Pharmacology of Alzheimers disease

First described by the German pathologist Alois Alzheimer in 1906, Alzheimer’s disease is a condition that afflicts approximately 30 million people worldwide. Medicines are only used to manage symptoms of the disease, as there is currently no cure.

Alzheimer’s disease is the most common cause of dementia, accounting for almost two-thirds of cases. Characteristic symptoms include short-term memory loss, difficulty with language, disorientation, mood swings, loss of motivation and behavioral disturbances.

There are currently five specific medicines used to treat Alzheimer’s disease:

  • Memantine
  • Tacrine
  • Rivastigmine
  • Galantamine
  • Donepezil

However, none of these medicines has been shown to delay or halt disease progression.

The medicines are most effective in mild-to-moderate treatment of the disease. Late stage Alzheimer’s shows very little, if any, clear benefit.

Other medicines – such as atypical antipsychotics – have been used for psychotic or aggressive aspects of the disease, but because they are linked to serious adverse effects and, according to some studies, an increased risk of death, they are generally avoided.

Mechanism of action

We can divide Alzheimers disease pharmacology into two distinct classes:

  • NMDA receptor antagonists
  • Acetylcholinesterase inhibitors

Memantine is a non-competitive NMDA receptor antagonist.

Glutamate is an important excitatory neurotransmitter in the brain. By inhibiting NMDA receptors, memantine inhibits the excitatory effects of its ligand, glutamate. Memantine is used to treat moderate-to-severe symptoms of Alzheimer’s disease.

The other four medicines are acetylcholinesterase inhibitors:

  • Tacrine
  • Rivastigmine
  • Galantamine
  • Donepezil

As their name suggests, acetylcholinesterase inhibitors inhibit the breakdown of the enzyme – acetylcholinesterase – that is used to breakdown acetylcholine. This means that more acetylcholine is available to conduct neuronal activity.

Alzheimer’s disease is thought, at least in part, to be caused by a cholinergic deficit – particularly in the cerebral cortex. By enhancing cholinergic levels, it is believed to play a positive role in alleviating mild-to-moderate Alzheimer’s disease.

Side effects

Side effects associated with memantine include:

  • Confusion
  • Dizziness
  • Drowsiness
  • Insomnia
  • Hallucinations
  • GI effects – constipation, diarrhea, nausea, vomiting
  • Rash
  • Hyperglycemia
  • Increased liver enzymes

Side effects associated with acetylcholinesterase inhibitors include:

  • Bradycardia
  • Hypotension
  • Nausea, vomiting, diarrhea
  • Headache
  • Dizziness

Rivastigmine has a higher incidence of decreased appetite and weight loss than the other three medicines.

Nausea and vomiting with acetylcholinesterases is caused by cholinergic excess.

Clinical considerations

When we talk about the clinical pharmacology of Alzheimer’s disease, we need to think about the following factors:

  • That memantine is used to treat moderate-to-severe Alzheimer’s disease, usually when patients have found acetylcholinesterase inhibitors ineffective. There is no clear benefit in using memantine for mild disease.
  • That patients should take oral forms of acetylcholinesterase inhibitors with food, to reduce the risk of nausea and vomiting. This is particularly true with rivastigmine, for which the risk of vomiting is greater.
  • CYP3A4 inhibitors – such as ketoconazole and erythromycin – increase the bioavailability of galantamine. Galantamine is also metabolised by CYP2D6 meaning its inhibitors – such as paroxetine – can increase galantamine levels.

Medicines have limited use in Alzheimer’s disease. While there are slight benefits, there are also risks that must be considered. Given that current treatment focuses on symptomatic relief, it is hoped that a more permanent, cure-based solution, is on the horizon.

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