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Graylands Hospital Drug Bulletin November 2016 Vol 23 No.3 Page 1 Graylands Hospital Drug Bulletin Anti -dementia drugs: Are they worthwhile? North Metropolitan Area Health Service - Mental Health November 2016 Vol 23 No.3 ISSN 1323-1251 Introduction aim to slow the progression and improve Dementia is a neurodegenerative disorder symptoms relating to behaviour, function 1 which leads to a decline in areas of cognition, and cognition. Beneficial effects from these including memory, communication, drugs may only been seen after 3-6 months attention, thinking and judgement.1, 2 The of therapy and adverse effects are common most common types of dementias are which can significantly reduce tolerance to 4 Alzheimer’s disease (AD), vascular dementia treatment. Currently, the evidence only and dementia with Lewy bodies. Dementia shows possible benefits of the use of these can also be present in other neurological drugs in AD, dementia with Lewy bodies and 5 disorders such as Parkinson’s disease and Parkinson’s disease dementia. The use of Huntington’s disease. cognitive enhancers in mild cognitive 6 impairment has not shown any benefits. This In February 2016, the National Health and drug bulletin aims to investigate the value of Medical Research Council (NHMRC) approved anticholinesterase inhibitors and NMDA the recommendations from the first antagonists in AD. Australian clinical practice guidelines for dementia. The guidelines and Anticholinesterase NMDA antagonists recommendations are available at this Inhibitors address: Donepezil (Aricept ®) Memantine (Ebixa ®) https://www.clinicalguidelines.gov.au/portal Galantamine (Reminyl ®) /2503/clinical-practice-guidelines-and- principles-care-people-dementia Rivastigmine (Exelon ®) Non-pharmacological treatment should be Table 1: Classes of drugs to treat AD first choice in managing dementia and includes measures such as adjusting the patients’ environment to ensure patient Anticholinesterase inhibitors safety, involving them in appropriate Although the exact aetiology of AD is activities and providing support to the family unknown, decline in the activity of the and carers. 3 The use of sedative and enzyme responsible for the synthesis of the cholinergic drugs should also be reviewed neurotransmitter acetylcholine (choline 1, 3 acetyltransferase) has been associated with and ceased if appropriate. 7 decline in cognition. It is not considered a cause of AD but does provide a target for the There are only two different classes of drugs 7 that are currently marketed for the treatment of AD. treatment of AD: anticholinesterase Anticholinesterase inhibitors prevent the inhibitors (donepezil, galantamine and breakdown of acetylcholine by rivastigmine) and N-methyl-D-aspartate acetylcholinesterases in the neuronal synapse, increasing the levels of (NMDA) antagonists (memantine). These 2, 8 drugs do not prevent or cure the disease but acetylcholine. Oral donepezil and Graylands Hospital Drug Bulletin November 2016 Vol 23 No.3 Page 1 galantamine, as well as rivastigmine patches outcomes.6, 9, 10 A dose of 10 mg has only are first line agents for AD. Oral rivastigmine been shown to be marginally more beneficial is considered second line. 14 than a dose of 5 mg but is associated with an increased incidence of adverse effects and The side effect profiles for the increased cost. A dose of 5 mg could, anticholinesterase inhibitors are very similar. therefore, be a better option for patients. 6 The most frequently reported are A trial of 23 mg daily failed to find superiority gastrointestinal side effects which are dose- over lower doses on the predefined related and can be managed by either measures. 7, 10 Despite this, the United States reducing the dose of the medication or Food and Drug Administration (FDA) have slower titration. See Table 2 for the approved high dose (23 mg) donepezil for precautions, contraindications and adverse use in patients with AD. The use of this effects of the acetylcholinesterase inhibitors. higher dose is not approved in Australia. If treatment with these drugs is interrupted Table 2: Acetylcholinesterase inhibitors precautions, contraindications and adverse effects 2 Precautions: History of peptic ulcer disease, seizures, heart Risk of aggravation block, bradyarrhythmias, Parkinson’s disease, asthma, obstructive pulmonary disease Treatment with anticholinergic drugs Antagonises action of anticholinesterases Treatment with drugs that can cause Increased risk of bradycardia and bradycardia hypotension Contraindications: Gastrointestinal or ureteric o bstruction Active peptic ulcer Adverse effects: 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, fainting Infrequent/Rare: bradycardia, heart block, seizure, agitation, hallucination, confusion, GI haemorrhage for several days, it is recommended that the It is recommended that donepezil (Aricept ®) patient recommence the medication at the be commenced at a dose of 5 mg a day and initial starting dose to reduce the incidence maintained for at least one month to allow 4 of side effects. the earliest clinical responses to be assessed. 11 The Aricept ® product Donepezil information mentions that the dose may be A recent meta-analysis showed that increased to 10 mg even though there is no donepezil at doses of 5 and 10 mg can statistically significant evidence that a improve cognitive function compared to greater treatment effect is obtained from the placebo at the 24-26 week mark by -1.95 and use of the 10 mg dose.11 -2.48 weighted mean difference (WMD), 8 Donepezil should be given in the evening; respectively, using the ADAS-Cog scale. however, patients who experience insomnia Improvements in global clinical state have or vivid dreams - or where adherence to been observed with both strengths and medication in the evening is inconsistent - modest benefits in behaviours have been consider giving the medication in the established. However, minimal, if any morning. 8 benefit, was observed for functional Graylands Hospital Drug Bulletin November 2016 Vol 23 No.3 Page 2 Galantamine Rivastigmine Evidence for improvement in cognitive Some benefits have been seen with 6 to 12 function compared to placebo after six mg orally per day and the 9.5 mg/24 hour months has been shown from all strengths of patch compared to placebo. Benefit has been galantamine. 12, 13 Based on the lack of a observed in areas of cognitive function statistical dose-response relationship for (WMD -1.79 on ADAS-cog scale), activities of efficacy and the relative incidence of side- daily living and the physicians rated global effects at each dose, a Cochrane review impression of change but Rivastigmine at this recommended the 16 mg/day dose as the dose, was unable to demonstrate most preferable initially. 12 The manufacturer, improvement in behavioural symptoms or however, continues to recommend an 8 mg impact on carers.14 The patches were starting dose. 13 associated with a lower incidence of gastrointestinal side effects with similar Galantamine (Reminyl ®) is a controlled- efficacy to the oral formulation. 14 Lower oral release capsule, available as an 8 mg, 16 mg doses of 1 to 4 mg and the 4.6 mg/24 hour or 24 mg strength. It should be noted that patch had much smaller benefits in cognition the majority of the studies viewed used and had no difference on activities of daily immediate-release galantamine and twice- living compared with placebo. 9, 14, 15 daily dosing. However, there appears to be similar efficacy and incidence of side-effects Rivastigmine (Exelon ®) is available as a between twice-daily dosing and the capsule and a patch. Since the rivastigmine prolonged-release once-daily dosing. 13 patches are of similar efficacy to the oral form 16 and have a lower incidence of side- The maximum dose of galantamine is 24 mg effects, the patches are considered one of per day. Patients should try to take this the first-line treatments in the treatment of medication with food in the morning and Alzheimer’s disease. 15-17 A patient drink plenty of fluids whilst been treated with commencing rivastigmine patches should this medicine. If a patient has swallowing initially receive the 4.6 mg/24 hour patch and difficulties, the capsule can be opened, the apply it once-daily for 24 hours. After four pellets mixed with a small amount of yoghurt weeks, the 9.6 mg/24 hour patch can be used or apple puree and the mixture then and this dose can be maintained if tolerated. swallowed without chewing the pellets. 13 Patches should be applied to the back, upper arm or chest, and the site of application Galantamine is contraindicated when should be rotated to avoid using the same creatinine clearance is less than 10 mL/min, area in a two-week period. 15 and in moderate hepatic impairment the dose should be reduced by half. It can cause Rivastigmine capsules should be taken twice- serious skin reactions including Stevens- daily with morning and evening meals to Johnson syndrome therefore, patients should reduce gastrointestinal side effects. 17 Due to be monitored for skin rash. Galantamine is the high incidence of gastrointestinal side substrate of CYP2D6 and CYP3A4. When effects with oral rivastigmine, it is using galantamine in combination with drugs recommended the weight of the patient be that inhibit these enzymes, there is an monitored and significant weight loss be increased risk of side-effects; a lower dose reported to medical practitioner.16
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