Cardiovascular manifestations of mast cell disease (Part 2 of 5)

Abnormalities of heart rate and rhythm can occur due to action of several mast cell mediators. Histamine binds at histamine receptors numbered in the order of identification: H1, H2, H3 and H4. Histamine binding at H1 receptors on cardiomyocytes (heart muscle cells) slows the heart rate, while histamine binding at H2 receptors increasing heart rate and the force of heart contraction.

As I mentioned in the previous post, histamine binding at the H3 receptor decreases the release of norepinephrine. Another mast cell product, renin, modulates angiotensin II, which can increase norepinephrine release.  Increased levels of norepinephrine triggers increases in heart rate and force of contraction.  This means that whether or not mast cell activation causes tachycardia depends largely on how much renin and histamine are released. Much less histamine is necessary to trigger the H3 inhibition of norepinephrine release relative to the amount needed to affect heart rate through H1 and H2 receptors.

Prostaglandin D2, a mast cell mediator, can also cause tachycardia.  Of note, prostaglandin D2 is not stored in mast cell granules.  It is made following mast cell activation and is considered part of the “late phase allergy response”, which can occur several hours after exposure to a trigger.

Tachycardia is a common symptom for mast cell patients.  The recommendation in a recent review article is to treat when the heart rate is perpetually over 100-120 bpm, or when it is extremely distressing to the patient. There are a number of options for treatment. As it can be caused directly by mast cell behavior, mast cell medications such as antihistamines (H1 and H2) should be adjusted for maximum effect. Renin inhibitors, such as aliskiren (Tekturna in the US), can be used to treat supraventricular tachycardia (SVT) in mast cell patients, as can angiotensin receptor blockers like losartan, valsartan and others. Patients on renin inhibitors or angiotensin receptor blockers can also decrease blood pressure.

Calcium channel blockers, like verapamil, are also an option.  The medication ivabradine treats tachycardia in patients who have a regular heart rhythm and does not affect blood pressure.  Ivabradine is not used to treat atrial fibrillation. β-blockers are contraindicated in mast cell patients because it interferes with the action of epinephrine, making patients more likely to have reactions and epinephrine less likely to treat effectively.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

Antihistamine Table: Generics and US brand names

 

First generation  
Benztropine Cogentin
Brompheniramine Dimetapp, Bromfed
Carbinoxamine Palgic
Chlorpheniramine Chlor-Trimetron
Clemastine Tavist
Cyproheptadine Periactin
Dexbrompheniramine Drixoral
Diphenhydramine Benadryl
Doxylamine Unisom, Nyquil
Hydroxyzine Atarax, Vistaril
Meclizine Antivert, Bonine, Dramamine
Orphenadrine Norflex
Prometheazine Phenergan
Second and third generation
Acrivastine Semprex-D
Cetirizine Zyrtec
Clemastine Tavist
Desloratadine Clarinex
Fexofenadine Allegra
Ketotifen N/A
Levocetirizine Xyzal
Loratadine Claritin
Tricyclic antidepressants
Amitriptyline Elavil
Clomipramine Anafranil
Desipramine Norpramin
Doxepin Silenor
Imipramine Tofranil
Nortriptyline Pamelor
Protriptyline Vivactil
Atypical antipsychotics
Aripiprazole Abilify
Asenapine Saphris
Clozapine Clozaril
Iloperidone Fanapt
Olanzapine Zyprexa
Paliperidone Invega
Quetiapine Seroquel
Risperdone Risperdal
Ziprasidone Geodon
Typical antipsychotics
Chlorpromazine Thorazine
Fluphenazine Prolixin
Perphenazine Trilafon
Prochlorperazine Compazine
Thioridazine Mellaril
Thiothixene Navane
Tetracyclic antidepressants
Amoxapine N/A
Loxapine Loxitane
Maprotiline Ludiomil
Mirtazapine Remeron

Histamine depletion in exercise

A long known and often repeated finding is that regular exercise can be protective against asthma. This finding was published in 1966 by a group that found the airways of asthmatics grew progressively less reactive following intervals of exercise. This finding was confirmed by several studies that followed. At the time, the reason why exercise protected against reactive airways was unclear, but an early hypothesis was that mediators were depleted after the initial round of exercise and that time was required to restore them.

In the 1980’s, there was a wave of research around the role of histamine in airway reactivity of asthmatics. There were a few competing theories at this point for why asthmatics became less reactive following exercise: depletion of mediators, mainly histamine from mast cells; that bronchial smooth muscle became less responsive to stimulation by histamine via the H1 receptor; and that release of catecholamines (such as epinephrine) by exercise suppresses bronchoconstriction. A number of studies made relevant findings.

Histamine is known to be released in the lungs due to exercise. It is also known to become depleted and quickly metabolized. When exposed to histamine, asthmatics recover quickly from the ensuing bronchoconstriction. Some asthmatic patients show an increase in plasma histamine during exercise.

Plasma epinephrine does not rise in asthma patients as a result of exercise, or at the very least is metabolized almost immediately, and thus is unlikely to be protective. Bronchial smooth muscle was not found to become less responsive to histamine. This was demonstrated in a study that compared repeated inhalation of histamine (such as might be induced by exercise) with actual repeated exercise. This study found that repeated exercise diminished airway reactivity, while repeated inhalation of histamine did not.

Another report indicated that inhalation of cromolyn before exercise can prevent or mitigate exercise induced asthma in most patients. Administration of H1 inverse agonists was found to offer similar protection.

A more recent study (2012) looked at the role of histamine in fatigue from exercise. Histamine is now known to be involved in regulation of oxygen/carbon dioxide exchange, which is important in exercise. In mice that were persistently exercised, the level of histidine decarboxylase was increased. HDC is the enzyme that makes and immediately releases histamine in response to an immediate need. This is different from degranulation, in which histamine is made ahead of time and stored inside the cell until needed.

This study found that treating the mice with an H1 antihistamine, H2 antihistamine, or HDC inhibitor decreased endurance in the mice. Mice deficient in HDC or H1 receptors also had less endurance. This means that histamine is partly responsible for inducing tolerance to exercise and that blocking action of histamine causes fatigue to set in more quickly.

Treatment with fexofenadine, an H1 antihistamine, decreased levels of nitric oxide and glycogen in the muscles of exercised mice. Taken together, these findings mean that histamine protects against fatigue from exercise; that this effect is achieved via H1 receptors and production of nitric oxide; and that at least some of this histamine is provided by immediate production and release of histamine via HDC. This means that your body does not simply release its histamine stores in response to exercise; it makes it on the fly so as not to exhaust its supply.

 

References:

Hahn, Allan G., et al. Histamine reactivity during refractory period after exercise induced asthma. Thorax 1984; 39: 919-923.

Niijima-Yaoita, Fukie, et al. Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion. Biol Pharm Bull 2012; 35; 91-97.

Schoeffel, Robin E., et al. Multiple exercise and histamine challenge in asthmatic patients. Thorax, 1980, 35, 164-170.

Graham P, Kahlson G, Rosengren E. Histamine formation in physical exercise, anoxia and under the influence of adrenaline and related substances. J. Physiol., 172, 174—188 (1964).

McNeill RS, Nairn JR, Millar JS, Ingram CG.Exercise-induced asthma. Q J Med 1966; 35: 55-67.

 

Mast cell medications: Antihistamines by receptor activity

The following medications listed are available in oral or intravenous formulation. Not all medications are available in the US or Europe. Topical and inhaled medications are not included in these lists.

H1 antihistamines interfere with the action of histamine at the H1 receptor. This can help with many symptoms, including flushing, itching, hives, burning skin, nasal congestion, sneezing, constriction of airway, shortness of breath, GI cramping, diarrhea, gas, abdominal pain, tachycardia, blood pressure variability or dizziness. What symptoms are best alleviated varies with the medication; they do not all address all symptoms equally.

First generation Second and third generation Atypical antipsychotics
Alimemazine Acrivastine Aripiprazole
Azatadine Astemizole Asenapine
Benztropine Azelastine Clozapine
Bepotastine Bepotastine Iloperidone
Brompheniramine Bilastine Olanzapine
Buclizine Cetirizine Paliperidone
Captodiame Clemastine Quetiapine
Carbinoxamine Clemizole Risperdone
Chlorcyclizine Clobenztropine Ziprasidone
Chloropyramine Desloratadine Zotepine
Chlorpheniramine Ebastine
Chlorphenoxamine Emedastine
Cinnarizine Epinastine Typical antipsychotics
Clemastine Fexofenadine Chlorpromazine
Cyclizine Ketotifen Flupenthixol
Cyproheptadine Latrepirdine Fluphenazine
Dexbrompheniramine Levocabastine Perphenazine
Dexchlorpheniramine Levocetirizine Prochlorperazine
Dimenhydrinate Loratadine Thioridazine
Diphenhydramine Mebhydrolin Thiothixene
Diphenylpyraline Mizolastine
Doxylamine Rupatadine
Embramine Setastine Tetracyclic antidepressants
Etodroxizine Talastine Amoxapine
Ethylbenztropine Terfenadine Loxapine
Etymemazine Maprotiline
Flunarizine Mianserin
Histapyrrodine Tricyclic antidepressants Mirtazapine
Homochlorcyclizine Amitriptyline Oxaprotiline
Hydroxyethylpromethazine Butriptyline
Hydroxyzine Clomipramine
Isopromethazine Desipramine
Meclizine Dosulepin
Mequitazine Doxepin
Methdilazine Imipramine
Moxastine Iprindole
Orphenadrine Lofepramine
Oxatomide Nortriptyline
Oxomemazine Proptriptyline
Phenindamine Trimipramine
Pheniramine
Phenyltoloxamine
Pimethixene
Prometheazine
Propiomazine
Talastine
Thonzylamine
Tolpropamine
Tripelennamine
Triprolidine

 

H2 antihistamines interfere with the action of histamine at the H2 receptor. This helps mostly with symptoms affecting the GI tract, such as abdominal pain, nausea, and diarrhea. To a lesser extent, H2 antihistamines can decrease vasodilation.

H2 antagonists
Cimetidine
Famotidine
Lafutidine
Nizatidine
Ranitidine
Roxatidine

 

There are few H3 antihistamines and for this reason, their exact effects are largely unknown.  However, in research, H3 antihistamines modulate nerve pain and may normalize the release of several neurotransmitters, including serotonin.

The only medication with known H3 activity available for patient use as an antihistamine anywhere in the world is betahistine. It is anti-vertigo drug used mostly in treatment of Meniere’s disease and other balance disorders. Betahistine actually increases release of histamine and for this reason has been associated with the risk of severe allergic events while taking it.

A 2014 paper described for the first time the H3 reverse agonist/ selective antagonist effects of two antiarrhythmic drugs, amiodarone and lorcainide. This is a very new finding and has not been investigated yet in humans; however, this behavior would explain some of the neurologic effects of these two medications.

H3 antihistamines
Amiodarone*
Betahistine
Lorcainide*

 

Thioperamide has shown promise in research as an H3 and H4 antihistamine, but is not available for patient use.

I have seen blurbs on forums and the internet in which people state that amphetamines are H3 antagonists and doxepin is an H4 antihistamine. I cannot find any evidence that this is the case. Amphetamines interact with the transport of histamine in a very complex way, and that can theoretically interfere with the ability of cells to use histamine. However, this is not the same as a true antihistamine, and the effect of amphetamines on histamine has been difficult to quantify.

Anti-inflammatory properties of H1 antihistamines

H1 antihistamines are also known to have anti-inflammatory properties. Some studies show that H1 antihistamines prevent histamine release, which is actually independent of the ability to bind H1 receptors. This effect is thought to occur by interfering with calcium activity on the cell membrane, which may be important in signaling to a cell to release histamine. However, other studies say the amount by which histamine release is reduced is not significant clinically.

H1 antihistamines have also been observed to reduce eosinophil accumulation near allergic sites. This may be due to the ability of H1 antihistamines to interfere with activation of a molecule called NF-kB. This molecule is important in production of inflammatory cytokines. NF-kB can be activated by several inflammatory molecules, including histamine and TNF. Low concentrations of cetirizine and azelastine have been shown to result in lower levels of NF-kB while also inhibiting the production of IL-1b, IL-6, IL-8, TNF and GM-CSF.

Bradykinin is a mediator released by mast cells that causes inflammation, pain and edema. H1 antihistamines such as chlorpheniramine and cetirizine have been reported to inhibit bradykinin induced formation of hives, which may mean that bradykinin triggers hitamine release, which in turn participates in hive formation. However, in testing, the amount of histamine found in these reactions was minimal. This implies that H1 antihistamines may be able to inhibit bradykinin action in another way. H1 antihistamines have also inhibited weal and flare responses by methacholine and platelet activating factor (PAF).

References:

Church, Diana S., Church, Martin K. Pharmacology of antihistamines. World Allergy Organization Journal 2011, 4 (Suppl 3): S22-S27.

Leurs, R., et al. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clinical and Experimental Allergy 32 (2002): 489-498.

Pharmacology of H1 antihistamines

H1 receptors are a type of G-protein-coupled-receptors (GPCRs), and exist in two different conformational states. A conformation is a shape, and the way a receptor is shaped affects its activity. One of the H1 receptor conformations makes it active, so it is effectively the “on” position. The other makes it inactive, so it is effectively the “off” position.

When histamine binds to the H1 receptor, it keeps the receptor in the “on” position. This causes many things to occur. If too many H1 receptors are bound in the “on” position for too long, it can cause airway constriction, difficulty breathing, dilation of blood vessels, hiving, pain and itching, among other symptoms.

In pharmacology, two terms are used to describe the effect a substance has when it binds to a receptor. An agonist fully activates the receptor it binds to. Histamine is an agonist of the H1 receptor because when it binds the receptor, it activates it and thus turns it on. An antagonist binds the receptor but doesn’t turn it on (which is not the same as turning it off). By the antagonist binding the receptor, it prevents histamine from binding there are turning it on.

The medications we use to mediate H1 receptor actions, like diphenhydramine or cetirizine, are often called H1 antagonists, but this is a misnomer. All known medications that act on H1 receptors are more correctly classed as H1 reverse agonists, which is a trickier concept. Basically this means that when these medications bind the H1 receptor, they turn it off. In turn, this prevents a series of actions that are executed by the action of histamine.

First generation H1 antihistamines have a wide ranging group of effects. I have described receptors in the past as being like locks, and the substances that bind them (called ligands) are like keys. In this analogy, first generation H1 antihistamines like diphenhydramine would be like a master key. They are capable of binding to many receptors, including muscarinic, serotonin and a-adrenergic receptors. They also cross the blood-brain barrier. Histamine is an important neurotransmitter with a lot of activity of the brain. By crossing into the brain, these first generation H1 antihistamines can interfere with the sleep-wake cycle, learning, memory, fluid balance, regulation of body temperature, regulation of the cardiovascular system, and stress release of ACTH and b-endorphin from the pituitary.

During the day, first generation H1 antihistamines often cause sleepiness, sedation, drowsiness, fatigue and impaired concentration and memory, even at recommended doses. At night, they delay the onset and reduce the duration of REM sleep. This in turn causes a lower quality sleep, with decreases in attention, vigilance and working memory still observable in the morning.

Second generation H1 antihistamines have largely dealt with the issues present in first generation formulations. Unlike first generation medications, they bind with excellent specificity to the H1 receptor, rather than binding promiscuously. They demonstrate very limited penetration of the blood brain barrier so there is little associated sedation. Desloratadine in the most potent antihistamine, followed by levocetirizine and then fexofenadine.

H1 antihistamines are universally well absorbed with the exception of fexofenadine, which relies on a unique transport mechanism that can be more variable. Studies have shown that in adults, the maximum inhibition of allergic response occurs about four hours after taking levocetirizine, fexofenadine or desloratadine. Loratadine requires metabolism to release the active portion of the molecule, and thus can take hours longer to become efficacious. Fexofenadine has a shorter duration of action at about 8.5 hours, compared to 19 hours for cetirizine at a typical dose.

References:

Church, Diana S., Church, Martin K. Pharmacology of antihistamines. World Allergy Organization Journal 2011, 4 (Suppl 3): S22-S27.

Leurs, R., et al. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clinical and Experimental Allergy 32 (2002): 489-498.

A comprehensive list of antihistamines: H1 receptor (part 2)

Chloropyramine is a first generation H1 antagonist. It is used for allergic eye and nasal symptoms, bronchial asthma, Quincke’s edema, and allergic reactions to food, medications and insect bites. It is available in several European countries as an oral or IV/IM preparation for emergent situations. It has the typical anticholinergic side effects seen in older H1 antihistamines. It is available under several names, including Allergosan, Suprastin, Supralgon and Avapena, in several countries, including Georgia, Hungary, Lithuania, Latvia, Russia, Croatia, Serbia, Bosnia and Herzegovina, Bulgaria and Mexico.

Chlorpheniramine is a first generation H1 alkylamine antihistamine. It is less sedating than other first generation antihistamines. It is sometimes used off label as an antidepressant and anti-anxiety medication as it has serotonin-norepinephrine reuptake inhibiting properties. It is available alone and in various combinations in the US, Canada, throughout Europe and Asia.

Chlorphenoxamine, more commonly known as Systral, is a medication with structural similarities to diphenhydramine. It is mostly used as an anti-Parkinsonian drug and is available in Latin American and Caribbean countries, as well as some European countries and Thailand.

Cinnarizine is an H1 antagonist that functions as both an antihistamine and also as a calcium channel blocker. It is a piperazine derivative. It improves blood flow to the brain and is used for cerebral apoplexy, cerebral symptoms following trauma and cerebral arteriosclerosis. It is also used for nausea and vomiting due to several causes. It is also antiserotinergic and antidopaminergic. Due to its action of dopamine receptors, it can cause parkinsonism if used frequently. It is not available in the US or Canada, but is available under a number of names in many countries, including Brazil, Peru, Philippines, Malaysia, China, Bangladesh, India, and Israel, among several others.

Clemastine is an H1 anthistamine. Though it can be sedating, it has fewer side effects than several other H1 medications. It is also a functional inhibitor of acid sphingomyelinase. It is available in many countries without prescription under brand names such as Tavist, Tavegil or Agasten. It is particularly effective for itching.

Cyclizine is an H1 antihistamine mostly used for nausea, vomiting and dizziness from motion sickness or medications, such as anesthesia. It is also used to potentiate the effects of opiates and opioids. It is a piperazine derivative and is available in the US and UK as IM/IV and oral formulations.

Cyproheptadine is a first generation H1 antihistamine. It is also antiserotonergic and for this reason is used to manage serotonin syndrome. It has a variety of unusual uses, including as a local anesthetic, to treat nightmares in children and due to PTSD, for hyperhidrosis, and to prevent migraine.

Dexbrompheniramine is a widely available medication with structural similarities to chlorpheniramine. It is used to manage general allergic symptoms. It is available in the US and Canada as Drixoral.

Dexchlorpheniramine is the one form of the drug chlorpheniramine. It is available in the US and Canada as Polaramine.

 

A comprehensive list of antihistamines: H1 receptor (part 1)

Alimemazine, also called trimeprazine, is a phenothiazine derivative, placing it in the same class as the more well known promethazine. It is used for a variety of purposes, including antipruritic (prevents itching), sedative, antiemetic, anxiety disorders, organic mood disorders and sleep disorders. It is a first generation H1 antagonist. It is not available for use in the US, but is available in many other countries, including several European countries, Japan, Taiwan, South Africa, Australia, New Zealand and throughout the Middle East.

Azatadine is a first generation H1 antagonist with structural similarities to loratadine. It is available as Zadine in India (note: Zadine is a brand name used in several countries for multiple drugs). It is used to treat allergic symptoms.

Bamipine is a first generation topical H1 antagonist used for itching and allergic rashes. It is sometimes combined with hydrocortisone and sold as a cream or gel. It is available in Austria, Germany and Poland.

Benztropine, also called benzatropine, is a first generation H1 antagonist. It is most commonly used in the treatment of Parkinson’s disease, and Parkinson-like symptoms, particularly tremors. It can also be used to treat dystonia. Benztropine is a widely acting medication. It also acts as a dopamine reuptake inhibitor, which can be helpful in treating narcolepsy and attention disorders, and a functional inhibitor of acid sphingomyelinase, which is sometimes used to treat depression. One study found that benztropine decreased symptoms and encouraged nerve re-myelination in MS patients.

Bepotastine is a non-sedating, second generation H1 antagonist. It is available as an oral and ophthalamic mediction in several Asian countries under the brand name Talion, with ophthalmic preparation only available in the US as Bepreve. Bepotastine has been well studied. In adult models, it inhibited histamine, antigen and PAF induced skin reactions, systemic shock, airway constriction and maintained appropriate vascular permeability. It may also inhibit leukotriene B4, NO production and substance P.

Brompheniramine is a first generation propylamine H1 antagonist. It is used for general allergic symptoms and is found over the counter in many countries. Additionally, it functions as a serotonin and norepinephrine reuptake inhibitor, giving it antidepressant properties. The first SSRI was derived from brompheniramine. It also potentiates the effects of opioid pain medication so less pain medication can be used.

Buclizine is an H1 antagonist derived from piperazine. It is mostly used for nausea. It is available in several countries, including India, Taiwan, Singapore and multiple European nations. In the UK, buclizine is available in a combination migraine medication, Migraleve.

Captodiame is an H1 antagonist derived from diphenhydramine. It is also a serotonin receptor antagonist and dopamine receptor agonist. It has antidepressant effects via a unique mechanism that raises brain-derived neurotrophic factor in the hypothalamus only. It can also mitigate CRF activity in the hypothalamus.

Carbinoxamine is an H1 antagonist readily available in many countries, including in the US. It is often combined with other medications, such as decongestants. It is used for urticarial, angioedema, dermatographism, hay fever and allergic rhinitis and conjunctivitis.

Chlorcyclizine is a first generation H1 antagonist derived from phenylpiperazine. It is used for general allergic symptoms and as an antiemetic. It also has local anesthetic properties and antagonizes serotonin receptors.

Anticholinergic use and dementia

I am going to take a quick break from the Lyme series to discuss something that has a lot of people concerned: whether or not antihistamines cause dementia.

A paper released online this week (“Cumulative use of strong anticholinergics and incident dementia,” by Gray and colleagues, JAMA Internal Medicine) was widely interpreted by the general media as proving that anticholinergic use causes dementia. It doesn’t. Studies like this get a lot of attention by the media – including reputable media – and they get sensationalist headlines.   This is generally not helpful. I think I have established well my distaste for tactics that scare the general public and this is a good example. Whether it is misinterpreted or intentionally misrepresented, news articles reporting on papers like this usually get it wrong.

Let’s look at what the paper actually says.

I actually like studies like this, because they have huge data sets to work with, and scientists usually like big data sets. (I’ll explain why that is in another post.) The study included 3434 patients 65 years of age or older who had no history of dementia when the study began. They were recruited to the study from 1994-1996 and then again from 2000-2003. Patients were followed up with every two years.

The purpose of this study was to determine if cumulative anticholinergic exposure over 10 years was linked to dementia, including Alzheimer’s disease. What is also interesting about this study is that the researchers had access to computerized pharmacy records for all these patients. This is important because it removes the uncertainty associated with patient reported information.   The researchers developed values for anticholinergic medications so that different medications could be compared meaningfully.

A lot of medications are anticholinergic. The more common medications include some antihistamines, tricyclic antidepressants, some antipsychotics, antispasmodics for the GI tract, bladder antimuscarinic medications, and medications used to treat Parkinson’s disease. In various studies, 8-37% of adults over the age of 65 have been found to regularly use anticholinergics. Cognitive disturbances (with memory, attention, “feeling slow,” etc) are well known side effects of anticholinergic medications. Older adults are thought to be more sensitive to these effects because of age related changes to the central nervous system.

Most researchers feel that these cognitive deficits are reversible by discontinuing the offending medication. However, some researchers have found that these deficits may be sustained, culminating in a range of effects from mild cognitive impairment to dementia. These studies had some noted limitations: they did not have solid proof of medication dosages or usage; they did not have information regarding dose or duration of therapy; the follow up periods were short; and they did not account for anticholinergic use to manage insomnia and depression, which can be seen in early, undiagnosed Alzheimer’s. This last one is very important because then the association would not be that anticholinergics cause dementia, but that they are used to manage symptoms of dementia.

The researchers also tried to control for health status, like a self-reported “poor” health status; hypertension; diabetes; APOE gene status; coronary heart disease; depressive symptoms; and benzodiazepine use, among other things. Some of these data were self-reported and some used a proxy, like the use of benzodiazepines for sleep or anxiety disorders.

78.3% of patients filled at least one anticholinergic prescription in the ten years before the study started. Antidepressants, antihistamines and bladder antimuscarinics accounted for more than 90% of all anticholinergic exposure. The most common medications from each of those categories were doxepin, chlorpheniramine and oxybutynin.

23.2% of patients (797 people) developed dementia in a mean period of time of 7.3 years from entry into the trial. 79.9% of those patients (637) were diagnosed with Alzheimer’s disease. This study found that patients in the highest exposure category had a statistically significant increased risk for dementia or Alzheimer’s. Participants in the next highest exposure category had a slightly elevated risk for dementia and Alzheimer’s compared to people who did not use any anticholinergics.

This is the take home message: this study found that people who used higher amounts of anticholinergics had an increased risk of dementia. They found that people with the most exposure took at least one of the following medications daily for more than three years: oxybutynin chloride, 5mg; chlorpheniramine maleate, 4mg; olanzapine, 2.5mg; meclizine hydrochloride, 25mg; doxepin hydrochloride, 10mg.

However, the study does not find that the medications CAUSED dementia. This is really important. It’s important because it’s possible that the conditions that required these medications may be linked to dementia. Or that these medications taken in conjunction with other medications to treat specific conditions might cause the increased risk of dementia. This study found an association. It found that high use of anticholinergics was correlated to increased risk of dementia. It did not find that high use of anticholinergics CAUSED increased risk of dementia. Associations like this are called correlative, not causative.

This study was well done. This was good science. I am a big believer in reducing anticholinergics where possible. I have a lot of lower GI problems and my need for huge doses of anticholinergics pretty much ground my motility to a halt. So I think it’s a good idea to examine medication regimens and reduce anticholinergics if possible, simply for the fact that they cause a lot of side effects.

The reality is that mast cell patients generally cannot avoid taking high doses of anticholinergic medications. I did a previous post on anticholinergic activity of antihistamines, so feel free to refer there. This is a topic I will keep an eye on, but I want to be clear: there is not yet any proof that anticholinergic medications cause dementia or Alzheimer’s disease.

 

References:

Grey, Shelley L., et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015.

Campbell, Noll L., Boustani, Malaz A. Adverse cognitive effects of medications: Turning attention to reversibility. JAMA Intern Med. 2015.

Cai X, et al. Long-term anticholinergic use and the aging brain. Alzheimers Dement. 2013; 9(4):377-385.

Fox C, et al. Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study. J Am Geriatr Soc. 2011;59(8):1477-1483.