26. Anti-Parkinsonian drugs and neuroleptics

Question 1

How is dopamine produced?

Answer 1

• L-tyrosine => L-DOPA [Tyrosine hydroxylase]

* L-DOPA => Dopamine [DOPA decarboxylase]

Question 2

What is the rate-limiting enzyme in the production of dopamine?

Answer 2

Tyrosine hydroxylase (TH)

Question 3

What transporters removed dopamine from the synaptic cleft?

Answer 3

Dopamine transporter (DAT) and noradrenaline transporter (NET)

Question 4

Which 3 enzymes metabolised DA?

Answer 4

MAO-A, MAO-B and Catechol-O-methyl transferase (COMT)

Question 5

Where are MAO and COMT enzymes found?

Answer 5

• MAO - intracellular, associated with mitochondria

* COMT - in mitochondria and post-synaptic

Question 6

Is DA breakdown mainly done by MAO or COMT?

Answer 6

MAO

Question 7

What are the 4 different dopaminergic pathways and what does inhibition (or increased activation of 1) of each cause?

Answer 7

• Nigostriatal - Parkinson’s
• Mesolimbic - activation => positive schizophrenia
• Mesocortical - negative schizphrenia
• Tuberoinfundibular - hyperprolactinaemia

Question 8

Describe the nigrostriatal pathway (location)?

Answer 8

• Cell bodies in substantia nigra pars compacta (SNc)

* Nerve project to the striatum

Question 9

Describe the mesolimbic pathway (location)?

Answer 9

• Cell bodies in the ventral tegmental area (VTA)

* Axons project to the nucleus accumbens (NAcc)

Question 10

Describe the mesocortical pathway (location)?

Answer 10

• Cell bodies in the VTA

* Project into the cerebrum (various areas of the cortex)

Question 11

What is activation of the mesocortical pathway associated with?

Answer 11

Positive schizophrenia symptoms

Question 12

Describe the tuberoinfundibular pathway (location)?

Answer 12

• Cell bodies in the arcuate nucleus

* Project to the median eminence

Question 13

Describe the pathophysiology of PD

Answer 13

• Sever loss of dopaminergic projection cells in nigrostriatal tract
• 80% of cells lost before symtpoms
• Lewy bodies + neurites found within cell bodies and axons
= abnormally phosphorylated neurofilaments, ubiquitin and α-synuclein

Question 14

Outline the clinical presentation of PD (3 types)

Answer 14

• Motor symptoms - resting tremor, bradykinesia, rigidity, postural instability
• ANS effects - olfactory deficits, orthostatic hypotension, constipation
• Neuropsychiatric - sleep disorders, memory deficits, depression, irritability

Question 15

What is the order of onset of the different types of PD clinical presentations

Answer 15

Autonomic => motor => neuropsychiatric

Question 16

Describe the gold standard treatment for PD

Answer 16

Levodopa (L-DOPA)
• Converted to DA by DOPA -D
• Can cross the BBB
• However it can cause nausea due peripheral breakdown by DOPA-D and CTZ actions
• Therefore, given with DOPA-D inhibitor e.g. Carbidopa

Only treats symptoms, not disease progression

Question 17

What can L-DOPA be given with to reduce the dosage and increase its effectiveness?

Answer 17

DOPA-D inhibitor and COMT inhibitor

Question 18

Why don’t DOPA-D inhibitors prevent conversion to DA in the brain?

Answer 18

Can’t cross the BBB

Question 19

What are the long-term side effects of L-DOPA?

Answer 19

• Dyskinesias

* On-off effects

Question 20

Describe the second option for PD treatment and any-side effects

Answer 20

Dopamine receptor agonists
• Useful if too many neurones have been broken down

Ergot derivatives e.g. bromocriptine
• Agonists of D2 receptors - (post-synaptic)
• Associated with cardiac fibrosis

Non-ergot derivates e.g. ropinirole
• Agonists of D2 receptors (post-synaptic)
• Available as extended-release formulation
• Not associated with cardiac fibrosis

Question 21

Describe the third option for PD treatment

Answer 21

MAO-B inhibitors e.g. selegiline
• Reduce the dosage of L-DOPA
• Can increase amount of time before before L-DOPA is needed
• Overall increase treatment time, as long-term L-DOPA usage has side-effects then no longer works

Question 22

Can schizophrenia be genetically influenced and why?

Answer 22

Yes - DISC1 gene known to be involved

Question 23

What is a main reason why a schizophrenia patient’s life expectancy decrease?

Answer 23

Increased likelihood to abuse drugs

Question 24

Explain and describe the ‘positive’ and ‘negative’ symptoms of schizophrenia

Answer 24

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

Negative
• Decreased mesocortical dopaminergic activity
• Affective flattening - lack of emotion
• Alogia - lack of speech
• Avolition/apathy

Question 25

Which type of symptoms do treatment of schizophrenia aim to reduce and why is this good/bad?

Answer 25

• Aim to reduce positive symptoms
• Negative symptoms still present
• Good for society but bad for the patient

Question 26

What was the treatment for psychosis before chlorpromazine was discovered in the 1950s?

Answer 26

Lobotomy and electroconvulsive therapy

Question 27

How does chlorpromazine work as an antipsychotic and what are the side-effects?

Answer 27

D2 receptor antagonism - first generation antipsychotic

Side effects (it is a histamine, muscarinic antagonist):
• High incidence: anti-cholinergic - sedation
• Low incidence: extrapyramidal side-effects (EPS) - problems with motor system

Question 28

How does Haloperidol work as an antipsychotic and what are the side-effects?

Answer 28

Very potent D2 receptor antagonist - first generation antipsychotic
• Good DA antagonism in mesolimbic pathway, but not mesocortical pathway
• Alleviate the positive symptoms
• Little impact on negative symptoms, maybe even worsening

Side effects:
• High incidence: EPS - problems with motor system

Question 29

What do second generation antipsychotics affect?

Answer 29

Serotonin, rather than dopamine

Question 30

How does clozapine work and what are the side-effects (second-generation)?

Answer 30

• Most effective antipsychotic - only drug that works in resistant schizophrenia and negative symptoms
• Potent 5-HT receptor antagonist
• Also acts on H1 and α-1 receptors, and inhibits D2 receptor

Side effects:
• Potentially fatal neutropenia
• Agranulocytosis
• Myocarditis
• Weight gain

Question 31

Describe how the following second-generation antipsychotics work:
• Risperidone
• Quetiapine
• Aripiprazole

Answer 31

• Risperidone - potent 5-HT and D2 receptor antagonist
• Quetiapine - potent H1 receptor antagonist
• Aripiprazole - partial 5-HT and D2 receptor agonist

Question 32

Describe how Aripiprazole work as an antipsychotic, even though it is an agonist

Answer 32

‘Partial’ 5-HT and D2 receptor agonist
• Where there is too much activity, it acts as an inhibitor - reduces positive symptoms
• When there is too little activity, it acts as an agonist - reduces negative symptoms

Question 33

Why is the heterogenous mechanism of action significant in schizophrenia treatment?

Answer 33

• Affects many different receptors

* This does not relate to clinical efficacy

Question 34

What are the side-effects of the following second-generation antipsychotics:
• Risperidone
• Quetiapine
• Aripiprazole

Answer 34

• Risperidone - hyperprolactinaemia (inhibition in tuberoinfundibular pathway)
• Quetiapine - EPS (lower incidence than others)
• Aripiprazole - hyperprolactinaemia and weight gain (lower incidence than others)