Parkinson's disease and Neuroleptics (04.03.2020) Flashcards

1
Q

Dopamine synthesis

A

Tyrosine -> L-DOPA (via tyrosine hydroxylase -> this is the rate limiting step, even if you have loads of tyrosine, you can only make so much DOPA as tyrosine hydroxylase can make)

L-DOPA -> Dopamine (via DOPA decarboxylase)

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2
Q

Dopamine metabolism

A
  • DA removed from synaptic cleft by dopamine transporter (DAT) & noradrenaline transporter (NET)
  • DAT is on presyn and glial cells; NET is on presyn cells;
  • Three enzymes metabolise DA:
    1) Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT (mitochondrial)
    2) MAO-B: metabolises DA (mitochondrial)
    3) Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines (cytoplasmic)
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3
Q

Most important dopaminergic pathways

A

1) Nigrostriatal pathway (SN pars compacta -> striatum)
2) Mesolimbic Pathway (VTA -> NAcc)
3) Mesocortical Pathway (VTA -> cortex)
4) Tuberoinfundibular Pathway (arcuate nucelus -> median eminence)

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4
Q

Lewy body dementia

A

x

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5
Q

Pathophysiology of PD

A
  • severe loss of dopaminergic projection cells in SNc pars compacta
  • Lewy bodies & neurites -> Found respectively within neuronal cell bodies & axons
  • Consist of abnormally phosphorylated neurofilaments, ubiquitin & alpha-synuclein
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6
Q

Lewy body dementia

A
  • second most common cause of neurodegenerative dementia
  • associated with PD
  • there is currently no cure
  • there are treatments to help with some of the synmptoms
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7
Q

What are the commonly early and late onset symptoms in PD?

A

Early onset: tremor, ANS symptoms

Late: rigidity

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8
Q

brak staging of PD???

A

??/

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9
Q

Staging of PD

A
  • “Braak staging”
  • refers to two methods used to classify the degree of pathology in PD and AD.
  • 6 stages
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10
Q

How can you identify PD early on?

A

look at early symptoms e.g. the loss of smell and other ANS symptoms such as postural hypotension

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11
Q

What are the different ways to treat PD?

A
  1. DA replacement
  2. Dopamine Receptor agonists
  3. Monoamine oxidase B inhibitors
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12
Q

Dopamine replacement at PD treatment

A
  • levodopa
  • Rapidly converted to DA by DOPA decarboxylase (DOPA-D)
  • Can cross blood-brain barrier (BBB)
  • Peripheral breakdown by DOPA-D -> Leads to NAUSEA & VOMITING
  • too much DA can cause dyskinesias
  • Long-term side-effects: dyskinesias & ‘on-off’ effects.
  • NOT disease-modifying (does not prolong life, just makes the QoL better in terms of motor symptoms. does not halt the progression of the disease
  • can utilise adjuvants to optimise treatment
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13
Q

Dopamine replacements - adjuncts

A
  • DA causes N&V
  • this is due to effects in the periphery
  • we add adjuncts to prevent some SE
  • DOPA decarboxylase inhibitors: Carbidopa & Benserazide
    *Do not cross BBB -> prevent peripheral breakdown of levodopa
    Reduce required levodopa dosage
  • COMT inhibitors: Entacapone & Tolcapone
  • increased amount of levodopa in the brain
  • increased duration of action in the brian, less likely to see the ‘off’ effects following DA usage.
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14
Q

Dopamine Receptor agonists

A

Ergot derivatives:

  • Bromocriptine & Pergolide
  • Act as potent agonists of D2 receptors
  • Associated with cardiac fibrosis

Non-ergot derivatives:

  • Ropinirole & Rotigotine
  • Ropinirole also available as extended-release formulation
  • Rotigotine also available as a patch
  • there is not necessarily loss of neurones that the DA-ergic neurones are targeting (postsynaptic) so if you give DOPA it is helpful.
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15
Q

MAO-B inhibitors

A
  • Selegiline (deprenyl) & Rasagiline
  • Reduce the dosage of L-DOPA required
  • Can increase the amount of time before levodopa treatment is required
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16
Q

Which receptors does dopamine act on?

A
  • Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors
  • DA is re-uptaken by the dopamine transporter (DAT) & metabolised by monoamine oxidase (MAO) enzymes
  • DA receptor agonists and MAO-B inhibitors work via receptor activation!!!
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17
Q

Schizophrenia epidemiology

A
  • Affects around 1% of population & has genetic influence
  • Onset of symptoms: between 15-35 years
  • Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)
  • Patients’ life expectancy - 20-30 years lower than average

=> there are genetic and environmental risk factors for schizophrenia (not all monozygotic twins get i)

  • late teens and 20s os onset of symptoms (most common)
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18
Q

Symptoms of schizophrenia

A

Positive symptoms

  • increased Mesolimbic dopaminergic activity
  • Hallucinations: Auditory & visual
  • Delusions: Paranoia
  • Thought disorder: Denial about oneself
Negative symptoms:
- decreased Mesocortical dopaminergic activity
- Affective flattening: lack of emotion
- Alogia: lack of speech
Avolition/ apathy: loss of motivation
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19
Q

Haloperidol

A
  • 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 - EPS

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20
Q

Chlorpromazine

A
  • Discovered whilst developing new antihistamines
  • Primary MoA – possibly D2 receptor antagonism

Side effects

  • High incidence - anti-cholinergic, especially sedation
  • Low incidence - extrapyramidal side-effects (EPS)

-> the SE are mainly anti-cholinergic for this drug

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21
Q

Haloperidol

A
  • Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
  • Therapeutic effects develop over 6-8 weeks
  • Little impact on negative symptoms
  • binding affinity highest for D2 but also acts on D3, D4 and alpha 1

Side effects

  • High incidence - EPS
  • > the side of this drug are mainly EPS
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22
Q

Clozapine

A
  • second generation / atypical antipsychotic
  • Most effective antipsychotic
    Very potent antagonist of 5-HT2A receptors
  • Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms

Side effects
- Can cause potentially fatal neutropenia, can cause fatal agranulocytosis, myocarditis & weight gain

23
Q

What is the only drug that treats the negative symptoms of schizophrenia?

A

Clozapine

24
Q

Clozapine

A
  • second generation / atypical antipsychotic
  • Most effective antipsychotic
  • Very potent antagonist of 5-HT2A receptors
  • Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms

Side effects
- Can cause potentially fatal neutropenia, can cause fatal agranulocytosis, myocarditis & weight gain

25
Q

Aripiprazole

A
  • more recent drug (2000s)
  • Partial agonist of D2 & 5-HT1A receptors (when you have too much activity it will cause inhibition, if you have too little it will cause activation)
  • No more efficacious than typical antipsychotics

Side effects
- Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics

First antipsychotic with a nano chip to control compliance.

26
Q

Risperidone

A
  • Very potent antagonist of 5-HT2A & D2 receptors (also some affinity for D4 and alpha 1)
  • Side effects: More EPS & hyperprolactinaemia than other atypical antipsychotics
27
Q

Quetiapine

A
  • Very potent antagonist of H1 receptors
  • Side effects: Lower incidence of EPS than other antipsychotics
  • highest affinity for alpha 1 and H1; after that D2
28
Q

Aripiprazole

A
  • more recent drug (2000s)
  • Partial agonist of D2 & 5-HT1A receptors (when you have too much activity it will cause inhibition, if you have too little it will cause activation)
  • No more efficacious than typical antipsychotics
  • highest affinity for D2 and D3 and after that 5HT1A

Side effects
- Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics

First antipsychotic with a nano chip to control compliance.

29
Q

What is a big problem with antipsychotics?

A

non-compliance due to the SE

30
Q

Why are non-ergot derivative DA agonists recommended over ergot-derivatives?

A

got derivatives are associated with cardiac fibrosis

31
Q

Which antipsychotic drug is associated with neutropenia and agranulocytosis?

A

Clozapine

32
Q

Which enzymes that metabolise dompamine are mitochondrial and cytoplasmic?

A
  • MAO-A and MAO-B are mitochondrial

- COM-T is cytoplasmic

33
Q

What does MAO-A metabolise?

A

= monoamine oxidase A

-> metabolises DA, NE & 5-HT

34
Q

What does MAO-B metabolise?

A

= monoamine oxidase B

-> metabolises dopamine

35
Q

What does COM-T metabolise?

A

= catechol-O-methyl transferase

-> wide distribution, metabolises all catecholamines

36
Q

Nigrostriatal pathway

A
  • susbstantia nigra pars compacta (SNc) to the striatum.

- Inhibition results in movement disorders

37
Q

Mesolimbic pathway

A
  • ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc)
  • Brain reward pathway
  • associated with schizophrenia
38
Q

Mesocortical pathway

A
  • VTA to the cerebrum (more diffuse pathway than some other DA-ergic pathways)
  • Important in executive functions & complex behavioural patterns.
  • associated with schizophrenia
39
Q

Tuberoinfundibular pathway

A
  • arcuate nucleus to the median eminence
  • Inhibition results in hyperprolactinaemia
  • this pathway is not targeted but we see side effects due to drugs also working on this pathway.
40
Q

Dopamine and pathways summary

A
Synthesis & Metabolism
- L-tyrosin ->  (i) L-DOPA (ii) ->  Dopamine (DA)
This process utilises the enzymes:
     - Tyrosine hydroxylase
     - DOPA decarboxylase

Neuronal pathways

  • Nigrostriatal pathway: inhibition results in movement disorders
  • Mesolimbic pathway: activation associated with positive schizophrenia symptoms
  • Mesocortical pathway: inhibition associated with negative schizophrenia symptoms
  • Tuberoinfundibular pathway: inhibition results in hyperprolactinaemia
41
Q

Dopamine and pathways summary

A
Synthesis & Metabolism
- L-tyrosin ->  (i) L-DOPA (ii) ->  Dopamine (DA)
This process utilises the enzymes:
     - Tyrosine hydroxylase
     - DOPA decarboxylase

Neuronal pathways

  • Nigrostriatal pathway: inhibition results in movement disorders
  • Mesolimbic pathway: activation associated with positive schizophrenia symptoms
  • Mesocortical pathway: inhibition associated with negative schizophrenia symptoms
  • Tuberoinfundibular pathway: inhibition results in hyperprolactinaemia
42
Q

Name some DOPA decarboxylase inhbitors

A

carbidopa

benserazide

43
Q

Entacapone & Tolcapone

A

= COMT inhibitors

- increase the amount of dopamine in the brain

44
Q

Carbidopa and Benserazide

A

DOPA decarboxylase inhibitors

  • cannot cross the BBB
  • added as an adjuvant to DOPA
  • decrease peripheral DOPA effects
  • less N&V
45
Q

PD summary

A

Pathophysiology & Symptoms

  • Severe loss of dopaminergic cells in SNc: Lewy bodies & neurites
  • Cardinal Symptoms: Resting tremor, bradykinesia, rigidity, postural instability
  • Non-motor symptoms: Olfactory & autonomic dysfunction, sleep disorder

Dopamine replacement

  • Levodopa
  • DOPA decarboxylase & COMT

Receptor activation

  • DA receptor agonists: ropinirole
  • MAOB inhibitors: selegiline
46
Q

Schizophrenia summary

A

Background

  • Mesolimbic pathway: Positive symptoms -> hallucinations
  • Mesocortical pathway: Negative symptoms  affective flattening

First generation antipsychotics
- Chlorpromazine: sedative & anti-muscarinic effects
- Haloperidol: potent DA receptor antagonist; extrapyramidal side-effects
Second generation antipsychotics
- Clozapine: Resistant schizophrenia; agranulocytosis
- Risperidone: D2, 5-HT2A; EPS & weight gain
- Quetiapine: H1 antagonist; low EPS
- Aripiprazole: Partial D2 & 5-HT1A agonist

47
Q

What drugs should you know for treatment of PD?

A

Dopamine replacement

  • Levodopa
  • DOPA decarboxylase & COMT inhibitor

Receptor activation

  • DA receptor agonists: ropinirole
  • MAOB inhibitors: selegilin

=5

48
Q

What drugs should you know for treatment of schizophrenia?

A

1st generation:

  • chlorpromazine
  • haloperidol

2nd generation:

  • clozapine
  • risperidone
  • quetapine
  • aripiprazole

=6

49
Q

LO1: Parkinson’s disease neuropathology: Identify the dopaminergic pathway in the brain which degenerates and how the loss of dopamine triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in Parkinson’s and what is the underlying pathological process

A

Nigrostriatal pathway - substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders
Severe loss of dopaminergic cells in SNc: Lewy bodies & neurites

50
Q

LO2: Parkinson’s disease clinical features: summarise the principle motor and non-motor clinical feature of the disease

A

Motor deficits - Bradykinesia, resting tremor, rigidity, postural instability

Non-motor deficitis - Olfactory & autonomic dysfunction, sleep disorders

51
Q

LO3:Anti-parkinsonian drugs: summarise and compare the mechanisms of action of drugs used to treat PD. Explain why they are used in conjunction and their limitations

A
  • DA replacement - Levodopa acts as DA precursor
  • DA receptor stimulation - D2 agonists: Bromocriptine, ropinirole
  • Prevention of breakdown - MAOB inhibitors (selegiline), COMT inhibitors (entacapone)
  • L-DOPA & carbidopa & selegiline - used in conjunction to reduce side-effects & required dosage
  • Limitations - not disease-modifying
  • Long-term side-effects associated with levodopa - Dyskinesias & on-off symptoms
52
Q

LO4: Schizophrenia: identify the principle neurotransmitter defects in schizophrenia

A
  • Increased DA in mesolimbic pathway: Positive symptoms -> hallucinations
  • Reduced DA in mesocortical pathway: Negative symptoms -> affective flattening
53
Q

LO5:
Dopaminergic drugs: explain how drugs targeting the dopaminergic system are utilized in the treatment of schizophrenia, which symptoms they treat and discuss the side effects associated with these treatments

A
  • Chlorpromazine: phenothiazine causing antimuscarinic side-effects
  • Haloperidol: potent D2 antagonist causing extrapyramidal side-effects
  • Clozapine: very effective but causes agranulocytosis
    Risperidone: effective but associated with weight gain & EPS
  • Quetiapine: low incidence of EPS
  • Aripiprazole: partial agonist, low incidence of hyperprolactinaemia