Prevent drug-drug interactions with cholinesterase inhi...

Prevent drug-drug interactions with cholinesterase inhibitors.

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 Alzheim-
er's disease (AD) patients such as Mr. B
can be serious and even life-threatening.
On average, persons age ≥65 use 4.5 pre-
scription agents and 2 over-the-counter
preparations per day,1 and the number of
concurrently used medications is a signifi-
cant predictor of adverse drug reactions.2

Cognitive enhancers, including ace-
tylcholinesterase inhibitors (AChEIs)
and memantine, are the most widely pre-
scribed agents for AD patients. The FDA
has approved galantamine and rivastig-
mine for mild to moderate dementia, me-
mantine 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 pharmacody-
namic 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
Agent..............Protein binding........CYP-450 activity............Other features

AChEIs
- Donepezil.............96%..................CYP 2D6, 3A4 substrate.....Once-daily dosing
- Rivastigmine........40%..................None.......................................Metabolized by cholinesterases
- Galantamine.........18%.................CYP 2D6, 3A4 substrate.....Nicotinic cholinergic receptor modulation

NMDA receptor antagonist
- Memantine.............45%................None......................................No 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 interac-
tions involve alterations in the plasma con-
centration of a drug by a second agent.3

Absorption of medications is decreased
in the elderly because of reduced intesti-
nal 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 tis-
sue increases. Because most psychotropics
are lipid-soluble, their volume of distri-
bution increases with age. This leads to
drug accumulation and longer half-lives.
On the other hand, water-soluble medica-
tions 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.6 Table 1 includes information
about cognitive enhancers' protein binding.

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


___
Clinical Point
Age-associated
decline in renal
clearance leads to
decreased excretion
of active metabolites
and lithium
___


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

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


________
Table 2

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

CYP 2D6 Substrates (substances metabolized by enzyme):
- Second-generation antipsychotics Second-generation
- Citalopram antipsychotics
- Donepezil Benzodiazepines
- Duloxetine Buspirone
- Galantamine Carbamazepine
- Haloperidol Donepezil
- Tricyclic antidepressants Galantamine
- Trazodone Haloperidol
- Venlafaxine Lamotrigine
CYP 2D6 Inhibitors
- Bupropion
- Cimetidine
- Duloxetine
- Fluoxetine
- Paroxetine
- Sertraline


CYP 3A4 Substrates (substances metabolized by enzyme):
- Second-generation antipsychotics
- Benzodiazepines
- Buspirone
- Carbamazepine
- Donepezil
- Galantamine
- Haloperidol
- Lamotrigine
- Mirtazapine
- Nefazodone
- Sertraline
- Tricyclic antidepressants
- Trazodone
- Zolpidem
CYP 3A4 Inhibitors
- 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
________


___
Clinical Point
Combining
memantine with
other NMDA
antagonists could
cause hallucinations,
dizziness, headache,
and confusion
___


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


Pharmacokinetics of AChEIs. AChEIs
have relatively few pharmacokinetic in-
teractions, although donepezil and galan-
tamine 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 pharmacokinet-
ic interactions with other medications. Riv-
astigmine did not lead to increased adverse
events when administered concomitantly
with 22 different classes of medications—in-
cluding antidiabetics, cardiovascular drugs,
gastrointestinal agents, and NSAIDs.9


Pharmacodynamics is the study of the time
course and intensity of drugs' pharmacolog-
ic effects. Pharmacodynamic interactions in-
volve 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 Do-
pamine neurons degenerate with aging, par-
ticularly after age 70, and the number of cho-
linergic receptors decreases in AD patients.
As a result, these patients may become more
sensitive to antipsychotics, selective sero-
tonin reuptake inhibitors (SSRIs)—which
indirectly reduce dopamine outflow—and
medications with anticholinergic effects.4

Memantine, an amantadine derivative
and N-methyl-D-aspartate (NMDA) re-
ceptor 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 in-
crease the risk of seizures.


________
Table 3

Potential drug-drug interactions
in AD patients taking cognitive enhancers

Interaction
- Mechanism:
- Potential sequela(e):
AChEIs + anticholinergics
- Mechanism: Decr Acetylcholine in CNS
- Potential sequela(e): Cognitive worsening, delirium

AChEIs + beta blockers
- Mechanism: Vagal stimulation and Bradycardia, syncope
sympathetic blockade

AChEIs + cholinergics
- Mechanism: Incr Acetylcholine in PNS
- Potential sequela(e): Cholinergic crisis: hypersalivation,
abdominal pain, diarrhea

AChEIs + antipsychotics (rare)
- Mechanism: Incr Acetylcholine/Decr dopamine in striatum
- Potential sequela(e): Parkinsonian syndrome, rigidity

Ginkgo biloba + warfarin
- Mechanism: Antiplatelet aggregation and anticoagulation
- Potential sequela(e): Gastrointestinal bleeding,
hematuria, subcutaneous ecchymosis

___
AChEIs: acetylcholinesterase inhibitors; PNS: peripheral nervous system
Source: References 3,5,10
________

________
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 blockers: Cimetidine, ranitidine

- Muscle relaxants: Cyclobenzaprine

- Tricyclic antidepressants: Amitriptyline, amoxapine, clomipramine, doxepin, imipramine, protriptyline

___
Source: References 5,13,14
________


___
Clinical Point
Concurrent use of
anticholinergics
and AChEIs is fairly
common but is rarely
appropriate because
of pharmacologic
antagonism
___


DDIs with cognitive enhancers

Anticholinergics. Because anticholinergic
drugs can worsen cognitive impairment
and cause delirium they are contraindi-
cated in older patients—especially those
with AD. Antihistamines, histamine H2
blockers, low-potency first-generation anti-
psychotics (FGAs), and tricyclic antide-
pressants 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, com-
pared 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 benefi-
ciaries aged ≥50 found that 35% of patients
taking AChEIs also received at least 1 anti-
cholinergic 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 parkin-
sonism has not been reported.15 In one
study, 25 PD patients stabilized on le-
vodopa/carbidopa were given donepe-
zil, 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 clini-
cally significant DDIs were observed.16

Cardiovascular agents. Concurrent use of
AChEIs and beta blockers, calcium chan-
nel 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 ziprasi-
done or haloperidol.
In patients taking these cardiovascu-
lar drugs, make sure that heart rate is >60
bpm before AChEI treatment, and monitor
regularly.

Other agents. AChEIs inhibit the me-
tabolism of succinylcholine and therefore
augment and prolong this drug's neuro-
muscular blockade. Discontinue AChEIs
before administering succinylcholine for
anesthesia, such as for electroconvulsive
treatment.

AChEIs may lead to toxicity when add-
ed to cholinergic agents such as bethan-
echol.11 Similarly, AChEIs may precipitate
a cholinergic crisis—with increasing weak-
ness, hypersalivation, abdominal pains,
and diarrhea—when used in conjunction
with peripheral acetylcholinesterase in-
hibitors such as the myasthenia gravis
agents pyridostigmine and neostigmine.
The mechanism is increased acetylcholine
available at the neuromuscular junction.


DDIs with other psychotropics

Antipsychotics. Nearly one-half of AD
patients experience delusions, often in the
middle stage of the disease, and many are
prescribed second-generation antipsychot-
ics (SGAs) to control delusions, hallucina-
tions, sundowning, agitation, or aggression.
Concomitant use of AChEIs and antipsy-
chotics may increase the risk of extrapyra-
midal symptoms by disrupting the acetyl-
choline/dopamine balance in the striatum.5

In AD patients taking donepezil and ris-
peridone, case reports describe parkinso-
nian syndrome and rigidity with immobil-
ity, which resolved after the antipsychotic
was discontinued.5,11 When rivastigmine
and risperidone were coadministered,
however, no clinically relevant adverse in-
teractions were noted in a 20-week, open-
label trial of 65 patients with AD, 10 with
vascular dementia, and 10 with both.17

The FDA has warned of increased risk
of death when SGAs are used to treat
behavioral disturbances in dementia pa-
tients. In a recent meta-analysis of 15
placebo-controlled trials, cognitive tests
scores worsened when AD patients took
aripiprazole, olanzapine, quetiapine, or
risperidone. A significant risk for cerebro-
vascular events was seen, especially with
risperidone, although no clear causal re-
lationship was established.18 Falls, injury,
and syncope were not increased, and pa-
tients with less severe dementia, outpa-
tients, and those selected for psychosis
were less affected. Thus, provide careful
follow-up and avoid long-term unwar-
ranted antipsychotic use in AD patients.


Highly anticholinergic FGAs such as
chlorpromazine are not recommended for
AD patients (Table 4, page 64).

Antidepressants. Up to 30% of AD pa-
tients experience major depression.19 SS-
RIs are the antidepressants most often
used to treat depression and anxiety in
AD patients.

Citalopram, escitalopram, or venla-
faxine are good choices for patients with
AD because of minimal CYP inhibitory
activity.4 Fluvoxamine, fluoxetine, and
paroxetine inhibit CYP 2C9, through
which warfarin and some other drugs
with a narrow therapeutic index are me-
tabolized.6

Benzodiazepines are contraindicated in
elderly patients (especially those with
AD) because of the high risk of delirium,
worsened cognitive function, paradoxical
disinhibition, and falls.20 If benzodiaze-
pines are necessary to control anxiety, use
intermediate-duration agents that do not
undergo oxidative metabolism and have
no active metabolites, such as lorazepam,
oxazepam, or temazepam.19 See Table 2
for more information on benzodiazepine
DDIs.


___
Clinical Point
The herbal
supplement
ginkgo biloba
inhibits platelet
aggregation and
can cause bleeding
complications
___

Herbal supplements. Ginkgo biloba
and huperzine A (Chinese club moss) are
the herbal supplements used most com-
monly by dementia patients. Ginkgo in-
hibits platelet aggregation and can cause
bleeding complications, with or without
concomitant antiplatelet or anticoagulant
therapy such as aspirin, warfarin, and
NSAIDs. Enzyme induction of CYP 2C19
by ginkgo, leading to subtherapeutic levels
of anticonvulsants, has been implicated in
a report of fatal seizures. Huperzine A is a
natural cholinesterase inhibitor and should
not be combined with AChEIs because of
the risk of additive adverse effects.10

________
BOTTOM LINE

Alzheimer's disease patients are at risk for pharmacokinetic and pharmacodynamic
drug-drug interactions (DDIs). When using potent cytochrome P-450 inhibitors, be
aware of medications the patient is taking that are substrates of these enzymes. Avoid
concomitant use of acetylcholinesterase inhibitors (AChEIs) and anticholinergics. Other
DDIs, such as AChEIs with antipsychotics or antiparkinsonian drugs, are rarely clinically
significant. Periodic follow-up and close monitoring of side effects may help prevent
iatrogenic adverse events.
________


________
Related Resources
• Jacobson SA, Pies RW, Greenblatt DJ. Handbook of geriatric
psychopharmacology. Washington, DC: American Psychiatric
Publishing; 2002.

• Sandson, NB. Drug-drug interaction primer. Washington,
DC: American Psychiatric Publishing; 2007.

Drug Brand Names
Amantadine • Symmetrel Hyoscyamine • Anaspaz,
Amitriptyline • Elavil Levbid, Levsin
Amoxapine • Asendin Imipramine • Tofranil
Aripiprazole • Abilify Itraconazole • Sporanox
Atropine • Sal-Tropine Lamotrigine • Lamictal
Benztropine • Cogentin Levodopa/carbidopa •
Bethanechol • Urecholine Sinemet
Biperiden • Akineton Lithium • Eskalith, Lithobid
Bupropion • Wellbutrin Lorazepam • Ativan
Buspirone • BuSpar Meclizine • Antivert
Carbamazepine • Tegretol Memantine • Namenda
Celecoxib • Celebrex Mirtazapine • Remeron
Chlorpheniramine • Nefazodone • Serzone
Chlor-Trimeton Neostigmine • Prostigmin
Chlorpromazine • Thorazine Olanzapine • Zyprexa
Cimetidine • Tagamet Oxazepam • Serax
Citalopram • Celexa Oxybutynin • Ditropan
Clomipramine • Anafranil Paroxetine • Paxil
Clozapine • Clozaril Pimozide • Orap
Cyclobenzaprine • Flexeril Promethazine • Phenergan
Cyproheptadine • Periactin Protriptyline • Vivactil
Dextromethorphan • Benylin, Pyridostigmine • Mestinon
Delsym, others Quetiapine • Seroquel
Dicyclomine • Bentyl Ranitidine • Zantac
Digoxin • Lanoxin Risperidone • Risperdal
Diphenhydramine • Benadryl Rivastigmine • Exelon
Disopyramide • Norpace Scopolamine • Scopace
Donepezil • Aricept Sertraline • Zoloft
Doxepin • Adapin, Sinequan Succinylcholine • Anectine
Duloxetine • Cymbalta Temazepam • Restoril
Escitalopram • Lexapro Thioridazine • Mellaril
Erythromycin • E-Mycin Tolterodine • Detrol
Fluconazole • Diflucan Trazodone • Desyrel
Fluvoxamine • Luvox Trihexyphenidyl • Artane
Fluoxetine • Prozac Valproate • Depakote
Galantamine • Reminyl, Venlafaxine • Effexor
Razadyne Warfarin • Coumadin
Haloperidol • Haldol Ziprasidone • Geodon
Hydroxyzine • Vistaril Zolpidem • Ambien
___
Disclosure
The author reports no financial relationship with any
company whose products are mentioned in this article or
with manufacturers of competing products.
________


References

1. Prescription drugs and the elderly: many still receive
potentially harmful drugs despite recent improvements.
Washington, DC: United States General Accounting Office;
1996. Publication HEHS 95-152.
2. Atkin PA, Veitch PC, Veitch EM, Ogle SJ. The epidemiology
of serious adverse drug reactions among the elderly. Drugs
Aging 1999;14:141-52.
3. Marangell LB, Martinez JM, Silver JM, Yudofsky SC, eds.
Concise guide to psychopharmacology. Washington, DC:
American Psychiatric Publishing; 2002:4-7, 129,173, 171-80.
4. Roose SP, Pollock BG, Devanand DD. Treatment during
late life. In: Schatzberg AF, Nemeroff CB, eds. Textbook of
psychopharmacology. 3rd ed. Washington, DC: American
Psychiatric Publishing; 2004:1083-5.
5. Bentue-Ferrer D, Tribut O, Polard E, Allain H. Clinically
significant drug interactions with cholinesterase inhibitors: a
guide for neurologists. CNS Drugs 2003;17:947-63.
6. Mulsant BH, Pollock BG. Psychopharmacology. In: Blazer
DG, Steffens DC, Busse EW, eds. Textbook of geriatric psychiatry.
3rd ed. Washington, DC: American Psychiatric Publishing;
2004:387-411.
7. Sandson NB, Marcucci C, Bourke DL, Smith-Lamacchia R.
An interaction between aspirin and valproate: the relevance
of plasma protein displacement drug-drug interaction. Am J
Psychiatry 2006;163:1891-6.
8. Spina E, Scordo MG, D'Arrigo C. Metabolic drug interactions
with new psychotropic agents. Fundam Clin Pharmacol
2003;17:517-38.
9. Grossberg GT, Stahelin HB, Messina JC, et al. Lack of adverse
pharmacodynamic drug interactions with rivastigmine and
twenty-two classes of medications. Int J Geriatr Psychiatry
2000;15:242-7.
10. Beier MT. Harmless herbs? Think again: merits of a complete
medication history. J Am Med Dir Assoc 2006;7:446-7.
11. [No authors listed]. Alzheimer's disease: beware of interactions
with cholinesterase inhibitors. Prescrire Int 2006;15:103-6.
12. Grossberg GT, Edwards KR, Zhao Q. Rationale for combining
therapy with galantamine and memantine in Alzheimer's
disease. J Clin Pharmacol 2006;46(suppl 1):S17-S26.
13. Roe CM, Anderson MJ, Spivack B. Use of anticholinergic
medications by older adults with dementia. J Am Geriatr Soc
2002;50:836-42.
14. Carnahan RM, Lund BC, Perry PJ, Chrischilles EA. The
concurrent use of anticholinergics and cholinesterase
inhibitors: rare event or common practice? J Am Geriatr Soc
2004;52:2082-7.
15. Schrag A. Psychiatric aspects of Parkinson's disease. J Neurol
2004;251:795-804.
16. Okereke CS, Kirby L, Kumar D, et al. Concurrent administration
of donepezil HCl and levodopa/carbidopa in patients with
Parkinson's disease: assessment of pharmacokinetic changes
and safety following multiple oral doses. Br J Clin Pharmacol
2004;58(suppl 1):41-9.
17. Weiser M, Rotmensch HH, Korczyn AD, et al. A pilot,
randomized, open-label trial assessing safety and
pharmacokinetic parameters of co-administration of
rivastigmine with risperidone in dementia patients with
behavioral disturbances. Int J Geriatr Psychiatry 2002;17:343-6.
18. Schneider LS, Dagerman K, Insel PS. Efficacy and adverse
events of atypical antipsychotics for dementia: meta-
analysis of randomized, placebo-controlled trials. Am J
Geriatr Psychiatry 2006;14(3):191-210.
19. Koenig HG, Blazer DG. Mood disorders. In: Blazer DG,
Steffens DC, Busse EW, eds. Textbook of geriatric psychiatry.
3rd ed. Washington, DC: American Psychiatric Publishing;
2004:254.
20. Jacobson SA, Pies RW, Greenblatt DJ. Anxiolytic and
sedative-hypnotic medications. In: Handbook of geriatric
psychopharmacology. Washington, DC: American Psychiatric
Publishing; 2002:249-312.

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Seritan AL. Prevent drug-drug interactions with cholinesterase inhibitors. Current Psychiatry 2008; 7(2):57-67.