Cholinesterase Inhibitors: Helping Nerves Communicate

Most people think of the nervous system as the body's electrical wiring. This is correct -- but only up to a point.



Nerve cells transmit impulses much like wires transmit electricity. But unlike wires, which are continuous filaments, nerve cells do not touch one another. They have microscopic gaps between them called synapses. Nerve impulses must jump these gaps to proceed on their way. They do it with the help of special chemicals called neurotransmitters.



As a nerve impulse passes through a nerve cell, it activates the release of neurotransmitters into the cell's synapses, allowing the impulse to jump the gap and proceed on its way. Once the impulse crosses the synapse, special enzymes eliminate the neurotransmitter, leaving the cell and synapse ready to react to the next impulse. One important neurotransmitter is acetylcholine (pronounced a-SEE-tull-KOH-leen).



During the late 1970s, researchers discovered that people with Alzheimer's disease suffer a loss of acetylcholine from their synapses. This observation fueled theories that Alzheimer's might disrupt the synthesis of acetylcholine, or that the disease triggers overproduction of the enzyme that eliminates it, acetylcholinesterase -- generally known as cholinesterase. Scientists speculated that drugs to either increase acetylcholine or inhibit cholinesterase might help treat Alzheimer's disease.



Cholinesterase inhibition has yielded the most promising results so far. The three drugs currently approved for treatment of Alzheimer's -- Cognex (tacrine), Aricept (donepezil), and Exelon (rivastigmine) -- are all cholinesterase inhibitors. They do not cure Alzheimer's disease, but can consistently produce small improvements in memory and function. Some people may even notice improvement in their ability to perform daily activities.



Several additional cholinesterase inhibitors are also being developed, and a few, such as Promem (metrifonate from Bayer Corporation Pharmaceutical Division), are close to Food and Drug Administration (FDA) approval. (Bayer Corporation Pharmaceutical Division is the provider of an unrestricted educational grant to Alzheimers.com).

Cognex (tacrine)

Cognex is one of only three drugs currently approved for treatment of Alzheimer's disease. The FDA approved it largely because a 30-week study showed that high doses improve cognition in people with mild to moderate Alzheimer's disease. It has also shown some benefit for those with advanced Alzheimer's.



But since its approval, clinical experience has been disappointing. Depending on the study, Cognex helps only 20-40% of those who take it. At this point, doctors cannot predict who will respond to Cognex, to what extent, and for how long. Cognex may help somewhat, but only for a minority of people with Alzheimer's diseases.



People taking Cognex typically start with 10 milligrams (mg) in pill form four times daily (40 mg per day) without food. If upset stomach occurs, then it can be taken with meals but the amount of drug reaching the bloodstream will be reduced. If, after four weeks of continuous treatment, with no changes in liver function and the dose is being tolerated, the dosage can be increased incrementally at four-week intervals to 80, 120, and 160 mg/d by your doctor as needed.



Cognex has significant side effects, including nausea and vomiting. But the one that has caused the most concern is the possibility of liver damage. Cognex may substantially increase levels of the liver enzymes AST (SGOT) and ALT (SGPT). The rise in liver enzymes occurs for most people by approximately the sixth week of treatment. Up to 50% of people who take this medication may have a mild increase in ALT, up to 25% may have ALT three times the upper limit of normal, and about 7% may have ALT elevations up to 10 times the upper limit of normal.



The long-term effects of high ALT levels remain unclear but liver enzymes generally return to normal four to six weeks after the dosage is reduced or stopped. Liver tests should be performed every other week from week four to at least week 16 of treatment. After that, liver tests can be done every three months. If liver function tests indicate elevations of two to three times the upper limit of normal, then testing should be performed weekly. If they rise to between three to five times the upper limit of normal, then the dose should be reduced by 40 mg per day and when the tests have returned to normal, then increased dosages can begin again. If they increase to more than five times the upper limit of normal, then Cognex should be discontinued and the dosage increases restarted when liver tests are normal. However, if liver tests are more than 10 times the upper limit of normal and/or symptoms of jaundice has occurred, then Cognex should not be used again. Another challenge with the drug is that the person with Alzheimer's might resist the periodic blood tests that the use of the drug requires.



A recent study by the San Francisco-based Technology Assessment Group (TAG) shows that despite its limited effectiveness, Cognex is cost-effective for those who respond to it. TAG estimated that the lifetime cost of Cognex plus medical monitoring of its use would be around $2,600. However, the drug is estimated to save an estimated $9,300 in lifetime medical costs ($114,500 with tacrine, $123,800 without it). Finally, to the extent that a good response to Cognex keeps people functional longer, it also shortens nursing home stays. Without Cognex, the typical Alzheimer's sufferer spends 2.7 years in a nursing home; with it, 1.5.



Cognex may be cost-effective for the minority of people who respond to it, but because of its limited effectiveness and side effects, the enthusiasm that greeted its approval has cooled considerably.

Aricept (donepezil)

The FDA approved this cholinesterase inhibitor in November 1996, based in part on a study reported at the spring 1996 meeting of the American Academy of Neurology in San Francisco. In the 24-week study, 473 people with Alzheimer's were divided into two groups. One group received a placebo; the other either 5 or 10 mg/d of Aricept. Compared with the placebo group, those taking Aricept showed significant improvement in cognitive skills and daily functioning.



Aricept is better targeted than Cognex. It affects only acetylcholine in the brain, preventing its breakdown, while Cognex affects related compounds throughout the body, according to Dr. Sharon Rogers, research chief at the drug's manufacturer, Easai America. Aricept's more targeted action means fewer side effects. Like Cognex, Aricept's possible side effects include nausea, vomiting, and diarrhea. But unlike Cognex, Aricept does not cause liver enzyme abnormalities. Users need not have regular liver-function tests.



In addition, Aricept is taken only once a day. As noted above, Cognex must be taken four times a day. The starting dose is 5 mg once daily. The dose may be increased to 10 mg per day if necessary but should not be considered until at least four to six weeks of continuous treatment with the 5 mg dose.

Exelon (rivastigmine)

Exelon was approved by the FDA in April 2000. One six-month trial involved 699 people with Alzheimer's, half of whom took the drug and half a placebo. Those on Exelon showed significant cognitive improvement. Side effects included nausea, vomiting, diarrhea, and loss of appetite. But like Aricept, liver-enzyme abnormalities are not a problem.



The suggested starting dose of Exelon is 1.5 mg taken twice daily (the morning and the evening) with food. If this dose is tolerated after two weeks of continuous treatment (for instance, if no nausea, vomiting, abdominal pain, or loss of appetite occurs), then it may be increased to 3 mg twice daily. After that, the dose may be increased every two weeks to 4.5 mg twice daily, then 6 mg twice daily as needed.

Drugs in the pipeline

Promem (metrifonate)



Promem is currently under review by the FDA for the treatment of mild to moderate Alzheimer's disease. In addition to improving cognition and the performance of activities of daily living, clinical trials have shown that it also helps minimize the disruptive behavior common among people with Alzheimer's.



In a six-month study by researchers at UCLA's Alzheimer's Disease Center, researchers gave 408 people with mild-to-moderate Alzheimer's either a placebo or Pronem (30 to 60 mg once a day based on their weight). Cognition tests showed that those taking the drug improved significantly. In addition, they also experienced significantly fewer typical Alzheimer's psychiatric and behavior problems, notably less depression, lethargy, and apathy, and fewer hallucinations.



Pronem is given once a day. Common side effects include nausea, diarrhea, and leg cramps.



The manufacturer petitioned the FDA to approve Pronem in 1997. The application is still pending as of September 2000.



Other cholinesterase inhibitors in development

• Physostigmine SR


• NXX-066


• Galantamine

Acetylcholine boosters in development

• Xanomeline


• Milameline


• Sabcomeline (SB-202026)


• Cevimeline (AF-102B)


• ABT-418

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