Evidence-Based Reviews

Prevent drug-drug interactions with cholinesterase inhibitors

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Avoid adverse events when prescribing medications for patients with dementia.


 

References

Mr. B, age 78, has a long history of well-controlled bipolar disorder and was diagnosed with Alzheimer’s dementia 6 months ago. He is living at home and has been taking donepezil, 10 mg/d, and lamotrigine, 100 mg bid.

This morning Mr. B’s wife calls and reports that he is experiencing sudden difficulty walking, dizziness, and “feeling drunk.” When you ask about Mr. B’s medications, his wife says that her husband’s internist had prescribed itraconazole, 200 mg/d, for onychomycosis, and Mr. B has taken 1 dose. You promptly discontinue the itraconazole, and Mr. B’s symptoms resolve.

Drug-drug interactions (DDIs) in Alzheimer’s disease (AD) patients such as Mr. B can be serious and even life-threatening. On average, persons age ≥65 use 4.5 prescription agents and 2 over-the-counter preparations per day,1 and the number of concurrently used medications is a significant predictor of adverse drug reactions.2

Cognitive enhancers, including acetylcholinesterase inhibitors (AChEIs) and memantine, are the most widely prescribed agents for AD patients. The FDA has approved galantamine and rivastigmine for mild to moderate dementia, memantine for moderate to severe dementia, and donepezil for mild to severe dementia (Table 1).3-5

To help you minimize adverse DDIs in AD patients, this article describes:

  • pharmacokinetic and pharmacodynamic effects of cognitive enhancers used in AD management
  • DDIs with medications commonly prescribed to AD patients
  • how to avoid adverse events related to antipsychotics, antidepressants, and benzodiazepines.

Table 1

Pharmacokinetic features of cognitive enhancers

AgentProtein bindingCYP-450 activityOther features
AChEIs
  Donepezil96%CYP 2D6, 3A4 substrateOnce-daily dosing
  Rivastigmine40%NoneMetabolized by cholinesterases
  Galantamine18%CYP 2D6, 3A4 substrateNicotinic cholinergic receptor modulation
NMDA receptor antagonist
  Memantine45%NoneNo hepatic metabolism
CYP-450: cytochrome P-450; AChEIs: acetylcholinesterase inhibitors; NMDA: N-methyl-D-aspartate
Source: References 3-5

Pharmacologic changes with aging

Pharmacokinetics is the study of the time course of drugs and their metabolites through the body. Pharmacokinetic interactions involve alterations in the plasma concentration of a drug by a second agent.3

Absorption of medications is decreased in the elderly because of reduced intestinal blood flow and motility. Absorption further decreases if patients concomitantly take antacids, high-fiber supplements, or anticholinergic medications.

Distribution. With aging, lean body mass typically decreases and adipose tissue increases. Because most psychotropics are lipid-soluble, their volume of distribution increases with age. This leads to drug accumulation and longer half-lives. On the other hand, water-soluble medications such as lithium distribute in a smaller volume and pose a higher risk of toxicity.

In plasma, drugs circulate freely or bound to proteins—mainly albumin and α1-acid glycoprotein. Aging can cause decreased plasma albumin and increased α1-acid glycoprotein.6 Additionally, malnutrition, diabetes mellitus, and hepatic and renal disease—all more common with advancing age—may cause hypoalbuminemia, which increases the free fraction of drugs bound to albumin.6Table 1 includes information about cognitive enhancers’ protein binding.

When 2 or more highly protein-bound drugs are coadministered, mutual displacement occurs and the free fraction of each drug increases. A recent case report described valproate toxicity with dizziness, ataxia, and falling in a 76-year-old man after aspirin was added to his regimen.7 The mechanism appeared to be mutual displacement from albumin combined with metabolism of valproate inhibited by aspirin.7

Metabolism. Liver size and hepatic blood flow decrease with aging.6 Cytochrome P-450 3A4 pathway activity slows, but the 2D6 pathway is not affected.4 Oxidative metabolism through CYP pathways is slower, but conjugation reactions are not.6Table 23,5,7,8 lists major substrates and inhibitors of CYP enzymes.

Azole antifungals are potent inhibitors of CYP 3A4,4 of which both donepezil and lamotrigine are substrates (Table 2). In Mr. B’s case, lamotrigine and donepezil levels increased because of this pharmacokinetic interaction. Because donepezil also is metabolized by the CYP 2D6 pathway, the increase in concentration is unlikely to modify the drug effect. Mr. B experienced symptoms consistent with lamotrigine toxicity.

Excretion. The age-associated decline in renal clearance related to a diminished glomerular filtration rate leads to decreased excretion of active metabolites and lithium, making older patients more susceptible to lithium toxicity. The magnitude of the decline in renal clearance varies among patients and is exacerbated by concomitant conditions—such as diabetes and hypertension—and medications—such as nonsteroidal anti-inflammatory drugs (NSAIDs).4 Thiazide diuretics, angiotensin-converting enzyme inhibitors, and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib may elevate lithium levels.3

Pharmacokinetics of AChEIs. AChEIs have relatively few pharmacokinetic interactions, although donepezil and galantamine are metabolized through the liver’s CYP 2D6 and 3A4 pathways.

Because rivastigmine does not undergo hepatic metabolism, it is least likely of the cognitive enhancers to have pharmacokinetic interactions with other medications. Rivastigmine did not lead to increased adverse events when administered concomitantly with 22 different classes of medications—including antidiabetics, cardiovascular drugs, gastrointestinal agents, and NSAIDs.9

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