Antiparkinson drugs

Question 1

Symptoms of Parkinson’s disease

Answer 1

Resting tremor
Muscle rigidity
Suppression of voluntary movement
‘The shaking palsy’ - Fine movement of face

Question 2

Post mortem neurophology

Answer 2

Loss of dopamine neurone (DA) cell bodies in the substantial nigra in a patient with Parkinsons disease

Question 3

Pathology of Parkinsons disease

Answer 3

Degeneration of DAergic neurones of nigrostriatal tract

Loss of DA neurotransmission in Striatum via D2 receptors

Question 4

Pathology of Parkinsonism

Answer 4

Any condition with loss of DA transmission in striatum.
Pharmacological blockade, brain lesion etc.
Stroke, tumour or infection.

Question 5

Pharmacotherapeutic aim

Answer 5

To increase DA neurotransmission in the striatum

Question 6

4 dopamine pathways in the brain

Answer 6

1. Nigrostriatal - Substantia nigra to striatum
2. Mesolimbic - Ventral tegmental area to nucleus accumbens.
3. Mesocortical - Ventral tegmental area to frontal cortex
4. Tuberoinfundibular - Accurate nucleus to pituitary glans

Question 7

Side effects of increasing DA

Answer 7

Psychosis and cognitive dysfunction.
Latreogenic parkinsonism -> Schizophrenia associated with increase in D2 mediated neurotransmission in mesocortical and mesolimbic systems. Antipsychotic drugs block D2 receptors in all 4 pathways, causing Parkinsonism.

Question 8

Dopamine neurotransmission: Synthesis

Answer 8

Tyrosine + Tyrosine hydroxylase ->
L-DOPA (dihydroxyphenylalanine) + DOPA decarboxylase ->
Dopamine

Question 9

Dopamine neurotransmission: Storage

Answer 9

VMAT transports DA into vesicles.

Newly synthesised DA is stored in vesicles.

Question 10

Dopamine neurotransmission: Metabolism

Answer 10

Monoamine oxidase (MAO) will metabolise DA outside the vesicles.
DA mainly metabolised by MAOb
MAOa and MAOb are products of different genes both on X chromosome.

DA + MAO ->
DOPAL + Aldehyde dehydrogenase ->
DOPAC + catechol-o-methyl transferase ->
HVA (homovanillic acid)

Question 11

Dopamine neurotransmission: Release

Answer 11

Depolarization of the terminal causes exocytosis.
Voltage-gated Ca2+ channels allow Ca2+ into the terminal.
Vesicles fuse with membrane.
Dopamine reuptake by transported (DAT)

Question 12

Dopamine neurotransmission: Dopamine receptors

Answer 12

All G-protein coupled
D1-like: Excitatory (Stimulate adenylate cyclase)
D2-like: Inhibitory (Inhibits adenylate cyclase or opens K+ channels (hyperpolarizing))

Question 13

Normal Nigrostriatal DA transmission

Answer 13

Nigrostriatal DA neurone -> Striatal output neurone (decrease in cAMP)

Question 14

Parkinsons Nigtostriatal DA transmission

Answer 14

Nigrostriatal DA neurone -> Striatal output neurone (increase in cAMP)

Question 15

Synthesis of L-DOPA

Answer 15

Precursor
Bypasses rate limiting enzyme
Lots of aromatic amino acid decarboxylase in the periphery
Given with a peripherally acting decarboxylase inhibitor, carbidopa.

Question 16

Why not give DA itself?

Answer 16

DA is polar so doesn’t cross membranes (we have transported for amino acids).
Metabolised by MAO in the gut
Can give sympathomimetic effects

Question 17

MAO inhibitor

Answer 17

Selegiline
Inhibitor of MAOb
Blocks intraneuronal metabolism of DA
Increases DA content in vesicles

Question 18

Interaction with target receptors (D2 receptors)

Answer 18

Bromocriptine, apomorphine, lisuride
D2 receptor agonist
Inhibit striatal output neurones directly

Question 19

Possibilities to increase DA transmission

Answer 19

Precursor = L-DOPA
MAOI = Selegiline
D2 agonist = Bromocriptine

Question 20

Therapeutics

Answer 20

L-DOPA given with Carbidopa.
Effcts of L-DOPA/Selegiline can wear off as neurones degenerate.
D2 agonists have more psychiatric symptoms than L-DOPA
Drugs often given in combination ( L-DOPA and Selegiline, L-DOPA and bromocriptine)