Applied Neuropharmacology Flashcards
1st step in synaptic transmission?
Synthesis and packaging of
neurotransmitter (usually) in presynaptic terminals
2nd step in synaptic transmission?
Na+ action potential comes firing down axon, reaches terminal and causes presynaptic terminal to depolarise
3rd step in synaptic transmission?
Activates voltage gated Ca+ channels
Calcium floods into cell down electrical and concentration gradients
4th step in synaptic transmission?
Triggers Ca2+ dependent exocytosis of prepackaged vesicles of transmitter
5th step in synaptic transmission?
Transmitter diffuses across cleft and binds to ionotropic (has ion channel) and/ or metabotropic (couples to G protein) receptors to evoke postsynaptic response
6th step in synaptic transmission?
Presynaptic autoreceptors inhibit further transmitter release
Blocks voltage-gated Ca channels and turns off release of more neurotransmitter
7th step in synaptic transmission?
Transmitter is (usually) inactivated by uptake into glia or neurons
8th step in synaptic transmission?
Transmitter is metabolised within cells, used to make more neurotransmitter and can be released again
Describe synaptic transmission
- Synthesis and packaging of
neurotransmitter (usually) in presynaptic terminals - Nat action potential reaches terminal
- Activates voltage gated Ca2+ channels
- Triggers Ca2+-dependent exocytosis of prepackaged vesicles of transmitter
- Transmitter diffuses across cleft and binds to ionotropic and / or metabotropic receptors to evoke postsynaptic response
- Presynaptic autoreceptors inhibit further transmitter release
- Transmitter is (usually) inactivated by uptake into glia or neurons
- Transmitter is metabolised within cells
Pharmacological ways to REDUCE synaptic transmission?
block voltage-gated Na+ channels (e.g. local anaesthetics like lidocaine)
- this prevents action potential
block voltage-gated Ca2+ channels (e.g. black widow spider venom)
block release machinery (e.g. botulinum)
- cleaves one of the synaptic proteins thats involved in vesicle fusion
block post synaptic receptors (e.g. competitive antagonists, non-competitive antagonists)
activate presynaptic inhibitory receptors
- blocks voltage-gated Ca channels so prevents release of neurotransmitter
increase uptake of transmitter
increase breakdown of transmitter
inhibiting synthesis and packaging of neurotransmitter
RECAP: competitive antagonist?
binds to receptor
has high affinity but low efficacy
so won’t activate the receptor thus no response
e.g. beta blocker competes with noradrenaline for beta adrenergic receptors
Pharmacological ways to POTENTIATE synaptic transmission?
Increase synthesis and packaging of neurotransmitter (e.g. by increasing availability of precursors)
Activate postsynaptic receptors with an agonist
- may lead to unwanted effects as receptors are always activated
Potentiate effects of transmitter on receptor (e.g. benzodiazepines)
- potentiate effects of neurotransmitter GABA on GABA-A receptors
once activated
Block breakdown of transmitter
(e.g. anti-cholinesterases used for myasthenia gravis)
- block AChE-ase enzyme that is responsible for breaking down AChE to choline
Block uptake of transmitter
(e.g. SSRIs)
what are the complications with neurotransmitters?
you can’t manipulate one neurotransmitter to produce one single effect
BBB - drugs that can’t cross the BBB will only act on the peripheral nervous system
what are the 4 pathways in the brain?
- nigrostriatal pathway
- mesocortical pathway
- tuberoinfundibular pathway
- mesolimbic pathway
what is the nigrostriatal pathways important for?
voluntary movement
describe the nigrostriatal pathway
cells in the substantia nigra which project to the basal ganglia to the dorsal striatum of the putamen
describe the mesolimbic pathway
it projects the ventral tegmental area to the nucleus accumbens and other limbic structures
what is the mesolimbic pathway important for?
role in reward and addiction
leads to positive symptoms of schizophrenia
leads to hallucinations that we see with treatment for Parkinsons
where does the mesocortical pathway project to?
prefrontal cortex
what is the mesocortical pathway important for?
involved in safety function
impairment in pathways is relevant for cognitive symptoms in PD and negative symptoms in schizophrenia
describe the tubero-infundibular pathway
dopamine in this pathway inhibits the release of prolactin from the pituitary
dopamine inhibitors can be used to prevent inhibit release
what areas are involved in control of vomiting?
area postrema and medulla
dopamine causes vomiting
what do we see in parkinson’s disease?
degeneration of dopaminergic cells in substantia nigra
deficiency of dopamine in basal ganglia due to neurodegeneration
leading to motor symptoms
can dopamine cross the BBB?
no but tyrosine can
so dopamine can’t be given as an oral tablet or injection in blood
what does tyrosine hydroxylase do?
converts tyrosine to DOPA
it is lost due to degeneration
can DOPA cross the BBB?
yes in the form of levodopa
it is converted into dopamine in the CNS in the brain with aromatic AA decarboxylase
what are the unwanted effects of DOPA?
it is converted to dopamine in the periphery leading to SE such as vomiting and hypotension
dopamine receptors
are not ionotropic so dopamine cannot evoke fast excitatory or inhibitory postsynaptic potential
5 subtypes of metabotropic receptors D1-D5
what is dopamine metabolised to?
homovanillic acid via 2 different pathways
COMT and MAO-B involved in both pathways just in different orders
how to increase dopaminergic function in PD?
give dopamine precursor like levodopa
give dopamine agonists
- ergot e.g. cabergoline, bromocriptine, pergolide
- not used as affects 5-HT receptors –> fibrosis
- non-ergot e.g. ropinirole, pramipexole, rotigotine
- apomorphine
what enzyme inhibitors can be given in PD?
peripheral AAAD inhibitors like carbidopa, benserazide
MAOB inhibitors e.g. selegiline, rasagiline
COMT inhibitors e.g. entacapone
what do peripheral AAAD inhibitors do?
decrease peripheral SE of levodopa and allows greater proportion of oral dose to reach CNS
what do MAOB and COMT inhibitors do?
both decrease the metabolism of dopamine and so increase effectiveness of levodopa
have no effect on synthetic dopamine agonists
describe a dopaminergic neuron
tyrosine –> levodopa –> dopamine
dopamine is released from vesicles and taken up by receptors on postsynaptic cleft
dopamine can be packaged or metabolised to homovanillic acid
