Common medicines used to treat conditions such as hay-fever, allergies, depression, asthma, stomach ulcers, pain relief and heart conditions have been linked to a decline in brain function and increased risk of death. Millions of people take these drugs as prescribed by their doctor or bought as over the counter remedies.
The findings, reported in the Journal of the American Geriatrics Society, result from the work of researchers in the UK and USA investigating the long term health impact of ‘anticholinergic’ medicines – so called because they affect a chemical in the brain called acetylcholine. Acetycholine is a neurotransmitter essential for the transmission of messages from one nerve cell to another.
Medicines with some degree of anticholinergic effect are wide-ranging. The drugs with the greatest impact include anti-depressants such as Amitriptyline, Imipramine and Clomipramine; tranquilisers such as Chlorpromazine and Trifluoperazine; bladder medication such as Oxybutynin; and antihistamines such as Chlorphenamine (in Piriton). Other drugs with anticholinergic effects include Atenolol, Furosemide and Nifedipine for heart problems; painkillers such as Codeine and Dextropropoxyphene; the asthma treatment Beclometasone; the epilepsy treatment Carbamazepine; and Timolol eyedrops which are used for glaucoma.
Anticholinergic medicines have long been associated with more minor side effects e.g., dry mouth, blurred vision, constipation and feeling drowsy. But this new finding of an association with serious and potentially life-threatening side effects is extremely worrying and indicates that the impact of these medicines on our health is not fully understood.
To determine the effects of anticholinergic medicines the researchers examined the medication records for more than 13,000 men and women aged 65 and over who had been enrolled in the Medical Research Council (MRC) Cognitive Function and Ageing Study between 1991 and 1993. Around half of those in the study population were found to use a medication with potential anticholinergic properties.
Eighty drugs were rated for their anticholinergic activity and each drug taken by participants was given a score based on the strength of its anticholinergic activity or AntiCholinergic Burden (ACB) – 0 for no effect, 1 for mild effect, 2 for moderate effect and 3 for severe effect. For example, Codeine (a painkiller) and Warfarin (a blood thinner) have a mild effect and therefore a score of 1, while Piriton (an antihistamine) and Seroxat (an antidepressant) have a severe effect and a score of 3. A full list of the drugs investigated and their scores is available on the University of East Anglia website.
A combined score for each of the 13,000 participants was calculated by adding together the scores for all the medicines they were taking, e.g., a patient taking one severe drug (score of 3) and two mild ones (scores of 1 each) would have an overall score of 5.
From their work the researchers found that:
- 20% of participants taking drugs with a total ACB of 4 or more had died by the end of the two-year study, compared with only 7% of those taking no anticholinergic drugs. This is the first time a link between anticholinergic medicines and death has been shown.
- For every additional ACB point scored the chances of dying increased by 26 per cent.
- Participants taking drugs with a combined score of 5 or more showed a 4% drop in brain function compared to those taking no anticholinergic medications. This confirms evidence from previous smaller studies of a link between anticholinergic drugs and cognitive impairment (memory problems).
- The increased risks from anticholinergic medicines were cumulative, based on the number of anticholinergic drugs taken and the strength of each drug’s anticholinergic activity, i.e., the greater the blockade of a patient’s medication on acetylcholine, the greater the degree of brain dysfunction and the greater the risk of death.
- Participants who were older, of lower social class, and with a greater number of health conditions tended to take the most anticholinergic drugs.
While this study reports an association between anticholinergic medicines and increased risk of brain decline and death it does not say that the drugs caused death or reduced brain function – only that there is a link. However, in analysing the data the researchers took into account underlying disease in the study participants and for which they were taking the medicines– and the increased risk does appear to be related to the anticholinergic effects of the drugs.
Dr Chris Fox who led the research at the University of East Anglia said: “This is the first large scale study into the long-term impact of medicines which block acetylcholine – a common brain neurotransmitter – on humans, and our results show a potentially serious effect on mortality. Clinicians should conduct regular reviews of the medication taken by their patients, both prescribed and over the counter, and wherever possible avoid prescribing multiple drugs with anticholinergic effects.
Dr Malaz Boustani, Associate Professor of Medicine at Indiana University, who reviews the benefits and harms of these medicines with patients at the Wishard Healthy Aging Brain Centre in Indianapolis, and played a key role in developing the ACB scoring system used in the study, said: “Our findings make it clear that clinicians need to review the cumulative anticholinergic burden in people presenting with cognitive impairment to determine if the drugs are causing decline in mental status. Every clinician has the duty to protect the brains of their patients and every patient needs to bring over the counter and prescription drugs to their doctor’s appointment for a comprehensive review.”
Participants in this study were aged 65 and older and the data analysed was for drugs used between 1991 and 1993. Translating the study’s findings (i.e., that half the participants took at least one anticholinergic drug with 4% in the highest category scoring 4 or more) to today’s UK population with 12 million aged over 65, would mean that nearly 6 million older people take these drugs and 480,000 are in the highest risk category.
But medicine has changed significantly in the past 20 years. Ian Maidment, an NHS pharmacist in Kent and Medway, and one of the report’s authors believes the situation today may be worse. He said the use of anticholinergic drugs had “probably increased as more things are being treated and more drugs are being used.” Importantly, many anticholinergic medicines are now being taken by younger people and over long periods of time. The impact of this on brain function and mortality is not known.
Decreased acetylcholine levels in the brain are a feature of dementia. The number of people developing dementia and other degenerative brain conditions is increasing without explanation. This research and work leading from it is vitally important in helping us to better understand what may be contributing to the increase.
Reference: ‘Anticholinergic medication use and cognitive impairment in the older population: The Medical Research Council Cognitive Function and Ageing Study (CFAS)’ by C Fox (UEA), K Richardson (University of Cambridge), I Maidment (Kent and Medway NHS and Social Care Partnership Trust), G Savva (University of Cambridge), F Matthews (MRC Biostatistics Unit), D Smithard (Kent Community Health NHS Trust), S Coulton (University of Kent), C Katona (University College London), M Boustani (Indiana University), and C Brayne (University of Cambridge) was published online by the Journal of the American Geriatrics Society on June 24 2011.
Announcing New Research – The ‘Common Medicines and Brain Cell Damage’ Project
BBRF is fundraising to support new research using cutting edge techniques to determine the levels of brain cell damage resulting from commonly prescribed and over the counter ‘anticholinergic’ medicines.
Two of the UK’s leading research groups led by Professor Michael Coleman from Aston University Birmingham and Dr Chris Fox from the University of East Anglia, have teamed up to take forward recent findings (see above) of a link between commonly used anticholinergic medicines and a decline in brain function and increased risk of death.
In groundbreaking work the researchers will use the best available human laboratory model of basic brain function – NTERA cells – which differentiate to form brain cells, both neurones and astrocytes, plus a recently developed cellular model of the human Blood Brain Barrier to:
- identify the biological and pharmacological mechanisms by which anticholinergic medicines exert their effects on brain cells
- identify which medicines, in which combinations and at what doses cause the worst effects
- determine if the effects of these medicines are transient or permanent, and cumulative
- determine the ability of the drugs to permeate the Blood Brain Barrier and hence exert their effects clinically. (It had been thought that the BBB prevented these medicines from entering the brain but this may not be the case and may depend on a person’s age or state of health).
Benefits from this research
This research will improve our understanding of anticholinergic medicines and how they exert their effects. It will enable us to establish which of these medicines, in which combinations and at what doses are most damaging and whether the effects are temporary or longer lasting. This will help us to assess the risks these medicines pose and develop treatment strategies to minimise any harm. If the research reveals that the recently reported link between anticholinergic medicines and brain decline and increased risk of death has no biological basis to it then this will also be of great value (and relief to many people) pointing the search for causal agents in other directions.
Why this research is vital
The number of people of all ages who use anticholinergic medicines is colossal and set to rise. If these medicines damage the brain we need to know about it in order to protect people from harm. This work is an essential next step in that process. Without it, we continue to risk the health of our brains.
Can you help?
Research is expensive but the payback from good research is priceless. The ‘Common Medicines and Brain Cell Damage’ project offers potential benefit to everyone who at some time in their life might need to use an anticholinergic medicine.
If you would like to help us fund this vital work please go to our Get Involved page to learn more about how you can make a donation.