Biological perspectives: Drugs used for cognitive symptoms of Alzheimer's disease

Perspectives in Psychiatric Care, Jan-Mar 2001 by Keltner, Norman L, Zielinski, Angela L, Hardin, M Sloan

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).