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Year 2 Collin > Pharm 28 - Anti Parkinsons-Disease drugs and Neuroleptics > Flashcards

Pharm 28 - Anti Parkinsons-Disease drugs and Neuroleptics Flashcards

1
Q

Explain how DA is synthesised

A

Synthesised in the neurone

  1. L-tyrosine —> L-DOPA (by Tyrosine hydroxylase)
  2. L-DOPA —> DA (by DOPA-decarboxylase)

Tyrosine hydroxylase is the rate limiting enzyme

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2
Q

In the metabolism of DA, what are the 2 means by which DA is removed from the synaptic cleft?

A
  1. Via DAT (Dopamine Transporter)

2. Via NET (noradrenaline transporter)

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3
Q

Which 3 enzymes metabolise DA?

A
  1. MAO-A (monoamine oxidase A)
  2. MAO-B - metabolises DA only
  3. COMT - metabolises all catecholamines, on postsynaptic membranes or in glial cells
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4
Q

Aside from DA, what other monoamines does MAO-A metabolise?

A

Noradrenaline, and 5-HT

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5
Q

What are MAO-A and MAO-B associated with?

A

Mitochondria

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6
Q

What are the 4 main dopaminergic pathways

A
  1. Nigrostriatal pathway - substantia nigra pars compacta (SNc) to striatum. Inhibition of this pathway result in movement disorders
  2. Mesolimbic pathway - VTA to NAcc. Brain reward pathway
  3. Mesocortical pathway - VTA to cerebrum. Important in executive functions and complex behavioural patterns.
  4. Tuberoinfundibular pathway - arcuate nucleus to median eminence - inhibition results in hyperprolactinaemia
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7
Q

Activation of which dopaminergic pathway is associated with positive schizophrenia symptoms?

A

Mesolimbic pathway

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8
Q

Activation of which dopaminergic pathway is associated with negative schizophrenia symptoms?

A

Mesocortical pathway

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9
Q

What is the main risk factor for Parkinson’s disease (PD)

A

Age

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10
Q

5% of early onset can be caused by genetic mutations. These includes?

A

SNCA, LRRK2

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11
Q

What is the pathophysiology behind PD

A

Severe loss of dopaminergic projection cells in SNc - Lewy bodies (neuronal cell bodies) and neuritis (axons) contain abnormally phosphorylated neurofilaments - ubiquitin and a-synuclein. This causes degeneration of neurones in the Nigrostriatal tract

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12
Q

What are the symptoms of PD

A

Motor symptoms - resting tremor, bradykinesia, rigidity, postural instability (cardinal symptoms)

ANS - Olfactory deficits, postural hypotension, constipation

Neuropsychiatric - sleep disorders, memory deficits, depression, irritability

(ANS and sleep affected before motor, dementia after motor affected)

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13
Q

What are the 3 general ways to treat PD

A
  1. Dopamine replacement + adjuncts
  2. DA receptor agonists
  3. MAO-B inhibitors
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14
Q

What drug can be given as dopamine replacement?

What is the good thing about this drug

A

L-DOPA (not L-Tyr as Tyrosine hydroxylase is rate limiting enzyme) - aka levodopa

Good thing about L-DOPA is that it crosses BBB and rapidly converted into DA by DOPA decarboxylase

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15
Q

What is the problem with giving L-DOPA as dopamine replacement?

A

It can also be broken down peripherally by DOPA-decarboxylase - the DA that is formed can activate the CTZ (outside BBB) - which causes nausea and vomiting

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16
Q

Does MAO or COMT break down most of the DA?

A

MAO

17
Q

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

A
  1. Dyskinesias
  2. “On-off” effects - i.e. works for a few hours then doesn’t

L-DOPA is not disease modifying, simply treats the symptoms

18
Q

Why are adjuncts given with L-DOPA?

Which Adjuncts are given

A

To prevent peripheral breakdown of DOPA

Adjuncts given =
1. DOPA-decarboxlase inhibitors - Carbidopa and Benserazide. These don’t cross BBB so prevent peripheral breakdown of L-dopa and reduce the dosage of L-dopa required

  1. COMT-inhibitors - Entacapone and Tolcapone. These increase the amount of L-dopa in the brain (helps treat on/off effects of DA)
19
Q

Which receptors can DA act on?

A
  1. D1, D5 = Gs linked

2. D2-4 = Gi linked receptors

20
Q

What are the 2 types of DA receptor agonists that can be given

A
  1. Ergot derivatives - Bromocriptine and Pergolide. These act as potent agonists of D2 receptors.

Ergot derivatives = associated with cardiac fibrosis

  1. Non-ergot derivatives - Ropinirole and Rotigotine.
    - (Ropinirole also available as extended-release formulation)
    - Rotigotine available as a patch
21
Q

What are MAO-B inhibitors that can be used to treat PD

A
  1. Selegiline (deprenyl)
  2. Rasagiline

MAO-B inhibitors reduce dosage of L-DOPA required. They may also increase the time before L-dopa treatment is needed.

22
Q

Schizophrenia (SP) affects about what percent of the population? What is the age of onset commonly?

A

1% of population affected - 15-35 common

Higher incidence in ethnic minorities, lower life expectancy by 20-30 years (lower LE due to drugs of abuse, not actual disorder)

23
Q

What are the positive symptoms of SP

A
  1. Hallucinations - auditory and visual
  2. Delusions: paranoia
  3. Thought disorder - denial about oneself

Positive SP symptoms caused by increased Mesolimbic DAergic activity (Increased VTA –> NAcc)

24
Q

What are the negative symptoms associated with SP

A
  1. Affective flattening - lack of emotion
  2. Alogia - lack of speech
  3. Avolition/apathy - loss of motivation

Negative symptoms caused by decreased mesocortical DAergic activity (VTA —> cerebrum)

25
Q

Name and describe the actions of 2 first generation/typical anti-psychotic (neuroleptic) drugs

A
  1. Chlorpromazine - possible D2 receptor antagonism
  2. Haloperidol - potent D2 receptor antagonist (50x more potent than chlorpromazine). Therapeutic effects take 6-8 weeks. Has little impact on negative SP symptoms
26
Q

What are the side effects of Chlorpromazine

A
  1. Anti-cholinergic - especially sedation (high incidence)

2. Extrapyramidal side effects (movement)

27
Q

What are the side effects of Haloperidol?

A

Extrapyramidal side effects (affects movement) - (high incidence)

Extrapyramidal system modifies pyramidal system

28
Q

Name some 2nd generation/atypical antipsychotic (neuroleptic) drugs

A
  1. Clozapine - most effective antipsychotic as it is the only licensed antipsychotic that has evidence of reducing negative symptoms. Only drug efficacious at treatment-resistant SP

It is a very potent antagonist of 5-HT2A receptors.

  1. Risperidone - very potent antagonist of 5-HT2A and D2 receptors
  2. Quetiapine - very potent agonist of H1 receptors
29
Q

What are the side effects of Clozapine

A

Can cause:
1. Potentially fatal neutropenia, agranulocytosis, myocarditis, weight gain

Hence used as a last resort

30
Q

What are the side effects of Risperidone

A
  1. Extrapyramidal side effects
  2. Hyperprolactinaemia
  3. Weight gain

Out of 2nd generation/atypical antipsychotics, Risperidone causes the most of these side effects.

31
Q

What are the side effects of Quetiapine

A

Lower incidence of Extrapyramidal side effects than other antipsychotics

32
Q

Apiprazole is a 2nd generation/atypical antipsychotic. It is the newest discovered antipsychotic. Describe it

A

Apiprazole = partial agonist of D2 receptors and 5-HT1A receptors

But no more efficacious than typical antipsychotics

Side effects include: Reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics.

33
Q

Which drug do you give for resistant SP

A

Clozapine

Year 2 Collin (114 decks)

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