Medication used in the treatment of dementia

Question 1

Which medications do not have any evidence for preventing the onset of dementia?

Answer 1

Acetylcholinesterase

Question 2

Which medications have mixed evidence for preventing the onset of dementia?

Answer 2

NSAIDs
HRT
Omega 3
Lithium
Statins
Vitamins including Vitamin B, C, E

Question 3

Which medications do have evidence for preventing the onset of dementia?

Answer 3

ACEI and diuretics
Small consumptions of beer
Oestrogen
Fish - consumed once a week, reduced risk by 60%

Question 4

Which medications are effective for slowing the progression of dementia when taken at onset?

Answer 4

Ginseng (OTC medication)

Question 5

Which medications have mixed evidence for preventing progression at the onset of dementia?

Answer 5

Vitamin E
Folic acid with or without Vitamin B12 (& multivitamins)
Omega 3

Question 6

Which medications are ineffective for slowing the progression of dementia when taken at onset?

Answer 6

Gingko (OTC medication)
Anti-amyloids (but do help at the start)

Question 7

What is ALZ-801/Tramiprostate?

Answer 7

An oral medication designed to inhibit amyloid oligomer formation - preventing the development of Alzheimer’s disease.
The drug failed Phase III trials in 2009 - 35% of patients had a misdiagnosis rate preventing developmental successful.
In 2021 the drug reached Phase III clinical trials again.

Question 8

What is Aducanumab?

Answer 8

It is an anti-amyloid antibody also recently entering clinical trials.
The Phase III trials aimed to evaluate the safety of Aducanumab and the effect it had on memory, thinking and day-to-day activities in people with a confirmed diagnosis of mild cognitive impairment (MCI) or mild Alzheimer’s disease.
Phase III clinical trials of Aducanumab in 2019 were halted as early indications suggested they would not benefit people in the early stages of Alzheimer’s

Question 9

How does Lecanemab work?

Answer 9

Known under the brand name Leqembi, was approved by FDA July 2023 and is administered as an IV infusion in early AD.

It is an Antiamyloid- B antibody agent and reduces markers of amyloid in early Alzheimer’s disease which resulted in moderately less decline on measures of cognition and function than placebo at 18 months
However it is associated with adverse events, such as fluid formation in the brain

Question 10

Which tau targeting therapies have reached Phase II clinical trials?

Answer 10

Four monoclonal antibodies anti-tau (gosuranemab, tilavonemab, semorinemab and zagotenemab) and one anti-tau vaccine (AADvac1) have
reached phase II, so far.

Question 11

What is the first line therapy for the management of mild to moderate Alzheimer’s?

Answer 11

Three acetylcholinesterase inhibitors are recommended for monotherapy in the treatment of mild to moderate Alzheimer’s disease, they are:
- Donepezil
- Galantamine
- Rivastigmine

Question 12

When is Memantine monotherapy used in the treatment of Alzheimer’s disease?

Answer 12

In patient’s with either:
- Moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE inhibitors
- Severe Alzheimer’s disease

Question 13

When is Memantine adjunctive therapy used in the treatment of Alzheimer’s disease?

Answer 13

• Consider memantine in addition to an AChE inhibitor if they have moderate disease
  -Offer memantine in addition to an AChE inhibitor if they have severe disease

Question 14

What is the usual dosing regimen for Donepezil and which formulations are available?

Answer 14

Dosing regimen: 5mg ON, then increased if necessary up to 10 mg daily, doses to be given at bedtime.

Available preparations include: Oral tablet, Oral solution, Orodispersible tablet

Question 15

Why is Donepezil usually taken at night?

Answer 15

Due to side effect profile of causing dizziness, bradycardia but also sleep disturbances and nightmares.

Question 16

How would you counsel a patient on managing the side effects of Donepezil?

Answer 16

• Diarrhoea – plenty of fluids
• Headache – paracetamol
• Monitor Bp – also on Amlodipine
• Red flags of Donepezil – abnormal dreams, or worsening symptoms

Question 17

What is the usual dosing regimen for Galantamine and which formulations are available?

Answer 17

Dosing regimen for immediate release tablets: Initially 4 mg twice daily for 4 weeks, increased to 8 mg twice daily for at least 4 weeks; maintenance 8–12 mg twice daily

Modified release is the same daily dose but once daily dosing regimens.

Available preparations include: Oral tablet, Modified release capsule, Oral solution

Question 18

When should the up-titration of doses of Donepezil and Galantamine occur?

Answer 18

Lower doses are usually initiated for 4 weeks before responses are then assessed and doses are potentially up-titrated

Question 19

What is the usual dosing regimen for Rivastigmine and which formulations are available?

Answer 19

Oral administration: initially 1.5 mg twice daily, increased in steps of 1.5 mg twice daily ; usual dose 3–6 mg twice daily (immediate release tablets)

For patches: Apply 4.6 mg/24 hours daily for at least 4 weeks, increased if tolerated to 9.5 mg/24 hours daily for a further 6 months, then increased if necessary to 13.3 mg/24 hours daily

Formulations available include:
Oral solution
Oral capsules
Transdermal patches

Question 20

How frequently should the dose titrations of Rivastigmine occur?

Answer 20

Response and potential up-titrations should occur every 2 weeks for oral formulations (increasing by 1.5mg at a time) and every 4 weeks for patches.

Question 21

Which acetylcholinesterase inhibitor is also licensed in the use of dementia associated with Parkinson’s?

Answer 21

Rivastigmine - helps with hallucinations in Parkinson’s

Question 22

Compare the half life and protein binding in all three AChEI.

Answer 22

Donepezil:
Half-life - 70 hours
Protein binding - 96%

Galantamine:
Half-life - 7-8 hours
Protein binding - 18%

Rivastigmine:
Half-life - 1 hours
Protein binding - 40%

Question 23

What are the fraction outcomes relating to change in symptoms following AChE inhibitor use?

Answer 23

Improvement - 1/3 experience an improvement in memory or ADLs with first medication which lasts for 6-24 months
Non-decline - 1/3 for 6-12 months
No response - 1/3 however 1/2 experience an improvement or non-decline when switched to another medication

Question 24

What are the benefits if medication improves symptoms or reduces the rate of decline

Answer 24

Reduces carer burden and transfer to care homes or time spent in hospital

Question 25

If AChEI medication to prevent decline doesn’t work?

Answer 25

Failure to benefit from one AChEI does not necessarily mean that someone will not respond to another.

Also, poor tolerance to one AChEI does not rule out good tolerance to another.

Question 26

Why do AChE have to be titrated slowly over weeks to months?

Answer 26

Slower titration has found to give patients better tolerance.
Furthermore Rivastigmine has been found to be more tolerable when administered with other medications and specifically patches are more tolerated over capsules.

Question 27

What considerations should be made regarding the choice of AChE inhibitor used first line?

Answer 27

Usually the least expensive is used first which is Donepezil (70-80% of the time).
However other factors should be taken into consideration including:
Side effects
Adherence
Co-morbidities
Drug interactions
Dosing profile

Question 28

Who should initiate AChE inhibitors?

Answer 28

Specialists unless GPs are trained

Question 29

What are some of the side effects of AChEIs?

Answer 29

Parasympathomimetic side effects including:
Nausea and Vomiting
Diarrhoea
Loss of appetite
Sleep disturbance
Abnormal dreams
Headache
Incontinence
Fatigue
Agitation

Question 30

What is a key side effect of AChEI that results in contra-indication to some conditions?

Answer 30

AChEI causes bradycardia which cautions its use in certain cardiac diseases including those with supraventricular abnormalities or at risk of torsades de pointes.
It should not be used alongside medications also causing bradycardia such as beta blockers, calcium channel blockers and digoxin.

Heart rate/pulse should be monitored every couple of months. Seek advice if heart rate drops to below 50 bpm.

Question 31

Aside from medications causing bradycardia what else is there to be aware of when using AChE inhibitors?

Answer 31

Acetylcholinesterase inhibitors should not be prescribed alongside drugs causing anticholinergic burden due to them being counterproductive.

Question 32

What is anticholinergic burden?

Answer 32

It is the cumulative effect on an individual of taking one or more medications with anticholinergic activity.

Question 33

List examples of drugs causing an anticholinergic burden.

*Add this to notes for Exam 3

Answer 33

Antihistamines
Tricyclic anti-depressants
Anti-psychotics
Drugs causing urinary incontinence
Hyoscine
Pain killers - Morphine
Asthma/COPD medicines

Question 34

What is a common side effect and mitigation strategy with transdermal use of Rivastigmine?

Answer 34

Patch can cause rash and therefore ensure to rotate the patch and use emollient cream

Question 35

If a patient is suffering with nausea and vomiting following AChE inhibitor use, what advice would you give?

Answer 35

Take following food or alternatively switch to Memantine or try another AChE inhibitor, as just because patients are tolerant to one if doesn’t mean they will experience the same side effect with another.

Question 36

What advantage does use of Donepezil have over Rivastigmine?

Answer 36

Plasma levels of Donepezil will not fall so rapidly due to the long-half of the medication being 70 hours so it doesn’t matter if a dose is missed however Rivastigmine has the shortest half-life of 1 hour and therefore if a dose is missed it may have to be re-titrated.

Question 37

What type of drug is Memantine?

Answer 37

NMDA antagonist

Question 38

What is the typical dosing regimen for Memantine and which formulations are available?

Answer 38

Initially 5 mg once daily, then increased in steps of 5 mg every week; usual maintenance 20 mg daily; maximum 20 mg per day
Although in some cases faster reuptitration is used.

Formulations available include:
Oral tablet
Orodispersible tablet
Oral solution

Question 39

What are some of the main side effects associated with Memantine use?

Answer 39

Headache
Constipation
Dizziness
Hypertension
Dyspnoea

Question 40

When is use of Memantine cautioned?

Answer 40

Epilepsy, history of convulsions; risk factors for epilepsy

Question 41

Which AChE inhibitors are used in the treatment of Lewy body dementia?

Answer 41

Offer donepezil or rivastigmine to people with mild to moderate dementia with Lewy bodies and consider using in severe dementia.

Only consider galantamine for people with mild to moderate dementia with Lewy bodies if donepezil and rivastigmine are not tolerated.

All use of these are unlicensed.

Question 42

Are AChE inhibitors and Memantine used in the treatment of vascular dementia?

Answer 42

Only consider AChE inhibitors or memantine for people with vascular dementia if they have suspected comorbid Alzheimer’s disease, Parkinson’s disease dementia or dementia with Lewy bodies

Question 43

Which type of dementia should AChE inhibitors and Memantine not be used for?

Answer 43

Frontotemporal dementia

Question 44

What is the evidence-based use for AChE inhibitors and Memantine?

Answer 44

17 new random controlled trials and 4 systematic reviews
Memantine improved cognition at 12 weeks and cognition at 24 weeks

Question 45

What was the key outcomes from key trials regarding AChE inhibitors and Memantine?

Answer 45

Reduced carer burden with galantamine
Adverse drug reactions more frequent with rivastigmine
No significant difference in cognitive function between AChE inhibitors
Significant delay in worsening symptoms with memantine (compared with placebo)

Question 46

Is it beneficial using AChE inhibitors and Memantine in combination?

Answer 46

There is no significant benefit of using a combination of AChE inhibitors and Memantine however in some patients there is a response/symptom improvement
This should only be initiated by a specialist and stopped if no benefit is seen

Question 47

What is the appropriate management for incontinence in dementia patients?

Answer 47

Antimuscarinics counteract the effects of acetylcholinesterase inhibitors so unlikely to use Oxybutynin.
If one is to be used a more selective B3 adrenergic drug Mirabegron could be considered as it has less anticholinergic burden, less risk of confusion, it helps with urinary incontinence as well and does not interact with donepezil
Also consider the risk of using drugs that cause urinary retention such as increased risk of infection.
Assess how incontinence is affecting daily life and weigh up with use of introducing another medication.