SUMMARY: Alzheimer’s, dementia, common medications increase risk; many medications have anticholinergic effects. Three most commonly used in elderly were associated with irreversible brain impact (dementia and Alzheimer’s) and despite knowledge of the need for reducing such use, 3/4 of the study cohort had been prescribed at least one (antihistamine, acid reducers, antidepressant…).
UPDATE: This post addresses the adverse cognitive impact in the elderly of common drugs due to anticholinergic effects. There is however another mechanism for dementia and Alzheimer’s. The later post, HEARTBURN DRUGS, DEMENTIA, ALZHEIMER’S RISK FOR ALL? T2D, IS IT THE CANARY IN THE COAL MINE!?! addresses this other mechanism for dementia and Alzheimer’s for common heartburn drugs (microbiome skew and B12 (and other) nutrient depletion) for proton pump inhibitors (PPIS) and Histamine H2 antagonists (H2RAs) .Last updated: January 10, 2017 at 21:47 pm
The goal of diet and lifestyle modifications
Reducing and/or eliminating medications using diet and lifestyle changes that improves health and immunity often times resolves disease symptoms; this is one goal of my awareness efforts. The unknowns of long term medication exposure(s) has always concerned me as studies are sorely lacking.
Is it really possible that diet and lifestyle changes can allow one to move off mediation? This UMass study showed success for 24 IBD patients eating a whole foods diet which follows the guidelines of a slightly modified SCD diet. Conclusion: “The SCD modified dietary protocol can be used as an adjunctive or alternative therapy for the treatment of IBD. Notably, 9 out of 11 patients were able to be managed without anti-TNF therapy, and 100% of the patients had their symptoms reduced. When you can take someone who can not digest (these folks were seriously ill long term) and turn health around to the point of not needing TNF medications, I don’t know how much more evidence you need that such is possible. See the post, FOOD MANAGING IBD & AUTISM: THE STUDIES, for more details of the diet UMass used with a focus on autism and IBD.
Commonly used medications are found to be associated wtih dementia and Alzheimer’s in the elderly
The study (just published Jan., 2015) Cumulative Use of Strong Anticholinergics and Incident Dementia exemplifies the long term medication exposure(s) concern as it is the first to show a dose response (for either higher doses or for a longer usage time) linking more risk for developing dementia, including Alzheimer’s disease, due to use of three common anticholinergic medications: tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. “20 to 50% of those 65 years of age or older use at least one medication with some anticholinergic activities.3,5–8 –The cognitive impact of anticholinergics: A clinical review
I want to stress that there is no evidence that anticholinergic drugs cause dementia, rather there is an association link.
What are anticholinergic effects, and what are these common medications that have anticholinergic effects?
Anticholinergic effects happen because some medications block the neurotransmitter called acetylcholine in the brain and body. That can cause many side effects, including drowsiness, constipation, retaining urine, and dry mouth and eyes. Older people are more likely to experience anticholinergic effects because the amount of acetylcholine in the body decreases with age or there may be an increase in acetylcholinesterase, the enzyme that breaks down acetylcholine. Consequently, anticholinergic drugs block a higher percentage of acetylcholine so that the aging body is less able to use what little acetylcholine is present. –Aging and Drugs, MERCK Home Manual.
The central nervous system of older patients is very sensitive to the above adverse anticholinergic effects due to the significant decrease in cholinergic neurons or receptors in the brain of older adults, the reduction in hepatic metabolism and renal excretion of medications, and the increase in blood–brain barrier permeability.9 –The cognitive impact of anticholinergics: A clinical review.
Franklin Institute, The Human Brain, provides:
Acetylcholine is the primary chemical carrier of thought and memory. This excitatory neurotransmitter is essential for both the storage and recall of memory, and partly responsible for concentration and focus. It also plays a significant role in muscular coordination . A deficit in acetylcholine is directly related to memory decline and reduced cognitive capacity.
Unlike other key neurotransmitters, acetylcholine is not made from amino acids. Its primary building block is choline, which doesn’t have to compete for entry into your brain. Therefore, the more choline you consume, the more acetylcholine you can produce. Choline belongs to the B family of vitamins and is a fat-like substance that’s necessary to metabolize fats. It is found in lecithin as phosphatidyl choline. Foods high in lecithin include egg yolks, wheat germ, soybeans, organ meats, and whole wheat products.
You can boost your acetylcholine levels by taking supplements of phosphatidyl choline, which is also the form of choline most important to the structure of your neural membranes. Vitamin C and B5 are needed for your brain to synthesize acetylcholine, in the presence of choline acetyltransferase, a key brain enzyme.
Acetylcholine levels tend to decline with age, in part because of a decreased ability to synthesize this enzyme. There also may be an increase in acetylcholinesterase, the enzyme that breaks down acetylcholine.
The study looked at 3434 participants 65 years or older with no dementia at study entry. The study considered the most common anticholinergic classes used which were: tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics:
- Tricyclic antidepressants like doxepin (Sinequan) 10 mg/day,
- First-generation antihistamines like chlorpheniramine, 4 mg/day (this dose is in one Chlor-Trimeton Allergy Relief, 4 Hour Tablet), also diphenhydramine drugs such as Nytol, Benadryl, or
- Antimuscarinics for bladder control like oxybutynin (Ditropan) 5 mg/day of oxybutynin.
- Results of the study found that greater risk for developing dementia occurs for people taking these meds for at least three or more years. In a mean followup of 7.3 years, 23.2% (797 people) developed dementia, of whom 79.9% ( 637) were thought to have Alzheimer’s disease.
- Some participants will have their brains autopsied after death; this will provide insight into whether participants who took anticholinergic medications actually have more Alzheimer’s-related pathology in their brains compared to nonusers.
- Additionally, the risk for dementia was similar when comparing adults with recent and past heavy use with nonusers, suggesting that the risk for dementia with anticholinergic use may persist despite discontinuation of therapy, and may not be reversible even years after people stop taking these drugs.
This ScienceDaily article also discusses the study: Higher dementia risk linked to more use of common drugs.
What drugs are anticholinergic drugs? A lot, and even your child likely took a few.
Nearly a fifth of the anticholinergic medications in the study had been bought over the counter. The below images show Anticholinergic Medications commonly used in Older Adults:
- Anticholinergic Pocket Reference Card, The University of Iowa, Health Effectiveness Research Center
- Iowa Center for Education and Research on Therapeutics The University of Iowa
- ABC Anticholinergic Burden Scale, Aging Brain Care (just sign in and download for free the various PDFs.)
These meds include sleep remedies, antihistamines, and medications for cough and cold, muscle spasms & pain, asthma, C.O.P.D., stomach and GI tract.
Honestly, what caught my eye in the study was the first-generation antihistamines association and that acid reflux meds like Zantac and tagamet, and even eye drops, are anticholinergic.
Antihistamines are used for allergies such as hay-fever or to aid sleep/promote drowsiness.
Such includes diphenhydramine drugs since they have anticholinergic effects; they block the action of acetylcholine and are used as a sedative because they cause drowsiness (see MedicineNet.com, diphenhydramine, Benadryl.)
Lots of children use allergy diphenhydramine meds and despite youth supposedly having a lot of acetylcholine and decrease in acetylcholinesterase, the enzyme that breaks down acetylcholine, children still experience anticholinergic effects, especially the drowsy effect. Still unknown would be:
- The brain impact on long term use (what ever that quantifiable might be) for the yet developing brain and
- Reversibility if brain impact occurs; it is not reversible for the aged given the findings from Cumulative Use of Strong Anticholinergics and Incident Dementia.
Diphenhydramine drugs having anticholinergic effects from MedlinePlus are:
- Alka-Seltzer Plus Allergy
- Benadryl Allergy Dye-Free LiquiGels
- Children’s Benadryl Allergy
- Children’s Triaminic Thin Strips Allergy
- Diabetic Tussin
- Karbinal ER
- PediaCare Children’s Allergy
- QlearQuil Nighttime Allergy Relief
- Simply Sleep
- Tranquil Nighttime Sleep Aid
- Unisom SleepGels
- Unisom SleepMelts
Acid reflux medications next caught my attention.
Those having anticholinergic effects include cimetidine (Tagamet) and ranitidine (Zantac). These medications are used by many long term and it seems at some point, acetylcholine levels would decrease with age making long term brain impact possible. I will note here just for the record: clients using these meds have been able to wean off them with dietary changes that incorporate:
Additionally, there are even more considerations for other meds that are considered anticholinergic
Drugs to Avoid in Patients with Dementia, PHARMACIST’S LETTER / PRESCRIBER’S LETTER, lists in addition to known medications with strong anticholinergic side effects, those drugs not typically associated with major anticholinergic side effects (e.g., narcotics, benzodiazepines) that have anticholinergic like effects such as urinary retention and dry mouth; these cause acute confusional states.3 The report also lists factors that may determine whether a patient will develop cognitive impairment when exposed to anticholinergics which includes: 1) total anticholinergic load (determined by number of anticholinergic drugs and dose of agents utilized), 2) baseline cognitive function, and 3) individual patient pharmacodynamic and pharmacokinetic features (e.g., renal/hepatic function).1 See the report for meds listed if below is not clear, as well as cite references:
Most importantly, there are alternative non-anticholinergic medications and therapies
Second-generation antihistamines that are not anticholinergic (see below slide from Drugs to Avoid in Patients with Dementia, PHARMACIST’S LETTER / PRESCRIBER’S LETTER) are loratadine (Claritin) and cetirizine (Zyrtec). For depression, selective serotonin re-uptake inhibitors that are not anticholinergic are citalopram (Celexa) or fluoxitene (Prozac). SSRIs are actually preferred over TCA due to TCA tolerance and safety issues — further discussion is below. Also note: diet and lifestyle modifications (exercise for one) can go far in managing depression. Regarding the bladder medications, while it doesn’t seem like medication alternatives are available, non-drug behavioral therapy for urinary incontinence may be a viable alternative to this medication.
Other studies support this anticholinergic – dementia study
- In the population-based study of French adults aged 65 and older, Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study:
- 520 of the 6912 subjects (7.5%) were taking anticholinergic drugs at base-line, of whom 36 subjects (6.9%) were taking two anticholinergic drugs simultaneously, and eight (1.5%) three.
- The main drug classes consisted of antidepressants (1.9%), digestive antispasmodics (1.6%), genital-urinary antispasmodics (1.3%), H1-anti-histaminics (1.0%), anxiolytics (0.9%), cardiovascular medications (0.5%), antiepileptics (0.5%), antipsychotics (0.3%), antiasthmatics (0.1%), and antiparkinson drugs (0.1%)
- Finding: A significant association between anticholinergic use at base-line and the risk of developing dementia at 4-year follow-up. Chronic anticholinergic users were at higher risk of incident dementia compared to non users, or persons having discontinued intake at the beginning of the follow-up. While this finding has not been previously reported, this agrees with the study by Perry et al. on autopsied Parkinson’s disease patients treated with anticholinergics; Alzheimer-type pathology being observed in patients who had been treated for more than two years compared to short-term anticholinergic treated or untreated cases.37
- Discontinuing anticholinergic treatment was associated with a decreased risk.
- Medical practitioners should monitor current anticholinergic drug use in elderly patients and seek pharmacological alternatives before considering administration of neuroprotective medications to persons with MCI, thus escalating a prescription cascade involving cholinesterase inhibitors and anticholinergic drugs.10, 41, 42 This is especially important considering that long-term concomitant therapy with anticholinergics may be associated with significant deleterious effects on acetylcholinesterase therapy, and may have adverse effects on the clinical course of Alzheimer’s disease.43,44
- Dr. Eric Larson, executive director of the Group Health Research Institute (who worked on the Cumulative Use of Strong Anticholinergics and Incident Dementia study, in an email to Reuters Health,) noted “showing that the risk of a permanent progressive brain disease like Alzheimer’s was associated with these drugs was extremely surprising as the anticholinergic drugs were felt to only have effects that were time limited – no structural brain changes were felt to be a consequence. Because of the surprising nature of the findings, there was a lot of skepticism, especially since drugs with these features are very commonly used. Thus, [the Cumulative Use of Strong Anticholinergics and Incident Dementia] study published in JAMA Internal Medicine confirms the results and in a much more rigorous design and in a second population. The findings confirming the earlier study make this a much more convincing and concerning finding.”
- The German study, Anticholinergic drug use and risk for dementia: target for dementia prevention, found for adults aged 75 or older, that any anticholinergic drug use over 4.5 years was associated with a greater than twofold increased risk of dementia compared with no use (adjusted HR 2.08).
Despite knowledge to minimize elderly exposure to these medications, 3/4 of the study cohort in the Cumulative Use of Strong Anticholinergics and Incident Dementia had been exposed to at least one strong anticholinergic in the 10 year study period.
While it makes clinical sense to minimize exposure to these medications among older adults, the contrary exposure occurred despite the American Geriatrics Society recognition that anticholinergics, benzodiazepines, and histamine H2 receptor antagonists are potentially inappropriate for older adults owing to their adverse cognitive effects. –Adverse Cognitive Effects of Medications Turning Attention to Reversibility
Histamine H2 receptor antagonists & benzodiazepines have adverse cognitive effects. Still more drugs with cognitive effects.. What are histamine H2 antagonist meds?
That certainly opens a can of worms. While this post is primarily limited to discussing anticholinergic antihistamines and brain impact, the above comment adds histamine H2 receptor antagonists and benzodiazepines into the mix of drugs having adverse cognitive effects. Benzodiazepines (prescribed for anxiety and sleep) are discussed below. But note the large amount of drugs that Mayo Clinic lists as histamine H2 antagonists in: Histamine H2 Antagonist (Oral Route, Injection Route, Intravenous Route, which further explains: these medications are also known as H2-blockers. They are used to treat gastric and duodenal ulcers and prevent their return. In over-the-counter (OTC) strengths, these medicines are used to relieve and/or prevent heartburn, acid indigestion, and sour stomach. Many people are on these long term. I do not know what the “cognitive impact” is due to these; you’ll need to do your own research if you are interested.
- Axid AR
- Axid Pulvules
- Heartburn Relief
- Pepcid AC
- Tagamet HB
- Zantac 150
- Zantac 150 Efferdose
- Zantac 25
Conclusions and Relevance from the study, Cumulative Use of Strong Anticholinergics and Incident Dementia:
- Higher cumulative anticholinergic use is associated with an increased risk for dementia.
- Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.
- Taking just two drugs with anticholinergic effects, such as some drugs for heart disease, antihistamines, antidepressants, antipsychotics, and even warfarin, can treble the risk of death in the over 65s. Doctors have been advised to assess the combined anticholinergic burden of all drugs that a patient is taking—prescribed drugs and those bought over the counter—before prescribing any additional ones. GPs have also been reminded of the importance of regularly reviewing patients’ drugs.–Anticholinergic effects of common drugs are associated with increased mortality in over 65s.
- Alternate meds should be tried first and if anticholinergic are used, the meds should at lowest effective dose and stopped if found to be ineffective.
Some details on the Tricyclic antidepressants:
Many guidelines recommend SSRIs rather than TCAs because of safety. Both are effective, and if safety is not an issue, then individual tolerability to side effects will determine types of medications used. –Efficacy and Tolerability of Tricyclic Antidepressants and SSRIs Compared With Placebo for Treatment of Depression in Primary Care: A Meta-Analysis and Review: selective serotonin reuptake inhibitors are as effective as tricyclic antidepressants overall but may be less effective in some patient subgroups.
Cyclic antidepressants are designated as tricyclic or tetracyclic, depending on the number of rings in their chemical structure — three (tri) or four (tetra). Tricyclic antidepressants approved by the FDA to treat depression, Tricyclic antidepressants and tetracyclic antidepressants, Mayo Clinic, are:
- Desipramine (Norpramin)
- Imipramine (Tofranil)
- Nortriptyline (Pamelor)
- Protriptyline (Vivactil)
- Trimipramine (Surmontil)
Antidepressants alter the balance of some chemicals in the brain called neurotransmitters. Neurotransmitter imbalance is thought to play a part in causing depression and other conditions. Cyclic antidepressants block the absorption of the neurotransmitters serotonin and norepinephrine, making more of these chemicals available in the brain. This seems to help brain cells send and receive messages, which in turn boosts mood. Most antidepressants work by changing the levels of one or more neurotransmitters. Cyclic antidepressants also affect other chemical messengers, which can lead to a number of side effects.