Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study | Dementia and Cognitive Impairment | JAMA Internal Medicine | JAMA Network
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    6 Comments for this article
    are there many other drugs in common use with anti-muscarinic effects?
    Thomas Perry |
    Any table of "anticholinergic" (anti-muscarinic) drugs will necessarily be incomplete. This may be partly because a parent drug is not notably active at muscarinic cholinergic receptors, but its active metabolite(s) is or are. One good example, used extensively in North America and featured in e Table 1, is quetiapine, which begets norquetiapine (desmethylquetiapine, also referred to as desalkylquetiapine), a more potent antagonist of muscarinic receptors. (1)

    Another example missing from Supplementary e Table 1 is widely used in Canada for historical reasons (Key Opinion Leader influence) rather than because of scientific evidence of superiority. The antipsychotic
    loxapine, and/or it's metabolite(s), causes typical anticholinergic (antimuscarinic) adverse effects. (2) This drug has multiple pharmacologically active metabolites, including amoxapine (desmethylloxapine), which was marketed decades ago as an "antidepressant". (3, 4)

    One of the antidepressant and sedative drugs now dominant in Canada, especially for older people, is mirtazapine. This too is a "moderate antagonist at muscarinic receptors", and the Canadian product monograph shows that it causes dry mouth, even while maintaining within the same document that "mirtazapine is virtually devoid of anticholinergic activity". (5)

    In terms of dose equivalence, I was surprised to see in e Table 1 the suggestion that a minimum effective daily dose in older people for diphenhydramine is "50 mg", but of dimenhydrinate is "200 mg". Dimenhydrinate, the 8-chlorotheophylline salt of diphenhydramine, consists of over 50% diphenhydramine by weight. Thus, 200 mg of dimenhydrinate contains > 100 mg of diphenhydramine. (6)

    As a practical test of whether a drug may be antimuscarinic in a human being, it is worth listening carefully to a patient's speech articulation, and inspecting the mouth and tongue for dryness. A mouth rinse with any aqueous liquid may improve articulation immediately, potential evidence that a drug (or metabolite) is suppressing muscarinic cholinergic neurotransmission.

    Thomas L. Perry MD, FRCPC
    Dept. of Anaesthesiology, Pharmacology & Therapeutics
    University of B.C., Vancouver, Canada

    Incomplete Control Group
    Win Butts |
    The controls do not include patients who have the underlying issue that led the the prescribing of the anticholinergic medication but are not taking that medication. As a result the conclusion can not eliminate the risk of dementia being caused by the underlying issue and not related to the medication.
    More limitations
    Robert Speth, Ph.D. | Nova Southeastern University
    This paper is noteworthy in identifying the ability of antimuscarinic drugs to increase the risk of dementia and sounding a warning on their use. But, it has some additional limitations beyond those noted by the authors:
    1: The generic classification of drugs that increase the risk of dementia as “anticholinergics” rather than antimuscarinics is sloppy (albeit common). Anticholinergics include both nicotinic acetylcholine receptor blockers and muscarinic receptor blockers. The drugs that increase the risk of dementia have antimuscarinic actions (muscarinic receptor antagonistic properties), not antinicotinic (nicotinic receptor antagonistic properties).
    2: The authors classify many of the drug classes
    as if their primary mechanism of action is as “anticholinergic” which is incorrect. “Antihistamines” work primarily by blocking H1 histamine receptors and their antimuscarinic actions are a side-effect. The same can be said for the antidepressant and antipsychotic drugs known to have strong antimuscarinic actions.
    3: The authors fail to discuss the importance of drug design with respect to the drugs' pharmacokinetic properties. Specifically, many antimuscarinic drugs are deliberately designed to have a charged ammonium ion, so as to substantially reduce their ability to cross the blood-brain-barrier and cause adverse central nervous system effects. This likely explains the lack of adverse effect of the antimuscarinic bronchodilator drugs, although the increased risk of dementia with bladder-directed antimuscarinic drugs, whose primary action is to antagonize muscarinic receptors in the bladder, is surprising in view of their quaternary ammonium design. A hint at the possible flaw in this argument comes from the work of McFerren et al., (1) who report an increase in CNS effects with oxybutynin, an antimuscarinic drug that has an active metabolite. This effect may be mitigated by transdermal versus oral administration to avoid the first-pass metabolism effect of orally administered drugs (1). Additionally, it has been noted that oxybutynin as well as tolterodine are highly lipophilic drugs that would be expected to gain access to the brain by virtue of this characteristic (2).
    4: An additional factor that should be noted is the existence of multiple subtypes of muscarinic receptors. There are reported to be 5 subtypes: M1 through M5. The subtype targeted for the bronchii and bladder smooth muscle is the M3 subtype, whereas the primary brain muscarinic receptor subtype is the M1 subtype (3). Thus, the muscarinic receptor selectivity of drugs with antimuscarinic properties should also be considered when evaluating “anticholinergic” drugs for their ability to increase the risk of dementia.
    1. McFerren SC, Gomelsky A. Treatment of Overactive Bladder in the Elderly Female: The Case for Trospium, Oxybutynin, Fesoterodine and Darifenacin. Drugs & aging. 2015;32(10):809-19.
    2. Hesch K. Agents for treatment of overactive bladder: a therapeutic class review. Proceedings (Baylor University Medical Center). 2007;20(3):307-14.
    3. Lebois EP, Thorn C, Edgerton JR, Popiolek M, Xi S. Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease. Neuropharmacology. 2018;136(Pt C):362-73.
    Anticholinergic drug exposure and increased risk of dementia; a predictable occurrence
    Herbert Allen, MD | Drexel University College of Medicine
    The worsening of dementia with anticholinergic drugs is at least partially explainable by the pathogen theory of the disease. Spirochetes have been cultured from affected brains and have been shown to make biofilms both in vivo and in vitro.(1) Most of the drugs listed in this article have been shown to be biofilm dispersers.(2) These "disrupted" biofilms seed new foci throughout the brain which leads to further interference in neurocircuitry.(3) The likely mechanism for this especially as regards the formation of beta amyloid and hyperphosphorylated tau has been identified.(3)

    1 Miklossy J. Bacterial amyloid and DNA are
    important constituents of senile plaques: further evidence of the spirochetal and biofilm nature of senile plaques. J Alz Dis 2016; 53: 1459-1473

    2 Allen HB, Hossain C, Abidi N et al. Penicillin: the old/new wonder drug. Adv Tech Biol Med. 2017; 5: 197.

    3 Allen HB, Allawh RM, Goyal K. A pathway to Alzheimer's disease. Curr Neurobiol 2018; 9(1): 29-32.
    Tiotropium was neglected
    Hans-Joachim Kremer, Dr. rer. nat. | Medical Writing Service
    eTable 1 lists ipatropium and glycopyrrolate, but not tiotropium (bromide), which is certainly also an anticholinergic. eTable 3 indicates that ipatropium was quantitatively much more important than glycopyrrolate (which got market authorisation in Europe in 2012). It is very likely that tiotropium (marketing authorisation in Europe in 2002) was even much more frequently prescribed during the study periods than the quite old (and maybe outdated) ipatropium.
    Parkinson’s disease, Parkinsonism or drug induced Parkinsonism?
    Peter Hobson, PhD, MSC, BSc (Hons) | Betsi Cadwaradr University Health Board, United Kingdom
    The AOR of 1.52 (95% CI, 1.16-2.00) reported in this study for antiparkinsonian drug I feel needs to be interpreted with a degree of caution. What we really need to know if the cases reported in this investigation had confirmed idiopathic Parkinson’s disease (IPD), parkinsonism or drug-induced parkinsonism. The reason for this is that the majority of the anticholinergic drugs listed in the investigation are not routinely used to treat IPD. What I suspect we are looking at is anticholinergic drugs used to treat drug-induced PD and parkinsonism rather than confirmed IPD. Many patients with neuropsychiatric conditions other than IPD, who are treated with antipsychotics listed in this investigation, develop parkinsonism as a side effect to exposure to these classes of drugs. On the other hand, through the course of their condition, many cases of IPD may have also been exposed to treatment with antipsychotics, anti bladder antimuscarinic drugs anticholinergic antidepressants. I suspect it would be difficult to control for all of these confounders in the antiparkinsonian drug group in this investigation. However, attributing an excess risk for dementia with antiparkinsonian drugs is questionable without this information.
    Original Investigation
    June 24, 2019

    Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study

    Author Affiliations
    • 1Division of Primary Care, University of Nottingham, Nottingham, England
    • 2Division of Psychiatry and Applied Psychology, Institute of Mental Health, Nottingham, England
    • 3University of Southampton Medical School, Primary Care and Population Sciences, Aldermoor Health Centre, Southampton, England
    • 4Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, England
    JAMA Intern Med. 2019;179(8):1084-1093. doi:10.1001/jamainternmed.2019.0677
    Key Points

    Question  Is the risk of dementia among persons 55 years or older associated with the use of different types of anticholinergic medication?

    Findings  In this nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls, there were statistically significant associations of dementia risk with exposure to anticholinergic antidepressants, antiparkinson drugs, antipsychotic drugs, bladder antimuscarinics, and antiepileptic drugs after adjusting for confounding variables.

    Meaning  The associations observed for specific types of anticholinergic medication suggest that these drugs should be prescribed with caution in middle-aged and older adults.


    Importance  Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia.

    Objective  To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.

    Design, Setting, and Participants  This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018.

    Exposures  The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date).

    Main Outcomes and Measures  Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables.

    Results  Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.

    Conclusions and Relevance  Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.