Eldepryl

This column focuses on agents used to improve, stabilize, or slow decline in cognitive performance in patients with Alzheimer's disease.

For some time now, nurses have been "warned" about the "costs" associated with an aging America. We use these terms purposefully because the implicit and explicit warnings are ones of concern for the impact (i.e., costs) of this aging phenomenon on society, health care, nursing care, and, most important, the older person. These presentations typically are peppered with demographic statistics that seem troubling on the one hand yet difficult to fully appreciate on the other. For example, a little more than 13% of Americans are over the age of 65, but a full 20% will reach that age by the year 2030. Perhaps what has helped many nurses grasp the significance of this issue is related to our own advancing years. To paraphrase from Pogo's famous utterance, "We have met the demographic variable and it is (or almost) us!"

With the increase in the over-65 cohort, there has been a concomitant increase in the number of people with dementia. Because of the devastating effect of this syndrome and its most common manifestation, Alzheimer's disease (~70% of all dementias), concerted efforts are aimed at developing treatment solutions. The most promising strategies to date are the pharmacologic approaches. The pharmacologic treatment of Alzheimer's disease (AD) addresses both cognitive and behavioral symptoms.

Pathology of AD-Cholinergic Pathways

Cholinergic pathways are selectively destroyed in AD. Because all layers of the cerebral cortex are innervated by cholinergic fibers (-90% arising from the basal nucleus of Meynert in the medial forebrain), loss of cholinergic input eventually causes catastrophic debilitation. Brain areas particularly rich in cholinergic innervation include the amygdala, hippocampus, and upper regions of the cortex. Initial efforts to compensate for cholinergic decline often focused on increasing brain levels of acetylcholine (ACh) by introducing an ACh precursor (e.g., choline, lethicin). This approach never produced the hoped-for results. The most promising antidementia compounds today are those that slow the metabolism of ACh. The four drugs discussed below are classified as cholinesterase (ChE) inhibitors, but first it is important to review enzymes, enzyme inhibition, types of ACh receptors, and types of cholinesterases.

Enzymes, Enzyme Inhibition, Receptors, and Cholinesterases

Enzymes. The energy and building material required for life occur because of biochemical reactions. Biochemical reactions are facilitated by catalysts called enzymes. An enzyme is configured in such a way that only those molecules matching that specific configuration (i.e., the enzymes substrates) can be metabolized by it. A single enzyme performs its metabolic task over and over, and in the case of ChE, metabolizes 5,000 molecules of ACh per ChE molecule per second (Purves et al., 1997). ChE splits the ACh molecule into choline and acetate, rendering it unable to activate cholinergic receptors. In AD there is too little ACh available due to the aforementioned selective cholinergic pathway destruction, thus the effort to "preserve" the remaining ACh is a logical approach to treating cognitive symptoms.

Enzyme inhibition. Nurses are familiar with the concept of enzyme inhibition. Drugs such as the monoamine oxidase (MAO) inhibitors exert their therapeutic effect by blocking enzymatic action on monoamines. The net result of enzyme inhibition is a longer period of "life" for the substrate. ChEs are blocked from catalyzing the metabolism of ACh, thus increasing the number of ACh molecules available to trigger cholinergic receptors in the key areas of the brain previously mentioned.

Types of ACh receptors. There are two types of ACh receptors, nicotinic and muscarinic, both of which have distinct subtypes. Muscarinic M-1 receptors are the most common muscarinic subtype in the brain with highest concentrations found in the cerebral cortex, hippocampus, nucleus accumbens, and a few other areas. Muscarinic receptors also are found peripherally accounting for the anticholinergic side effects common to many drugs. In the brain, nicotinic receptors are found primarily in the thalamus and substantia nigra. Peripheral nicotinic receptors are located at neuromuscular (nicotinic-M) and preganglionic autonomic (nicotinic-N) synapses.

Types of cholinesterase. Knowledge of enzyme subtypes is incorporated into psychiatric nursing practice. For example, the anti-Parkinsonian drug selegiline (Eldepryl) is a selective inhibitor of MAOB while moclobemide (Aurorex) is identified as a reversible inhibitor of MAOA (or a RIMA), a new class of antidepressant. Likewise, ChEs can be divided into the major subtypes acetylcholinesterase (AChE) and butylcholinesterase (BChE). It seems that AChE is more common in neural tissue, whereas BChE is more prominent in peripheral tissue (Rogers, Doody, Mohs, & Friedhoff, 1998). The ideal cognitive-enhancing agent provides selective inhibition of brain AchE without causing the cholinergic side effects associated with peripheral blockade of BChE (e.g., nausea, vomiting, diarrhea, facial flushing, sweating, rhinorrhea, bradycardia, and leg cramping).

The Cognitive-Enhancing Drugs Tacrine

Tacrine (Cognex) was the first ChE inhibitor approved in the United States (in 1993) for treatment of AD. It was synthesized in 1945 and, in combination with morphine, was used to ameliorate pain in cancer patients (Terpstra & Terpstra, 1998). It first attracted widespread attention as an antidementia drug in 1986, when Summers, Majovski, Marsh, Tachiki, and Kling (1986) published their report on its efficacy among AD patients (a dramatic response was reported in 12 of 17 patients). Methodologic flaws were later detected, resulting in a published rebuke, which muted initial enthusiasm for the drug (Keltner, 1994).

Tacrine is a reversible unselective inhibitor of ChE. It accomplishes inhibition by binding near the active site on the enzyme. It has near equal affinity for both AChE and BChE, the latter resulting in a number of adverse responses to the drug. It also may stimulate the release of ACh.

Tacrine is metabolized by the cytochrome P-450 (CYP) isoenzymes 1A2 and 2136. Women routinely exhibit higher serum concentrations (-50%) of this drug, which may be related to gender differences in expression of CYP 1A2 (Samuels & Davis, 1997). Cigarette smoking induces this enzyme and, as might be expected, smokers tend to have lower serum levels when dosage is controlled. Tacrine has a relative short half-life (-3 hours) requiring 4/day dosing patterns. Bioavailability ranges from 17% to 37%. Absorption is hampered if this drug is given with meals. It is moderately bound to plasma proteins (55%) and is excreted in the urine with less than 1% unchanged.

Tacrine use has declined since the mid-1990s because of its hepatotoxic effects. Elevated serum alanine aminotransferase (ALT) levels have been observed in 49% of AD patients treated with tacrine (Nordberg & Svensson, 1998). These hepatic effects, along with the inconvenience of multiple dosing requirements (40-160 mg/day in 4 divided doses), have reduced use of this drug.

Donepezil

Donepezil (Aricept or E2020), a second-generation ChE inhibitor that gained FDA approval in 1996, is a reversible ChE inhibitor using both noncompetitive and competitive mechanisms (Nordberg & Svensson, 1998). At its introduction it was said to represent a major step in dementia treatment because it differed from tacrine in several important ways. These differences include a preference for AChE over BChE by a factor of 1,200 (Geldmacher, 1997). Systemically, this preference results in fewer peripheral side effects compared to tacrine-particularly gastrointestinal effects, because BChE is the prominent ChE in the gut. Further, donepezil does not cause the high rate of hepatotoxicity associated with tacrine.

Pharmacokinetics are another area in which donepezil holds some advantage. It is rapidly absorbed from the gastrointestinal tract, with 100% bioavailability (food does not alter bioavailability), will reach peak plasma levels in 3 to 4 hours. is excreted mostly in the urine and partly in feces, and is highly bound to plasma proteins. Further, its longer half-life (-70 hours) permits once-per-day dosing, which is not possible with tacrine, contributing to treatment adherence. A portion of donepezil is excreted unchanged (~17%) and the remainder metabolized by the CYP-450 2D6 and 3A4 isoenzymes (Nordberg & Svensson, 1998). Donepezil has the potential to interact with other drugs using these pathways.

Major side effects include nausea, vomiting, diarrhea, insomnia, headache, and dizziness (Ross & Shua-- Haim, 1998). Bradycardia (in patients with underlying cardiac problems) and syncope have been reported as well (Keltner & Folks, 2001). Typical dosage is 5-10 mg/day at hour of sleep. In clinical trials, significant dropout occurred at the 10-mg dose.

Rivastigmine

Rivastigmine (Exelon) was approved for the treatment of AD in 2000. It also is a ChE inhibitor, but blocks the enzyme somewhat differently from tacrine or donepezil. While these last two ChE inhibitors cause a reversible inhibition of the enzyme, rivastigmine is said to cause a pseudo-irreversible binding. Because of the way it attaches to the enzyme, rivastigmine actually forms a covalent bond that "lasts" until slowly metabolized. This contributes to the conceptually intriguing phenomenon in which its plasma half-life (2 hours) is considerably shorter than its inhibition half-life (10 hours) (Keltner & Folks, 2001). AChE function is restored 24 hours after cessation of rivastigmine. Rivastigmine is not metabolized via the CYP-450 system and, accordingly, does not interact with drugs metabolized by this system. It is metabolized in its interaction with ChEs.

Rivastigmine differs from tacrine in that it is more selective for AChE than for BChE. Hence, it has fewer and less severe peripheral side effects. Most common effects include nausea, vomiting, and dizziness. Administering it with food reduces side effects (Alagiakrishnan, Wong, & Blanchette, 2000). Rivastigmine is dosed at 6-12 mg/day in two divided doses.

Galantamine

Galantamine (Reminyl) is a reversible, competitive ChE inhibitor with greater affinity for AChE than for BChE. It also modulates brain nicotinic receptors; however, the exact benefit of this activity is far from clear. Two potentially positive effects of nicotinic involvement are the increase in ACh related to presynaptic nicotinic receptor stimulation, and the enhanced effect on nicotinic receptors when galantamine and ACh bind simultaneously (Raskind, Peskind, Wessel, & Yuan, 2000). It is thought that nicotinic receptors play an important role in memory and learning (Tariot et al., 2000).

Galantamine is readily absorbed; it has a bioavailability of -85% and a half-life of about 6 hours (Nordberg & Svensson, 1998). Twice daily dosing is required. It does not bind to plasma proteins. Galantamine is metabolized by CYP 2D6 and has potential interactions with other drugs metabolized by this system. Liver toxicity has not been associated with galantamine. Relatively common side effects include nausea, diarrhea, and anorexia but these can be minimized with careful dose titration.

Summary

AD is a devastating disease that is increasing in real numbers as our population ages. The toll on individuals, families, health care, and society will continue to escalate unless more effective treatment approaches are developed. To date, the most effective treatments are those that increase brain ACh levels by retarding the enzymatic breakdown of this neurotransmitter. These agents have proved modestly effective but are far from being the answer to AD. Further, when these drugs are withdrawn, patients rapidly decompensate to the state of disability suffered by those receiving placebo, indicating the deteriorative process continues unabated. The long-term effects on cognition of these drugs also is not known, but most clinicians are not overly optimistic. Other pharmacologic approaches include vitamin E, ginkgo biloba, estrogen, and the nonsteroidal anti-inflammatory drugs. Clinical trials do not robustly support their efficacy at this time, but there are numerous anecdotal reports to promote any or all of these approaches. Newer strategies under study include antiamyloid agents and nootropics (which enhance neuronal metabolic activity). The value of these approaches remains to be confirmed.

References

Alagiakrishnan, K., Wong, W., & Blanchette, P.L. (2000). Use of donepezil in elderly patients with Alzheimer's disease-A Hawaii based study. Hawaii Medical Journal, 59,57-59.

Geldmacher, D.S. (1997). Donepezil (Aricept) therapy for Alzheimer's disease. Comprehensive Therapy, 23,492-493.

Keltner, N.L. (1994). Tacrine: A pharmacological approach to Alzheimer's disease. Journal of Psychosocial Nursing and Mental Health Services, 320, 37-39.

Keltner, N.L., & Folks, D.G. (2001). Psychotropic drugs Ord ed.). Philadelphia: Harcourt Health Sciences.

Nordberg, A., & Svensson, A. (1998). Cholinesterase inhibitors in the treatment of Alzheimer's disease. Drug Experience, 19, 465-480.

Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., LaMantia, A.S., & McNamara, J.0. (1997). Neuroscience. Sunderland, MA: Sinauer Associates.

Raskind, M.A., Peskind, E.R., Wessel, T., & Yuan, W. (2000). Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology, 54, 2261-2268.

Rogers, S.L., Doody, R.S., Mohs, R.C., & Friedhoff, L.T. (1998). Donepezil improves cognition and global function in Alzheimer's disease. Archives of Internal Medicine, 158,1021-1031.

Ross, J.S., & Shua-Haim, JR. (1998). Aricept-induced nightmares in Alzheimer's disease: 2 case reports (letter). Journal of the American Geriatric Society, 46, 119-120.

Samuels, S.C., & Davis, K.L. (1997). A risk-benefit assessment of tacrine in the treatment of Alzheimer's disease. Drug Safety, 16, 66-77.

Summers, W.K., Majovski, LN., Marsh, G.M., Tachiki, K, & Kling, A. (1986). Oral tetrahydroanfoacridine in long-term treatment of senile dementia, Alzheimer type. New England Journal of Medicine, 315, 1241-1245.

Tariot, P.N., Solomon, P.R., Morris, J.C., Kershaw, P., Lilienfeld, S., & Ding, C. (2000). A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology, 54, 2269-2276.

Terpstra, T., & Terpstra, T. (1998). Treating Alzheimer's disease with cholinergic drugs, Part 1. Nurse Practitioner, 23, 90-102.

Search terms: Alzheimer's disease, donepezil, galantamine, rivastigmine, tacrine

Thank you!

We would like to thank the following people

who, in addition to members of the Editorial Board, reviewed manuscripts in 2000:

Kari Winters, Sherman Oaks, CA Lois Whidly, Orange, CA

Cheryl St. George, Pasadena, CA

Teresa Steele, Husson College, Bangor, ME Helanie Shimei, Montrose, NY

Marie McQueen, Anchorage, AL

Barbara Reynolds Caldwell, Springfield, VA

Norman L. Keltner, EdD, RN

Professor, University of Alabama School of Nursing

Angela L. Zielinski, BSN, RN

Brookwood Medical Center, Birmingham

M. Sloan Hardin, SN

University of Alabama at Birmingham School of Nursing

Author contact: keltnern@son.uab.edu, with a copy to the Editor: mary77@concentric.net

Copyright Nursecom, Inc. Jan-Mar 2001
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