Dementia is an acquired syndrome of intellectual and emotional impairment that occurs due to a disease of the brain in which important and complex neurological functions such as memory, reasoning, perception, emotion, language, learning and judgement are affected. Although consciousness itself is not blurred, the loss of these “higher brain functions” is typically accompanied by deteriorations in motivation, social behaviour and the ability to carry out the activities of daily living (ADL).
Rough estimates suggest that 10 % of people over 65 years of age and approximately 20 % of individuals over the age of 80 will be affected by dementia. Presenile (early onset) dementia is a term used by clinicians to describe dementia in affected individuals under the age of 70 but the symptoms experienced by this group do not differ from those seen in the older age group. In global terms, these figures amount to an estimated 36 million people that currently suffer from dementia.
As the life expectancy of individuals in the industrialised world is increasing, this figure is thought to also increase by at least threefold in the next 100 years. Increased prevalence of dementia would generate a huge drain on financial resources required to meet the cost of caring for patients with dementia. Therefore, timely and appropriate intervention in terms of assessment and diagnosis, coupled with effective drug treatment will be of vital importance in offsetting the cost required for care, in addition to minimising the emotional and financial burden placed on family members.
Unfortunately, at present the early identification of dementia is hampered by the subtle nature of the disease and symptom variabilities experienced by patients at the onset of the disease. Moreover, the same person may suffer from more than one type of dementia, making it difficult to define the individual disease components of dementia. In those instances, the response to treatment in an individual with mixed dementias may significantly differ from that seen in a patient displaying symptoms of a single, well-defined cognitive disease. These factors make the diagnosis of dementia at an early stage extremely difficult. Nevertheless, there are a number of validated cognitive screening tests that are available. While not providing absolute diagnostic capabilities, these tests can help the clinician to determine whether or not the presenting patient requires referral for further specialist assessment. Furthermore, cognitive screening should be conducted along with routine blood tests in an attempt to rule out treatable potential causes of any presenting cognitive deficits (e.g. diabetes, thyroid disease, stroke, vitamin deficiencies, depression, high blood pressure and elevated cholesterol levels).
The biggest obstacle facing patients and clinicians is finding medicines that will appropriately manage the disease. Current medicines do not provide a cure or even halt or reverse the progressive nature of the disease but merely slow down the rate of neurological damage progression seen in dementia.
Alzheimer’s disease (AD) is thought to be responsible for an estimated 50-70 % of all cases of dementia and is characterised by a loss of cognitive function (memory loss, language difficulties and loss of planning, reasoning and logical thought processes), difficulties performing ADL (dressing, washing, eating unaided) and psychiatric/behavioural abnormalities (depression, delusions, social withdrawal and hallucinations). The memory loss typically seen in patients with Alzheimer’s disease is anterograde in nature, in other words, the patient finds it extremely difficult or impossible to remember current events or what they have just said or done. In contrast, retrograde memory (memory of past events such as childhood) is relatively well preserved.
Alzheimer’s disease is characterised by the destruction of nerves that release the neurochemical acetylcholine (Acetylcholine). Destruction of these so-called cholinergic nerves and the subsequent reduction of acetylcholine levels occur in areas of the brain responsible for learning and memory processes. Moreover, studies using brain samples from deceased patients with Alzheimer’s disease have consistently revealed the presence of protein-rich plaques and excessive deposits of the insoluble protein amyloid in the nerve cell body.
Despite a lack of evidence identifying a single abnormal event leading to the development of Alzheimer’s disease, several risk factors have been identified that increase the likelihood of an individual developing the disease. These include age (> 90 % of all Alzheimer’s disease cases occur in individuals over 60 years of age), head trauma/injury, high blood pressure, diabetes, depression and a family history of Alzheimer’s disease.
The increased risk of developing Alzheimer’s disease, if a family member has previously been diagnosed with the disease, points towards a genetic component playing an important role in the manifestation of the condition. Indeed, three genes (amyloid precursor protein, presenilin 1 and presenilin 2) have been identified in the development of early-onset Alzheimer’s disease. In contrast, only one gene (apolipoprotein E4) has been found to increase the risk of developing the disease in late onset Alzheimer’s disease. However there is controversy surrounding this gene as there is no connection between its presence and development of Alzheimer’s disease across all races (up to 50 % of white patients with Alzheimer’s disease do not carry the genetic component thought to be responsible).
Vascular dementia is a form of dementia caused by an interruption of normal blood supply to the brain that subsequently causes damage to the organ. It is thought to account for approximately 25 % of all European cases and can be distinguished from Alzheimer’s disease due to differences in its onset, clinical features and disease progression. Risk factors for this form of dementia include high blood pressure and cholesterol levels but it is most commonly encountered in patients who have undergone a stroke. The variability of symptoms encountered in this form of dementia is largely due to which part of the brain is damaged by the stroke(s).
Lewy body dementia (LBD) is attributed to an estimated 15 % of dementia cases in Europe. Lewy bodies are abnormal protein deposits that occur inside nerve cells (neurons) in the brain ultimately causing death of the nerve. In LBD the lewy bodies are accompanied by plaques and tangles that are similar to those seen in Alzheimer’s disease.
However, differences exist between LBD and Alzheimer’s disease as the plaques and tangles seen in Alzheimer’s disease are largely restricted to one area of the brain (the hippocampus and the surrounding parahippocampal gyrus) whereas in LBD these pathological markers are present throughout the whole brain.
Symptoms of LBD include fluctuating disruptions to memory, thought and perception processing, hallucinations and behavioural deficits.
Pick’s disease is the second most common presenile dementia (after Alzheimer’s disease) and is characterised by a progressive degeneration and shrinkage of brain tissue that is initially restricted to the brain tissue at the front and side of the head (frontotemporal regions of the cerebral cortex). In addition, patients with this disease have “Pick bodies” which are substances inside neurons that contain an abnormal amount (or form) of a specific protein called “tau”. Symptoms include personality changes (impulsiveness, abnormal/inappropriate social behaviour, apathy, compulsiveness) neurological changes (progressive memory loss, increased muscle tone) and difficulty speaking or understanding speech (aphasia).
Currently there are no drugs available that will halt or reverse the steady destructive processes that underly the disease cause (pathogenesis) of dementia. Instead, existing drug treatments serve to maintain some degree of cholinergic nerve activity and thereby delay the onset of symptoms seen with fully expressed dementia.
Drug treatment options available can be broadly divided into two classes:
Acetylcholine-Esterase Inhibitors (AchEI’s)
Drugs of this class maintain levels of cholinergic neuronal activity by blocking the activity of the enzyme Acetylcholine-Esterase (AchE), an enzyme in the brain whose primary function is to breakdown acetylcholine.
Inhibiting the breakdown of this important neurochemical allows it to act at its sites of action within the brain for longer thereby reducing the cognitive, emotional and behavioural deficits typically seen in dementia patients. Drugs currently used in this approach include donepezil, galantamine and rivastigmine. These agents reversibly inhibit acetylcholine-esterase and have been found to be well tolerated and offer improvements in cognitive and behavioural symptoms in mild to moderate Alzheimer’s disease. There appears to be little difference in clinical effectiveness between the acetylcholine-esterase inhibitors and patients intolerant of one particular drug may well find better suitability with another.
Side Effects of Acetylcholine-esterase inhibitors
The main problems encountered with the use of Acetylcholine-esterase inhibitors are that the heightened actions of acetylcholine are not exclusive to the brain. The autonomic nervous system that controls functions of non-conscious control such as heart rate, gut movement and gland secretions also has a component that is reliant on acetylcholine. Heightened effects of acetylcholine in the autonomic nervous system will cause the heart rate to decrease, increase salivation, stimulate gut movement and induce narrowing of the airways in the lung (bronchospasm). Consequently, most of the adverse effects of acetylcholine-esterase inhibitors result from increased action of acetylcholine outside the brain. These include: nausea/vomiting (especially at the start of therapy), shortness of breath, abnormal/irregular heartbeats, weight loss, sleep disturbances, headaches, diarrhoea and increased urinary frequency.
Cautions with Acetylcholine-esterase Inhibitors
Due to their actions on acetylcholine outside the brain acetylcholine-esterase inhibitors may slow the heart rate due an increased action of acetylcholine on cardiac muscle. This can have serious consequences in individuals in who suffer from certain heart conditions such as ‘sick sinus syndrome’ or other heartbeat abnormalities. Therefore drugs of this type should be used with extreme caution in affected individuals.
Narrowing of the lung airways is a consequence of increased actions of acetylcholine on lung smooth muscle. This can have dangerous implications in patients with pre-existing lung disorders such as asthma or chronic obstructive pulmonary disorder (Bronchitis and Emphysema).
Acetylcholine activity has a positive effect on gut movement and stomach acid secretion and is therefore advisable to be used with extreme caution in patients with a history of peptic ulcer disease.
Donezepil (Aricept, Aripez, Donesyn, Donecept)
Donezepil is a reversible inhibitor of Acetylcholine-esterase that is licensed for use in patients with mild to moderate Alzheimer’s disease. Typically, the starting dose is 5 mg taken once daily at bedtime for at least one month to allow for steady blood concentrations of drug to be reached and to assess for clinical effectiveness. In individuals in whom clinical benefit has not been found, the dose may be increased to a maximum of 10 mg taken once daily at bedtime.
As donepezil is broken down in the liver, individuals with liver damage are at risk of increased drug levels in the blood and of prolonged exposure thereby increasing the incidence of undesirable side-effects (typically nausea/vomiting, diarrhoea, headaches, sleep disturbances and muscle cramps). In affected patients, dose increases should be carefully monitored and conducted with regard to the individual’s tolerability to the drug.
Galantamine (Reminyl, Reminyl XL)
In addition to reversibly inhibiting acetylcholine-esterase, galantamine enhances brain cholinergic activity by increasing the potency of acetylcholine at its sites of action. Galantamine is used to treat mild to moderate Alzheimer’s disease with a starting daily dose of 8 mg/day in two divided doses (Reminyl) or as a single dose in the morning (Reminyl XL) with food to mimimise cholinergic side effects. Assessment of clinical response is usually carried out four weeks after drug initiation and if necessary the dose may be increased to 8 mg twice daily (Reminyl) or 16 mg once daily (Reminyl XL) for a further four-week assessment period.
Breakdown of galantamine is also by the liver and therefore individuals with liver damage are at risk of prolonged exposure to the drug and are more likely to encounter side effects (typically nausea/vomiting, weight loss, abdominal cramps and diarrhoea). Patients will usually experience nausea and vomiting when first starting the drug and therefore it is vital to ensure that adequate fluid intake is maintained during this time to prevent dehydration (i.e. drink plenty of water).
Galantamine is not recommended in patients with kidney damage, obstruction in urinary outflow e.g. enlarged prostate, or in those who have undergone recent bladder surgery.
Rivastigmine is clinically used for the treatment of mild to moderate Alzheimer’s disease and dementia associated with Parkinson’s disease of unknown cause. It sticks to acetylcholine-esterase and reduces its activity thereby promoting acetylcholine survival and prolonging its duration of action.
Initial treatment with rivastigmine is conducted at a dose of 1.5 mg twice a day with morning and evening meals. Subsequent dosage increases (if tolerated) should be conducted at least two weeks after initiation to allow for clinical evaluation of response to the initial drug dose. The dose may be doubled at intervals of no less than two weeks up to a maximum of 12 mg/day depending on clinical response and side-effects.
A transdermal patch is available that gradually releases rivastigmine through the skin and into the blood supply over a period of time. This formulation allows the patient to be exposed to the drug at a more gradual rate than would be experienced following taking tablets or capsules. Gradually increasing drug levels combined with tighter control over fluctuations in blood levels of the drug may offer greater tolerability in patients.
When switching from the capsule to the patch formulation, the concentration of patch used is determined by the dose and tolerability of the capsule used immediately prior to the switchover. Patients who previously took capsules at a dose of 3-6 mg/day (or who could not tolerate 9 mg daily) should be started on the 4.6 g/24 hour patch. Individuals who could tolerate doses of 9-12 mg daily should be switched to the 9.5 mg/24 hour patch. In all cases, the first patch should be applied 24 hours following the last oral dose of medication.
The patch is typically applied to clean, dry, non-hairy, non-irritated skin on the arms, back or chest and left in place for 24 hours before removal and replacement of a new patch at a different site on the body (current guidelines suggest avoidance of a previously used area for 14 days).
Levels of glutamate in the brains of dementia patients are significantly raised and are thought to cause pro-dementia effects, at least in part, via the activation of one subtype of glutamate receptor – the N-Methyl D-Aspartate (NMDA) receptor. Prolonged and repetitive activation of the NMDA receptor is thought to cause a cascade of events that result in acetylcholine death and brain dysfunction.
Glutamate is the most common excitatory neurochemical in the human brain and therefore reduction of glutamate activity can have wide-ranging and potentially serious consequences.
Memantine blocks NMDA receptors via a “use dependent” mechanism whereby the drug can only elicit its effects once the NMDA receptor has been activated by glutamate. NMDA receptors that are activated by glutamate will be more likely to be blocked by memantine than those undergoing normal levels of stimulation. Memantine is licensed for use in moderate to severe dementia in Alzheimer’s disease and typically involves a starting dose of 5 mg/day that can be increased weekly in 5 mg increments up to a maximum of 20 mg/day.
Side effects of memantine include high blood pressure, constipation, drowsiness and headache.
It is estimated that up to 90 % of all dementia patients exhibit behavioural and psychological deficits in parallel to their cognitive decline. Accompanying symptoms often include depression, anxiety, agitation, psychosis, social withdrawal and apathy. Clinical evaluation of these co-existing medical conditions with appropriate and patient-specific drug treatment (e.g. the use of antidepressants to treat accompanying depression) may prove beneficial to the patient and may offset some of the burden placed on patient carers.
Non-medicinal approaches to dementia management should be explored prior to the initiation of drug treatment particularly when a definitive diagnosis of the dementia being presented has not been achieved and where the symptoms are not causing distress to the patient or associated family members.
Although non-drug approaches have been proven to be ineffective in treating established memory deficits in dementia patients, undertaking recreational pursuits, physical exercise, memory stimulation and retraining techniques have been shown to offer support and improve the sense of well being in individuals with mild dementia. This is important as improving the patient’s sense of self may offset the anxiety and/or depression that often accompanies this condition.
Analysis of accompanying medical conditions, lifestyle or dietary factors that increase the likelihood of cognitive decline should be reviewed and addressed.
Regardless of the strategy adopted, any non-drug approach should be tailored to meet the specific needs of the individual. Good communication between the patient, their family and the healthcare professional coupled with close and frequent interaction is essential in the early stages of dementia management. This approach will lay the foundations of support; not only for the patient, but also for the patient’s family and carers, many of whom may require continued medical support after the patient has been entered into residential care.
Prof. Peter Weedle is a community pharmacist and adjunct Professor of Clinical Practice at the School of Pharmacy, University College Cork. Peter has a wide range of interests in the area of pharmacy but in particular, medicine use by the elderly, drug interactions, legal and ethical matters. He is co-author of two books: Pharmacy and Medicines Law in Ireland and Medicines: A guide for everybody. This series is based on Medicines: A guide for everybody which was originally published by Penguin, London. Peter can be contacted at: email@example.com
Dr. Mark Ledwidge is a pharmacist with a research and teaching interest in Cardiovascular Disease. In particular, his interests include medication adherence in chronic illness, telemedicine and cardiovascular therapeutics. He is Director of Heart Failure Research in St Vincent’s University Hospital and Adjunct Senior Lecturer in the School of Medicine in University College, Dublin.
Dr. Andrew Fisher is a community pharmacist in Cork City, with an extensive research background in neurological disorder and disease. His particular areas of interest include the pathophysiology and treatment of basal ganglia disorders and epilepsy. Andrew has a wide range of interests within the field of pharmacy including patient compliance, pharmacovigilance and therapeutic drug monitoring.
Mr. Nigel Moloney is a Superintendent Pharmacist in Cork city. Nigel comes from a UK Hospital Pharmacy background and his primary interests are in Acute Medicine, Psychiatry and Risk Management. Nigel has published articles in the scientific press on Risk Management Quantification and Communication between Primary and Secondary Care.
Dr. John McAninly is a community pharmacist in Mallow, Co. Cork who worked in hospital and community pharmacy in the UK, before moving to Ireland. As a former teacher he has a special interest in pharmacy education.
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