What is Alzheimer’s disease

Alzheimer’s disease is a progressive mental deterioration of the brain; itself accounting for almost three-fifths of dementia cases.

To put the disease in some context, there are just over 5 million cases of Alzheimer’s disease in the United States in 2016 – the vast majority of those being over 65 years of age. In fact, Alzheimer’s disease is the sixth leading cause of death in the United States.

The disease kills more people than prostate cancer and breast cancer combined, yet it’s also a disease for which very little clinical progress has been made. Most of the medicines outlined below have negligible benefit for afflicted patients.

While there is no cure for Alzheimer’s disease, the condition is treatable. Below, we assess the pharmacology of Alzheimer’s disease thus far – mostly reviewing two major drug classes, anticholinesterases and NMDA receptor antagonists.

Alzheimer’s disease pharmacology

There are two major drug classes in the pharmacology of Alzheimer’s disease. They are:

  • Anticholinesterases
  • NMDA receptor antagonists

Examples of anticholinesterases include donepezil, galantamine and rivastigmine. The central theory is this: that Alzheimer’s disease is linked to the terminal loss of cholinergic neurons. These neurons are predominantly destroyed in the basal forebrain nuclei.

Damage to these neurons, in turn, leads to diminished output from the hippocampus and neocortex; the two major sites involved in cognition and memory. As an enzyme, cholinesterase is involved in breaking down acetylcholine. Thus, anticholinesterases prevent this breakdown and act to enhance cholinergic transmission.

Drugs used in Alzheimer's Disease

So, what are the differences, if any, between the above three medicines?

  • Donepezil (Aricept) is a reversible inhibitor of acetylcholinesterase; it is associated with a high degree of specificity for the central nervous system. Common side effects include gastrointestinal upset, loss of appetite, difficulty sleeping, diarrhea and muscle cramps.
  • Galantamine is a reversible competitive inhibitor of acetylcholinesterase; it also has agonist effects at presynaptic nicotinic receptors by allosterically buttressing the receptor’s response to the acetylcholine molecule. Gastrointestinal side effects are also, as with donepezil, quite common with galantamine.
  • Rivastigmine is also a reversible inhibitor of acetylcholinesterase, but markedly slower than the other two drugs. Unlike donepezil, rivastigmine also inhibits butyrylcholinesterase, a mechanism that is also believed to have a positive clinical effect. Side effects include nausea, vomiting, diminished appetite and weight loss.

The next class in our pharmacology of Alzheimer’s disease, NMDA receptor antagonists, are often given in conjunction with acetylcholinesterases – for example, donepezil and memantine are frequently prescribed together.

Memantine is the only clinically approved NMDA receptor antagonist in the treatment of Alzheimer’s disease. It is a derivative of the antiviral drug, amantadine. It acts as a non-competitive antagonist of glutamate NMDA receptors.

Memantine has a relatively modest effect in moderate-to-severe Alzheimer’s disease, while also being a well-tolerated drug. Side effects, should they occur, include dizziness, confusion, headache, agitation and hallucinations.

Memantine is believed to work by preventing glutamate-induced excitotoxicity, yet it achieves this without disrupting the effects of glutamate at cognitive and memory sites. Memantine is also a 5-HT3 receptor antagonist, but its clinical significance is currently unclear.

Parkinson’s disease is another degenerative disorder of the central nervous system. If you’re finished with the pharmacology of Alzheimer’s, why not check out this page to learn more about drug treatments for Parkinsonian patients.

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