Dementia, especially Alzheimer’s disease (AD), is a chronic and usually progressive condition. Various types of dementia, including AD, affect more than 5 million people in the United States, and the prevalence increases with age (Plassman et al., 2007). Because dementia is a leading cause of age-related disability and placement in long-term care facilities, the development of effective treatments for dementia and milder cognitive impairment has very important public health implications. In this article, I review several classes of drug therapies used for the treatment of cognitive impairment and dementia.
Acetylcholinesterase Inhibitor Drugs
The neurotransmitter acetylcholine is involved in cognitive processing, arousal, and attention. The effects of acetylcholine on cholinergic transmission are terminated by the action of cholinesterases (enzymes that metabolize acetylcholine). Acetylcholinesterase inhibitor drugs block the effects of this enzyme, and they are used clinically to boost cholinergic function.
Currently available acetylcholinesterase inhibitor drugs include tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®, Exelon Patch®), and galantamine (Reminyl®, Razadyne®) (Sadock, Sadock, & Sussman, 2006). All are approved by the U.S. Food and Drug Administration (FDA) for the treatment of cognitive impairment in AD, which is characterized in part by the selective loss of cholinergic neurons in the brain. They also are commonly used for all forms of dementia. These drugs do not halt or correct the underlying degenerative process in dementia, but they can slow the progression of memory impairment and secondarily diminish the apathy, depression, anxiety, hallucinations, agitation, and other associated psychological and behavioral problems in these patients.
Potential adverse effects of these drugs include nausea, vomiting, dizziness, headache, diarrhea, abdominal pain, anorexia, fatigue, sedation, and muscle cramps. Use of cholinesterase inhibitor drugs is associated with increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia (Gill et al., 2009). Donepezil is generally better tolerated than the other drugs. Tacrine is poorly tolerated by many patients and can cause liver toxicity.
Glutamate is the major excitatory amino acid neurotransmitter in the brain. Glutamate is important in many normal and abnormal physiological processes, including neurotrophism (neuronal growth and maintenance), cognition (learning and memory), and neurodegeneration (neuronal damage or death) (Howland, 2007). Glutamate systems have been directly or indirectly implicated in various neurodegenerative disorders, including AD. Glutamate is released from neurons, binds to receptors, and is removed by reuptake transporters. Glutamate receptor systems are very complex, and they can be segregated into various distinct receptor subtypes according to their molecular and pharmacological properties. One important type of glutamate receptor is the N-methyl-D-aspartate (NMDA) receptor, which has multiple subtypes.
Memantine (Namenda®) is an FDA-approved treatment for AD, and it has been investigated in other cognitive and neurodegenerative disorders (Howland, 2007). Memantine is not an acetylcholinesterase inhibitor, but it is a weakly binding NMDA receptor antagonist. The rationale for using memantine in AD is based on the belief that persistent glutamate activation of NMDA receptors contributes to neuronal cell death and the symptoms of AD. Memantine inhibits the damaging effects of excessive glutamate by blocking the NMDA receptor. It does not affect the inhibitory amino acid gamma-aminobutyric acid (GABA) or other neurotransmitter receptors. Possible adverse effects include dizziness, headache, constipation, and confusion, but it is not associated with serious adverse neuropsychiatric effects.
Nootropic agents refer to a class of drugs that are purported to improve cognitive function. These types of drugs have also been called “smart drugs,” memory enhancers,” and “cognitive enhancers.” However, the term nootropic was first used to describe the cognitive effects of the compound piracetam, which was synthesized in 1964, and nootropic agents most specifically describe the larger class of drugs that are chemically related to piracetam (Malykh & Sadaie, 2010). Piracetam and piracetam-like drugs are cyclic derivatives of GABA. The precise mechanism of action of these drugs is unclear, but they have anticonvulsant and antioxidant properties, may enhance the function of cholinergic receptor systems, and might modulate glutamate receptor systems.
Piracetam is manufactured outside of the United States under various trade names (Nootropil®, Nootrop®, Nootropyl®). In the United States, the drug is designated by the FDA as an orphan drug for the treatment of myoclonus. Myoclonus is a type of epilepsy that is characterized by brief involuntary muscle twitching. Orphan drugs are designated as such for the treatment of rare diseases or conditions (FDA, 2009a). Piracetam is not otherwise regulated by the FDA, and it can be obtained in the United States without a prescription.
A meta-analysis of 19 double-blind, placebo-controlled studies in a diverse group of patients with age-related dementia or cognitive impairment demonstrated a significant benefit for piracetam (Waegemans et al., 2002). However, this benefit was based on the outcome measure of clinical global impression of change, rather than other standard measures of cognitive function. The long-term effects of piracetam in these patients are not known.
Possible adverse effects of piracetam include anxiety, insomnia, irritability, headache, agitation, tremor, and nausea. Elevations of liver enzymes have been reported rarely. Because the drug is cleared through the kidneys, patients with impaired renal function have a higher risk of adverse effects. Abrupt discontinuation can be associated with seizures.
There are more than a dozen nootropic agents, but none have been as well studied as piracetam. Levetiracetam (Keppra®) is currently the only nootropic agent that is FDA approved. Levetiracetam is the S-enantiomer of the racemate drug etiracetam (Howland, 2009a, 2009b). Etiracetam is structurally similar to piracetam. Levetiracetam is FDA approved as adjunctive therapy for partial seizures, generalized seizures, and myoclonic seizures. The drug appears to have fewer adverse cognitive effects compared with other anticonvulsant drugs. It has not been well studied for cognitive impairment or dementia, but an ongoing clinical trial is investigating its use for mild cognitive impairment ( http://www.clinicaltrials.gov/ct2/show/NCT01044758?term=Levetiracetam&rank=81). Common adverse effects of levetiracetam are dizziness, somnolence, weakness, and irritability. Behavioral changes, hallucinations, and psychosis have been reported.
Ginkgo biloba is obtained from the leaves of the Ginkgo biloba tree, formerly known as Salisburia adiantifolia. It is used alone or is sometimes added as a supplement in various “natural” food products. It has antioxidant, anti-inflammatory, and anti-platelet effects. Because ginkgo produces arterial vasodilation, inhibits arterial spasms, decreases blood viscosity, and increases tissue perfusion and cerebral blood flow, it has been used and studied for peripheral vascular insufficiency, cerebrovascular disease, mild cognitive impairment, dementia, and sexual dysfunction. Early clinical trials for AD, vascular dementia, and mild memory and cognitive impairment found modest but inconsistent benefits for ginkgo compared with placebo on some cognitive and psychosocial outcome measures (Birks & Grimley Evans, 2009). A recent double-blind, randomized trial found that it was not effective in preventing or treating dementia (DeKosky et al., 2008). A second double-blind, randomized trial found it also not effective for preventing cognitive decline in older adults (Snitz et al., 2009).
Common side effects are nausea, vomiting, diarrhea, headache, irritability, and dizziness. Bruising and bleeding may occur, with rare reports of serious intracranial bleeding (e.g., subdural hematoma). Seizures have been reported in children who ingested large amounts. Potential drug interactions include anticoagulant and anti-platelet drugs (e.g., aspirin and other nonsteroidal anti-inflammatory medications). Ginkgo may affect liver metabolic enzymes, but this has not been extensively investigated.
Axona® is designated by the FDA as a medical food (Accera, Inc., 2009). A medical food is defined as:
a food which is formulated to be consumed or administered enterally [or orally] under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.
Medical foods are exempt from FDA labeling requirements for health claims and nutrient content, and they are not reviewed or approved by the FDA. They must comply with good manufacturing practice regulations and labeling practices for protection against food allergens.
Axona contains a proprietary formulation of medium-chain triglycerides (mostly caprylic triglyceride). It is currently being marketed for the “clinical dietary management of the metabolic processes associated with mild to moderate Alzheimer’s disease” (Accera, Inc., 2009, para. 1). The rationale for the use of Axona is based on the finding that cerebral hypometabolism (i.e., impaired glucose metabolism) is an early sign of AD. Medium-chain triglycerides are metabolized in the liver, resulting in the production of the ketone body beta-hydroxybutyrate. Beta-hydroxybutyrate is transported into the brain and provides an alternative fuel source for cerebral metabolism.
A randomized, placebo-controlled, crossover study in 15 patients with AD and 5 patients with mild cognitive impairment found that a single oral dosage of Axona produced an increase in serum ketones and an immediate statistically significant improvement in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) (Reger et al., 2004). More recently, a double-blind, randomized, 90-day, placebo-controlled trial in 152 patients with mild to moderate AD found a significant improvement in the ADAS-cog in patients treated with Axona at 45 days but not at 90 days (Constantini, Barr, Vogel, & Henderson, 2008).
Medium-chain triglycerides in general and caprylic triglyceride in particular are generally considered safe. In the Axona clinical trials, approximately 25% of patients developed diarrhea. A few patients showed clinically significant increases in serum triglyceride concentrations. Because Axona contains milk and soy products, it should not be consumed by patients allergic to either. The longer-term efficacy, tolerability, and safety of Axona are unknown.
Many different drug therapies have been developed for the treatment of dementia and cognitive impairment. Nurses should be familiar with these types of drugs, especially those that are available to patients without a prescription. Although I have focused on drug therapies in this article, it also should be noted that social, mental, and physical activities are associated with better brain function. (For more information, see the article by Vance, Roberson, McGuinness, and Fazeli, on pages 23–30.) Engaging in these activities may reduce the risk or delay the onset of dementia. All patients should be counseled about healthy brain activities.
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