Anti-parkinsonian drugs and neuroleptics

Question 1

Mesocortical pathway

Answer 1

Dopaminergic pathway

• ventral tegmental area to the cerebrum
• important in executive functions and complex behavioural patterns
• inhibition associated with negative schizophrenia symptoms (stimulation has opposite effect with positive)

Question 2

Mesolimbic pathway

Answer 2

Dopaminergic pathway

• ventral tegmental area to the nucleus accumbens
• ‘the brain reward pathway’
• involved in emotion
• activation associated with positive schizophrenia symptoms (inhibition has opposite effect with negative)

Question 3

Nigrostriatal pathway

Answer 3

Dopaminergic pathway

• substantia nigra pars compacta to the striatum
• inhibition results in movement disorders (involved in movement regulation)
• degenerates to give Parkinson’s disease

Question 4

Tuberoinfundibular pathway

Answer 4

Dopaminergic pathway

• arcuate nucleus of the hypothalamus to the median eminence
• inhibition leads to hyperprolactinaemia (prolactin release regulation from the anterior pituitary gland)

Question 5

L-DOPA adjuncts

Answer 5

Increases efficacy and safety of L-DOPA by preventing peripheral breakdown

DOPA-D inhibitors (eg: Carbidopa, Benserazide)
-inhibition of peripheral DOPA-D only to prevent peripheral L-DOPA breakdown
-can’t cross the blood brain barrier
-reduces required L-DOPA dosage
COMT inhibitors (eg: Entacapone, Tolcapone)
-increases L-DOPA levels reaching the brain by inhibiting peripheral metabolism
-reduces ‘on-off’ long term side effect

Question 6

L-DOPA limitations

Answer 6

Peripheral breakdown by DOPA-D
-poor efficacy (low DOPA-D levels reach the brain)
-peripheral L-DOPA breakdown by DOPA-D=stimulate the chemoreceptor trigger zone (N&V)
Long-term side effects
-dyskinesias
-on-off effects (depends on plasma L-DOPA levels)

Question 7

Dopamine receptor agonist examples

Answer 7

• Ergot derivatives

- Non-ergot derivatives

Question 8

Ergot derivatives

Answer 8

• Act as potent agonists of Dopamine D2 receptors
• Associated with cardiac fibrosis
• Eg: Bromocriptine and Pergolide

Question 9

Non-ergot derivatives

Answer 9

• Eg: Ropinirole and Rotigotine
• Ropinirole also available as extended-release formulation
• Rotigotine also available as patch

Question 10

Monoamine oxidase B inhibitors

Answer 10

• Eg: Selegiline (Deprenyl) and Rasagiline
• reduces the dosage of L-DOPA required
• Can increase the amount of time before Levodopa (L-DOPA) treatment is required

Question 11

First generation antipsychotics

Answer 11

• Chlorpromazine

- Haloperidol

Question 12

Second generation antipsychotics

Answer 12

• Clozapine
• Risperidone
• Quetiapine
• Aripiprazole

Question 13

Chlorpromazine

Answer 13

First generation antipsychotic

Question 14

Haloperidol

Answer 14

First generation antipsychotic

Question 15

Schizophrenia positive symptoms

Answer 15

Increased mesolimbic dopaminergic activity associated with positive symptoms

• hallucinations (auditory and visual)
• delusions (paranoia)
• thought disorder (denial about oneself)

Question 16

Schizophrenia negative symptoms

Answer 16

Decreased mesocortical dopaminergic activity associated with negative symptoms

• affective flattening (lack of emotion)
• alogia (lack of speech)
• avolition/apathy (loss of motivation)

Question 17

Quetiapine

Answer 17

Second generation antipsychotic

Question 18

Aripiprazole

Answer 18

Second generation antipsychotic

Question 19

Chlorpromazine

Answer 19

First generation antipsychotic
-discovered during new antihistamine development

Side effects:

• High incidence= of anti-cholinergic, especially sedation
• Low incidence of extrapyramidal symptoms

Question 20

Haloperidol

Answer 20

First generation antipsychotic

• very potent dopamine D2 receptor antagonist (~50 times more potent than Chlorpromazine)
• Therapeutic effects develop over 6-8 weeks
• Little impact on negative symptoms

Side effects:
-High incidence of extrapyramidal symptoms

Question 21

Clozapine

Answer 21

Second generation antipsychotic

• Most effective antipsychotic
• Very potent 5-HT2A receptor antagonist
• Only drug to show efficacy in treatment resistant schizophrenia and negative symptoms

Side effects:
-potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain

Question 22

Risperidone

Answer 22

Second generation antipsychotic
-Very potent 5-HT2A receptor and dopamine D2 receptor antagonist

Side effects:
-More extrapyramidal symptoms and hyperprolactinaemia than other atypical antipsychotics

Question 23

Quetiapine

Answer 23

Second generation antipsychotic
-Very potent H1 receptor antagonist

Side effects:
-Lower extrapyramidal symptom incidence compared to other antipsychotics

Question 24

Aripiprazole

Answer 24

Second generation antipsychotic

• Partial dopamine D2 receptor and 5-HT2A receptor agonist
• No more effective than typical antipsychotics

Side effects:
-reduced incidences of hyperprolactinaemia and weight gain compared to other antipsychotics

Question 25

Dopamine synthesis

Answer 25

1) L-tyrosine converted to L-DOPA by Tyrosine hydroxylase 2) L-DOPA converted to Dopamine by DOPA decarboxylase OCCURS IN THE NEURONE

Question 26

Dopamine metabolism

Answer 26

-dopamine removed from synaptic cleft by dopamine transporter and noradrenaline transporter 3 enzymes metabolising dopamine: 1) Monoamine oxidase A (MAO-A) metabolises dopamine, NE, and 5-HT 2) Monoamine oxidase B (MAO-B) metabolises dopamine 3) Catechol-O methyl transferase (COMT)=wide distribution and metabolises all catecholamines

Question 27

Parkinson's disease epidemiology

Answer 27

- 1 to2% of individuals over 60 years old | - around 5% of cases are due to mutations in certain genes (eg: SNCA, LRRK2)

Question 28

Parkinson's disease pathophysiology

Answer 28

- severe loss of dopaminergic projection cells in substantia nigra pars compacta - Lewy bodies and Lewy neurites=found respectively within neuronal cell bodies and axons - neurofilaments and proteins (ubiquitin and alpha-synuclein) become abnormally phosphorylated, aggregating within Lewy bodies and Lewy neurites

Question 29

Parkinson's disease clinical presentation

Answer 29

``` MOTOR (BEFORE NON-MOTOR/COGNITIVE SYMPTOMS) -resting tremor -bradykinesia -rigidity -postural instability -stooped, shuffling gait -loss of arm swing -hypomimia -micrographia NON-MOTOR (AUTONOMIC) -anosmia (olfactory deficits) -orthostatic hypotension -constipation -erectile dysfunction -urinary incontinence -hypersalivation NON-MOTOR (NEUROPSYCHIATRIC) -insomnia (sleep disorders) -cognitive decline -dementia (memory deficits) -depression -anxiety -irritability ```

Question 30

Schizophrenia epidemiology

Answer 30

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Question 31

Receptor activation in Parkinson's disease

Answer 31

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Question 32

Dopamine replacement

Answer 32

L-tyrosine converted to dopamine | -rate limiting enzyme is tyrosine hydroxylase