Alzheimer's Disease - Therapeutic agents

Reversible, competitive acetylcholinesterase inhibitors

donepezil  (Aricept ®):
 Indications: mild to moderate dementia of the Alzheimer's type.
Dosing (initial): 5 mg po qd. Usual range: 5 - 10 mg po qd. Because the incidence of untoward effects may be influenced by the rate of dose escalation, treatment with a dose of 10 mg should not be contemplated until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
[Supplied: 5,10mg tabs]

Galantamine  (RAZADYNE™,  Reminyl ® )
Indications: mild to moderate dementia of the Alzheimer's type.
Dosing (initial): 4 mg po bid (tablets) or 8 mg (ER - capsule) qd. After a minimum of 4 weeks of treatment, if this dose is well tolerated, the dose should be increased to 8 mg twice a day (16 mg/day). A further increase to 12 mg twice a day (24 mg/day) should be attempted only after a minimum of 4 weeks at the previous dose. Recommended dosage range: 16-24 mg (e.g. 8-12 mg po bid). Reminyl ® should be administered twice a day, preferably with morning and evening meals.
[Supplied: 4,8,12mg tabs and 8, 16, 24 mg ER capsules]

rivastigmine  (Exelon ®):
 Indications: treatment of mild to moderate dementia of the Alzheimer's type.
Initial dose: 1.5 mg po bid. If this dose is well tolerated, after a minimum of two weeks of treatment, the dose may be increased to 3 mg BID. Subsequent increases to 4.5 mg BID and 6 mg BID should be attempted after a minimum of 2 weeks at the previous dose. If adverse effects such as nausea & vomiting, abdominal pain or loss of appetite cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose level. The maximum dose is 6 mg BID (12 mg/day). Exelon should be taken with meals in divided doses in the morning and evening.
[Supplied: 1.5, 3, 4.5, 6mg caps]

tacrine   (Cognex ®):
 Initial dosing: 10mg po qid. This dose should be maintained for a minimum of 4 weeks with every other week monitoring of transaminase levels beginning 4 weeks after initiation of treatment. It is important that the dose not be increased during this period because of the potential for delayed onset of transaminase elevations.
Dose Titration: Following 4 weeks of treatment at 40 mg/day (10 mg qid), the dose of Cognex® should then be increased to 80 mg/day (20 mg qid), providing there are no significant transaminase elevations and the patient is tolerating treatment. Patients should be titrated to higher doses (120 and 160 mg/day, in divided doses on a qid schedule) at 4-week intervals on the basis of tolerance.
[Supplied: 10,20,30,40mg capsules]
Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist

memantine (Namenda ®):
Indication: moderate to severe alzheimer's dementia. (Persistent activation of N-methy-D-asparatate (NMDA) receptors by excitatory amino acid glutamate has been hypothesized to contribute to the symptoms of AD).

Starting dose: 5 mg orally once daily, with an eventual target dose of 10 mg orally twice daily (20mg/day). The dose should be increased at 5 mg increments (wait at least 1 week between dosage increments). Sample regimen: 5 mg once daily --> (7 days later) 5 mg orally twice daily --> (7 days later) 5 mg in the morning and 10 mg in the evening, etc. Reduce dose in patients with moderate renal insufficiency and AVOID use in patients with severe renal insufficiency.
[Supplied: 5mg , 10mg tablets]

Combination therapy / Other:
Manju T. Beier, PharmD, FASCP, Elaine R. Peskind, MD, Mark Sey, RPh, CGP, FASC. March 2004. Optimizing Care Management Plans Across the Spectrum of Alzheimer's Disease. Source: (Clinical Geriatrics) http://www.hmpcommunications.com/cg/displayArticle.cfm?articleID=cgsupp1952

"Treatment guidelines from the AAN recommend cholinesterase inhibitors in patients with mild-to-moderate Alzheimer’s disease, where symptomatic benefit is seen in 20-30% of patients, and 70-80% stabilize.41 Vitamin E can be taken as 1000 IU twice a day. Selegiline is second-line therapy because vitamin E was numerically superior in the Sano et al trial,20 and selegiline does have side effects.41 Nonsteroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 inhibitors, and estrogen do not have sufficient supportive data and are not advocated by the AAN at this time for the treatment of already-established dementia.41 Patients with unspecified dementia may benefit from Gingko biloba, but evidence-based efficacy data are insufficient.

In summary, cholinergic agents are considered first-line treatment in patients with mild-to-moderate AD because they have been in use the longest. These drugs initially improve and transiently maintain cognitive abilities. Cognitive abilities worsen over time, indicating that treatment does not stop but may delay the progression of Alzheimer’s disease. Recently-approved memantine is now recommended for the treatment of moderate-to-severe dementia of the Alzheimer’s type as monotherapy or in combination with AChE inhibitors.

The dual-therapy study showed that combination memantine and donepezil demonstrated superior efficacy to treatment with donepezil alone. Severely impaired nursing home patients showed improvement on both functional and global measures, as well as reduced care dependence. "
 

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David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.

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