Case 9 - Drug Action in the CNS Flashcards
what are the four things that happen to neurotransmitters
synthesised
stored
released
inactivated
what is ChAT
specific to cholinergic neurones and is present in neuronal terminal in excess I.e enzyme is not saturated.
is a precursor
transfer acetate ion from acetyl-CoA to choline to form acetylcholine (I think)
where is acetylcholine stored
synaptic vesicles in the axonal terminal
Where is acetylcholine released
into the synaptic cleft upon the arrival of an action potential and influx
where does acetylcholine bind
to postsynaptic receptors
what are the post synaptic receptors
muscarinic (M1-M5)
nicotinic
what happens to 40-50% of the choline formed from ACh breakdown
is taken up into presynaptic terminal by active, high affinity transporter specific to cholinergic cells
what breaks down acetylcholine
AChE (acetylcholine-esterase) breaks down acetylcholine into choline and acetate
what then happens to the choline
it is taken back up into pre synaptic terminals
diagram showing acetylcholine reuptake/inactivation
diagram showing acetylcholine reuptake/inactivation
where do the cholinergic pontomesencephalon neurones project
onto the hindbrain, thalamus, hypothalamus and basal forebrain
what are the two groups of cholinergic neurones that the basal forebrain contains
medial septal group
nucleus Basilis group
what is activation of acetylcholine terminated by
AChE
sequence of events of acetylcholine at the neuromuscular junction
the neuromuscular junction is a chemical synapse between a motor neurone and skeletal muscle fibre. communication between these two cells is carried out by acetylcholine
release of acetylcholine is initiated by the arrival of an action potential propagating along the axon of the motor neurone
depolarisation of the nerve endings leads to opening of presynaptic voltage gated Ca2+ channels and transmitter release Ca2+ dependent vesicle exocytosis
postsynaptic ligand gated ion channels on muscle (nicotinic acetylcholine receptors) open and let Na+ ions into the muscle cell, thus causing depolarisation
action potential is then generated on the membrane of skeletal muscle cell, this allows Ca2+ entry into the muscle cell and this leads to muscle contraction
what is myasthenia gravis
an autoimmune condition that affects the nerves and muscles
what happens in myasthenia gravis
the immune system produces antibodies (proteins) that block or damage muscle acetylcholine receptors, which prevents the muscles contracting
this prevents messages being based from the nerve endings to the muscles, which results in the muscles not contracting (tightening) and becoming weak
which muscles are most commonly affected
eye and facial muscles and those that control swallowing
what medications are prescribed for myasthenia gravis
pyridostigmine - prevents the breakdown of acetylcholine
what do agonists at dopamine receptors induce
psychotic symptoms
which pathways being blocked lea to side effects e.g parkinsonian side effected
mesolimbic pathway
mesocortiyal pathway
tuberoinfundibulnar pathway
what is the usual route of pathway 4 and what happens if you are taking an antipsychotic
dopamine uuallly inhibits prolactin but if taking an antipsychotic, you are blocking the inhibition and get the hyperprolactiaemia
how is dopamine made
tyrosine
L-dopa
dopamine
what is the dynamic target of seizure control in management of epilepsy
is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsyantpic potential (IPSP)
what factors lead to a seizure
EPSPs
Na+ influx
Ca++ currents
paroxysmal depolarisation
what leads to control and not a seizure
IPSPs
K+ efflux
Cl- influx
pumps
Low pH
what two levels does physiological protection against repetitive firing occur via inhibition
the cellular level e.g Na+ Chanel inactivation
the network level e.g GABA mediated inhibition
what are the four categories of anticonvulsants
- drugs that inhibit Na+ channels
- drugs that inhibit Ca2+ channels
- drugs that enhance GABA mediated inhibition
- drugs that inhibit glutamate receptors
where do calcium ions flow through
T-type calcium channels
features of drugs that inhibit Na+ channels
enhanced Na+ channel inactivation
AEDs that target the sodium channels prevent the return of these channels to the active state by stabilising them in the inactive state
features of drugs that inhibit Ca2+ channels
reduced current through T type calcium channels
AEDs that inhibit these T calcium channels are particularly useful for controlling absence seizures
high voltage activated channels - involved in neurotransmitter release
what are absence seizures
brief, sudden lapse of consciousness
what is the syntheses of drugs that enhance GABA mediated inhibition mediated by
glutamic acid decarboxylase (GAD)
where are drugs that enhance GABA mediated inhibition stored
GABA is packaged into presynaptic vesicle by a transporter (VGAT)
where is GABA released
in response to an action potential and the presynaptic elevation of intracellular Ca2+, GABA is released into the synaptic cleft by fusion of GABA containing vesicles with the presynaptive membrane
where is GABA released
in response to an action potential and the presynaptic elevation of intracellular Ca2+, GABA is released into the synaptic cleft by fusion of GABA containing vesicles with the presynaptic membrane
reuptake of GABA:
neurones and glia take up GABA via specific GABA transporters (GATS)
what are the 4 GATs
GAT-1, GAT2, GAT3, GAT4. each with a specific characteristic distribution in the CNS
what enzyme metabolises and breaks down GABA
GABA-transmaminase (GABA-T)
what do GABA receptor agonists do
increase inhibition
what do GABA reuptake inhibitors do
increase inhibition as would stay around for a bit longer
what do GABA transaminase inhibitors do
increase inhibition
what are the two types of glutamate receptors in the brain
ionotropic and metabotropic subtypes
what are examples of inotropic receptors and what is a features of these receptors
AMPA
Kainate
N-methly-D-aspartate (NMDA)
fast neurotransmission
what do AMPA and kainite sites do
open a channel through the receptor, allowing sodium and small amounts of calcium to enter
what does the NMDA site do
opens a channel that allows large amounts of calcium to enter along with the sodium ions. this channel is blocked by magnesium in. the resting state (open later on than the others. excitatory signals)
what facilitates the opening of the NMDA receptor channel
glycine
what is the metabotropic site regulated by
complex reactions and its response is mediated by second messages
what pathway are cocaine and drugs concerned with
the dopamine reward pathway with is the mesolimbic pathway
what is cocaine and how does it work
dopamine reuptake transporter inhibitor.
when cocaine enters the Brain, it blocks the dopamine transporter from pumping dopamine bak into the presynaptic neurone, flooding the synapse with dopamine.
this intensifies and prolongs the stimulation of posynaptic neurones in the brain’s pleasure circuits causing a cocaine high
what does methamphetamine do
inhibits reuptake transporter but can also increase dopamine production
what does nicotine do
nicotine receptor is on presynaptic neurone
causing an increase in the release of dopamine
important for feeling of reward pathway
what can people who have midl to moderate Alzheimer’s benefit from
could benefit from taking a cholinesterase inhibitor.
how do cholinesterase inhibitors work
by increasing the amount of a chemical called acetylcholine which helps messages travel around the brain. cholinesterase inhibitors do not prevent the disease from progressing but may help people to function at a slightly high level than they wold do without the drug
what are the three cholinesterase inhibitors used
donepezil (Aricept)
Rivastigmine (Exeton)
Galantamine (Reminyl)
what is increased ACh availability important for
controlling memory and cognition
what do current treatments for AD provide
temporary symptomatic benefits without modifying disease process egg donepezil, galantamine
what is the new treatment method for AD
amyloid, amyloid plaques are the main marker in SD
what are the novel approaches to AD include
secretase modulators: decrease Abeta42 production
Anti-aggregants: prevent Abeta aggregation
Immunotherapies : clear Abeta deposition
