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pharm > 27. Anti-Parkinsonian drugs and neuroleptics > Flashcards

27. Anti-Parkinsonian drugs and neuroleptics Flashcards

1
Q

how is dopamine synthesised and which enzymes are involved?

A
  1. Tyrosine hydroxylase (rate-limiting enzyme) converts L-tyrosine –> L-DOPA
  2. DOPA decarboxylase converts L-DOPA –> dopamine
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2
Q

how is dopamine metabolised?

A
  • removed from the synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET)
  • metabolised by MAO-A, MAO-B and COMT
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3
Q

what is the difference between MAO and COMT?

A
  • MAO enzymes are intracellular so only break down dopamine once it has been taken up into the presynaptic knob
  • MAO-A metabolises dopamine, NE and 5-HT
  • MAO-B metabolises dopamine only
  • COMT is found in the mitochondria and post-synaptic enzymes
  • COMT is widely distributed and metabolises all catecholamines
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4
Q

what is the nigrostriatal pathway?

A

The cell bodies of the nerve are present within the substantia nigra pars compacta (SNc), and the nerves project up to the striatum. Inhibition of these neurones results in movement disorders

IMPORTANT IN PARKINSONS DISEASE

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5
Q

what is the mesolimbic pathway (reward pathway)?

A

cell bodies are located in the ventral tegmental area (VTA) and the axons project up to the Nucleus Accumbens

IMPORTANT IN SCHIZOPHRENIA

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6
Q

what is the mesocortical pathway?

A

cell bodies start in the VTA but this time project to the cerebrum

important in executive functions and complex behavioural patterns

IMPORTANT IN SCHIZOPHRENIA

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7
Q

what is the tuberoinfundibular pathway

A

cell bodies in the arcuate nucleus –> projection to the median eminence

regulates prolactin secretion

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8
Q

what is the pathophysiology of parkinson’s?

A
  • severe loss of dopaminergic projecton cells in nigrostriatal tract
  • 80% of dopaminergic cells are lost before symptoms arise
  • lewy bodies and neurites are found within neuronal cell bodies and axons
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9
Q

what is the clinical presentation of parkinson’s?

A
  • motor symptoms: resting tremor, bradykinesia, rigidity, postural instability
  • ANS effects: olfactory deficits, orthostatic hypotension, constipation
  • neuropsychiatric sign: sleep disorders, memory deficits, depression, irritability
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10
Q

what are lewy bodies and neurites?

A
  • lewy bodies are located within cell bodies of the nerves
  • lewy neurites are located within the axons and dendrites
  • they consist of abnormally phosphorylated neurofilaments, ubiquitin and a-synuclein
  • a-synuclein plaques are thought to be responsible for neurodegeneration of neurones in the nigrostriatal tract
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11
Q

how is dopamine replacement used to treat parkinson’s?

A

levodopa (L-DOPA) treatment:

  • is converted to dopamine by DOPA decarboxylase
  • can cross the BBB
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12
Q

why is dopamine not given?

A

dopamine will enter the periphery –> peripheral breakdown by DOPA decarboxylase –> act on CTZ –> nausea and vomiting

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13
Q

why is L-DOPA given with DOPA decarboxylase inhibitors?

A
  • DOPA decarboxylase enzyme can be found in the systemic circulation
  • L-DOPA can therefore be converted to dopamine in the periphery –> nausea
  • DOPA decarboxylase inhibitors (carbidopa and benserazide) prevent this and do not cross the BBB so conversion of L-DOPA in the CNS can still occur
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14
Q

what do COMT inhibitors do? give examples of COMT inhibitors

A

increase amounts of L-DOPA in the brain, so can be given with L-DOPA

e.g. entacapone and tolcapone

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15
Q

how are dopamine receptor agonists used to treat parkinson’s?

A

instead of increasing levels of dopamine, we can activate the dopamine receptors via ergot derivatives and non-ergot derivatives

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16
Q

what do ergot derivatives do? give examples

A
  • act as potent agonists of dopamine D2 receptors - act on the post-synaptic receptors
  • associated with cardiac fibrosis and increased likelihood of valvular disease

e.g. bromocriptine and pergolide

17
Q

give 2 examples of non-ergot derivatives

A

ropinirole and rotigotine

18
Q

how are MAOb inhibitors used to treat parkinson’s? give examples

A
  • reduce the dosage of L-DOPA required
  • increase the amount of time before L-DOPA treatment is required

e.g. selegiline and rasagiline

19
Q

outline the epidemiology of schizophrenia

A
  • affects 1% of population
  • increased activity in the mesolimbic dopaminergic pathway
  • onset between 15-35 years old
  • higher incidence in ethnic minorities
  • patient’s life expectancy is 20-30 years lower than average due to increased likelihood of drug abuse
20
Q

what are the ‘positive’ symptoms of schizophrenia?

A
  • increased mesolimbic dopaminergic activity
  • hallucinations: auditory and visual
  • delusions: paranoia
  • thought disorder: denial about oneself
21
Q

what are the ‘negative’ symptoms of schizophrenia?

A
  • decreased mesocortical dopaminergic activity
  • affective flattening (lack of emotion)
  • lack of speech
  • loss of motivation
22
Q

what is chlorpromazine? what are its side effects?

A
  • first generation antipsychotic
  • inhibits dopamine D2 receptors

SIDE EFFECTS:

  • anti-cholinergic effects (especially sedation)
  • extrapyrimidal side-effects
23
Q

what is haloperidol? what are its side effects?

A
  • first generation antipsychotic
  • potent D2 antagonist
  • therapeutic effects develop over 6-8 weeks
  • may worsen the negative symptoms (only alleviate ‘positive’ symptoms)

SIDE EFFECTS:
- extra-pyramidal side effects

24
Q

what are second generation antipsychotics?

A

those that affect serotonin rather than dopamine

25
Q

what is clozapine? what are its side effects?

A
  • second generation antipsychotics
  • most effective
  • very potent 5-HT2a receptor antagonist
  • also acts on H1 receptors, a1 receptors and D2 receptors

SIDE EFFECTS:

  • potentially fatal neutropenia
  • agranulocytosis
  • myocarditis
  • weight gain
26
Q

what is risperidone? what are its side effects?

A
  • second generation antipsychotic
  • very potent 5-HT2a and D2 receptor antagonist

SIDE EFFECTS:

  • extra-pyramidal side effects
  • hyperprolactinaemia
  • weight gain
27
Q

why does treatment with risperidone result in hyperprolactinaemia?

A

medication is inhibiting dopamine receptors in the tuberoinfundibular pathway

28
Q

what is quetiapine? what are its side effects?

A
  • second generation antipsychotic
  • very potent H1 receptor agonist

SIDE EFFECTS:
- extra-pyramidal side effects

29
Q

what is aripiprazole? what are its side effects?

A
  • second generation antipsychotic
  • partial agonist of D2 and 5-HT1a receptors
  • when there is too much activity the partial agonist act as an inhibitor (reduced positive symptoms)
  • when there is little activity the partial agonist increases activity (reduces negative symptoms)

SIDE EFFECTS:

  • hyperprolactinaemia
  • weight gain

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