# 14 - 29.14 Cholinesterase Inhibitors and Memantine

# 29.14 Cholinesterase Inhibitors and Memantine

concentrations early in the course of treatment because hyponatremia may be clinically
silent. In severe cases, confusion and seizure may occur.
Dosing and Administration
Oxcarbazepine dosing for bipolar disorder has not been established. It is available in
150-, 300-, and 600-mg tablets. The dose range may vary from 150 to 2,400 mg per day
given in divided doses twice a day. In clinical trials for mania, the doses typically used
were from 900 to 1,200 mg per day with a starting dose of 150 or 300 mg at night.
Drug Interactions
Drugs such as phenobarbital and alcohol, which induce CYP34A, increase the clearance
and reduce oxcarbazepine concentrations. Oxcarbazepine induces CYP3A4/5 and
inhibits CYP2C19, which may affect the metabolism of drugs that use that pathway.
Women taking oral contraceptives should be told to consult with their gynecologists
because oxcarbazepine may reduce concentrations of their contraceptive and thus
decrease its efficacy.
REFERENCES
Alvarez G, Marsh W, Camacho IA, Gracia SL. Effectiveness and tolerability of carbamazepine vs. oxcarbazepine as mood
stabilizers. Clin Res Reg Affairs. 2003;20:365.
Benedetti A, Lattanzi L, Pini S, Musetti L, Dell’Osso L. Oxcarbazepine as add-on treatment in patients with bipolar manic,
mixed, or depressive episode. J Affect Disord. 2004;79:273.
Ghaemi NS, Ko JY, Katzow JJ. Oxcarbazepine treatment of refractory bipolar disorder: A retrospective chart review.
Bipolar Disord. 2002;4(1):70.
Hartong EG, Moleman P, Hoogduin CA, Broekman TG, Nolen WA. Prophylactic efficacy of lithium versus carbamazepine
in treatment-naive bipolar patients. J Clin Psychiatry. 2003;64:144.
Isojarvi JI, Huuskonen UE, Pakarinen AJ, Vuolteenaho O, Myllyla VV. The regulation of serum sodium after replacing
carbamazepine with oxcarbazepine. Epilepsia. 2001;42(6):741.
Ketter TA, Wang PW, Becker OV, Nowakowska C, Yang YS. The diverse roles of anticonvulsants in bipolar disorders. Ann
Clin Psychiatry. 2003;15:95.
Post RM, Frye MA. Carbamazepine. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of
Psychiatry. 9th ed. Vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2009:3073.
Wagner KD, Kowatch RA, Emslie GJ, Findling RL, Wilens TE, McCague K. A double-blind, randomized, placebo-controlled
trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry.
2006;163(7):1179.
Weisler RH, Kalai AK, Ketter TA. A multicenter, randomized, placebo-controlled trial of extended-release carbamazepine
capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004;65(4):478.
Zhang ZJ, Kang WH, Tan QR, Li Q, Gao CG, Zhang FG. Adjunctive herbal medicine with carbamazepine for bipolar
disorders: A double-blind, randomized, placebo-controlled study. J Psychiatr Res. 2007;41(3–4):360.
 29.14 Cholinesterase Inhibitors and Memantine

Donepezil 
(Aricept), 
rivastigmine 
(Exelon), 
and 
galantamine 
(Reminyl) 
are
cholinesterase inhibitors used to treat mild to moderate cognitive impairment in
dementia of the Alzheimer’s type. They reduce the inactivation of the neurotransmitter
acetylcholine and, thus, potentiate cholinergic neurotransmission, which in turn
produces a modest improvement in memory and goal-directed thought. Memantine
(Namenda) is not a cholinesterase inhibitor, producing its effects through blockade of Nmethyl-d-aspartate (NMDA) receptors. Unlike the cholinesterase inhibitors, which are
indicated for the mild to moderate stages of Alzheimer’s disease, memantine is indicated
for the moderate to severe stages of the disease. Tacrine (Cognex), the first
cholinesterase inhibitor to be introduced, is no longer used because of its multiple daily
dosing regimens, its potential for hepatotoxicity, and the consequent need for frequent
laboratory monitoring. Routine clinical practice often combines a cholinesterase
inhibitor with memantine, and recent studies have shown that this combination may
provide 
beneficial 
response 
compared 
with 
only 
cholinesterase 
inhibitor
pharmacotherapy.
PHARMACOLOGICAL ACTIONS
Donepezil is absorbed completely from the gastrointestinal (GI) tract. Peak plasma
concentrations are reached about 3 to 4 hours after oral dosing. The half-life of
donepezil is 70 hours in elderly persons, and it is taken only once daily. Steady-state
levels are achieved within about 2 weeks. The presence of stable alcoholic cirrhosis
reduces clearance of donepezil by 20 percent. Rivastigmine (Exelon) is rapidly and
completely absorbed from the GI tract and reaches peak plasma concentrations in 1
hour, but this is delayed by up to 90 minutes if rivastigmine is taken with food. The halflife of rivastigmine is 1 hour, but because it remains bound to cholinesterases, a single
dose is therapeutically active for 10 hours, and it is taken twice daily. Galantamine
(Reminyl) is an alkaloid similar to codeine and is extracted from daffodils of the plant
Galanthus nivalis. It is readily absorbed, with maximum concentrations reached after 30
minutes to 2 hours. Food decreases the maximum concentration by 25 percent. The
elimination half-life of galantamine is approximately 6 hours.
Tacrine (Cognex) is absorbed rapidly from the GI tract. Peak plasma concentrations
are reached about 90 minutes after oral dosing. The half-life of tacrine is about 2 to 4
hours, thereby necessitating four-times-daily dosing.
The primary mechanism of action of cholinesterase inhibitors is reversible,
nonacylating inhibition of acetylcholinesterase and butyrylcholinesterase, the enzymes
that catabolize acetylcholine in the central nervous system (CNS). The enzyme inhibition
increases synaptic concentrations of acetylcholine, especially in the hippocampus and
cerebral 
cortex. 
Unlike 
tacrine, 
which 
is 
nonselective 
for 
all 
forms 
of
acetylcholinesterase, donepezil appears to be selectively active within the CNS and has
little activity in the periphery. Donepezil’s favorable side effect profile appears to
correlate with its lack of inhibition of cholinesterases in the GI tract. Rivastigmine
appears to have somewhat more peripheral activity than donepezil and is thus more

likely to cause GI adverse effects than is donepezil.
THERAPEUTIC INDICATIONS
Cholinesterase inhibitors are effective for the treatment of mild to moderate cognitive
impairment in dementia of the Alzheimer’s type. In long-term use, they slow the
progression of memory loss and diminish apathy, depression, hallucinations, anxiety,
euphoria, and purposeless motor behaviors. Functional autonomy is less well preserved.
Some persons note immediate improvement in memory, mood, psychotic symptoms, and
interpersonal skills. Others note little initial benefit but are able to retain their cognitive
and adaptive faculties at a relatively stable level for many months. A practical benefit
of cholinesterase inhibitor use is a delay or reduction of the need for nursing home
placement.
Donepezil and rivastigmine may be beneficial for patients with Parkinson’s disease
and Lewy body disease and for treatment of cognitive deficits caused by traumatic brain
injury. Donepezil is under study for treatment of mild cognitive impairment that is less
severe than that caused by Alzheimer’s disease. People with vascular dementia may
respond to acetylcholinesterase inhibitors. Occasionally, cholinesterase inhibitors elicit
an idiosyncratic catastrophic reaction, with signs of grief and agitation, which is selflimited after the drug is discontinued. Use of cholinesterase inhibitors to improve
cognition by nondemented individuals should be discouraged.
PRECAUTIONS AND ADVERSE REACTIONS
Donepezil
Donepezil is generally well tolerated at recommended dosages. Fewer than 3 percent of
those taking donepezil experience nausea, diarrhea, and vomiting. These mild symptoms
are more common with a 10-mg dose than with a 5-mg dose, and when present, they
tend to resolve after 3 weeks of continued use. Donepezil may cause weight loss.
Donepezil treatment has been infrequently associated with bradyarrhythmias, especially
in those with underlying cardiac disease. A small number of persons experience syncope.
Rivastigmine
Rivastigmine is generally well tolerated, but recommended dosages may need to be
scaled back in the initial period of treatment to limit GI and CNS adverse effects. These
mild symptoms are more common at dosages above 6 mg a day, and when present, they
tend to resolve after the dosage is lowered. The most common adverse effects associated
with rivastigmine are nausea, vomiting, dizziness, headache, diarrhea, abdominal pain,
anorexia, fatigue, and somnolence. Rivastigmine may cause weight loss, but it does not
appear to cause hepatic, renal, hematologic, or electrolyte abnormalities.
Galantamine

The most common side effects of galantamine are dizziness, headache, nausea,
vomiting, diarrhea, and anorexia. These side effects tend to be mild and transient.
Tacrine
Tacrine is the least used of the cholinesterase inhibitors but requires more discussion
than the others because it is cumbersome to titrate and use, and it poses the risk of
potentially significant elevations in hepatic transaminase levels. These increases occur
in 25 to 30 percent of persons. Aside from elevated transaminase levels, the most
common specific adverse effects associated with tacrine treatment are nausea, vomiting,
myalgia, anorexia, and rash, but only nausea, vomiting, and anorexia have been found
to have a clear relation to the dosage. Transaminase elevations characteristically
develop during the first 6 to 12 weeks of treatment, and cholinergically mediated events
are dosage related.
Hepatotoxicity.
 Tacrine is associated with increases in the plasma activities of
alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The ALT
measurement is the more sensitive indicator of the hepatic effects of tacrine. About 95
percent of patients who develop elevated ALT serum levels do so in the first 18 weeks of
treatment. The average length of time for elevated ALT concentrations to return to
normal after stopping tacrine treatment is 4 weeks.
For routine monitoring of hepatic enzymes, AST and ALT activities should be
measured weekly for the first 18 weeks, every month for the second 4 months, and
every 3 months thereafter. Weekly assessments of AST and ALT should be performed for
at least 6 weeks after any increase in dosage. Patients with mildly elevated ALT activity
should be monitored weekly and not be rechallenged with tacrine until the ALT activity
returns to the normal range. For any patient with elevated ALT activity and jaundice,
tacrine treatment should be stopped, and the patient should not be given the drug
again.
Table 29.14-1 summarizes the incidence of major adverse side effects associated with
each of the cholinesterase inhibitors.
Table 29.14-1
Incidence of Major Adverse Side Effects with Cholinesterase Inhibitors (%)
Drug Interactions

All cholinesterase inhibitors should be used cautiously with drugs that also possess
cholinomimetic 
activity, 
such 
as 
succinylcholine 
(Anectine) 
and 
bethanechol
(Urecholine). The coadministration of cholinesterase inhibitors and drugs that have
cholinergic antagonist activity (e.g., tricyclic drugs) is probably counterproductive.
Paroxetine (Paxil) has the most marked anticholinergic effects of any of the newer
antidepressant and anxiolytic drugs and should be avoided for that reason, as well as its
inhibiting effect on the metabolism of some of the cholinesterase inhibitors.
Donepezil undergoes extensive metabolism via both CYP2D6 and 3A4 isozymes. The
metabolism of donepezil may be increased by phenytoin (Dilantin), carbamazepine
(Tegretol), dexamethasone (Decadron), rifampin (Rifadin), and phenobarbital
(Solfoton). Commonly used agents such as paroxetine, ketoconazole (Nizoral), and
erythromycin can significantly increase donepezil concentrations. Donepezil is highly
protein bound, but it does not displace other protein-bound drugs, such as furosemide
(Lasix), digoxin (Lanoxin), or warfarin (Coumadin). Rivastigmine circulates mostly
unbound to serum proteins and has no significant drug interactions.
Similar to donepezil, galantamine is metabolized by both CYP2D6 and 3A4 isozymes
and thus may interact with drugs that inhibit these pathways. Paroxetine and
ketoconazole should be used with great caution.
Laboratory Interferences
No laboratory interferences have been associated with the use of cholinesterase
inhibitors.
Dosage and Clinical Guidelines
Before initiation of cholinesterase inhibitor therapy, potentially treatable causes of
dementia should be ruled out and the diagnosis of dementia of the Alzheimer’s type
established.
Donepezil is available in 5- and 10-mg tablets. Treatment should be initiated at 5 mg
each night. If well tolerated and of some discernible benefit after 4 weeks, the dosage
should be increased to a maintenance dosage of 10-mg each night. Donepezil absorption
is unaffected by meals.
Rivastigmine is available in 1.5-, 3-, 4.5-, and 6-mg capsules. The recommended initial
dosage is 1.5 mg twice daily for a minimum of 2 weeks, after which increases of 1.5 mg
a day can be made at intervals of at least 2 weeks to a target dosage of 6 mg a day,
taken in two equal dosages. If tolerated, the dosage may be further titrated upward to a
maximum of 6 mg twice daily. The risk of adverse GI events can be reduced by
administration of rivastigmine with food.
Galantamine is available in 4-, 8-, and 16-mg tablets. The suggested dose range is 16
to 32 mg per day given twice a day. The higher dose is actually better tolerated than the
lower dose. The initial dosage is 8 mg per day, and after a minimum of 4 weeks, the
dose can be raised. All subsequent dosage increases should occur at 4-week intervals and
should be based on tolerability.

Tacrine is available in 10-, 20-, 30-, and 40-mg capsules. Before the initiation of
tacrine treatment, a complete physical and laboratory examination should be conducted,
with special attention to liver function tests and baseline hematologic indexes.
Treatment should be initiated at 10 mg four times a day and then raised by increments
of 10 mg a dose every 6 weeks up to 160 mg a day; the person’s tolerance of each
dosage is indicated by the absence of unacceptable side effects and lack of elevation of
ALT activity. Tacrine should be given four times daily—ideally 1 hour before meals
because the absorption of tacrine is reduced by about 25 percent when it is taken during
the first 2 hours after meals. If tacrine is used, the specific guidelines for tacrine-induced
ALT listed above should be followed.
MEMANTINE
Pharmacological Actions
Memantine is well absorbed after oral administration, with peak concentrations reached
in about 3 to 7 hours. Food has no effect on the absorption of memantine. Memantine
has linear pharmacokinetics over the therapeutic dosage range and has a terminal
elimination half-life of about 60 to 80 hours. Plasma protein binding is 45 percent.
Memantine undergoes little metabolism, with the majority (57 to 82 percent) of an
administered dose excreted unchanged in urine; the remainder is converted primarily to
three polar metabolites: the N-gludantan conjugate, 6-hydroxy memantine, and 1nitroso-deaminated memantine. These metabolites possess minimal NMDA receptor
antagonist activity. Memantine is a low- to moderate-affinity NMDA receptor
antagonist. It is thought that overexcitation of NMDA receptors by the neurotransmitter
glutamate may play a role in Alzheimer’s disease because glutamate plays an integral
role in the neural pathways associated with learning and memory. Excess glutamate
overstimulates NMDA receptors to allow too much calcium into nerve cells, leading to
the eventual cell death observed in Alzheimer’s disease. Memantine may protect cells
against excess glutamate by partially blocking NMDA receptors associated with
abnormal transmission of glutamate while allowing for physiologic transmission
associated with normal cell functioning.
Therapeutic Indications
Memantine is the only approved therapy in the United States for moderate to severe
Alzheimer’s disease.
Precautions and Adverse Reactions
Memantine is safe and well tolerated. The most common adverse effects are dizziness,
headache, constipation, and confusion. The use of memantine in patients with severe
renal impairment is not recommended. In a documented case of an overdose with up to
400 mg of memantine, the patient experienced restlessness, psychosis, visual

hallucinations, somnolence, stupor, and loss of consciousness. The patient recovered
without permanent sequelae.
Drug Interactions
In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, 2A6,
2C9, 2D6, 2E1, and 3A4) showed minimal inhibition of these enzymes by memantine.
No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.
Because memantine is eliminated in part by tubular secretion, coadministration of
drugs that use the same renal cationic system, including hydrochlorothiazide triamterene
(Dyrenium), cimetidine (Tagamet), ranitidine (Zantac), quinidine, and nicotine, could
potentially result in altered plasma levels of both agents. Coadministration of
memantine and a combination of hydrochlorothiazide and triamterene did not affect the
bioavailability of either memantine or triamterene, and the bioavailability of
hydrochlorothiazide decreased by 20 percent.
Urine pH is altered by diet, drugs (e.g., carbonic anhydrase inhibitors, topiramate
[Topamax], sodium bicarbonate), and the clinical state of the patient (e.g., renal tubular
acidosis or severe infections of the urinary tract). The clearance of memantine is
reduced by about 80 percent under alkaline urine conditions at pH 8. Therefore,
alterations of urine pH toward the alkaline condition may lead to an accumulation of
the drug with a possible increase in adverse effects. Hence, memantine should be used
with caution under these conditions.
Laboratory Interferences
No laboratory interferences have been associated with the use of memantine.
Dosage and Clinical Guidelines
Memantine is available in 5- and 10-mg tablets, with a recommended starting dose of 5
mg daily. The recommended target dose is 20 mg per day. The drug is administered
twice daily in separate doses with 5-mg increment increases weekly depending on
tolerability.
Patients with mild to moderate disease receiving memantine in combination with a
cholinesterase inhibitor have not been found to experience significantly greater benefit
in cognition or overall function than those who receive a cholinesterase inhibitor alone.
REFERENCES
Auchus AP, Brasher HR, Salloway S, Korczyn AD, DeDeyn PP. Galantamine treatment of vascular dementia: A randomized
trial. Neurology. 2007;69:448.
Black SE, Doody R, Li H, McRae T, Jambor KM. Donepezil preserves cognition and global function in patients with severe
Alzheimer’s disease. Neurology. 2007;69:459.
Cummings J, Lefevre G, Small G, Appel-Dingemanse S. Pharmacokinetic rationale for rivastigmine patch. Neurology.
2007;69(4 Suppl 1):S10.