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The fourth of our series of articles on mental health reviews dementia, in particular Alzheimer’s disease.

Key Points

• Four types of dementia contribute to 90 per cent of the cases seen: Alzheimer’s disease is the most common and affects memory as well as language, behaviour and performance of tasks.

• In Alzheimer’s disease there is a progressive loss of acetylcholine nerve cells in the brain.

• Common treatment strategies attempt to reduce the decline of function by enhancing remaining acetylcholine.

• Cholinesterase inhibitors have numerous side effects and should not be used in some co-morbid conditions.

• Pharmacists can play a role in the management of patients with dementia by monitoring on an informal basis to ensure treatment is appropriate, and to avoid interactions.

Reflect

What is the rationale behind the drugs used in Alzheimer’s disease? What are their potential side effects and what are the main drug interactions? What is Lewy body dementia?

Plan

This article describes the four most common types of dementia, particularly Alzheimer’s disease and the drugs used in its management.

Act

• Read the BNF section on drugs for dementia, noting in particular the starting doses and how they should be increased.

• Find out more about the difference between memantine and the anticholinesterases, and list the drugs with which memantine might interact.

• Read the Nice quick reference guide (September 2007) on drugs used in

Alzheimer’s disease (www.nice.org.uk/cg42) , which gives recommendations on

their NHS availability.

• Check your PMRs for people taking drugs for dementia. Are any other drugs being prescribed at the same time? If so, can you simplify the regimens to make it easier for patients or their carers to remember?

• Check if any of these patients are also taking prescription medicines with anticholinergic side effects, such as antidepressants or antipsychotics. What should you do about this?

• Some OTC medicines have anticholinergic side effects. Make a note of those that should be used with caution or avoided in Alzheimer’s disease. Add this to your relevant patient records.

• Look at the Alzheimer’s Society website (www.alzheimers.org.uk) for factsheets that might be useful to patients or their carers. Read about the different types of dementia, its diagnosis and progression, risk factors and tips for reducing risks.

Make a note of the Alzheimer’s Society helpline and your local branch for possible future reference.

Evaluate

• Could you answer queries on drugs used in Alzheimer’s disease, how they act and their side effects, as well as their NHS availability?

CPD - The College of Pharmacy Practice: 

This course (Module 1441), in association with multiple choice questions being published in C+D July 5, provides one hour’s continuing education. This article can help in the following CPD competencies: G1a, G1c, G1e, G1f, C1a, C1c, C3b.

Update

One of the greatest fears that individuals may have of increasing age is the likelihood of dementia. Remembering everyday details seems to become more difficult as we get older, but this is not quite the same as dementia, which is a term used to describe gradual long-term disruption of a range of key brain functions, including memory. It also affects language, emotion, personality and visuospatial skills.

Memory loss is key to the common perception of dementia, but it is characteristically different from the routinely encountered ‘senior moments’. To lose your keys or forget someone’s name are common examples of age-related memory loss. Unfortunately in dementia, the individual is more likely to forget what the keys are for or who the person is. This is particularly disturbing when it is somebody close, such as a spouse or relative.

It is the loss of the individual personality, the essence of being, that makes us people and makes dementia especially upsetting for the relatives caring for that individual.

Types of dementia

Four different dementia illnesses account for 90 per cent of cases encountered:

Alzheimer’s disease - 50 per cent

Lewy body dementia - 15 per cent

Frontal temporal dementia - 15 per cent

Vascular dementia - 10 per cent

Alzheimer’s disease is characterised by difficulty in learning and retaining new information. Over time there are also difficulties with calculation, visuospatial skills, performance of tasks and language.

Lewy body dementia is characterised by the presence in the brain of Lewy bodies – small, spherical, protein deposits. The condition has similar symptoms to those for Alzheimer’s, in respect of cognitive dysfunction. However, visual hallucinations and features of Parkinson’s disease can also occur. Lewy bodies are found in patients with Parkinson’s disease, and PD patients can develop a form of dementia similar to Lewy body dementia. This suggests a possible link between the two conditions.

Frontotemporal dementia is characterised by earlier onset of behavioural changes, while visuospatial skills are still intact. An individual may exhibit poor hygiene, lack of social tact and possible sexual disinhibition.

Vascular dementia results from interruption of blood supply to the brain, either as a result of haemorrhagic or ischaemic events. Along with symptoms of cognitive decline, there may be symptoms suggestive of a stroke. Sometimes patients with vascular dementia will have periods of stability followed by sudden declines in cognitive function, correlating to another cerebral vascular event occurring.

The remaining 10 per cent of dementia cases are made up of a range of diverse disorders such as Creutzfeld-Jakob disease, Aids-related dementia and Huntington’s disease. The rest of this article will focus upon Alzheimer’s disease as this is the most prevalent form of dementia.

Alzheimer’s disease

In Alzheimer’s disease there is general shrinkage (atrophy) of the brain, especially in the frontal, parietal and temporal lobes in areas responsible for functions such as memory, personality, speech and language. Overall brain volume may be reduced by as much as 15 per cent, with a corresponding reduction of central neurones and reduced neurotransmitter levels, particularly acetylcholine.

A key finding on post-mortem is widespread neurofibrillary tangles and neuritic (senile) plaques – the remains of defective or dying nerve cells. They are associated with normal ageing but in Alzheimer’s disease greater numbers are found and their occurrence corresponds with disease duration, severity and presence of greatest nerve cell loss.

Neurotransmitter hypothesis

Cholinergic neurones, which utilise acetylcholine as the key neurotransmitter, are crucial to cognitive functions including memory. Depletion of cholinergic nerve cells and corresponding decline in neurotransmitter level correlates with the loss of memory and cognitive decline.

By the time mild symptoms of Alzheimer’s disease are detectable, significant loss of acetylcholine will already have occurred. Often the level of acetycholine will have halved before a diagnosis is made or treatment is commenced, but in moderate to severe disease the levels may have reduced by anything between 40 and 90 per cent. This is important to remember when considering the current treatment strategies for managing Alzheimer’s disease, as most rely on enhancement of existing acetycholine for their therapeutic effect.

Progression and staging

Table 1 outlines how symptoms develop in Alzheimer’s disease as the illness progresses with continued loss of nerve cell function.

The Mini Mental State Examination (MMSE) is a brief, 30 point questionnaire for assessing cognitive function. Different questions and tasks are used to assess a range of functions including orientation, recall, spatial perception and simple arithmetic. Possible scores range from 0 to 30 and, although some debate exists, a score less than 24 is suggestive of mild cognitive decline. Scores between 10 and 20 suggest moderately severe cognitive decline, while a score of less than 10 indicates severe decline. Although the MMSE is not perfect, and is influenced by premorbid educational level, it is nevertheless widely used in both psychiatry and general medicine.

After establishing the presence of impaired memory and cognition, Alzheimer’s disease is usually diagnosed only after other causes have been excluded, eg general medical conditions or psychiatric disorders that might reduce cognitive function.

Treatment strategies

As yet there are no treatments for Alzheimer’s disease or any other forms of dementia. Nothing has been discovered that can reverse or even halt the decline of brain function. Current drug strategies slow disease progression and may bring about some degree of symptomatic improvement in the initial stages of therapy.

Unfortunately the disease will progress, and ultimately the individual will continue to experience decline in memory and cognitive function.

Cholinesterase inhibitors (ChEIs)

This group of drugs forms the mainstay of symptom management in Alzheimer’s disease. In clinical trials they have been found to produce significant, although clinically modest, effects on cognitive function. Often the trials have been criticised because of their short duration and other methodological flaws.

The therapeutic effect of this class of drugs is thought to result from inhibition of the enzyme cholinesterase, which is responsible for cleavage of acetylcholine in the nerve synapse – inhibiting this enzyme is believed to enhance remaining neurotransmitter levels.

Table 2 details specific examples of ChEIs and some of their side effects, which are due to increased acetylcholine levels outside the CNS.

Although the three ChEIs are fairly similar, subtle differences do exist in terms of individual tolerability and prescribing. For example, donepezil and galantamine are both hepatically metabolised and can form the substrate for drug interactions mediated via hepatic enzymes (specifically CYP2D6 or CYP3A4). Rivastigmine is not hepatically metabolised so does not have the same interaction potential.

The ChEIs are licensed only for the treatment of Alzheimer’s disease. There is growing support for their use in other dementia types, particularly vascular and Lewy body dementias. Such off-label use is difficult to justify within the NHS when Nice strictly controls the use of these agents for their licensed indication.

Memantine

Memantine has a different mechanism of action from the ChEIs. It reduces the cascade of nerve cell death that is thought to contribute to dementia disease progression. It is licensed for use in severe Alzheimer’s disease, where the effect of enhancing acetylcholine levels is minimal following a large decline in neurotransmitter level. The most common adverse effects of memantine are hallucinations, confusion, dizziness, headache or drowsiness.

What does Nice say?

Despite considerable controversy and objections from professional groups, patient groups and pharmaceutical companies, Nice has maintained its recommendations on the pharmacological interventions for the cognitive symptoms of Alzheimer’s disease.

Donepezil, galantamine and rivastigmine can be used in disease of moderate severity only (MMSE score 10-20), providing they are initiated by specialists in the care of dementia and that patients are reviewed at least six-monthly.

Memantine can only be initiated for moderate to severe dementia if this is part of a well designed clinical study.

These prescribing guidelines do not reflect concern over the safety of these drugs, rather they are an attempt to ensure good economic return on NHS investment.

Drug interactions

As previously mentioned, drugs that inhibit or induce the activity of hepatic enzymes (CYP2D6 or CYP3A4) can either increase the activity of ChEIs, which will lead to greater side effects, or reduce their activity, possibly resulting in a loss of effect. Rivastigmine is not hepatically metabolised so will not be affected by these interactions. Table 3 gives examples of drugs likely to alter hepatic enzyme activity.

There is a potential for all ChEIs to interact with any medicine that inhibits cholinergic activity. Such medicines may be specific antimuscarinics, eg procyclidine or oxybutynin. The use of anticholinergic medicines in a patient with cognitive dysfunction is questionable, regardless of whether they are prescribed a ChEI or not. Some anticholinergic medicines will affect central acetycholine function and can lead to reduced cognition even in otherwise healthy adult patients.


Table 1: The development of symptoms in Alzheimer’s disease – illness stage and clinical presentation

Further reading

Nice Clinical Guideline 42 – Supporting People with Dementia and their Carers in Health and Social Care

Table 2: Cholinesterase inhibitors and their potential side effects

This table is not a complete list. It illustrates some of the commonly encountered enzyme inhibitors or inducers of CYP2D6 or CYP3A4


Stuart Gill-Banham MRPharmS, MCMHP, is a clinical lecturer at Medway School of Pharmacy. From 2003 to 2007 he was registrar of the College of Mental Health Pharmacists.