Anti-Parkinsonian drugs and neuroleptics

Question 1

Which dopaminergic pathway in the brain degenerates in Parkinson’s disease?

Answer 1

Nigrostriatal pathway - cell bodies originate in substantia nigra zona compacta (SNC) and project to striatum (putamen and caudate nucleus) - involved in movement

Question 2

How does loss of dopamine trigger motor clinical symptoms?

Answer 2

Nigrostriatal pathway(which is a dopinergic pathway) that is degenerated is involved in movement

Question 3

Which other neuronal pathways are affected in Parkinson’s disease? What are they involved in?

Answer 3

1. Mesolimbic pathway - ventral tegmental area (VTA) –> nucleus accumbens, frontal cortex, limbic cortex, olfactory tubercule - emotion 2. Tuberoinfundibular system - arcuate nucleus of hypothalamus –> median eminence + pituitary gland - hormone secretion 3. Mesocortical pathway - VTA to cerebrum - executive functions + behaviour patterns

Question 4

What is the underlying pathological process of PD?

Answer 4

• Severe loss of dopaminergic projection cells in substantia nigra leads to a marked reduction in caudate nucleus/putamen dopamine content
• Lewy bodies (in neuronal cell bodies) + neurites (in axons)
• consist of abnormally phosphorylated neurofilaments (ubiquitin, a-synuclein)
• Genetics (5% cases) - SRRK2

Question 5

What are the principle clinical features of PD?

Answer 5

Motor: - Postural instability - Rigidity - Bradykinesia - Resting tremor Non-motor: - Orthostatic hypotension - Olfactory deficits - Neuropsychiatric: sleep disorders, instability, memory loss, depression - Autonomic NS: constipation

Question 6

Which drugs are used to treat PD?

Answer 6

1. Levodopa - dopamine replacement 2. Dopamine receptor agonists 3. DOPA-Decarboxylase inhibitors 4. MAO-B inhibitors 5. COMT inhibitors

Question 7

Why are anti-Parkinsonian drugs used in conjunction with one another?

Answer 7

• MAO-B inhibitors reduce the dosage of levodopa required + can increase time before levodopa treatment is needed - The effectiveness of L-dopa declines with chronic use

Question 8

What is Parkinson’s disease?

Answer 8

Progressive neurodegenerative disorder of movement

Question 9

How does levodopa alleviate the symptoms of PD?

Answer 9

• Levodopa rapidly crosses BBB - Converted to dopamine by DOPA-Decarboxylase

Question 10

How do dopamine receptor agonists alleviate the symptoms of PD?

Answer 10

• Ergot derivatives or non-ergot derivatives - Potent agonists of D2Rs

Question 11

How do MAO-B inhibitors help in alleviating the symptoms of PD?

Answer 11

Selegiline: - Prevent breakdown of dopamine within brain - Can be given on its own in early stages of disease - Or in combination w/L-DOPA –> reduces dose of L-DOPA required –> reduce side effects Rasagiline (new): - Neuroprotective effects in-vivo by inhibiting apoptosis - May also slow disease down?

Question 12

How do COMT inhibitors alleviate the symptoms of PD?

Answer 12

E.g. tolcapone, entacapone - Prevent breakdown of dopamine within brain - Prevents breakdown of L-DOPA –> 3-OMD in periphery - Tf 3-OMD can’t compete w/L-DOPA for same transport mechanism to cross BBB –> can’t gain access to brain - Increases amount of L-DOPA in brain

Question 13

What are the side effects of levodopa?

Answer 13

Acute: - Nausea and vomiting (also converted to dopamine in periphery) - Hypotension - Psychological effects – schizophrenia like syndrome w/delusions and hallucinations - Confusion, disorientation - Insomnia, nightmares Chronic: - Dyskinesias – abnormal movements which affect face+limbs; start within 2y; disappear if dose reduced but clinical symptoms reappear - “On-Off” Effects – rapid fluctuations in clinical state, where hypokinesia and rigidity may suddenly worsen

Question 14

What are the side effects of dopamine receptor agonists?

Answer 14

Ergot derivatives: - Cardiac fibrosis - Valvular disease Non-ergot derivatives do not have these effects

Question 15

Why are COMT inhibitors given with L-DOPA?

Answer 15

Increase amount of L-DOPA in brain

Question 16

How is nausea caused by L-DOPA treatment be prevented?

Answer 16

• Peripherally acting dopamine antagonist (domperidone) - DOPA-D inhibitor - can’t cross BBB, prevents peripheral breakdown (carbidopa)

Question 17

Why does L-DOPA become less effective the longer it’s taken?

Answer 17

• L-DOPA requires intact neurones to convert the L-DOPA to dopamine - As the disease progresses there are fewer and fewer neurones to convert the drug

Question 18

Why is a DOPA-Decarboxylase inhibitor always given with L-DOPA?

Answer 18

E.g. carbidopa - Does not cross BBB - Prevents peripheral breakdown of L-DOPA - Reduces required dose of L-DOPA - Reduces nausea and vomiting associated w/peripheral breakdown

Question 19

How is dopamine metabolised?

Answer 19

Removed from cleft by dopamine transporter (DAT) and NA transporter (NET) Broken down by: MOA-A: DA, NA, 5-HT, MOA-B metabolises DA COMT: wide distribution, all catecholamines

Question 20

How is dopamine synthesised?

Answer 20

L-tyrosine –> L-dopa (by tyrosine hydroxylase - rate-limiting) L-dopa –> dopamine (by DOPA-Decarboxyase)

Question 21

Give examples of ergot derivatives or non-ergot derivatives for dopamine receptor agonists

Answer 21

Bromocriptine(ergot-derived) and Ropinirole(non-ergot-derived)