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YR2 LCRS Pharm > Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia > Flashcards

Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Flashcards

1
Q

List the 4 main dopaminergic pathways in the brain

A

Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular system

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2
Q

Where are each of the dopaminergic pathways found?

A

Nigrostriatal: substantia nigra pars compacta to striatum
Mesolimbic: VTA to nucleus accumbens, frontal cortex, limbic cortex + olfactory tubercle
Mesocortical: VTA ot cerebrum
Tuburoinfundibular system: arcuate nucleus in hypothalamus to median eminence + pituitary gland

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3
Q

What are the roles of the dopaminergic pathways?

A

Nigrostriatal: control of movement
Mesolimbic: Reward pathway
Mesocortical: Executive functions + complex behavioural patterns
Tuburoinfundibular system: regulate hormone secretion

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4
Q

Describe dopamine synthesis.

A

L-Tyrosine is converted by tyrosine hydroxylase to L-DOPA

L-DOPA is converted by DOPA decarboxylase to Dopamine

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5
Q

Is Parkinson’s disease more common in males or females?

What percentage of all cases of Parkinson’s disease is accounted for by familial Parkinson’s disease?

A

Males – 4:1

5% due to genetic mutations

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6
Q

What are the cardinal signs of Parkinson’ disease?

A

Resting tremor
Rigidity (stiffness: limbs feel weak + heavy)
Bradykinesia (slowness of movement)
Postural instability

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7
Q

Describe the pathophysiology of Parkinsons disease

A

Degeneration of nigrostriatal tract

Associated with formation of Lewy bodies + Neurites

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8
Q

What non-motor symptoms accompany Parkinson’s disease?

A

Neuropsychiatric: Sleep disorders, depression, memory defects, irritability
ANS: olfactory defects, orthostatic hypotension, constipation

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9
Q

What proportion of dopaminergic neurones of the nigrostriatal dopaminergic pathway must be lost before symptoms occur?

A

80-85% of dopaminergic neurones + 70% of striatal dopamine must be depleted before symptoms appear

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10
Q

Why do such high proportions of dopaminergic neurones of the nigrostriatal dopaminergic pathway have to be lost before symptoms occur?

A

There are compensatory mechanisms e.g. neurone overactivity + increase in dopamine receptors

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11
Q

What other type of drug has to be given with L-DOPA in dopamine replacement therapy and why? List examples

A

Peripheral DOPA decarboxylase inhibitors (that don’t cross BBB)
Prevents conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase (can cause nausea + vomiting)
Carbidopa + Benserazide

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12
Q

Why is Levodopa prescribed to Parkinsons patients?

A

Can cross BBB
L DOPA is rapidly converted by DOPA decarboxylase to DA
Post synaptic D2 receptors intact, so DA can bind

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13
Q

What are the acute side effects of L-DOPA?

A

Nausea

Vomiting

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14
Q

What are the chronic side effects of L-DOPA?

A

Dyskinesias

Rapid fluctuations in clinical state (“on-off” effects)

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15
Q

Name three dopamine agonists. What types of derivatives are these?

A

Bromocriptine + Pergolide (Ergot derivatives)

Ropinerol (Non-ergot derivative)

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16
Q

Which receptors do dopamine agonists act on?

A

D2 receptor

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17
Q

What are the benefits of dopamine agonists over L-DOPA?

A

Longer duration of action
Smoother + more sustained response
Actions independent of dopaminergic neurones (which are progressively degenerating)
Incidence of dyskinesias is less

18
Q

What unwanted effect arose due to ergot derived dopamine receptor agonists?

A

Increased likelihood of cardiac fibrosis, leading to valve disorders

19
Q

What unwanted effect arises due to non-ergot derived dopamine receptor agonists?

A

Development of addictive behaviour e.g. gambling

20
Q

Name two MAO-B inhibitors.

A

Selegiline

Rasagiline

21
Q

Why is use of MAO-B inhibitors limited in treatment of Parkinsons disease?

A

MAO-B is also responsible for breakdown of Tyramine

Thus, cheese reaction may result

22
Q

Name two COMT inhibitors.

A

Tolocapone (CNS + PNS)

Entacapone (PNS)

23
Q

What are the effects of COMT inhibition in the CNS?

A

Prevents breakdown of dopamine in the brain

Thus less likely to experience OFF effects

24
Q

What percentage of the general population is affected by schizophrenia? What is linked to development of schizophrenia? What is the age of onset of symptoms?

A

1%
Genetic influence
Age 15-35

25
Q

What are the positive symptoms of schizophrenia?

A

Overt symptoms that should NOT be present
Hallucinations (auditory + visual)
Delusions + Paranoia
Thought disorder (denial)

26
Q

What is meant by an atypical antipsychotic?

A

Newer antipsychotics

Have fewer extrapyramidal side effects

27
Q

Name 3 second generation/ atypical antipsychotics

A

Clozapine
Risperidone
Quetiapine

28
Q

Name and describe the most effective antipsychotic

A

Clozapine
Very potent antagonist of 5-HT 2A receptors
Only drug effective in treatment resistant schizophrenia + negative symptoms

29
Q

What are the extrapyramidal side effects of antipsychotics caused by?

A

Blockade of dopamine receptors in the nigrostriatal system can induce
Parkinson-like side effects

30
Q

What are the negative symptoms of schizophrenia?

A

Affective flattening: Lack of emotion
Alogia: Lack of speech
Avolition/ apathy: loss of motivation

31
Q

Availability of which enzyme in dopamine synthesis is the rate limiting step?

A

Tyrosine hydroxylase

32
Q

How is dopamine metabolised?

A 
Transporters on presynaptic + glial cells take DA back into cells (DAT + NET)
Enzymatic degradation (mitochondrial MAO-A + MAO-B and COMT enzyme in glial cells + membrane of postsynaptic cell)
33
Q

Which dopaminergic pathway is primarily effected in Parkinson’s disease?

A

Nigrostriatal pathway

34
Q

What are the positive and negative symptoms of schizophrenia thought to be caused by?

A

Positive: Increased mesolimbic dopaminergic activity
Negative: Decreased mesocortical dopaminergic activity

35
Q

List 2 first generation (typical) antipsychotic drugs and their mechanism of action

A

Chlorpromazine: D2 receptor antagonist
Haloperidol: Potent D2 antagonist

36
Q

What side effects accompany the 2 first generation (typical) antipsychotic drugs?

A

Chlorpromazine: Anticholinergic side effects + EPS
Haloperidol: EPS

37
Q

What are the side effects of Clozapine?

A

Neutropenia
Agranulocytosis
Myocarditis
Weight gain

38
Q

Describe the action and side effects of Risperidone

A

Very potent antagonist of 5-HT 2A + D2 receptors

EPS, weight gain + hyperprolactinaemia

39
Q

Describe the action and side effects of Quetiapine

A

Very potent antagonist of H1 receptors

Lower EPS

40
Q

Describe the action, efficacy and side effects of Aripiprazole

A

Partial agonist of D2 + 5-HT 1A receptors
No more efficacious than typical antipsychotics
Reduced incidences of hyperprolactinaemia + weight gain

YR2 LCRS Pharm (34 decks)

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