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Year 2 Pharma > Anti-parkinsonian drugs and neuroleptics > Flashcards

Anti-parkinsonian drugs and neuroleptics Flashcards

1
Q

What are 4 major dopaminergic pathways in the brain

A

Nigrostriatal - MOST IMPORTANT for PD
Mesolimbic
Mesocortical
Tuberoinfundibular

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2
Q

What is the nigrostriatal pathway and what is it important in? What condition is this impacted in

A

Substantia nigra zona compacta -> striatum
Important in initiating, fine tuning and ending movement control
Impacted in parkinsons

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3
Q

What is the mesolimbic pathway and what is it important in? What condition is this impacted in

A

VTA -> NAcc (nucleus accumbens), frontal cortex, limbic cortex, olfactory tubercle
Involved in emotion, and is brain reward pathway
Impacted in schizophrenia

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4
Q

What is the mesocortical system and what is it important in

A

VTA (ventral tegmental area) -> cerebrum

Important in executive functions and complex behavioural patterns

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5
Q

What is the difference in the amount of men and women affected by parkinsons

A

4x as many men as women

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6
Q

What are causes of parkinsons

A

Familial cases are 8% of cases

Idiopathic is 92% of cases

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7
Q

What are the 4 cardial motor symptoms of parkinsons?

A

Resting tremor
Rigidity
Bradykinesia
Postural instability

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8
Q

What are ANS effects of parkinson’s disease

A

Olfactory deficits, orthostatic hypotension, constipation

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9
Q

What is the main affected area in PD

A

Substantia nigra (pars compacta) which projects into the caudate and putamen

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10
Q

What does the substantia nigra lose in PD

A

Loss of dopaminergic projection cells in SNc and neuro melanin pigment (the function of this is unknown)

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11
Q

What are lewy bodies and neurites, where are they found and what do they consist of?

A

Aggregations of proteins in neuronal cell bodies and axons respectively, and consist of abnormally phosphorylated neurofilaments; ubiquitin and alpha-synuclein

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12
Q

What are the different stages of parkinson’s and what happens in them

A

Stages 1 & 2 – Synuclein deposition in the DM, RN and LC – pre-symptomatic.
Stages 3 – Synuclein deposition in SN – onset of motor deficits.
Stage 4, 5, 6 – deposition in the amygdala and cortical areas.

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13
Q

Synthesis of dopamine

A

L-Tyrosine -> L-DOPA (via tyrosine hyroxylase - rate limiting) -> Dopamine (via DOPA decarboxylase) in the neurone and stored in the neurone vesicle

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14
Q

Dopamine metabolism

A

Different ways

  1. DA removed from synaptic cleft via dopamine transporter and noradrenaline transporter and sends it back to neuronal cell - recycles dopamine
  2. enzymatic metabolism with different enzymes:
    - MAO-A breaks down DA, NE and 5HT, MAO-B breaks down DA, COMT breaks down all catecholamines
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15
Q

What is the tuberoinfundibular pathway and what is it involved in

A

Acuate nucleus -> median eminance
Endocrine pathway where inhibition leads to hyperprolactinaemia - not really targeted for PD/Schizophrenia drugs but can account for some side effects

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16
Q

What are neuropsychiatric symptoms of PD

A

Sleep disorders
Memory deficits
Depression
Irritability

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17
Q

PD treatment options:

A
  1. dopamine replacement

2. receptor activation via dopamine receptor activation

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18
Q

What drug is given for dopamine replacement and why is dopamine not given directly

A

Give L-DOPA aka levodopa because tyrosine hyroxylase making L-DOPA is the rate limiting step so you skip that step but dopamine not given directly because it causes effects in the periphery before reaching the CNS
Body can convert L-DOPA into DOPA decarboxylase

19
Q

Why does dopamine replacement work as an effective treatment for PD symptoms

A

Because the dopamine D2 receptors in the brain still exist, it is only the dopamine forming cells in the nigrostriatal tract that are degenerating, therefore giving dopamine replacement makes the cells that still are there work overtime to make enough dopamine

20
Q

Side effect of Levodopa

A

Can cause induced dyskinesias (sudden uncontrolled movement due to too much dopamine) and on/off effects as dopamine can just run out - doesn’t mimic natural dopamine release.
Peripheral breakdown of DOPA-D can lead to nausea and vomiting
And it is not disease modifying - increases quality of life but doesn’t affect survival

21
Q

What some commonly used DOPA decarboxylase inhibitors

A

Carbidopa and benserazide

22
Q

What drugs are given with Levodopa to help with nausea and vomiting

A

DOPA decarboxylase inhibitors - they don’t cross BBB but protects the levodopa from breaking down peripherally, this can also allow you to reduce dose of levodopa as it is not lost in periphery

23
Q

What drugs can be given with Levodopa to increase time that levodopa is effective in the brain

A

COMT inhibitors eg Entacapone and tolcapone as they prevent breakdown of dopamine it increases the amount in the brain. Reduces on/off effect

24
Q

What are examples of dopamine receptor agonists

A
  1. Ergot derivative: Bromocriptine or pergolide that act as potent D2R agonists
  2. Non-ergot derivatives (synthetic):
    Ropinirole and Rotigotine
  3. MAO B inhibitors eg selegilinen and rasagiline (cheese reaction)
25
Q

Why are dopamine receptor agonists good for treatment of PD

A

Don’t require intact presynaptic neurones and as they are disappearing in PD this is a good treatment

26
Q

What is the problem of using ergot derivatives as treatment for PD

A

They are associated with cardiac fibrosis; cause fibrosis of cardiac valves - increase valve disorders

27
Q

What are side effects of dopamine agonists

A

Hallucinations
Compulsive gambling
(affect mesolimbic+mesocortical pathways)

28
Q

What is the cheese effect?

A

An acute attack of hypertension that can occur in a person taking a monoamine oxidase inhibitor (MAOI) drug who eats cheese, caused by an interaction of the MAOI with tyramine, formed in ripe cheese when bacteria provide an enzyme that reacts with the amino acid tyrosine in the cheese

29
Q

Who does schizophrenia affect and what are environmental factors

A

Affects 1% of population and has genetic influence, onset of symptoms between 15-35 years and high incidence in ethnic minorities that migrate to other countries that don’t integrate into the larger society

30
Q

What is the patient life expectancy of a patient with schizophrenia and what is it due to

A

20-30 years and this isn’t due to any schizophrenia based degeneration etc its more due to the lifestyle eg drinking and drugs that is associated with the condition

31
Q

What are ‘positive’ symptoms of schizophrenia?

A

Increased mesolimbic dopaminergic activity leading to
hallucinations; auditory and visual,
delusions, paranoia,
thought disorder; denial about onset

32
Q

What are ‘negative’ symptoms of schizophrenia

A

Decreased mesocortical dopaminergic activity leading to
Affective flattening: lack of emotion
alogia: lack of speech
Avolition/apathy: loss of motivation

33
Q

What types of symptoms do drugs target in schizophrenia

A

positive symptoms, the negative ones are really hard to treat

34
Q

What are the first generation antipsychotics aka ‘typical antipsychotic’

A

Chlorpromazine (developed as antihistamine as an antimuscarinic) - inhibits the D2R
Haloperidol - potent D2 receptor antagonist (50x more effective than chorpromazine)

35
Q

What are the side effects of chlorpromazine

A

High incidence anticholinergic- especially sedation

Low incidence extrapyramidal side effects so mainly motor disorders

36
Q

What are side effects of haloperidol

A

High incidence extrapyramidal side effects -> motor disorders

37
Q

What are the second generatio nantipsychotics or ‘atypical antipsychotics’

A

Clozapine - potent 5HT antagonist and is most effective antipsychotic
Risperidone - potent 5HT an D2R antagonist
Quetiapine - potent H1 receptor antagonist

38
Q

What are positives and negatives of Clozapine

A

+ve: is only drug that affects negative symptoms of schizophrenia
-ve: can cause fatal agranularcytosis so can cause degradation of white blood cells, neutropenia

39
Q

Side effects of Clozapine

A

Potentially fatal neuropenia, agranulocytosis, myocarditis, and weight gain

40
Q

Side effects of risperidone

A

EPS (motor) and hyperprolactinaemia

41
Q

Side effects of quetiapine

A

Lower incidence of EPS than other antipsychotics

42
Q

How does aripiprazole work to treat schizophrenia

A

Too much activity -> causes inhibition

Too little -> increase activity

43
Q

What is one of the main problems with schizophrenia drugs

A

The side affects are all really bad and patients don’t want to deal with them so compliance is low

44
Q

Side effects of aripiprazole compared to other antipsychotics

A

Hyperprolactinaemia and weight gain have reduced incidences compared to other antipsychotics

Year 2 Pharma (34 decks)

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