Cognitive Enhancers

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Cognitive Enhancers
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Dementia

• A syndrome due to disease of the brain,
  characterised by progressive, global
  deterioration in intellect including
• Memory
• Learning
• Orientation
• Language
• Comprehension
• Judgement

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Dementia

• Mainly affects older people
• 2 - 10 of all cases start before the age of 65
• After this prevalence doubles with every 5 year
  increment in age
• Dementia is one of the major causes of disability
  in later life.
• World Alzheimer Report 2009

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Dementia subtypes
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• In general the order in which symptoms become
  apparent, and their severity depends on the
  aetiology of the dementia

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Plaques and Tangles

• video

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The role of Neurotransmitters in memory

• 1985 small trial of Tacrine (Cognex)
• approved for clinical use in 1993
• modestly improved memory in people with AD but
  significant effect on liver function
• Since superseded by donezepil, rivastigmine,
  galantamine and memantine.

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The role of Neurotransmitters in memory

• The role of acetylcholine in cognition and memory
  formation is well established. In early stages of
  AD levels of Acetylcholine are reduced.
• Acetylcholinesterase breaks down acetylcholine in
  the synaptic cleft
• Acetylcholinesterase inhibitors eg Donepezil
  (Aricept) prevent this action, thereby increasing
  levels of acetylcholine.

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Cognitive EnhancersCholinesterase inhibitors

• Donepezil, galantamine and rivastigmine are used
  in the treatment of mild to moderate dementia due
  to Alzheimer's disease and may be helpful in the
  treatment of dementia with Lewy bodies. They
  enhance cholinergic function in the CNS through
  reversible inhibition of acetylcholinesterase.

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Cognitive EnhancersCholinesterase inhibitors

• There are few comparative trials of
  anticholinesterases. Donepezil, rivastigmine and
  galantamine seem to have similar efficacy, but at
  full dose oral rivastigmine may have more GI
  adverse effects.

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Cognitive EnhancersCholinesterase inhibitors

• Deterioration of cognition is delayed by 6 months
  in 2550 of patients, and by 1 year in 1220 of
  patients with mild-to-moderate Alzheimers
  disease. As there are no reliable predictors of
  response, carefully assess benefit after 3 months
  of treatment at full or highest tolerated dose.
  Stop treatment if there are significant adverse
  effects, poor compliance or lack of stabilisation
  or improvement of symptoms.

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Cognitive EnhancersCholinesterase inhibitors

• Limited data show that some patients unresponsive
  to one anticholinesterase show improvement when
  switched to another.

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Cognitive EnhancersCholinesterase inhibitors

• Cognition. Cholinesterase inhibitors improve
  cognition (memory, thinking, and language) in
  about two thirds of people with Alzheimers
  disease and may slow cognitive decline in some.
  If a patient does improve, the amount of
  improvement over one year is roughly equal to the
  amount of decline typically observed in untreated
  people with Alzheimers disease over 8 to 12
  months.

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• Daily function and behavior. Cholinesterase
  inhibitors and Memantine can also help with
  deficits in daily functioning and behaviour that
  are prevalent in people with Alzheimers disease.
  Even small improvements in daily functioning and
  behaviour are important because these problems
  are major reasons why caregivers end up placing
  Alzheimers disease patients in nursing homes.

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Common Adverse EffectsDonepezil,
Rivastigmine,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

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Common Adverse EffectsDonepezil and Rivastigmine

• Contraindications
• Liver disease
• Peptic ulcer
• Hypersensitivity
• Pregnancy
• Problematic for
• Asthma, seizures, bradycardia, cardiac conduction
  disorders

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The role of Neurotransmitters in memory

• Glutamate -Excitatory neurotransmitter, allows
  Ca to enter cell, exciting the neuron.
  Excitatory activity, if excessive, leads to
  neuronal cell death
• Memantine (Ebixa) is a glutamate receptor
  antagonist which addresses the excitotoxic
  effects of glutamate by occupying NMDA receptor
  sites.
• Memantine displaces mag from N-Methyl-D-Aspartat
  e (NMDA) receptors,thus moderating the excitatory
  effect of glutamate

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The role of Neurotransmitters in memory cont.

• Memantine indicated for moderate to severe AD
• Common adverse effects include confusion,
  dizziness, drowsiness, headache, insomnia,
  agitation and hallucinations.

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Cognitive EnhancersNMDA antagonist

• Memantine, an antagonist of N-methyl-D-aspartate
  (NMDA), is a treatment for moderate to severe
  Alzheimer's disease and is thought to protect
  neurones from overstimulation and excitatory
  damage associated with glutamate transmission and
  calcium overload.

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Memantine

• Adverse effects
• Common
• confusion, dizziness, drowsiness, headache,
  insomnia, agitation, hallucinations, dyspnoea
• Infrequent
• vomiting, anxiety, hypertonia, VTE
• Rare
• seizures, rash, renal failure, cholestatic
  hepatitis, heart failure, bradycardia

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References

• Australian Medicines Handbook
• http//www.amh.net.au/online/view.php
• Therapeutic Guidelines (Psychotropic) eTG
  Complete July 2010
• http//online.tg.org.au/ip/
• Fundamentals of Pharmacology 5th Ed. Bullock.S.,
  Manias,E., Galbraith,A.,Pearson Education
  Australia.