Kaplan + Sadock's Synopsis of Psychiatry, 11e

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29.14 Cholinesterase Inhibitors and Memantine

Table 29.14-1 Incidence of Major Adverse Side Effects with Cholinesterase Inhibitors (%) Drug Dose (mg/day) Nausea Vomiting Diarrhea Dizziness

Muscle Cramps

Insomnia

Donepezil Donepezil

5

4

3

9

15 13 15 24

9

7 8

10

17 14 48

10

17 10 17

12

Rivastigmine Rivastigmine Galantamine Galantamine Galantamine

1–4

7

NR NR NR NR NR

NR NR NR NR NR

6–12

27

8

5.7

3.6 6.1 9.9

5

NR NR NR

16 24

13.3 16.5

12.2

5.5

NR, not reported from clinical trial data; incidence less than 5%.

Dosage and Clinical Guidelines Before initiation of cholinesterase inhibitor therapy, potentially treatable causes of dementia should be ruled out and the diagno- sis 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. Done- pezil absorption is unaffected by meals. Rivastigmine is available in 1.5-, 3-, 4.5-, and 6-mg cap- sules. 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 adminis- tration 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 spe- cial 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 guide- lines for tacrine-induced ALT listed above should be followed.

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 there- after. Weekly assessments of AST andALT 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 elevatedALT 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. Drug Interactions All cholinesterase inhibitors should be used cautiously with drugs that also possess cholinomimetic activity, such as succi- nylcholine (Anectine) and bethanechol (Urecholine). The coad- ministration 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 cholines- terase 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 phenobar- bital (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 (Couma- din). 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.

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