Case 9 - Drug Action in the CNS

Question 1

what are the four things that happen to neurotransmitters

Answer 1

synthesised
stored
released
inactivated

Question 2

what is ChAT

Answer 2

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)

Question 3

where is acetylcholine stored

Answer 3

synaptic vesicles in the axonal terminal

Question 4

Where is acetylcholine released

Answer 4

into the synaptic cleft upon the arrival of an action potential and influx

Question 5

where does acetylcholine bind

Answer 5

to postsynaptic receptors

Question 6

what are the post synaptic receptors

Answer 6

muscarinic (M1-M5)
nicotinic

Question 7

what happens to 40-50% of the choline formed from ACh breakdown

Answer 7

is taken up into presynaptic terminal by active, high affinity transporter specific to cholinergic cells

Question 8

what breaks down acetylcholine

Answer 8

AChE (acetylcholine-esterase) breaks down acetylcholine into choline and acetate

Question 9

what then happens to the choline

Answer 9

it is taken back up into pre synaptic terminals

Question 10

diagram showing acetylcholine reuptake/inactivation

Question 10

diagram showing acetylcholine reuptake/inactivation

Question 11

where do the cholinergic pontomesencephalon neurones project

Answer 11

onto the hindbrain, thalamus, hypothalamus and basal forebrain

Question 12

what are the two groups of cholinergic neurones that the basal forebrain contains

Answer 12

medial septal group
nucleus Basilis group

Question 13

what is activation of acetylcholine terminated by

Answer 13

AChE

Question 14

sequence of events of acetylcholine at the neuromuscular junction

Answer 14

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

Question 15

what is myasthenia gravis

Answer 15

an autoimmune condition that affects the nerves and muscles

Question 16

what happens in myasthenia gravis

Answer 16

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

Question 17

which muscles are most commonly affected

Answer 17

eye and facial muscles and those that control swallowing

Question 18

what medications are prescribed for myasthenia gravis

Answer 18

pyridostigmine - prevents the breakdown of acetylcholine

Question 19

what do agonists at dopamine receptors induce

Answer 19

psychotic symptoms

Question 20

which pathways being blocked lea to side effects e.g parkinsonian side effected

Answer 20

mesolimbic pathway
mesocortiyal pathway
tuberoinfundibulnar pathway

Question 21

what is the usual route of pathway 4 and what happens if you are taking an antipsychotic

Answer 21

dopamine uuallly inhibits prolactin but if taking an antipsychotic, you are blocking the inhibition and get the hyperprolactiaemia

Question 22

how is dopamine made

Answer 22

tyrosine
L-dopa
dopamine

Question 23

what is the dynamic target of seizure control in management of epilepsy

Answer 23

is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsyantpic potential (IPSP)

Question 24

what factors lead to a seizure

Answer 24

EPSPs Na+ influx Ca++ currents paroxysmal depolarisation

Question 25

what leads to control and not a seizure

Answer 25

IPSPs K+ efflux Cl- influx pumps Low pH

Question 26

what two levels does physiological protection against repetitive firing occur via inhibition

Answer 26

the cellular level e.g Na+ Chanel inactivation the network level e.g GABA mediated inhibition

Question 27

what are the four categories of anticonvulsants

Answer 27

1. drugs that inhibit Na+ channels 2. drugs that inhibit Ca2+ channels 3. drugs that enhance GABA mediated inhibition 4. drugs that inhibit glutamate receptors

Question 28

where do calcium ions flow through

Answer 28

T-type calcium channels

Question 29

features of drugs that inhibit Na+ channels

Answer 29

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

Question 30

features of drugs that inhibit Ca2+ channels

Answer 30

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

Question 31

what are absence seizures

Answer 31

brief, sudden lapse of consciousness

Question 32

what is the syntheses of drugs that enhance GABA mediated inhibition mediated by

Answer 32

glutamic acid decarboxylase (GAD)

Question 33

where are drugs that enhance GABA mediated inhibition stored

Answer 33

GABA is packaged into presynaptic vesicle by a transporter (VGAT)

Question 34

where is GABA released

Answer 34

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

Question 34

where is GABA released

Answer 34

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

Question 35

reuptake of GABA:

Answer 35

neurones and glia take up GABA via specific GABA transporters (GATS)

Question 36

what are the 4 GATs

Answer 36

GAT-1, GAT2, GAT3, GAT4. each with a specific characteristic distribution in the CNS

Question 37

what enzyme metabolises and breaks down GABA

Answer 37

GABA-transmaminase (GABA-T)

Question 38

what do GABA receptor agonists do

Answer 38

increase inhibition

Question 39

what do GABA reuptake inhibitors do

Answer 39

increase inhibition as would stay around for a bit longer

Question 40

what do GABA transaminase inhibitors do

Answer 40

increase inhibition

Question 41

what are the two types of glutamate receptors in the brain

Answer 41

ionotropic and metabotropic subtypes

Question 42

what are examples of inotropic receptors and what is a features of these receptors

Answer 42

AMPA Kainate N-methly-D-aspartate (NMDA) fast neurotransmission

Question 43

what do AMPA and kainite sites do

Answer 43

open a channel through the receptor, allowing sodium and small amounts of calcium to enter

Question 44

what does the NMDA site do

Answer 44

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)

Question 45

what facilitates the opening of the NMDA receptor channel

Answer 45

glycine

Question 46

what is the metabotropic site regulated by

Answer 46

complex reactions and its response is mediated by second messages

Question 47

what pathway are cocaine and drugs concerned with

Answer 47

the dopamine reward pathway with is the mesolimbic pathway

Question 48

what is cocaine and how does it work

Answer 48

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

Question 49

what does methamphetamine do

Answer 49

inhibits reuptake transporter but can also increase dopamine production

Question 50

what does nicotine do

Answer 50

nicotine receptor is on presynaptic neurone causing an increase in the release of dopamine important for feeling of reward pathway

Question 51

what can people who have midl to moderate Alzheimer's benefit from

Answer 51

could benefit from taking a cholinesterase inhibitor.

Question 52

how do cholinesterase inhibitors work

Answer 52

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

Question 53

what are the three cholinesterase inhibitors used

Answer 53

donepezil (Aricept) Rivastigmine (Exeton) Galantamine (Reminyl)

Question 54

what is increased ACh availability important for

Answer 54

controlling memory and cognition

Question 55

what do current treatments for AD provide

Answer 55

temporary symptomatic benefits without modifying disease process egg donepezil, galantamine

Question 56

what is the new treatment method for AD

Answer 56

amyloid, amyloid plaques are the main marker in SD

Question 57

what are the novel approaches to AD include

Answer 57

secretase modulators: decrease Abeta42 production Anti-aggregants: prevent Abeta aggregation Immunotherapies : clear Abeta deposition