T

Environmental and psychosocial interventions

Depression

Psychos«

Other agtabon

*

1

Citatopram or

Olanzapine or

T

from above

from above

Ruoxe&ne.

rvarAva*

Quet»apine

Citatapram or cafbamazeone

FIGURE 35-2. Treatment algorithm for AD. A. Cognitive treatment. B. Treatment of psychiatric or behavioral symptoms. (AD, Alzheimer's disease; MMSE, Mini Mental Status Examination; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association.) (From Faulkner JD, Bartlett J, Hicks P. Alzheimer's disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005:1164, with permission.)

Table 35-5 Dosing Strategies for Cognitive Agents

Tacrine

Donepezii

ftivastigmine

|J n 1 jn tnrrii ne

Mem amine

■¡CuijncjO

[Aridrpr)

(Exrlonl

(HAÎadyncI'

{Hamrndal

Starting dew

10 mg 4 X daily

S ring daily

Iimg2x daily or 4,2 mg/74 hours appliid did}1 (patcW

4 mg 2 * daily of i mg daily

; mg daily

MarTïnenflniif

jo-.to ting

5-ip ring

3-ti nig 2 v dv\y(x

a-12 mg ï K (tally çy

1Q iwvj ? v. duly

da»

4 if daily

daily

9.S mg/2A iiouis ipfJiiiKliily ijnatihi

1Ö- 54 mg daily

liirH"

A r^WiH^i

J irtit^K l> T il.i :*■: 1

it

l

dose

4 weeks fof palch

odjuilments

Dosage

Oo nor

None

None

Cio not esceed l&nngfcx

Caution should he

adjus(ments

od mi" ist«

nnxtoalely ins wired

taken irpalients

for Jifnal or

In hiYniiir

iKYiHrir tï rswl ruiK ivint

wiTh yrfTf heiwmk"

hepalic

imparrnent

do non administer m severe

Imnairmenf

jrti[>hrEncnE

EL'n.iJtjr hi^pyVii in■::.i nrh'nl

Fnirci filiff, 3ft

Table 35-6 Comparative Common Adverse Effects of AD Medications From Clinical Trial Data0

Tacrine (%] Donep«ll fW| ftlvastlgmlne M Galan^mime pi) Memanilne rc)

ftdvfrt? Even;_fn-6M) (n _(n* UB9I_[n - jjjgj)_(n 9«W

Table 35-6 Comparative Common Adverse Effects of AD Medications From Clinical Trial Data0

Tacrine (%] Donep«ll fW| ftlvastlgmlne M Galan^mime pi) Memanilne rc)

ftdvfrt? Even;_fn-6M) (n _(n* UB9I_[n - jjjgj)_(n 9«W

Elcvaied livfr function

m

Nft

Nfl

NFC

|JjUM.Dor voaniling

2&

NH

NR

NR

NR

Mause?

MR

11

a

NR

^railing

NR

5

31

ï

□iairhua

16

10

19

9

m

Haadacha

11

iO

17

6

6

Diüincvs

6

21

S

7

Musileiramps

9

s

HR

NR

NR

Insomnia

i

9

9

$

MR

Fnöom

4

s

9

S

1

Anorexia

9

1

17

9

NR

3

â

7

NR

Atxiçaiiv»! dri\im\

NR

3

Nft

nr

MR

Weight decrease

Î

1

i

7

MR

Abdominal pain

t

nr

13

$

;nR

Agilolfen

7

MR

NR

NR

Nt

ShrlVltE

S

MR

4

4

MR

Caution « mged «1 making-compiHiions between drugs tusod on those dala, as iifufent cBncal dials often collect feberce Mm data using FrtirnHifi:, S5-39L

Rivastigmine is approved for the treatment of mild-to-moderate dementia of AD at an initial dose of 1.5 mg twice daily; if this dose is tolerated for at least 2 weeks, then the dose can be increased to 3 mg twice daily. Increases to 4.5 mg twice daily and 6 mg twice daily should be attempted only after at least 2 weeks at the previous dose. Tolerability and absorption are improved when the dose is given with food.

Rivastigmine is also available in a patch formulation, with an initial dose of 4.2 mg/24 hours applied once daily. The maintenance dose of the patch is 9.5 mg/24 hours applied once daily. A minimum of 4 weeks of treatment and good tolerability with the previous dose should be observed before consideration of an increase in dose. When switching from the oral formulation to the patch, if the patient is taking less than 6 mg/day of oral, then the 4.2 mg/24 hours patch is recommended. If the patient is taking 6 to 12 mg/day of oral, then the 9.5 mg/24 hours patch is recommended. The first

patch should be applied on the day following the last oral dose.

Cholinergic side effects are common with rivastigmine, but are usually well tolerated if the recommended dosing schedule is followed. If side effects cause intolerance, several doses can be held, then dosing can be restarted at the same or next lower dose. There are no pharmacokinetic drug interactions with drugs metabolized via CYP1A2, 2D6, 3A4/5, 2E1, 2C9, 2C8, or 2C19. Drugs that induce or inhibit

CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Galantamine

© Galantamine is a ChE inhibitor, which elevates Ach in the cerebral cortex by

slowing the degradation of Ach. It also modulates the nicotinic Ach receptors to increase Ach release from surviving presynaptic nerve terminals. In addition, it may increase glutamate and serotonin levels. The clinical benefit of action of these additional neurotransmitters is unknown.

Galantamine is approved for the treatment of mild-to-moderate dementia of AD. It can be dosed once or twice daily (if using the immediate-release tablet or extended-release capsule). The initial dose is 8 mg daily (or 4 mg twice daily) for 4 weeks. If tolerated the dose can be increased if needed to 16 mg daily (or 8 mg twice daily) for at least 4 weeks. Again, if this dose is tolerated, the dose can be increased if needed to 24 mg daily (or 12 mg twice daily).

The adverse reactions associated with galantamine are similar to that observed with the ChE inhibitors.

CYP3A4 and 2D6 are the major enzymes involved in the metabolism of galantam-ine. Pharmacokinetic studies with inhibitors of this system have resulted in increased galantamine concentrations or reductions in clearance. Similarly to donepezil, if inhibitors are given concurrently with galantamine, monitoring for increased choliner-

gic side effects should be done. NMD A Receptor Antagonist Memantine

© Memantine is a noncompetitive antagonist of the NMDA type of glutamate receptors, which are located ubiquitously throughout the brain. It regulates activity throughout the brain by controlling the amount of calcium that enters the nerve cell, a process essential for establishing an environment required for information storage. Overstimulation of the NMDA receptor by excessive glutamate allows too much calcium into the cell, disrupting information processing. Blocking NMDA receptors with memantine may protect neurons from the effects of excessive glutamate without disrupting normal neurotransmission.39

Memantine is indicated for the treatment of moderate-to-severe dementia of the Alzheimer's type. The initial dose is 5 mg/day with increases to 20 mg/day if needed, with a minimum of 1 week between dosage increases. Doses greater than 5 mg/day should be given in two divided doses. A suggested titration is: 5 mg/day for at least 1 week, 5 mg twice daily for at least 1 week, 15 mg/day (5 mg in the morning and 10 mg in the evening) for at least 1 week, then 10 mg twice daily. If the patient has a creatinine clearance of 5 to 29 mL/min, then the target dose should be 5 mg twice daily. It is likely to be given as monotherapy, but can be given in combination with ChE inhibitors.

Adverse reactions associated with memantine include constipation, confusion, dizziness, headache, coughing, and hypertension. Extra monitoring should be done if memantine is given concurrently with a ChE inhibitor.

In vitro studies have shown that memantine produces minimal inhibition of CYP450 enzymes CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. These data indicate that no pharmacokinetic interactions with drugs metabolized by these enzymes should be expected.39

Future Therapies

0 Future therapies for AD may be based on disease-modifying therapies. Current investigations involving the amyloid hypothesis are reviewing various compounds in the secondary prevention of AD. Mechanisms by which these compounds are thought to work include10:

• Decreasing the production of Ap

• Stimulation of clearance of Ap formed

• Prevention of aggregation of Ap into amyloid plaques

• Prevention of neuronal damage by limiting inflammation and neurotoxicity caused by Ap

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