CNS- Dementia

Cholinergic inhibitors

These are cholinesterase inhibitors which inhibit the breakdown of ACh, consequently increasing ACh levels in the brain. Examples include:

• Donepezil

• Rivastigmine

• Galantamine 

Role of ACh in the brain

ACh is an important neurotransmitter for memory function, body functions and smooth muscle contractions. Loss of cholinergic neurones and decreasing levels of ACh → cognitive degeneration

Glutamate NMDA receptors antagonist

Memantine

Anticholinergic burden

Cumulative effect of medications with cholinergic active results in cognitive impairment.

Examples of drugs which can have a cholinergic effect include:

• Some anti-depressants

• Anti-psychotics

• Anti-spasmatics

• Anti-histamines

Drugs with ABC score of 0

• Mirabegron

• Ondansetron

• Sertraline

• Bisacodyl

• Metoclopramide

Drugs with ABC score of 1

• Domperidone

• Codeine

• Cetirizine

• Mirtazapine

• Diazepam

Drugs with an ABC score of 2

• Carbamazepine

• Nefopam

Drugs with an ABC score of 3

• Oxybutynin

• Solifenicin

• Olanzapine

• Amitriptyline

• Hyoscine hydrobromide

Cumulative effects of medications with cholinergic burden can result in cognitive impairment

MHRA alert for dementia

Anti-psychotics can be used in dementia however there is an increased risk of strokes and a small increase of death. So anti-psychotics can only be used at the lowest effective dose for the shortest period of time possible - review every 6 weeks.

EPSE symptoms

In lewy body dementia patients are susceptible to EPSE when treated with anti-psychotics and anti-psychotics exacerbate these symptoms- symptoms include muscle stiffness, rigidity and tremors. Quetiapine can be used instead (unlicensed)

What are the two anti-psychotics licensed for behavioural and psychological symptoms in dementia?

• Risperidone 

• Haloperidol 

Risperidone is preferred as haloperidol can have an effect on the heart and the cardiac muscle (QT prolongation)

Can valproate be used in dementia

No - it should not be used as a mood stabiliser unless indicated for another previous condition

Benzodiazepines use in dementia

Often used in BPSD for short term use PRN to relive agitation - lorazepam is preferred as it is short acting

Sleeping medication in dementia?

No - should be AVOIDED

Donepezil

Reversible long acting selective inhibitor of AChE used in mild to moderate dementia

• Dose → 5mg ON for 1 month then asses and increase to 10mg if needed

Cautions with donepezil

Cautions in respiratory conditions such as asthma and COPD as it increases the risk of bradycardia and persistent bradycardia (<60bpm) - this is because ACh is important in slowing down heart rate.

Also needs to be used in caution with any other CYp450 inhibitors as its broken down in the liver

Notable interactions with donepezil

Any drugs which can cause QTC prolongation:

• Amiodarone

• Sotalol

• Citalopram

• Clarithromycin

• B-blockers

Rivastigmine

Reversible non competitive inhibitor of AChE indicated for mild to moderate dementia.

Must be re-titrated if 3 days missed

Dose → BD dosing, 1.5-6mg daily. Increased in 2 week intervals.

Patches → 4.6mg/24hr for 4 weeks→ 9.5mg/24hr for 6 months → 13.3mg/24hrs if necessary.

Patches must NOT be applied on the thigh or abdomen due to reduced bioavailability

Interactions with rivastigmine

• B-blockers

• Anti-arrhythmics

• Smoking → increases oral clearance of rivastigmine

Treatment should be held if patients experience prolonged vomiting and diarrhoea

Galantamine

Indicated for mild and moderately SEVERE dementia. Its a reversible inhibitor of acetylcholinesterase and acts at nicotinic receptors.

Dose → 4mg BD IR for 4 weeks, maintenance dose is then 8-12mg BD

Contraindication with galantamine

Unlike donepezil and rivastigmine their is a contraindication in severe hepatic and renal impairment.

In moderate hepatic impairment max dose is 8mg BD/16mg OD

Interactions of galantamine

• Paroxetine

• Fluoxetine

• Erythromycin

• Ketoconazole

• Beta-blockers

• Anti-arrhythmias

Glutamate pathway

Only one drug which acts here → Memantine 

In alzhimers’s disease there is an excess of glutamate causing excitotoxicity leading to brain cell damage, as excess glutamate causes an influx of neurones causing cell damage. This excess release of glutamate can be triggered by amyloid plaques.

Memantine

NMDA receptor antagonist - blocks the receptor glutamate binds to.

Memantine is only indicated in SEVERE dementia. You can have as monotherapy or it can be added on when there is deuteriation of disease despite treatment

Dose of memantine

5mg OD increased by 5mg every week. Maintenance dose of 20mg. Aim is to get to max tolerated dose

Cautions with memantine

• Epilepsy

• In renally impaired max dose is 10mg daily and avoid if eGFR is less than 5ml/min

• Shouldn’t prescribe with other NMDA antagonists eg - ketamine and amantadine as risk of psychosis