Alzheimer's Disease

Question 1

Define Alzheimer’s disease.

Answer 1

A degenerative disorder that attacks the brain’s nerve cells resulting in loss of memory, thinking and language skills, and behavioral changes.

Question 1

What areas of the brain does Alzheimer’s disease affect?

Answer 1

Alzheimer’s disease affects most areas of the brain.

Question 2

Alzheimer’s disease is the most common cause of dementia.
What is dementia?

Answer 2

A group of brain disorders that cause the loss of intellectual and social skills.

Question 3

Dementia of the Alzheimer’s type has three distinguishing features.
Mention them.

Answer 3

1. Accumulation of senile plaques (β-amyloid accumulations).
2. Formation of numerous neurofibrillary tangles.
   Explanation: In Alzheimer’s disease, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside neurons. These tangles block the neuron’s transport system, which harms the synaptic communication between neurons.
3. Loss of cortical neurons, particularly cholinergic neurons.

Question 4

Do the pharmacologic agents available to manage Alzheimer’s disease cure it?

Answer 4

No. Pharmacologic interventions for Alzheimer’s disease are only palliative and provide modest short-term benefit.

Question 5

What is the strategy of treatment of Alzheimer’s disease?

Answer 5

Current therapies are aimed at:

1. Improving cholinergic neurotransmission in the CNS.
2. Preventing the excitotoxic actions resulting from the overstimulation of NMDA-glutamate receptors in selected brain areas.

Question 6

What is acetylcholinesterase?

Answer 6

An enzyme that metabolites acetylcholine. It exists centrally and peripherally.

Question 7

What are acetylcholinesterase inhibitors (AChE)?

Answer 7

Drugs that inhibit acetylcholinesterase enzyme thereby improving the cholinergic neurotransmission within the brain cortex, at least in the functioning surviving cholinergic neurons.
They are used primarily to treat mild to moderate Alzheimer’s disease.

Question 8

What are the four reversible AChE inhibitors that are approved for the treatment of mild to moderate Alzheimer’s disease?

Answer 8

Donepezil.
Galantamine.
Rivastigmine.
Tacrine.

Question 9

Which AChE inhibitors are non-competitive?

Answer 9

Donepezil.
Rivastigmine.
Tacrine.

Question 10

Which AChE inhibitors are competitive?

Answer 10

Galantamine.

Question 11

Galantamine, in addition to being an AChE inhibitor, has an additional mechanism of action.
What is this additional mechanism?

Answer 11

In addition to inhibiting acetylcholinesterase, galantamine also increases cholinergic neurotransmission by stimulating nicotinic receptors in the CNS.

Question 12

What are the drug-drug interactions of acetylcholinesterase inhibitors?

Answer 12

All of these drugs are substrates for cytochrome P450 and have a strong potential of drug-drug interactions.

Question 13

Which anti-Alzheimer’s disease drug has the safest drug-drug interaction profile?

Answer 13

Rivastigmine. This drug is hydrolyzed by acetylcholinesterase enzyme in the liver to a carbamylated metabolite and therefore has no interactions with drugs that alter the activity of cytochrome P450-dependent enzymes (like acetylcholinesterase inhibitors).

Question 14

What are the adverse effects of acetylcholinesterase inhibitors?

Answer 14

Nausea.
Diarrhea.
Vomiting.
Anorexia.
Bradycardia.
Muscle cramps.

Tacrine is associated with hepatotoxicity.

Question 15

What is the most commonly used NMDA-receptor antagonist?

Answer 15

Memantine.

Question 16

Why is overstimulation of glutamate receptors, particularly of the NMDA type, results in excitotoxic effects on neurons?

Answer 16

The overstimulation of glutamate receptors, particularly of the NMDA type, triggers apoptotic programmed cell death processes. Also, excess intracellular Ca+2 can activate a number of processes that damage the neurons.

Question 17

How does memantine work?

Answer 17

Memantine acts by physically blocking the NMDA receptor-associated ion channel, but at therapeutic doses, only a fraction of these channels are actually blocked.

So, memantine ultimately limits Ca+2 influx, decreasing intracellular ca+2.

Question 18

Why has memantine replaced phencyclidine?

Answer 18

Phencyclidine blocks all NMDA receptor-associated ion channels, whereas memantine is selective for hyperactive channels (due to it being voltage-dependent), minimizing NMDA receptor excitation without inhibiting natural NMDA receptor processes.

Question 19

How are NMDA receptor antagonists used?

Answer 19

They have been shown to slow the rate of memory loss, but there is no evidence that they prevent the degeneration of neurons or that they are more effective than acetylcholinesterase inhibitors, so they are used in combination with acetylcholinesterase inhibitors.

Question 20

What are the side effects of NMDA receptor antagonists?

Answer 20

Although they are well tolerated, they are known to cause:
Confusion.
Agitation.
Restlessness.
These symptoms are indistinguishable from the symptoms of Alzheimer’s disease.