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Savvy Psychopharmacology


How to manage your patient’s dementia by discontinuing medications

Vol. 9, No. 7 / July 2010

Mrs. J, age 75, has moderate Alzheimer’s dementia and lives at home with her husband. Since her Alzheimer’s disease (AD) diagnosis 2 years ago, Mrs. J generally has been cooperative and not physically aggressive, but has experienced occasional depressive symptoms. However, Mr. J reports that recently his wife is becoming increasingly confused and agitated and wanders the house at night. His efforts to calm and coax her back to bed often lead to increased agitation and yelling. On 1 occasion Mrs. J pushed her husband. Mr. J is concerned that if these behaviors continue he may not be able to care for her at home. Mr. J read online that antipsychotics might reduce aggressive behavior, but is concerned about the increased risk of mortality and stroke with these medications.

Mrs. J receives donepezil, 10 mg/d, sertra-line, 50 mg/d, and extended-release oxybutynin, 10 mg/d. Her over-the-counter (OTC) medications include acetaminophen, 650 mg as needed for pain, ranitidine, 150 mg/d, and docusate sodium, 100 mg/d. Several nights last week, Mr. J gave his wife an unknown OTC sleep medication, hoping it would stop her nighttime wandering, but it did not help. Physical examination, laboratory testing, and urine culture are all normal.

Practice Points

  • During the initial evaluation of cognitive complaints, look to discontinue medications that may cause cognitive impairment, including anticholinergics.
  • In addition to worsening cognitive impairment, anticholinergic medications may contribute to behavioral disturbances, psychosis, and delirium in patients with dementia.
  • Side effects of acetylcholinesterase inhibitors can prompt anticholinergic use, which is likely to negate the beneficial effects of the acetylcholinesterase inhibitor.
  • Nonpsychiatric medications, including over-the-counter drugs, can have anticholinergic properties. Consult with nonpsychiatric clinicians to discontinue inessential medications that may be harmful for dementia patients.

Most dementia patients experience neuropsychiatric disturbances, especially at later stages, that often lead to caregiver distress and nursing home placement. Although these symptoms may signal progressing dementia, environmental factors, medical conditions, and medications may worsen functioning and should be considered in the assessment.1

Mrs. J has no medical problems that were identified as possible triggers for her behavior. Mr. J’s interference with his wife’s wandering could have increased her agitation, but he is gentle toward her and she has become agitated with no apparent trigger. “Sundowning” and poor sleep also may be involved, as sleep deprivation can lead to delirium and worsen cognitive deficits and behavioral problems.1 Depression also should be considered.1 Finally, Mrs. J is taking several medications with anticholinergic properties—oxybutynin, ranitidine, and an unknown OTC sleep medication, which likely contains diphenhydramine or doxylamine—that might contribute to her agitation.

Patients with dementia are highly sensitive to the cognitive and psychiatric adverse effects of anticholinergic medications. In studies of patients with mild or moderate Alzheimer’s dementia who received the potent anticholinergic scopolamine, adverse effects included:

  • memory impairment
  • restlessness
  • disjointed speech
  • motor incoordination
  • drowsiness
  • euphoria
  • agitation
  • hallucinations
  • hostility.

Many of these effects worsened with increasing doses.2,3 Age-matched controls experienced less severe memory impairment and no behavioral symptoms, which suggests that dementia-related damage to the cholinergic system leads to increased sensitivity to anticholinergics.

A cross-sectional study of 230 patients with AD identified anticholinergic use as a risk factor for psychosis (odds ratio 2.13, 95% confidence interval, 1.03 to 4.43), after adjusting for age and cognition.4 Among patients receiving 2 or 3 anticholinergics, 69% had psychotic symptoms compared with 48% of those receiving 1 anticholinergic and 32% of those receiving no anticholinergics.4 Anticholinergic overdoses can cause psychotic symptoms and delirium. A subtle presentation of delirium from prescribed anticholinergics may be confused with worsening dementia.1 The sum of the evidence suggests that drugs with anticholinergic effects can contribute to agitation and psychosis in dementia.

When to discontinue

When diagnosing dementia it is important to address other potential causes of cognitive impairment, including medications. Approximately one-third of patients with dementia receive anticholinergic drugs, which suggests that providers often do not recognize the potential for harm with these medications.5 After patients receive acetylcholinesterase inhibitors (AChEIs)—which are used to enhance cognition in dementia patients—increased anticholinergic use may follow, often to treat adverse effects of AChEIs.5 This may negate the benefits of AChEIs and pose risk of further harm from the anticholinergics.1,5 Although any time is a good time to discontinue an inessential anticholinergic in a patient with dementia, providers might consider screening for these drugs at the initial diagnosis, after initiating a cholinesterase inhibitor or increasing a dose, or if the patient develops psychotic or behavioral symptoms.

For Mrs. J, ranitidine and oxybutynin likely were used to treat gastrointestinal complaints and urinary frequency, which are known adverse effects of AChEIs. Many OTC preparations for insomnia, respiratory symptoms, and allergies contain older, anticholinergic antihistamines. Advise caregivers of dementia patients about possible adverse effects of OTC medications to prevent anticholinergic exposure. The Table provides a partial list of medications thought to have clinically significant anticholinergic effects.

‘Pharmacologic debridement’ refers to tapering and discontinuing medications that are no longer necessary or appropriate. Prescribers often are hesitant to discontinue medications prescribed by other clinicians and may assume that a medication used long term has been tolerated and helpful. However, as patients age—particularly if they develop dementia—their ability to tolerate a medication can change. Patients with dementia also may have difficulty attributing adverse experiences to medications and communicating these effects to providers. Some medical providers may not recognize adverse psychiatric and cognitive effects of the nonpsychiatric medications they prescribe because they do not have sufficient dementia expertise. Consulting with these providers may help determine the risk-benefit considerations of these medications.

Generally, anticholinergics should be discontinued if they are not essential to a patient’s health or if safer non-anticholinergic alternatives are available.5 Tapering may be necessary to prevent adverse effects from cholinergic rebound if a potent anticholinergic has been used chronically.5 The first step in addressing Mrs. J’s agitation is to discontinue the anticholinergic medications and monitor her symptoms. This pharmacologic debridement may avert the use of antipsychotics, which carry serious risks for dementia patients.1

Table
Drugs with clinically significant anticholinergic effects*

Drug class

Medication(s)

Anticonvulsants

Carbamazepine

Antidepressants

Amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, paroxetine, protriptyline, trimipramine

Antihistamines

Azelastine nasal spray, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, hydroxyzine, mepyramine olopatadine nasal spray, phenyltoloxamine, promethazine, triprolidine

Antiparkinsonian agents

Benztropine, procyclidine, trihexyphenidyl

Antipsychotics

Chlorpromazine, clozapine, loxapine, molindone, olanzapine, pimozide, promethazine, quetiapine, thioridazine

Asthma and chronic obstructive pulmonary disease medication

Glycopyrrolate, ipratropium, tiotropium

Bladder antispasmodics

Darifenacin, flavoxate, oxybutynin, solifenacin, tolterodine, trospium

Gastrointestinal antispasmodics

Atropine, belladonna alkaloids, clidinium, dicyclomine, hyoscyamine, methscopolamine, propantheline

Insomnia medications

Diphenhydramine, doxylamine

Motion sickness/dizziness/nausea medications

Dimenhydrinate, meclizine, prochlorperazine, promethazine, scopolamine, trimethobenzamide

Muscle relaxants and pain medications

Cyclobenzaprine, meperidine, orphenadrine, phenyltoloxamine

Ulcer and acid reflux agents

Cimetidine, glycopyrrolate, ranitidine

*Not a comprehensive list
Unknown whether CNS effects are important Source: Reference 5

Related Resources

  • Cancelli I, Beltrame M, D’Anna L, et al. Drugs with anticholinergic properties: a potential risk factor for psychosis onset in Alzheimer’s disease? Expert Opin Drug Saf. 2009;8(5):549-557.
  • Meeks TW, Jeste DV. Beyond the black box: what is the role for antipsychotics in dementia? Current Psychiatry. 2008;7(6): 50-65.
  • Centers for Education and Research on Therapeutics. Anticholinergic pocket reference card. www.chainonline.org/home/content_images/Anticholinergic%20Pocket%20Card%20CLR%203_12_10.pdf.

Drug Brand Names

  • Amitriptyline • Elavil
  • Atropine • Sal-Tropine
  • Azelastine nasal spray • Astelin
  • Belladonna alkaloids • Donnatal
  • Benztropine • Cogentin
  • Brompheniramine • Dimetane
  • Carbamazepine • Carbatrol, Tegretol, others
  • Carbinoxamine • Palgic
  • Chlorpheniramine • Chlor-Trimeton
  • Chlorpromazine • Thorazine
  • Cimetidine • Tagamet
  • Clemastine • Tavist
  • Clidinium • Quarzan
  • Clomipramine • Anafranil
  • Clozapine • Clozaril
  • Cyclobenzaprine • Flexeril
  • Cyproheptadine • Periactin
  • Darifenacin • Enablex
  • Desipramine • Norpramin
  • Dexbrompheniramine • Drixoral
  • Dexchlorpheniramine • Polaramine
  • Dicyclomine • Bentyl
  • Dimenhydrinate • Dramamine
  • Diphenhydramine • Benadryl, Sominex, others
  • Docusate Sodium • Colace
  • Donepezil • Aricept
  • Doxepin • Adapin
  • Doxylamine • Aldex, Unisom, others
  • Flavoxate • Urispas
  • Glycopyrrolate • Robinul
  • Hydroxyzine • Atarax
  • Hyoscyamine • Cystospaz, Levbid
  • Imipramine • Tofranil
  • Ipratropium • Atrovent
  • Loxapine • Loxitane
  • Meclizine • Antivert
  • Meperidine • Demerol
  • Mepyramine • Anthisan
  • Methscopolamine • Pamine
  • Molindone • Moban
  • Nortriptyline • Aventyl
  • Olanzapine • Zyprexa
  • Olopatadine nasal spray • Patanase
  • Orphenadrine • Norflex
  • Oxybutynin extended-release • Ditropan XL
  • Paroxetine • Paxil
  • Phenyltoloxamine • Dologesic, Durayin, others
  • Pimozide • Orap
  • Prochlorperazine • Compazine
  • Procyclidine • Kemadrin
  • Promethazine • Phenergan
  • Propanthelin • Pro-Banthine
  • Protriptyline • Vivactil
  • Quetiapine • Seroquel
  • Ranitidine • Zantac
  • Scopolamine • Scopace
  • Sertraline • Zoloft
  • Solifenacin • VESIcare
  • Thioridazine • Mellaril
  • Tiotropium • Spiriva
  • Tolterodine • Detrol
  • Trihexyphenidyl • Artane
  • Trimethobenzamide • Tigan
  • Trimipramine • Surmontil
  • Triprolidine • Actifed
  • Trospium • Sanctura

Acknowledgements

This work was supported by an Agency for Healthcare Research and Quality (AHRQ) Centers for Education and Research on Therapeutics cooperative agreement #5 U18 HSO16094.

Disclosure

Dr. Carnahan receives grant/research support from the Agency for Healthcare Research and Quality.

References

1. Swanson KA, Carnahan RM. Dementia and comorbidities: an overview of diagnosis and management. J Pharm Pract. 2007;20:296-317.

2. Sunderland T, Tariot P, Murphy DL, et al. Scopolamine challenges in Alzheimer’s disease. Psychopharmacology (Berl). 1985;87(2):247-249.

3. Sunderland T, Tariot PN, Cohen RM, et al. Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls. A dose response study. Arch Gen Psychiatry. 1987;44(5):418-426.

4. Cancelli I, Valentinis L, Merlino G, et al. Drugs with anticholinergic properties as a risk factor for psychosis in patients affected by Alzheimer’s disease. Clin Pharmacol Ther. 2008;84(1):63-68.

5. Carnahan RM, Lund BC, Perry PJ, et al. The concurrent use of anticholinergics and cholinesterase inhibitors: rare event or common practice? J Am Geriatr Soc. 2004;52:2082-2087.

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