Week 9 - Chapter 22 Drugs for Alzheimer's Disease

Question 1

Acetylcholinesterase

Answer 1

Cholinesterase inhibitors prevent the breakdown of acetylcholine by Actetylcholinesterase, and thereby increase the availability of acetylcholine at cholinergic synapses.

Question 2

Apolipoprotein E4

One of many factors that cause AD

Answer 2

Apolipoprotein E4, long known for its role in cholesterol transport, may also contribute to AD. ApoE has three forms, named apoE2, apoE3, and apoE4. Only one form—apoE4—is associated with AD. Genetic research has shown that individuals with one or two copies of the gene that codes for apoE4 are at increased risk for AD; however, many people with AD do not have the gene for apoE4.

Question 3

Beta-amyloid

Answer 3

Neuritic plaques, which form outside of neurons, are a hallmark of AD. These spherical bodies are composed of a central core of Beta-amyloid (a protein fragment) surrounded by neuron remnants. Neuritic plaques are seen mainly in the hippocampus and cerebral cortex.
In patients with AD, Beta-amyloid is present in high levels and may contribute to neuronal injury. Accumulation of Beta-amyloid begins early in the disease process, perhaps 10 to 20 years before the first symptoms of AD appear. Because of the central role that Beta-amyloid appears to play in AD, treatments directed against Beta-amyloid are in development.

Question 4

Cholinesterase Inhibitors

Mechanism of action?

Answer 4

Cholinesterase inhibitors prevent the breakdown of acetylcholine by acetylcholinesterase (AChE), and thereby increase the availability of acetylcholine at cholinergic synapses. In patients with AD, the result is enhanced transmission by central cholinergic neurons that have not yet been destroyed. Cholinesterase inhibitors do not cure AD, and they do not stop disease progression—although they may slow progression by a few months.

Question 5

Cholinesterase Inhibitors

Therapeutic effect?

Answer 5

All cholinesterase inhibitors are approved for patients with mild to moderate symptoms. Benefit are seen through improvements in quality of life and cognitive functions (eg, memory, thought, reasoning). However, these improvements are modest and short lasting. There is no convincing evidence of marked improvement or significant delay of disease progression. Nonetheless, although improvements are neither universal, dramatic, nor long lasting, and although side effects are common, the benefits may still be worth the risks for some patients.

Question 6

Cholinesterase Inhibitors

Adverse effects?

Answer 6

By elevating acetylcholine in the periphery, all cholinesterase inhibitors can cause typical cholinergic side effects. Gastrointestinal effects—nausea, vomiting, dyspepsia, diarrhea—occur often. Dizziness and headache are also common. Elevation of acetylcholine at synapses in the lungs can cause bronchoconstriction. Accordingly, cholinesterase inhibitors should be used with caution in patients with asthma or chronic obstructive pulmonary disease (COPD).
Cardiovascular effects, although uncommon, are a serious concern. Increased activation of cholinergic receptors in the heart can cause symptomatic bradycardia, leading to fainting, falls, fall-related fractures, and pacemaker placement. If a patient is experiencing bradycardia, fainting, or falls, drug withdrawal may be indicated, especially if cognitive benefits are lacking.

Question 7

Cholinesterase Inhibitors

Drug Interactions?

Answer 7

Drugs that block cholinergic receptors (eg, first-generation antihistamines, tricyclic antidepressants, conventional antipsychotics) can reduce therapeutic effects, and should be avoided.

Question 8

Cholinesterase Inhibitors

Dosage and Duration of Treatment?

Answer 8

Dosage should be carefully titrated, and treatment should continue as long as clinically indicated. The highest doses produce the greatest benefits—but also the most intense side effects. Accordingly, dosage should be low initially and then gradually increased to the highest tolerable amount. Treatment can continue indefinitely, or until side effects become intolerable or benefits are lost.

Question 9

Endoplasmic Reticulum-Associated Binding Protein

One of many factors that cause AD

Answer 9

The discovery of endoplasmic reticulum–associated binding protein (ERAB) adds another piece to the AD puzzle. ERAB is present in high concentration in the brains of patients with AD. These high concentrations of ERAB enhance the neurotoxic effects of beta-amyloid.

Question 10

Homocysteine

One of many factors that cause AD

Answer 10

Elevated plasma levels of homocysteine are associated with an increased risk of AD. Fortunately, the risk can be easily 192reduced: Levels of homocysteine can be lowered by eating foods rich in folic acid and vitamins B6 and B12, or by taking dietary supplements that contain these compounds.

Question 11

Neuritic plaques

One of many factors that cause AD

Answer 11

Neuritic plaques, which form outside of neurons, are a hallmark of AD. These spherical bodies are composed of a central core of beta-amyloid (a protein fragment) surrounded by neuron remnants. Neuritic plaques are seen mainly in the hippocampus and cerebral cortex.

Question 12

Neurofibrillary Tangle

One of many factors that cause AD

Answer 12

Like neuritic plaques, neurofibrillary tangles are a prominent feature of AD. These tangles, which form inside of neurons, result when the orderly arrangement of microtubules becomes disrupted (Fig. 22–1). The underlying cause is production of an abnormal form of tau….

Question 13

Tau

One of many factors that cause AD

Answer 13

The underlying cause is production of an abnormal form of tau, a protein that, in healthy neurons, forms cross-bridges between microtubules, and thereby keeps their configuration stable. In patients with AD, tau twists into paired helical filaments that form tangles.

Question 14

N-methyl-D-aspartate “Memantine”

What is it and its classification?

Answer 14

Memantine [Namenda, Namenda XR, Ebixa image] is a first-in-class N-methyl-D-aspartate (NMDA) receptor antagonist. Unlike the cholinesterase inhibitors, which can be used for mild AD, memantine is indicated only for moderate or severe AD. We don’t yet know if memantine is more effective than the cholinesterase inhibitors, but we do know it’s better tolerated. Although memantine helps treat symptoms of AD, there is no evidence that it modifies the underlying disease process.

Question 15

N-methyl-D-aspartate “Memantine”

Therapeutic effect?

Answer 15

• Modest benefits; indicated for moderate to severe AD, not mild AD
• Slows decline of cognitive and day-to-day functions
• May act synergistically with Donepezil

Question 16

N-methyl-D-aspartate “Memantine”

Mechanism of action?

Answer 16

• –Memantine modulates the effects of glutamate (the major excitatory transmitter in the central nervous system) at NMDA receptors, which are believed to play a critical role in learning and memory. The NMDA receptor—a transmembrane protein with a central channel—regulates calcium entry into neurons. Binding of glutamate to the receptor promotes calcium influx.
• –Under healthy conditions, an action potential releases a burst of glutamate into the synaptic space. Glutamate then binds with the NMDA receptor and displaces magnesium from the receptor channel, permitting calcium entry (Fig. 22–2A ). Glutamate then quickly dissociates from the receptor, permitting magnesium to reblock the channel, and thereby prevents further calcium influx. The brief period of calcium entry constitutes a “signal” in the learning and memory process.

Question 17

N-methyl-D-aspartate “Memantine”

Pharmacokinetics?

Answer 17

Memantine is well absorbed following oral dosing, both in the presence and absence of food. Plasma levels peak in 3 to 7 hours. The drug undergoes little metabolism, and is excreted largely unchanged in the urine. The half-life is long—60 to 80 hours. Clearance is reduced in patients with renal impairment.

Question 18

N-methyl-D-aspartate “Memantine”

Adverse effects?

Answer 18

Memantine is well tolerated. The most common side effects are dizziness, headache, confusion, and constipation. In clinical trials, the incidence of these effects was about the same as in patients taking placebo.

Question 19

N-methyl-D-aspartate “Memantine”

Drug interactions?

Answer 19

• –In theory, combining memantine with another NMDA antagonist, such as amantadine [Symmetrel] or ketamine [Ketalar], could have an undesirable additive effect. Accordingly, such combinations should be used with caution.
• –Sodium bicarbonate and other drugs that alkalinize the urine can greatly decrease the renal excretion of memantine. Accumulation of the drug to toxic levels might result.

Question 20

Donepezil

What is it and its classification?

Answer 20

—Donepezil = Cholinesterase Inhibitor

—Donepezil [Aricept, Aricept ODT] is indicated for mild, moderate, or severe AD.

Question 21

Donepezil

Mechanism of action? (

Answer 21

The drug causes reversible inhibition of AChE—but is more selective for the form of AChE found in the brain than that found in the periphery. Like other cholinesterase inhibitors, donepezil does not affect the underlying disease process.

Question 22

Donepezil

Pharmacokinetics?

Answer 22

Donepezil is well absorbed following oral administration and undergoes metabolism by hepatic cytochrome P450 enzymes. Elimination is mainly in 194the urine and partly in the bile. Donepezil has a prolonged plasma half-life (about 60 hours), and hence can be administered just once a day.

Question 23

Donepezil

Adverse effects?

Answer 23

Although donepezil is somewhat selective for brain cholinesterase, it can still cause peripheral cholinergic effects; nausea and diarrhea are most common. Like other drugs in this class, donepezil can cause bradycardia, fainting, falls, and fall-related fractures.