Anticholinergic Drugs Linked With Increased Risk Of Dementia

Use of anticholinergic drugs, is associated with increased risk of dementia, even when taken 20 years before diagnosis of cognitive impairment, a large study has found. Anticholinergics are a class of drugs commonly prescribed in the United States and United Kingdom as antidepressants and incontinence medications.

An international research team from the US, UK and Ireland analyzed more than 27 million prescriptions as recorded in the medical records of 40,770 patients over age 65 diagnosed with dementia compared to the records of 283,933 older adults without dementia.

The researchers found greater incidence of dementia among patients prescribed anticholinergic antidepressants, anticholinergic bladder medications and anticholinergic Parkinson’s disease medications than among older adults who were not prescribed these drugs. Dementia increased with greater exposure to anticholinergic medications.

Cognitive Impairment

Regenstrief Institute and Indiana University Center for Aging Research investigator Noll Campbell, PharmD, MS, a co-author of the study, said:

“Anticholinergics, medications that block acetylcholine, a nervous system neurotransmitter, have previously been implicated as a potential cause of cognitive impairment. This study is large enough to evaluate the long-term effect and determine that harm may be experienced years before a diagnosis of dementia is made.”

The study, which was led by the University of East Anglia and funded by the Alzheimer’s Society, both in the UK, utilized data from the Clinical Practice Research Datalink which includes anonymized diagnosis, referral and prescription records for more than 11 million patients from 674 primary care practices across the UK. The data is broadly representative of the UK population in terms of age, sex and ethnicity.

“These findings make it clear that clinicians need to carefully consider the anticholinergic burden of their patients and weigh other options. Physicians should review all the anticholinergic medications – including over-the-counter drugs – that patients of all ages are taking and determine safe ways to take individuals off anticholinergic medications in the interest of preserving brain health,”

said study co-author Malaz Boustani, M.D., MPH, a Regenstrief Institute and IU Center for Aging Research investigator.

Conclusions

The authors highlighted in their conclusions the following points:

“What is already known on this topic:

  • Use of drugs with anticholinergic activity is associated with impaired cognition in the short term
  • It is not known if the reported associations between the use of anticholinergic drugs and future cognitive decline and dementia incidence can be attributed to anticholinergic activity

What this study adds:

  • Antidepressant, urological, and antiparkinson drugs with definite anticholinergic activity are linked to future dementia incidence, with associations persisting up to 20 years after exposure
  • Gastrointestinal and cardiovascular anticholinergic drugs are not positively associated with later dementia incidence
  • There is no evidence for a cumulative harm of drugs considered possibly anticholinergic”

Anticholinergics

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. These agents inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells.

The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, and many other parts of the body.

Examples of commonly used anticholinergics include:

Atropine
Benztropine (Cogentin)
Biperiden
Chlorpheniramine (Chlor-Trimeton)
Dicyclomine (Dicycloverine)
Dimenhydrinate (Dramamine)
Diphenhydramine (Benadryl, Nytol, Advil PM, etc.)
Doxepin (Sinequan, Deptran)
Doxylamine (Restavit, Unisom)
Glycopyrrolate (Robinul)
Ipratropium (Atrovent)
Orphenadrine (Norflex)
Oxitropium (Oxivent)
Oxybutynin (Ditropan, Driptane, Lyrinel XL)
Propantheline bromide (Pro-Banthine)
Tolterodine (Detrol, Detrusitol)
Tiotropium (Spiriva)
Tricyclic antidepressants (28 compounds with numerous trade names)
Trihexyphenidyl (Artane)
Scopolamine
Solifenacin
Tropicamide
Bupropion (Zyban, Wellbutrin) – Ganglion blocker
Dextromethorphan – Cough suppressant and ganglion blocker
Doxacurium – Nondepolarizing skeletal muscular relaxant
Hexamethonium – Ganglion blocker
Mecamylamine – Ganglion blocker and occasional smoking cessation aid
Tubocurarine – Nondepolarizing skeletal muscular relaxant

Nicotine counteracts anticholinergics by activating nicotinic acetylcholine receptors. Caffeine (although an adenosine receptor antagonist) is able to counteract the anticholinergic symptoms by reducing sedation and increasing acetylcholine activity, thereby causing alertness and arousal.

Richardson Kathryn, Fox Chris, Maidment Ian, Steel Nicholas, Loke Yoon K, Arthur Antony et al.
Anticholinergic drugs and risk of dementia: case-control study
BMJ 2018; 361 :k1315

Image: Confocal image of axons making contact with muscle fibres at neuromuscular junctions. The neurotransmitter acetylcholine (red) sends the signals from the nerve to make the muscle contract. Credit: Tom Gillingwater. CC BY