Anti-Parkinsonian drugs and neuroleptics

Question 1

How is dopamine synthesised?

Answer 1

L-tyrosine → L-DOPA → dopamine (DA).
Tyrosine hydroxylase catalyses the conversion of L-tyrosine to L-DOPA.
DOPA decarboxylase catalyses the conversion of L-DOPA to dopamine (DA).

Question 2

How is dopamine metabolised?

Answer 2

Dopamine is removed from the synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET).

3 enzymes metabolise dopamine:

• monoamine oxidase A (MAO-A) metabolises DA, NE and 5-HT
• MAO-B metabolises DA
• catechol-O-methyl transferase (COMT)- wide distribution, metabolises all catecholamines.

Question 3

What 3 enzymes metabolise dopamine?

Answer 3

Monoamine oxidase A (MAO-A) metabolises DA, NE and 5-HT.

MAO-B metabolises DA.

Catechol-O-methyl transferase (COMT)- wide distribution, metabolises all catecholamines.

Question 4

What are the major dopaminergic pathways?

Answer 4

Nigrostriatal pathway
Mesolimbic pathway
Mesocortical pathway
Tuberoinfundibular pathway

Question 5

What is the nigrostriatal pathway?

Answer 5

Substantia nigra pars compacta (SNc) to the striatum

Question 6

What does inhibition of the nigrostriatal pathway result in?

Answer 6

Movement disorders.

Question 7

What is the mesolimbic pathway?

Answer 7

Ventral tegmental area (VTA) to the nucleus accumbens (NAcc).
Brain reward pathway.

Question 8

What does inhibition of the mesolimbic pathway result in?

Answer 8

Associated with negative schizophrenia symptoms.

Question 9

What is the mesocortical pathway?

Answer 9

Ventral tegmental area to the cerebrum.

Important in executive functions and complex behavioural patterns.

Question 10

What does inhibition of the mesocortical pathway result in?

Answer 10

Associated with positive schizophrenia symptoms.

Question 11

What is the tuberoinfundibular pathway?

Answer 11

Arcuate nucleus to the median eminence.

Question 12

What does inhibition of the tubuloinfundibular pathway result in?

Answer 12

Hyperprolactinaemia.

Question 13

What percentage of individuals over 60 years old have Parkinson’s disease?

Answer 13

1-2%.

Question 14

What percentage of Parkinson’s disease cases are due to mutations in certain genes, e.g. SNCA, LRRK2?

Answer 14

Around 5%.

Question 15

Describe the pathophysiology of Parkinson’s disease.

Answer 15

Severe loss of dopaminergic projection cells in SNc.
Lewy bodies and neurites → found respectively within neuronal cell bodies and axons.
Consist of abnormally phosphorylated neurofilaments, ubiquitin and alpha-synuclein.

Question 16

What is the clinical presentation of Parkinson’s disease?

Answer 16

Motor symptoms: resting tremor, bradykinesia, rigidity, postural instability (cardinal symptoms).
Autonomic nervous system effects → olfactory deficits, orthostatic hypotension, constipation.
Neuropsychiatric → sleep disorders, memory deficits, depression, irritability.

Question 17

What are the cardinal motor symptoms of Parkinson’s disease?

Answer 17

Resting tremor, bradykinesia, rigidity, postural instability.

Question 18

What is the rate-limiting enzyme in dopamine metabolism?

Answer 18

Tyrosine hydroxylase.

Question 19

What are the different treatment options for Parkinson’s disease?

Answer 19

Dopamine replacement.
Dopamine receptor agonists.
Monoamine oxidase B (MAO-B) inhibitors.

Question 20

How can dopamine replacement be used to treat Parkinson’s disease?

Answer 20

Levodopa (L-DOPA):

• rapidly converted to DA by DOPA decarboxylase (DOPA-D)
• can cross blood-brain barrier
• peripheral breakdown by DOPA-D leads to nausea and vomiting
• long-term side effects: dyskinesias and ‘on-off’ effects, not disease-modifying

Need to be given with adjuncts:

• DOPA decarboxylase inhibitors: carbidopa and benserazide
• do no cross BBB → prevent peripheral breakdown of levodopa
• reduce required levodopa dosage

COMT inhibitors: entacapone and tolcapone increase the amount of levodopa in the brain.

Question 21

What are the 2 types of dopamine receptor agonists and how can they be used to treat Parkinson’s disease?

Answer 21

Ergot derivatives- bromocriptine and pergolide:

• act as potent agonists of D2 receptors
• associated with cardiac fibrosis

Non-Ergot derivatives- ropinirole and rotigotine:

• ropinirole also available as extended-release formulation
• rotigotine also available as a patch

Question 22

How can monoamine oxidase B (MAO-B) inhibitors be used to treat Parkinson’s disease?

Answer 22

Selegiline (deprenyl) and rasagiline.
Reduce the dosage of L-DOPA required.
Can increase the amount of time before levodopa treatment is required.

Question 23

What are the limitations of anti-Parkinsonian drugs?

Answer 23

Not disease-modifying.

Question 24

Discuss the epidemiology of schizophrenia.

Answer 24

Affects around 1% of the population and has genetic influence.
Onset of symptoms- between 15-35 years.
Higher incidence in ethnic minorities, e.g. Afro-Caribbean immigrants.
Patients’ life expectancy is 20-30 years lower than average due to drug abuse.

Question 25

What are the positive symptoms of schizophrenia?

Answer 25

Increased mesolimbic dopaminergic activity
Hallucinations- auditory and visual
Delusions- paranoia
Thought disorder- denial about oneself

Question 26

What are the negative symptoms of schizophrenia?

Answer 26

Decrease mesocortical dopaminergic activity
Affective flattening- lack of emotion
Alogia- lack of speech
Avolition/apathy- loss of motivation

Question 27

What is chlorpromazine?

Answer 27

First generation anti-psychotic.
Discovered whilst developing new antihistamines.
Primary mechanism of action- possibly D2 receptor antagonism.
Side effects:
-high incidence- anticholinergic, especially sedation
-low incidence- extrapyramidal side effects (EPS)

Question 28

What is haloperidol?

Answer 28

First generation anti-psychotic.
Very potent D2 antagonist (~50x more potent than chlorpromazine).
Therapeutic effects develop over 6-8 weeks.
Little impact on negative symptoms.
Side effects: high incidence of extrapyramidal side effects (EPS).

Question 29

What is clozapine?

Answer 29

Most effective antipsychotic, second generation.
Very potent antagonist of 5-HT2A receptors.
Only drug to show efficacy in treatment resistant schizophrenia and negative symptoms.
Side effects: can cause potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain.

Question 30

What is risperidone?

Answer 30

Second generation anti-psychotic.
Very potent antagonist of 5-HT2A and D2 receptors.
Side effects: more extrapyramidal side effects (EPS) and hyperprolactinaemia than other atypical antipsychotics.

Question 31

What is quetiapine?

Answer 31

Second generation anti-psychotic.
Very potent antagonist of H1 receptors.
Side effects: lower incidence of extrapyramidal side effects (EPS) than other antipsychotics.

Question 32

What is aripiprazole?

Answer 32

Partial agonist of D2 and 5-HT1A receptors.
No more efficacious than typical antipsychotics.
Side effects: reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics.

Question 33

What are the principle neurotransmitter defects in schizophrenia?

Answer 33

Increased dopamine in mesolimbic pathway: positive symptoms- hallucinations.

Reduced dopamine in mesocortical pathway: negative symptoms- affective flattening.