Prevent drug-drug interactions with cholinesterase inhibitors

Table 2

DDIs in AD patients: CYP-450 substrates and inhibitors*

	CYP 2D6	CYP 3A4
Substrates (substances metabolized by enzyme)	Second-generation antipsychotics Citalopram Donepezil Duloxetine Galantamine Haloperidol Tricyclic antidepressants Trazodone Venlafaxine	Second-generation antipsychotics Benzodiazepines Buspirone Carbamazepine Donepezil Galantamine Haloperidol Lamotrigine Mirtazapine Nefazodone Sertraline Tricyclic antidepressants Trazodone Zolpidem
Inhibitors	Bupropion Cimetidine Duloxetine Fluoxetine Paroxetine Sertraline	Erythromycin Fluconazole Fluvoxamine Grapefruit juice Itraconazole Nefazodone
*All cytochrome P (CYP) 450 enzymes are induced by barbiturates, phenytoin, carbamazepine, and rifampicin. Smoking also induces CYP 1A2.
DDIs: drug-drug interactions; AD: Alzheimer’s disease
Source: References 3,5,7,8

Pharmacodynamics is the study of the time course and intensity of drugs’ pharmacologic effects. Pharmacodynamic interactions involve changes in a drug’s action at a receptor or biologically active site.³ Pharmacodynamic interactions may result from an antagonistic or synergistic mechanism (Table 3).^3,5,10 Dopamine neurons degenerate with aging, particularly after age 70, and the number of cholinergic receptors decreases in AD patients. As a result, these patients may become more sensitive to antipsychotics, selective serotonin reuptake inhibitors (SSRIs)—which indirectly reduce dopamine outflow—and medications with anticholinergic effects.⁴

Memantine, an amantadine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, is a weak dopaminergic agonist with atropinic effects.¹¹ Because memantine is not metabolized by the CYP-450 pathway, it lacks pharmacokinetic DDIs.¹² However, combining memantine with other NMDA antagonists—such as amantadine or dextromethorphan—could cause hallucinations, dizziness, headache, fatigue, and confusion.¹¹ Concurrent use with drugs that lower seizure threshold, such as tricyclic antidepressants, may increase the risk of seizures.

Table 3

Potential drug-drug interactions in AD patients taking cognitive enhancers

Interaction	Mechanism	Potential sequela(e)
AChEIs + anticholinergics	↓ Acetylcholine in CNS	Cognitive worsening, delirium
AChEIs + beta blockers	Vagal stimulation and sympathetic blockade	Bradycardia, syncope
AChEIs + cholinergics	↑ Acetylcholine in PNS	Cholinergic crisis: hypersalivation, abdominal pain, diarrhea
AChEIs + antipsychotics (rare)	↑ Acetylcholine/↓ dopamine in striatum	Parkinsonian syndrome, rigidity
Ginkgo biloba + warfarin	Antiplatelet aggregation and anticoagulation	Gastrointestinal bleeding, hematuria, subcutaneous ecchymosis
AChEIs: acetylcholinesterase inhibitors; PNS: peripheral nervous system
Source: References 3,5,10

DDIs with cognitive enhancers

Anticholinergics. Because anticholinergic drugs can worsen cognitive impairment and cause delirium they are contraindicated in older patients—especially those with AD. Antihistamines, histamine H2 blockers, low-potency first-generation antipsychotics (FGAs), and tricyclic antidepressants are common medications with anticholinergic effects (Table 4).^5,13,14

Anticholinergics can counteract AChEIs’ beneficial effect. Concurrent use of anticholinergics and AChEIs is fairly common in clinical practice but is rarely appropriate because of pharmacologic antagonism. In a retrospective study of 836 community-living older adults (age ≥65) with probable dementia, Roe et al¹³ compared anticholinergic use in 418 who were taking donepezil with 418 matched controls who were not taking donepezil. They found:

• 33% of those taking donepezil also were receiving anticholinergics, compared with 23% of controls
  
• 26% of all patients in the study used multiple anticholinergic medications.
  

Similarly, a study of pharmacy claims for AChEIs among 557 Medicaid beneficiaries aged ≥50 found that 35% of patients taking AChEIs also received at least 1 anticholinergic drug.¹⁴

Antiparkinsonian agents. Interaction of antiparkinsonian medications with AChEIs could limit the efficacy of either drug when treating comorbid AD and Parkinson’s disease (PD),⁵ although in practice, clinical deterioration of parkinsonism has not been reported.¹⁵ In one study, 25 PD patients stabilized on levodopa/carbidopa were given donepezil, 5 mg/d, or placebo for two 2-week courses separated by a washout of at least 2 weeks. At steady state, pharmacokinetic parameters were unchanged and no clinically significant DDIs were observed.¹⁶

Cardiovascular agents. Concurrent use of AChEIs and beta blockers, calcium channel inhibitors, or digoxin could worsen bradycardia and cause syncope. The risk is higher in patients:

• with sick sinus syndrome or other bradyarrhythmias
  
• taking antipsychotics that could induce torsades de pointes,¹¹ such as ziprasidone or haloperidol.
  

In patients taking these cardiovascular drugs, make sure that heart rate is >60 bpm before AChEI treatment, and monitor regularly.

Other agents. AChEIs inhibit the metabolism of succinylcholine and therefore augment and prolong this drug’s neuromuscular blockade. Discontinue AChEIs before administering succinylcholine for anesthesia, such as for electroconvulsive treatment.

AChEIs may lead to toxicity when added to cholinergic agents such as bethanechol.¹¹ Similarly, AChEIs may precipitate a cholinergic crisis—with increasing weakness, hypersalivation, abdominal pains, and diarrhea—when used in conjunction with peripheral acetylcholinesterase inhibitors such as the myasthenia gravis agents pyridostigmine and neostigmine. The mechanism is increased acetylcholine available at the neuromuscular junction.

Table 4

Medications with moderate to strong anticholinergic activity

Class	Examples
Antiarrhythmics	Disopyramide
Antiemetics	Meclizine
Antiparkinsonians	Benztropine, biperiden, trihexyphenidyl
Antipsychotics	Chlorpromazine, clozapine, olanzapine, pimozide, thioridazine
Antihistamines	Chlorpheniramine, cyproheptadine, diphenhydramine, hydroxyzine, Promethazine
Gastrointestinal/urinary antispasmodics	Atropine, belladonna alkaloids, dicyclomine, hyoscyamine, oxybutynin, scopolamine, tolterodine
H2 histamine	Cimetidine, ranitidine
Muscle relaxants	Cyclobenzaprine
Tricyclic antidepressants	Amitriptyline, amoxapine, clomipramine, doxepin, imipramine, protriptyline
Source: References 5,13,14

DDIs with other psychotropics