Psychostimulants and Alzheimer's Flashcards
caffeine
- adenosine receptor antagonist
- binds to adenosine receptors
- blocks adenosine from binding which doesn’t allow for the signal for sleep (adenosine is the byproduct of ATP production)
- indirectly enhances signalling of adrenaline and norepinephrine
- this is because it blocks phosphodiesterase which is responsible for the breakdown of camp by which is the second messenger of these NTs so it amplifies their signal
- does not cause addiction
- causes physical dependence and sometimes tolerance
- side effects: agitation, nausea, racing heart, dry mouth, diarrhea, in rare cases fatal OD due to cardiac arrest
How do psychostimulants mediate their effects?
- most are DAT and NET blockers –> attention effects are mediated by DAT
- addictive based on dose and administration
- fast onset causes a large change in DA which mimics natural reward
- still prescribed because it is safe and not addictive to the person taking it
- side effects: euphoria in high doses, suppressed appetite, insomnia, agitation, restlessness, dry mouth, racing heart, GI upset, paranoia, grandiosity, psychosis
cocaine and methamphetime effects on on DA recycling
cocaine
- blocks DAT which prevents reuptake of DA into neurone and there is more available in the synapse and more DA receptors are activated
methamphetamine
- recognized by DAT and brought into the neuron
- taken up by VMAT into vesicles and it pushes out DA from vesicles into synapse
- this means that there is more DA inside the cell than outside in the synapse
- more DA leaves the neuron and binds to DA receptors
neuropathology of Alzheimer’s
- amyloid plaques and neurofibrillary tangles visible by microscopy in AD brains
- AD characterized by gross diffuse atrophy of the brain and loss of neurons, neuronal processes and synapses in cerebral cortex and subcortical regions
- results in gross atrophy of affected regions including degeneration of temporal and parietal lobe, prefortanal cortex and cingulate gyrus
- levels of acetylcholine are reduced
- NE and 5HT reduced
- Glu elevated
pharmacotherapy of Alzheimer’s
- cholinesterase inhibitors to amplify acetylcholine
- low affinity NMDA receptor antagonists to reduce glutamate transmission
cholinergic deficits in AD
- reduction of cholinergic neurons in the brain –> reduced availability of acetylcholine
- the loss of these cells is believed to cause memory impairments
- acetylcholine is an excitatory NT in central and peripheral nervous system
types of cholinergic receptors
muscarinic: GPCRs
nicotinic: sodium channels
cholinesterase inhibitors MOA
- inhibit enzyme that breakdown acetylcholine in the synapse (acetylcholinesterase)
- this increases the amount of acetylcholine in the synapse
- allows more acetylcholine to bind to receptors
reversible cholinesterase inhibitors drugs
increase cortical acetylcholine
- donepezil
- galantamine
- rivastigmine
efficacy of reversible cholinesterase inhibitors
- clinical improvement is measured with objective and subjective instruments
- activities of daily living
- AD assessment scale - cognitive sub scale has tasks for memory, language and attention
- donepezil improves cognition in patients with AD
- dose dependent improvement in cognition - doesn’t prevent neuron loss but allows remaining NTs to have more of an effect
- improves symptoms of AD such as memory recall it doesn’t help memory retrieval in healthy brains –> not a neurotrophic drug
adverse events of cholinesterase inhibitors
peripherally seen
- the peripheral nervous system responds to acetylcholine which promotes digestion
- nausea, GI cramping, vomiting, diarrhea
- bradycardia (PNS effects), anorexia, vivid dreams
memantine MOA
- non competitive NMDA receptor antagonist with low affinity
- high on/off kinetics –> key for therapeutic effect –> preserves enough NMDA receptor for learning but prevents excitotoxicity
- associated with reduced rate of deterioration on cognitive and functional measures and behavioural improvements
- can be used in combination with acetylcholinesterase inhibitors
how does memantine reduce decline in cognition?
- excessive activation of NMDA leads to excitotoxicity
- when neurons due they release glutamate that can trigger excitotoxicity
- memantine has neuroprotective factors against excititoxicity
memantine adverse effects
minor: headache, body ache, fatigue, dizziness
