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Pharmacology > Drugs & treatment of Parkinson's (L14) > Flashcards

Drugs & treatment of Parkinson's (L14) Flashcards

1
Q

what is Parkinsonism?

A

drug/stroke/infection induced symptoms

symptoms:
• resting tremor
• muscle rigidity
• suppression of voluntary movements

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2
Q

DA neurones in Parkinsons

A

post mortem neuropathy shows loss of dopamine ell bodies in the substantial nigra in patients with Parkinson’s

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3
Q

pathology of Parkinson’s

A

degeneration of DAergic neurones of the nigostriatal tract

loss of DA neurotransmission in the striatum as the neurones die

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4
Q

pathology of Parkinsonism

A

any condition with less of stratal DA transmission

a person may exhibit symptoms of Parkinson’s without actually having the disease

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5
Q

what are the 4 dopamine pathways in the brain?

A

nigostriatal

mesolimbic

mesocortical

tuberoinfundibular

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6
Q

nigostriatal pathway

A

substance nigra to striatum

the pathway that dies off in patients with Parkinson’s

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7
Q

mesolimbic pathway

A

ventral tegmental area to nucleus accumbens

the ventral segmental area contained lots of DA cell bodies

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8
Q

mesocortical pathway

A

ventral tegmental area to frontal cortex

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9
Q

tuberoinfundibular pathway

A

arcuate nucleus to pituitary gland

here dopamine acts to control prolactin release

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10
Q

where is there decreased DA neurotransmission in Parkinson’s?

A

in the stratum via D2 receptors

if input into these receptors is lost, there is lost inhibition

D2 receptors are inhibitory

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11
Q

what is the pharmacotherapeutic aim of Parkinson’s drugs?

A

to increase DA neurotransmission in the striatum

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12
Q

what happens in the nigrostriatal DA system?

A

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

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13
Q

nigrostriatal system in Parkinson’s disease

A

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

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14
Q

dopamine synthesis

A

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

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15
Q

dopamine metabolism

A

dopamine can be broken down by monamine oxidase

• removes the monoamine group and oxidises it, producing an aldehyde

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16
Q

what are the 2 isoforms of MAO

A

MAO A
MAO B

separate gene products both on X chromosome and are produced as 2 separate isoforms

DA mainly metabolised by MAO B

17
Q

dopamine storage and release

A

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

18
Q

dopamine reuptake

A

gets taken up my dopamine transporters into the nerve terminal where its broken down by MAO

reuptake by transporter DAR

19
Q

how many DA receptors are there?

A

5

they are classified into 2 groups
• D1-like group: D1 and D5
• D2-like group: D2, D3 and D4

20
Q

D2-like DA receptor group

A

inhibitory

inhibit adenylate cyclase which reduces the amount of cAMP produced or open K+ channels

21
Q

D1-like DA receptor group

A

excitatory

stimulate adenyl cyclase

22
Q

what group are the receptors on the stratal output neurone?

A

D2 type

23
Q

L-DOPA synthesis

A

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

24
Q

increasing DA neurotransmission

A

increasing synthesis

decreasing intraneural breakdown

interaction with target receptors

25
Q

increasing DA synthesis

A

by giving L-DOPA together with a decarboxylase inhibitor (carbidopa)

26
Q

why give carbidopa instead of DA itself?

A

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

27
Q

decreasing DA intraneural breakdown

A

MAO inhibitor - selegiline

  • inhibitor of MAO-B
  • blocks metabolism of DA
  • increases DA content of vesicles
  • each vesicle released, releases more DA
28
Q

interaction with target receptors to increase DA transmission

A

D2 receptor agonists

a drug that mimics DA is inserted and interacts with its receptors

inhibits striatal output neurone directly

eg. bromocriptine, apomorphine, lisuride

29
Q

what is used in the therapy of Parkinson’s

A

increasing DA transmission
• presynaptic
• L-DOPA
• selegiline

mimic DA transmission
• postsynaptic
• bromocriptine
• apomorphine

drugs are often given in combination

30
Q

is L-DOPA or D2 agonists better?

A

D2 agonists have more psychiatric symptoms than L-DOPA

31
Q

what are the issues with increasing DA?

A

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

32
Q

what is psychosis?

A

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

33
Q

what do antipsychotic drugs do?

A

block D2 receptors in all 4 pathways

cause Parkinsonism

34
Q

what is associated with increased D2 mediated transmission in the mesocrtical and mesolimbic systems?

A

schizophrenia

psychotic illnesses

Pharmacology (24 decks)

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