What effect do drugs from the dopaminergic system have on working memory?
• DA antagonists, 6-OHDA lesions of prefrontal cortex impair WMF
• DA agonists reported to both improve and impair WMF
• Optimal level of activity required for optimal WMF performance
• Improvements best observed in patients with impaired DA function
• Dopaminergic deficits in prefrontal cortex believed responsible for cognitive symptoms in schizophrenia
What effects does Bromocriptine have on working memory?
• Improved WMF reported but associated with side effects and drop outs (nausea, sedation)
What affects can amphetamines have on working memory?
• COMT allele variation in effect
- val/val allele associated with increased prefrontal cortex DA catabolism vs met/met
- val/val = poorer WMF vs met/met
- val/val improved with amphetamine, met/met performance was impaired
What affect does levodopa have on working memory?
• Reported to improve WMF in Parkinson's Disease
What affects do drugs like CLONIDINE and GUANFACINE from the noradrenergic system have on working memory?
• Alpha-2 adrenergic (partial) agonists reported to improve WMF
• Long term treatment with clonidine reported to improve WMF in schizophrenics
• Impaired function seems key to observing improvements
- (i.e. no good for healthy students taking exams!
What are some non-pharmacological ways of preventing dementia?
• Mental stimulation
• Activity is protective factor for cognitive decline and dementia
What are some non-pharmacological treatments of dementia?
- Music, touch, tactile stimulation, aromas, pets, relaxation, Eden Alternative, etc
• Reality orientation
• Validation therapy
• Reminiscence therapy
• Memory training
- Light therapy
Briefly describe some pharmocological options to treat both the cognitive and non-cognitive symptoms of dementia;
- Depression, anxiety, agitation, aggression, psychoses, sleep and appetite disturbances
- Memory impairment, attention, language problems, orientation, praxis
• Anticholinesterases, e.g. rivastigmine, donepezil
• Glutamatergics, e.g. memantine (Ebixa)
• Combined donepezil and memantine?
What are some issues with prescribing drug treatments for dementia?
• None of them work very well.
• Very expensive
• Use characterised by desperate need to do something, not by clinical improvement
• Strict criteria for PBS availability - still can get prescribed privately if pay full price
What are the three psychoanaleptics available on PBS?
What is the mechanism of action of DONEPEZIL (ARICEPT)?
• Selective acetylcholinesterase inhibitor
• More specific for CNS Ach
What are some of the side-effects of DONEPEZIL (ARICEPT)?
• Most common
- N&V, diarrhoea, anorexia, headache, dizziness
• Less common
- Abdominal pains, dyspepsia, fatigue, muscle cramps, sweating, urinary incontinence,
- Tremor, impaired mobility
- Syncope, bradycardia
- Insomnia, drowsiness
- Depression, agitation, hallucination, seizure
What are the interactions, cautions and contraindications of DONEPEZIL (ARICEPT)?
• Caution with bradyarrhythmias, PD, asthma, COPD
• Not recommended for vascular dementia
• Avoid concomitant anticholinergic drugs
• No hepatotoxicity
• Drug interactions - CYP3A4 substrate
What is the mechanism of action of RIVASTIGMINE (EXELON)?
• "Pseudo-irreversible" selective inhibitor of acetylcholinesterase & butyryl-cholinesterase
• Fewer interactions
What are the side-effects of RIVASTIGMINE (EXELON)?
• Nausea, vomiting, diarrhoea, abdominal pain, dizziness, headache and anorexia
What is the mechanism of action and effect of GALANTAMINE?
• Competitive, reversible inhibitor of actylcholinesterase
• Nicotinic acid receptor blocker
• Improves cognition, behaviour, ADLs
What are the side-effects of GALANTAMINE?
• N&V, anorexia, diarrhoea and weight loss
What types of dementia is GALANTAMINE most effective in treating?
• Effective in AD with cerebrovascular disease or probable vascular dementia
What is the mechanism of action of MEMANTINE (EBIXA)?
• Uncompetitive antagonist at NMDA glutamate receptor
- Glutamate released in excess amounts by cells damaged by Alzheimer's disease leading to Ca2+-mediated neurotoxicity
• Non-competitive antagonist nicotinic acetylcholinergic receptors
• D2 agonist
What type of dementia is MEMANTINE most effective in treating?
• Treatment of moderately severe to severe AD
• Slows the progress of symptoms in some patients with more severe disease
What is the major problem with prescribing acetylcholinesterase inhibitors?
• 5-11% of patients can withdraw from treatment due to ADRs
• Least = donepezil
What drugs produce agitation?
• Anticholinergic drugs
• Antihypertensive agents
- Agonists - bromocriptine
- Antagonists - metoclopramide
• Stimulants, e.g. caffeine
• Digoxin (especially at levels > 1.5mg/L)
• H2 antagonists (especially cimetidine)
What drugs are used to treat agitation and what are the issues to consider when prescribing them?
• Antipsychotics, e.g. risperidone
- Cerebrovascular events
- 3-fold increase risk of stroke
- Extrapyramidal effects
- Ataxia, LFTs, dizziness, nausea, sedation
- Side effects, confusion, levels
• Tremor, dizziness, LFTs, ataxia
What is the problem with prescribing antidepressants in dementia?
• Insufficient evidence to support safety and efficacy of antidepressants in dementia
What are some 'unapproved' treatments for dementia?
- Preventative for "at risk" patients
- Preventative for "at risk" patients
- Oestrogen - preventative
• Complementary medicines
- GINKGO BILOBA only CAM with evidence-base