Drugs & treatment of Parkinson's (L14) Flashcards
what is Parkinsonism?
drug/stroke/infection induced symptoms
symptoms:
• resting tremor
• muscle rigidity
• suppression of voluntary movements
DA neurones in Parkinsons
post mortem neuropathy shows loss of dopamine ell bodies in the substantial nigra in patients with Parkinson’s
pathology of Parkinson’s
degeneration of DAergic neurones of the nigostriatal tract
loss of DA neurotransmission in the striatum as the neurones die
pathology of Parkinsonism
any condition with less of stratal DA transmission
a person may exhibit symptoms of Parkinson’s without actually having the disease
what are the 4 dopamine pathways in the brain?
nigostriatal
mesolimbic
mesocortical
tuberoinfundibular
nigostriatal pathway
substance nigra to striatum
the pathway that dies off in patients with Parkinson’s
mesolimbic pathway
ventral tegmental area to nucleus accumbens
the ventral segmental area contained lots of DA cell bodies
mesocortical pathway
ventral tegmental area to frontal cortex
tuberoinfundibular pathway
arcuate nucleus to pituitary gland
here dopamine acts to control prolactin release
where is there decreased DA neurotransmission in Parkinson’s?
in the stratum via D2 receptors
if input into these receptors is lost, there is lost inhibition
D2 receptors are inhibitory
what is the pharmacotherapeutic aim of Parkinson’s drugs?
to increase DA neurotransmission in the striatum
what happens in the nigrostriatal DA system?
there is the cell body of a DA neurone in the substance nigra with a long projection to the striatum where there is the axon terminal that releases DA to act on D2 receptors on the stratal output neurone
nigrostriatal system in Parkinson’s disease
the DA neurone starts to die and it releases less dopamine so there is less activation of the D2 receptors so reduced inhibition of stratal neurones
stratal neurones then fire to much and interferes with voluntary muscle control
dopamine synthesis
synthesised from tyrosine (an essential AA)
DA neurones contain tyrosine hydroxylase which converts tyrosine to L-DOPA
DOPA decarboxylase removes the carboxyl group from L-DOPA creating dopamine
tyrosine hydroxylase is the rate limiting step
dopamine metabolism
dopamine can be broken down by monamine oxidase
• removes the monoamine group and oxidises it, producing an aldehyde
what are the 2 isoforms of MAO
MAO A
MAO B
separate gene products both on X chromosome and are produced as 2 separate isoforms
DA mainly metabolised by MAO B
dopamine storage and release
VMAT transports DA into vesicles
if neurone fires AP, flows down axon from substantial nigra and it depolarises the membrane of the axon terminal
this allows Ca++ to enter the cell and vesicles to exocytose contents
dopamine reuptake
gets taken up my dopamine transporters into the nerve terminal where its broken down by MAO
reuptake by transporter DAR
how many DA receptors are there?
5
they are classified into 2 groups
• D1-like group: D1 and D5
• D2-like group: D2, D3 and D4
D2-like DA receptor group
inhibitory
inhibit adenylate cyclase which reduces the amount of cAMP produced or open K+ channels
D1-like DA receptor group
excitatory
stimulate adenyl cyclase
what group are the receptors on the stratal output neurone?
D2 type
L-DOPA synthesis
precursor
bypasses the rate limiting step - tyrosine hydroxylase
there is lots of DOPA decarboxylase in the periphery so the majority of L-DOPA would get metabolised
increasing DA neurotransmission
increasing synthesis
decreasing intraneural breakdown
interaction with target receptors
increasing DA synthesis
by giving L-DOPA together with a decarboxylase inhibitor (carbidopa)
why give carbidopa instead of DA itself?
carbidopa inhibits peripheral DOPA decarboxylase so more L-DOPA gets to the brain
DA:
• is polar so cannot cross membranes
• metabolised by MAO in the gut
decreasing DA intraneural breakdown
MAO inhibitor - selegiline
- inhibitor of MAO-B
- blocks metabolism of DA
- increases DA content of vesicles
- each vesicle released, releases more DA
interaction with target receptors to increase DA transmission
D2 receptor agonists
a drug that mimics DA is inserted and interacts with its receptors
inhibits striatal output neurone directly
eg. bromocriptine, apomorphine, lisuride
what is used in the therapy of Parkinson’s
increasing DA transmission
• presynaptic
• L-DOPA
• selegiline
mimic DA transmission
• postsynaptic
• bromocriptine
• apomorphine
drugs are often given in combination
is L-DOPA or D2 agonists better?
D2 agonists have more psychiatric symptoms than L-DOPA
what are the issues with increasing DA?
increasing DA will have effects on all of the dopamine pathways
psychosis and cognitive dysfunction are side effects associated with increased DA in the ventral segmental area and frontal cortex and nucleus accumbens
what is psychosis?
too much neurotransmission through D2 receptors in the frontal cortex and in the limbic system of the brain
to reduce transmission, a D2 receptor antagonist is used to stop DA activating the D2 receptors
what do antipsychotic drugs do?
block D2 receptors in all 4 pathways
cause Parkinsonism
what is associated with increased D2 mediated transmission in the mesocrtical and mesolimbic systems?
schizophrenia
psychotic illnesses
