How Tacrine, the First Pill Approved to Treat Alzheimer’s, Paved the Way for Future Drugs

By Lecia Bushak | September 27th, 2019

Tacrine, also known as its brand name Cognex, was the first drug approved by the FDA for the treatment of Alzheimer’s disease.

At the time of its approval in 1993, tacrine was considered an effective therapy for mild-to-moderate Alzheimer’s. The drug was able to pass through the blood-brain barrier quickly, a significant feat when it comes to treating brain disorders, and research showed that it was actually able to boost cognitive function in people with Alzheimer’s.

Tacrine fell out of use by 2013, when it was withdrawn from the market due to concerns over its link to liver toxicity. But its legacy led to improved drugs that are now beneficial to Alzheimer’s patients, and it paved the way for research into future therapies that aim to slow the progression of the disease.

How Tacrine Works

Tacrine falls under the category of a class of drugs known as cholinesterase inhibitors, or acetylcholinesterase inhibitors. Other drugs that are now used to treat cognitive decline, like donepezil (Aricept), rivastigmine (Exelon) and galantamine (Razadyne), are also cholinesterase inhibitors.

This class of drugs hones in on a chemical in the brain known as acetylcholine, which is a neurotransmitter necessary for memory and function. When acetylcholine is broken down, neurons responsible for memory don’t work as well. Cholinesterase inhibitors work to slow down the breakdown of acetylcholine, aiming to boost this chemical’s function in keeping a person’s memory working properly.

“Cholinesterase inhibitors were designed to improve communication or efficiency of neurons in the brain,” Rebecca Edelmayer, Director of Scientific Engagement at the Alzheimer’s Association, said in an interview with Being Patient. “They block a breakdown of a messenger known as acetylcholine from breaking down between cells. So when acetylcholine is not broken down, it increases the efficiency of cross-talking between the cells. I equate it to turning up the volume between the cells so they can hear each other better.”

Tacrine, which came in the form of a pill or capsule, was able to be quickly absorbed through the gastrointestinal tract. It also crossed the blood-brain barrier fairly easily an important achievement as this barrier is a major obstacle for the development of many Alzheimer’s drugs. The blood-brain barrier forms an “iron curtain” that only allows specific molecules to enter the brain.

Even though tacrine was considered a success as the first Alzheimer’s drug, it came with a slew of side effects, including diarrhea, vomiting, nausea, dizziness, anxiety and insomnia. It was also eventually linked to hepatotoxicity, or liver toxicity, and was considered unsafe enough to be removed from the market by 2013. Around this time, other cholinesterase inhibitors, which were effective and didn’t have the negative side effects tacrine did, had already been developed and became more commonly used.

Paving the Way for the Future

Though it was discontinued, tacrine ultimately paved the way for improved therapies in treating cognitive decline symptoms associated with Alzheimer’s disease, Edelmayer said.

There are currently five FDA-approved medications used to treat Alzheimer’s symptoms. Three of those are cholinesterase inhibitors (donepezil, galantamine and rivastigmine). The other two include memantine, or Namenda an NMDA receptor antagonist drug and Namzaric, a combination of memantine and donepezil.

“When you’re doing drug development, you’re always trying to improve upon the medicines created,” Edelmayer said. “After tacrine, better cholinesterase inhibitors were developed, and we will continue to develop even better medicines than that. We’re now looking more at drugs that are going to block the disease process in the brain in the first place.”

Edelmayer adds that once brain cells become sick and start dying, such as in Alzheimer’s, cholinesterase inhibitors no longer have ways to improve cognition, because the cells they work on are no longer there. In short, the drugs become less effective over time as the disease progresses further. One report out of the American Association for Retired Persons (AARP) even found that 70 percent of dementia patients were still on these prescription drugs for longer than could be helpful.

This is one reason why Edelmayer hopes the research will soon move beyond these classes of drugs, and diversify into developing different channels that target the disease before it’s started to progress.

“We need to do more research to design better drugs that are going to slow down the progression of Alzheimer’s,” Edelmayer said. “That’s why there’s a number of efforts underway to increase the amount of ideas and different therapeutic approaches that should be developing to slow or potentially even stop the disease.”

But while the effects of these drugs differ for each patient, and their efficacy dwindles with time, they can still offer one way to fight the disease.

“People should know that there are medicines that can be useful for improving cognition that have been approved by the FDA,” Edelmayer said, “and they should be having conversations with their doctors about how this can help them.”

Edelmayer notes that scientists are working to get more research for new therapies down the pipeline. “We will continue the fight to make sure that research is completed, so that we find a drug that slows down the progression of this disease,” she said.

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