Module 4.4.2 (Management of Dementia) Flashcards
What is dementia defined as?
Distinguished from lifelong intellectual disability and single learning disorders as dementia develops during life, and involves alteration in two or more cognitive functions
What is used to treat primary symptoms such as memory loss in alzheimers?
Anticholinesterases
NMDA antagonists
What is used to treat seconday symptoms such as depression and hallucinations in alzheimers?
Antipsychotics and Sedatives
Summary of different types of dementia?
What is the amyloid hypothesis?
- Imbalanced production or removal of beta amyloid causes accumulation and clumping of this peptide in the brain
> reduce amount of amyloid to improve symptoms
- Beta amyloid is both toxic itself and stimulates neurodegeneration and loss of brain tissue
> Treatments targeting amyloid have been found to confer virtually no clinical benefit
Any success with verubecestat?
BACE-1 (beta site amyloid precursor protein cleaving enzyme 1) inhibitor
- BACE-1cleaves amyloid precursor protein to produce amyloid-beta peptides
- BACE-1 levels often elevated in late-onset Alzheimer’s
> Ceased in February 2017 as “virtually no chance of finding a positive clinical effect”
Why are some theories as to why anti-beta amyloid therapies have failed?
- Administered too late in the disease to be effective
- Inaccurate diagnoses meant they have been trialled in unresponsive patients
- Inadequate penetration into the brain
- Up to half of people with positive Aβ PET scans will not develop dementia
How do anticholinesterases work?
Donepezil (AriceptTM), galantamine (ReminylTM) and rivastigmine (ExelonTM)
Accumulation of AB (beta amyoloid) peptide results in destruction of cholinergic neurones and a fall in ACh concentration
> neurotransmitter essential for learning and memory
- Cholinesterase inhibitors (CIs) inhibit breakdown of ACh to increase concentrations in synaptic cleft
> enhances cholinergic function and reduces loss of cholinergic neurotransmitter activity
All three CIs seem to have similar efficacy, they dont alter pathology of AD, so how do they work?
> donepezil may be slightly more effective
temporarily delay progression and improve symptoms according to subjective measurements or cognitive assessment tools (e.g. MMSE)
> not everyone responds to treatment
What are the adverse effects (CIR) associated with CI? Which one has most GI adverse effects?
Adverse effects occur frequently with all three agents
Better tolerated if slowly titrated to target dose –> increase every four to six weeks
> full dose oral rivastigmine may have more GI adverse effects than donepezil or galantamine
Common
- nausea, vomiting, diarrhoea, anorexia, abdominal pain, dyspepsia, headache, insomnia, vivid dreams, depression, fatigue, drowsiness, dizziness, tremor, weight loss, muscle cramps, urinary incontinence, increased sweating, hypertension, syncope
Infrequent or rare
- bradycardia, heart block, seizure, agitation, hallucination, confusion, GI haemorrhage
Which non-alzheimer dementia should CI be used in?
There is good evidence to support treatment with rivastigmine and donepezil in in dementia with Lewy bodies and Parkinson’s disease dementia
Properties of memantine? MOA, is it effective? Who is it used for?
Thought to protect against elevated levels of glutamate
- NMDA antagonist
- but memantine does not stop AD progression
Marginally less deterioration compared to placebo over 6-months in moderate to severe AD
Generally reserved for severe dementia or those intolerant to CIs
Factors to consider in relation to continuing CI/ memantine use is? How is this demonstrated?
clinically meaningful response achieved and any adverse effects that may be present
Clinically meaningful response to treatment may be demonstrated by the person’s:
- quality of life
- cognitive function
- behavioural symptoms
> The presence of adverse effects that impact on quality of life and clinical symptoms should prompt a review of the ongoing need for the agent
> People who demonstrate ongoing, meaningful clinical benefit (functionally and/ or cognitively stable) should continue on the medication with ongoing monitoring for continued benefit or the development of any adverse effects
Guidelines for deprescribing summary
What are behavioural symptoms associated with dementia?
physical aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviours, sexual disinhibition, hoarding, cursing and shadowing.
What are psychological symptoms associated with dementia?
anxiety, depressive mood, hallucinations and delusions
1st line treatment for psychological and behavioural symptoms?
Non-pharmacological approaches first line for responsive behaviours because of a favourable balance of benefits and harms
> Drug therapy should not be first-line for patients with responsive behaviours
Who are antipsychotics reserved for? What symptoms are they ineffective for? Why risk of AE so high?
Reserve for residents with distressing agitation, aggression, delusions or psychoses
- Ineffective in treating wandering or disinhibition
AE: increased risk of mortality, stroke and extrapyramidal symptoms
what antipsychotics to use for hallucinations, delusions or seriously disturbed behaviour?
Risperidone or olanzapine
AE of antipsychotics?
AEs frequent as antipsychotics affect multiple neurotransmitter receptor types and subtypes
- Common: sedation, anxiety, agitation, EPSE, orthostatic hypotension, tachycardia, sexual adverse effects, weight gain, hyperprolactinaemia (may result in galactorrhoea and/ or gynaecomastia)
> EPSE and orthostatic HTN with risperidone
> Olanzapine and some older agents: blurred vision, mydriasis, constipation, nausea, dry mouth, urinary retention
> Avoid typical antipsychotics in residents with Lewy bodies dementia or Parkinson’s disease –> worsen movement disorders
When is extrapyramidal side effects highest? What drugs to avoid?
Incidence dose-related
> highest with haloperidol, lowest with some of the newer agents
- Reduce antipsychotic dose to avoid recurrent EPSE when possible
- Avoid anticholinergic drugs (e.g. benztropine)
> may add to anticholinergic effects and worsen tardive dyskinesia and cognition
What are some extrapyramidal side effects that may be mistaken for responsive behaviours when using antipsychotics?
Dystonias
- Torticollis, carpopedal spasm, trismus, perioral spasm, oculogyric crisis, laryngeal spasm and opisthotonos
Akathisia
- Feeling of motor restlessness; usually occurs 2–3 days (up to several weeks) after starting treatment and may subside spontaneously
- May present as agitation secondary to psychosis
Parkinsonism
- Tremor, rigidity or bradykinesia; usually develops after weeks or months
Tardive dyskinesia
- Involuntary movements of the face, mouth or tongue, and sometimes head and neck, trunk or limbs
Clozapine, olanzapine and quetiapine, associated with?
increased blood glucose, weight gain and dyslipidaemia
- clozapine and olanzapine associated with increased risk of type 2 diabetes
Increased death rate in which antipsychotics?
Increased risk of fatal and non-fatal strokes and TIAs in which antispychotics?
Increased death rate noted in placebo-controlled trials of aripiprazole, olanzapine, quetiapine and risperidone in dementia patients (due to CVD events or infections)
Olanzapine and risperidone associated with increased risk of fatal and non-fatal strokes and TIAs
use for lowest possible dose and shortest amount of time
Risk of CVA increased for patients being treated with _________ for vascular or mixed dementia, compared with those taking it for Alzheimer’s dementia
Risperidone
> TGA approval for use in responsive behaviour is limited to treatment (up to 12 weeks) of moderate to severe dementia only of the Alzheimer type
What are other indications for risperidone?
- treatment of schizophrenia and related psychoses •
- short-term treatment of acute mania associated with bipolar 1 disorder •
- treatment of conduct and other disruptive behaviour disorders in children (>5y.o.), adolescents and adults with sub-average intellectual functioning or mental retardation in whom destructive behaviours are prominent •
- treatment of behavioural disorders associated with autism in children and adolescents
Points for withdrawal of antipsychotics?
- • Most responsive behaviours tend to be transient exacerbations
- Many will resolve naturally as dementia progresses •
- Regular monitoring and dose reduction/ withdrawal attempts should be undertaken to minimise exposure to antipsychotic use
- E.g. halve the dose every two weeks until the lowest possible dose is achieved, treat for a further two weeks then cease
- Antipsychotic treatment can always be reintroduced if required
How do BZDs work? what ar they used for? Which one to use?
Potentiate inhibitory effects of GABA throughout CNS –> results in anxiolytic, sedative, hypnotic, muscle relaxant and antiepileptic effects
- Short term use may assist some behavioural and psychological symptoms of dementia (BPSD), especially insomnia, anxiety, irritability and tension
- also use as premedication for anxiety-inducing events
> To relieve symptoms of severe anxiety and agitation, use: oxazepam 7.5 mg orally, 1 to 3 times daily
AE of BZD? What happens if used for more than 2 weeks?
Worsen cognitive impairment, impair gait and increase the risk of falls
- Particularly long-acting agents, such as nitrazepam and diazepam
- Associated with increased risk of hip fracture among older people by >50%
Use >2 weeks associated with tolerance to sedative effect
- Longer term use results in dependence
- Cognition and gait effects maintained
_____ ______ are often amongst the most difficult symptoms of dementia to adequately support. What medications have been used to try to alleviate these symptoms?
Responsive behaviouurs
- anticonvusaltant mood stabilisers, antidepressants, clonidine, cannabis, dextropropoxyphene
> citalopram for agitation has been shown to be effective
What is the most effective strategy for this: responsive behaviours are often amongst the most difficult symptoms of dementia to adequately support
Identifying and addressing the unmet need/ sources of responsive behaviour is typically the most effective strategy
> Specialist services are available for these situations –> DBMAS, SBRT, OAMHS
Comment on if the following CAM are useful in dementia:
A) Antioxidants
B) vitamins
C) gingko biloba
D) fish oil
Coconut oil • Tumeric • CoEnzyme Q10 • Phosphatidylserine = benefits are minimal, and not recommended
A)
- No convincing data to suggest that antioxidants can prevent AD
- Potential risks of premature death with high dose vitamin E supplementation
B)
- Low levels of folate, vitamin B6, and vitamin B12 associated with risk of dementia…
- .but supplementation does not seem to prevent or slow progression of dementia
C)
Ineffective in preventing progression to dementia in healthy people or those with mild cognitive impairment
- May increase bleeding risk in people taking antithrombotics (e.g. aspirin, warfarin)
D)
- Some observational evidence of minor benefit in preventing dementia, but this has not been replicated in prospective studies
- Clinical trials have found fish oil to be ineffective in treating dementia
What is Souvenaid? What may it do?
A nutritional drink containing a combination of fatty acids, vitamins and other nutrients
- Developed with the aim of preventing the loss of important connections between brain cells that occurs in Alzheimer’s disease.
- May slightly improve some kinds of memory in people in the early stages of Alzheimer’s disease or mild cognitive impairment
> No evidence that people who take Souvenaid are less likely to develop alzheimers.
> Expensive ($170/month)
Summary
- Development of disease- modifying treatments has been unsuccessful
- Current pharmacological treatments for dementia are generally of limited effectiveness
> This includes medications for both the cognitive and behavioural/ psychological aspects of the condition
- Any medication used in managing dementia symptoms requires regular review for ongoing effectiveness and adverse effects
> Particularly antipsychotics and other sedatives
