Antidementia drugs

Definition

Antidementia drugs are pharmaceutical agents that may slow the progression or otherwise benefit patients with dementia of the Alzheimer's type. Other types of dementia such as post-traumatic, alcoholic, post febrile, toxic, multi-infarct, and others will not normally respond to these treatments.

Description

As of 2008, there were five drugs that had been approved by the United States Food & Drug Administration for treatment of dementia. Memantine is an N-methyl D-aspartate (NMDA) receptor antagonist. It is the only drug in this class, and the only agent approved for moderate to severe dementia.

Memantine appears to act by blocking the effects of glutamate, which is an excitatory neurotransmitter in the central nervous system. There is some belief that constant high levels of glutamate cause the degeneration of nerve cells associated with Alzheimer's dementia. In theory, blocking the reaction of glutamate and the NMDA receptor slows or prevents the progression of dementia, but as of 2008 this had not been confirmed in well-controlled trials.

Although there is no clear demonstration of alteration in disease progression, memantine was approved by the FDA on the basis of three limited studies that showed a retardation of disease progression as compared to placebo. In a press release dated October 17, 2003, the Food & Drug Administration (FDA) stated that the first two six-month long double-blind studies conducted in the United States showed that the patients taking the drug had a lower level of deterioration than the patients taking the placebo. A third 12-week study was conducted on 166 nursing home patients in Latvia. They too also showed slower deterioration on the memantine than the patients taking the placebo. All three studies used several criteria tools to evaluate the effectiveness of memantine.

The remaining drugs approved for use in dementia of the Alzheimer's type are cholinesterase inhibitors:

• Donepezil
• Galantamine
• Rivastigmine
• Tacrine

These drugs are approved for treatment of mild to moderate dementia and all work in the same manner, as competitive inhibitors of acetylcholinesterase. While the cause of Alzheimer's Disease is unknown as of 2008, it is believed to be related to degeneration of nerve cells that produce acetylcholine, leading to low acetylcholine levels in the brain. Since acetylcholine is broken down by the enzyme acetylcholinesterase, blocking the enzyme will maintain higher actylcholine levels and retard disease progression. For most patients the duration of effectiveness of these drugs is limited, since the progressive loss of acetylcholine producing cells results in lower levels of acetylcholine even though the enzyme is blocked. Studies vary, but as a rule, at the end of six months of treatment, roughly half of the patients who have been able to continue anticholinergic therapy at maximum dose levels show either small improvement or no progression in their disease.

Some evidence indicates these drugs may have a secondary mode of action. Galantamine appears to stimulate the release of acetylcholine, whereas rivastigmine may block a second enzyme also responsible for acetylcholine breakdown. Nonetheless, there is no evidence of clinical superiority in any of these drugs, and no demonstrated advantage to combining the acetylcholinesterase inhibitors with each other, although they may be combined with memantine.

The British Health Technology Assessment Programme made repeated efforts to evaluate both the clinical and cost effectiveness of these drugs. After careful review of both published and unpublished studies, the HTA concluded that all drugs were essentially equal in clinical effectiveness. None, however, provided major improvement in function or reduced the need for full time care by less than 2 months over a 5 year period. The evaluation concluded that none of these drugs could be considered cost effective since the cost reductions resulting from their limited benefits were considerably lower than the costs of the medication. In most cases, the benefits last for six months to a year, although some patients show more dramatic and prolonged effects.

The acetylcholinesterase inhibitors and memantine are used to slow the progression of dementia. In addition to these drugs, anti-psychotic agents have been used to control the psychosis and aggressive behavior that is commonly observed among patients with Alzheimer's disease. These drugs are not approved by the Food and Drug Administration for this purpose, and a careful review of the published literature concluded that while two drugs, risperidone and olanzapine, are useful in reducing aggression and risperidone in reducing psychosis, these agents are associated with a high frequency of severe adverse effects, including an elevated risk of death from cardiovascular causes. For this reason, these drugs should not be used to treat patients with dementia unless aggressive behavior is severe enough to represent a risk to the patient and/or caregiver .

The drug tramiprosate, under study as of 2008, had offered a great deal of hope for an advance in treatment of Alzheimer's disease. Preliminary studies had indicated disease stabilization for periods up to 36 months, and the Food & Drug Administration had granted the drug fast-track status. However, on August 26, 2007, Neurochem, the company developing tramiprosate, reported that the Phase III studies of the drug had failed to demonstrate clear benefits. A large part of the problem appears to have been due to variations in how individual study sites interpreted their protocol, both in terms of length of time patients were on the investigational drug and concomitant use of other anti-dementia agents. These variations complicated the statistical analysis so that the results were unclear. The company reported that it was reviewing the study results. In addition, a Phase III study being conducted in Europe was fully enrolled, and the protocol was being reviewed in the hope of avoiding some of the problems seen in the North American study. However, a paper published in September 2007 indicated the possibility that the basis for this research might be unproductive, and patients were cautioned not to use taurine, an amino acid supplement with possible actions similar to tramiprosate, since it might actually accelerate rather than retard disease progression.

Recommended dosage

Dosing should be individualized based on patient response. If adverse reactions are severe, dose adjustments should be discontinued.

• Donepezil: 5 or 10 milligrams taken at bedtime, with or without food. In general, there is no established advantage to the higher dose, but some patients appear to benefit from the higher dose level and so a trial may be justified. It is recommended that patients be on a 5 milligram/day dose for 4 to 6 weeks before increasing the dose.
• Galantamine: Initiate treatment at 4 milligrams twice daily. After a minimum of 4 weeks of treatment the dose may be increased to 8 milligrams twice daily. After a minimum of 4 weeks, the dose may be increased to 12 milligrams twice a day. An extended release formulation is also available, which is used at the same total daily dose levels, but only requires one dose each day.
• Rivastigmine: For Alzheimer's disease, initiate dosing at 1.5 milligrams twice daily, with food. Dose increases may be made at 2 week intervals up to a maximum of 12 milligrams per day. For treatment of dementia associated with Parkinson's disease, the interval between dose adjustments should be 4 weeks. Rivastigmine is available as a transdermal patch that is applied once daily.
• Tacrine: The initial dose is 40 milligrams daily, given as 10 milligrams 4 times a day. Dose may be increased at 4 week intervals to a maximum of 40 milligrams 4 times a day.
• Memantine: The recommended starting dose of memantine is 5 milligrams once daily. The recommended target dose is 20 milligrams/day. The dose should be increased in 5 milligram increments to 10 milligram/day (5 milligrams twice a day), 15 milligrams/day (5 milligrams and 10 milligrams as separate doses), and 20 milligrams/day (10 milligrams twice a day). The minimum recommended interval between dose increases is one week. The product is available in a calendar package that provides the appropriate dose levels based on this dose escalation schedule.

Precautions

There are no specific warnings with regard to these drugs. The only contraindications are hypersensitivity to the drug or any component of the formulation.

Side effects

The adverse effects of the cholinesterase inhibitors are those typically associated with acetylcholine elevations:

• Bradycardia (slowed heart rate)
• Increased gastric acid secretion
• Nausea
• Vomiting
• Loose stools
• Urinary retention
• Seizures, due to the nature of the drug, but seizures may also result from Alzheimer's disease and cannot be distinguished based on cause.

Nausea and vomiting are the most common adverse effects associated with the cholinesterase inhibitors, but these effects can generally be minimized by following the guidelines for adjusting doses. For memantine, dizziness has been the most often reported adverse effect, but most adverse effects have been only 1 to 2% above the rate seen with placebo.

Tacrine has been associated with alterations in liver function. For this reason it has largely fallen into disuse.

Interactions

Neither the acetylcholinesterase inhibitors nor memantine are subject to the most common interactions, including antacids , warfarin, digoxin, or other high-risk drugs. The acetylcholinesterase inhibitors should be expected to have an additive effect with other cholinomimetic agents.

Caregiver concerns

Caregivers are responsible for assuring that the medication is taken reliably. Because patients may be uncooperative, it may be necessary to verify that oral solids have been swallowed. For patients using the rivastigmine transdermal patch, the patch should be applied to the back or other area where removal by the patient is difficult.

KEY TERMS

Acetylcholine —A neurotransmitter that causes cardiac inhibition, vasodilatation, gastrointestinal peristalsis, and other parasympathetic effects.

Cholinomimetic —A drug that causes reactions similar to those produced by acetylcholine.

Dementia —An organic mental disorder characterized by a general loss of intellectual abilities, impaired memory, judgment, and thought processes as well as changes in personality.

Glutamate —An excitatory neurotransmitter in the central nervous system.

Psychosis —A mental disorder marked by loss of awareness of reality.

Transdermal —Through the skin, in context, a patch that delivers medication when it is applied to a skin area.

Observe patient for significant adverse effects, particularly severe constipation and urinary retention. Consider use of high fiber diets or stool softeners to relieve constipation.

Resources

BOOKS

PERIODICALS

Aisen, P. S., et al., “Alzhemed: A Potential Treatment for Alzheimer's Disease.” Curr Alzheimer Res 4, no. 4 (September 2007): 473–478.

Ballard, C., and J. Waite. “The Effectiveness of Atypical Antipsychotics for the Treatment of Aggression and Psychosis in Alzheimer's Disease.” Cochrane Database Syst Rev 25, no. 1 (January 2006): CD003476.

Daiello, L. A. “Current Issues in Dementia Pharmaco-therapy.” Am J Manag Care 13, Suppl. 8 (December 2007): S198–202.

Lecanu, L., and V. Papadopoulos. “Cutting-edge Patents in Alzheimer's Disease Drug Discovery: Anticipation of Potential Future Treatments.” Recent Patents CNS Drug Discov 2, no. 2 (June 2007): 113–123.

Loveman, E., C. Green, J. Kirby, et al. “The clinical and Cost-Effectiveness of Donepezil, Rivastigmine, Galantamine and Memantine for Alzheimer's Disease.” Health Technol Assess 10, no. 1 (January 2006): iii–iv, ix–xi, 1–160.

Maidment, I. D., C. G. Fox, M. Boustani, et al., “Efficacy of Memantine on Behavioral and Psychological Symptoms Related to Dementia: ASystematic Meta-analysis.” Ann Pharmacother 42, no. 1 (January 2008): 32–38.

Miller, L. J. “The Use of Cognitive Enhancers in Behavioral Disturbances of Alzheimer's Disease.” Consult Pharm 22, no. 9 (September 2007): 754–762.

Paraskevas, K. I., A. A. Tzovaras, and D. D. Briana, “Emerging Indications for Statins: A Pluripotent Family of Agents with Several Potential Applications.” Curr Pharm Des 13, no. 35 (2007): 3622–3636.

Roose, S. P. “Identifying and Treating Cognitive Impairments in Elderly Patients.” J Clin Psychiatry 68, no. 12 (December 2007): e31.

Santa-Maria, I., F. Hernandez, J. Del Rio, et al., “Tramiprosate, a Drug of Potential Interest for the Treatment of Alzheimer's Disease, Promotes an Abnormal Aggregation of Tau.” Mol Neurodegener 6, no. 2 (September 2007): 17.

ORGANIZATIONS

Alzheimer's Association, 225 N. Michigan Ave., FlOOR 17, Chicago, IL, 60601–7633, (312) 335–8700, (800) 272–3900, [email protected], http://www.alz.org.

Alzheimer Society of Canada, 20 Eglinton Ave. W, Ste. 1200, Toronto, ON, Canada, M4R1K8, (416) 488–8772, (416) 488–3778, [email protected], http://www.alzheimer.ca.

Sam Uretsky PharmD