Cognitive Enhancers

1. Cognitive Enhancers

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

3. 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

4. Dementia subtypes

5. In general the order in which symptoms become apparent, and their severity depends on the aetiology of the dementia

6. Plaques and Tangles • video

7. 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for clinical use in 1993 • modestly improved memory in people with AD but significant effect on liver function • Since superseded by donezepil, rivastigmine, galantamine and memantine.

8. 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.

10. 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.

11. 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.

12. Cognitive EnhancersCholinesterase inhibitors • Deterioration of cognition is delayed by 6 months in 25–50% of patients, and by 1 year in 12–20% of patients with mild-to-moderate Alzheimer’s 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.

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

14. Cognitive EnhancersCholinesterase inhibitors • Cognition. Cholinesterase inhibitors improve cognition (memory, thinking, and language) in about two thirds of people with Alzheimer’s 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 Alzheimer’s disease over 8 to 12 months.

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

16. 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

17. Common Adverse EffectsDonepezil and Rivastigmine • Contraindications • Liver disease • Peptic ulcer • Hypersensitivity • Pregnancy • Problematic for • Asthma, seizures, bradycardia, cardiac conduction disorders

18. 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-Aspartate (NMDA) receptors,thus moderating the excitatory effect of glutamate

19. 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.

21. 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.

22. 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

23. 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.