is that the methyl group can be removed from the aiming on the right-hand side of the structure and that generates a compound called nor codeine now the problem with any pro drug strategy is that you’re relying on the enzymes within the liver of the patient to convert the drug into its active form and the key issue is that

Your liver activity depends on you as an individual every individual patient will have a slightly different response to codeine because you have different levels of the key enzymes which convert codeine into its active forms morphine the sugar conjugated version of codeine and so on some patients are slow metabolizers of codeine and actually they take the drug and

They get a limited pain-killing effect because their metabolism is inefficient at converting codeine into the active form it has also been argued that some patients are ab smart ab eliza’s of codeine and will take a normal dose of codeine but will get a much higher dose of potentially pain killer active analgesic medication because they rapidly convert the codeine

Into more active forms interestingly as many as 10% of the caucasian population can have problems in metabolizing codeine too slowly not having the necessary enzymes at the necessary levels to turn codeine into the pain relief form however more problematic are those individuals that are potentially fast metabolizers and a key paper was published in 2004 in the new

England journal of medicine and it is worth a little look at this paper so it’s important to note that this paper only deals firstly with a single patient secondly that the single patient was sick when he came into hospital and thirdly that he was taking other medication however the conclusions were that this patient became intoxicated by coding because firstly he

Metabolized it very rapidly to morphine and secondly some of the other drugs that he was taking were interfering with some of the other metabolic pathways that help to excrete the codeine in particular the conversion of codeine to nor codeine was being blocked so if we look back at the reaction scheme what that means is that codeine is much more rapidly converted

Into morphine and not so effectively converted into nor codeine and that is the reason that was given why morphine type toxicity was observed in this patient the question is how common was the response of this patient to codeine i would suggest this was a very very rare response to coding because codeine has long been used as an over-the-counter medication and this

Kind of effect has rarely been seen the other problem with codeine is of course it’s addictive character codeine generates morphine in the body morphine is a known addictive substance now codeine is only taken at low dose and only generates small amounts of morphine but nonetheless there is both physical and psychological addiction as a possibility with codeine

And people have many people over the years have had codeine addictions but for example elvis presley was found with codeine in his body at the time of his death and some have suggests that it may have played a role in his ultimate demise and mel smith the comedian has also stated that he had an addiction to neurofen plus calling it his dark secret the other thing

Worth noting is if you’re breastfeeding i wouldn’t advise you to take codeine and morphine can be passed on through the breast milk of mothers who are breastfeeding babies if they’ve taken over the counter codeine medications and that can be significantly harmful to the young baby that’s feeding so should codeine be banned well i think it’s right to remove it

From children’s medications any drug that relies on metabolism to be activated is particularly variable in children in terms of their developing metabolic pathways so i think it’s right to withdraw it for children in terms of adults no i don’t think it should be banned and it does provide useful pain relief it’s an opiate class drug so it is a much stronger pain

Reliever than paracetamol or aspirin there are occasions when a patient is going to need to get pain relief of that type so i believe in slightly more regulation of codeine definitely not a ban at this point we still want access to the medication but perhaps there should be a pharmacy based scheme electronic registration where you give your name and address that

Information is held on a central database to which pharmacists have access they can check whether you have previously purchased the drug recently from another pharmacy in that way we can control access to the drug hopefully limit the harm that it does and codeine in my view at this point doesn’t need to be banned outright

Transcribed from video
Codeine – Chemistry Behind the Headlines 4 By ProfessorDaveatYork