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262B Pharmacology > L14 - Dopamine: Parkinson's disease and schizophrenia > Flashcards

L14 - Dopamine: Parkinson's disease and schizophrenia Flashcards

1
Q

What are the roles dopamine has in the body?

A
  • major role in reward- motivated behaviour
  • involved in motor control
  • role in controlling release of various hormones and chemicals
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2
Q

What are the different hormones and chemicals that dopamine regulates the release of?

A
  • in blood vessels: noradrenaline
    inhibits NA release and acts as a vasodilator
  • kidneys:
    increases sodium excretion and urine output (hypertension)
  • reduces insulin production and reduces GI motility
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3
Q

What are the 2 types of dopamine receptor and how are the different?

A

dopamine D1 type receptors
- Gs receptors = activation of adenylate cyclase
dopamine D2 type receptors
- Gi receptors = inhibition of adenylate cyclase

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4
Q

What do the dopamine D1 type receptors consist of?

A

D1 and D5 receptors

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5
Q

What do the dopamine D2 type receptors consists of?

A

D2, D3 and D4 receptors

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6
Q

What downstream effect does dopamine D1 receptor activation have?

A

activation of protein kinase A

- important in neuronal activity and modulating the activity of other ion channels in the synapse

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7
Q

What downstream effect does dopamine D2 receptor activation have?

A
  • pre-synaptic receptors (D2) important to reduce release of further dopamine and other neurotransmitters = prevent vesicle release
  • post-synaptically inhibit adenylate cyclase
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8
Q

How is dopamine removed from the synapse?

A 
dopamine transporter:
- dopamine active transporter (DAT)
broken down:
- monoamine oxidase A + B (MAOa MAOb)
- catechol-O-methyltransferase (COMT)
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9
Q

What is the effect of dopamine active transporter (DAT)?

A

located pre- and post-synaptically

- reuptake of dopamein into the cell

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10
Q

What is the effect of monoamine oxidase (MAO) and why does it affect dopamine?

A
  • breaks down dopamine

- dopamine is a monoamine

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11
Q

What is different about the different types of monoamine oxidase? MAOa + MAOb

A 
MAOa:
- liver
- vascular
- GIT
- placenta
MAOb:
- brain
- platelets
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12
Q

Where are MAO and COMT located?

A

in the synapse

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13
Q

Why does COMT have an effect on dopamine?

A

dopamine is a catecholamine

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14
Q

What is the pathological role of dopamine in the CNS?

A

too little dopamine = Parkinson’s Disease

too much dopamine = Schizophrenia

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15
Q

What pathways in the brain is dopamine involved in?

A
  • frontal cortex
  • striatum
  • substantia nigra
  • nucleus accumbens
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16
Q

What is the pathway involved in Parkinson’s Disease?

A

nigrostriatal pathway:

  • dopamine cells in the substantia nigra progressively die
  • no dopamine released into striatum
  • results in reduced dopamine levels in the striatum
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17
Q

What are the causes of Parkinson’s Disease?

A

cause unknown:

  • genetic (15%)
  • mostly environmental factors (pesticide exposure, head injuries)
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18
Q

What is the age of onset of Parkinson’s disease?

A

60+ years

early onset: <50 years

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19
Q

What is Parkinson’s Disease?

A

progressive neurodegenerative disorders affecting movement

- low dopamine receptor activation in striatum

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20
Q

What are the symptoms of Parkinson’s Disease in the early stages?

A
  • barely noticeable hand tremor
  • little/no facial expression
  • arms don’t swing when walking
  • slurred speech
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21
Q

What are the motor symptoms associated with Parkinson’s Disease?

A
  • resting tremor
  • bradykinesia (slow movement and impaired ability to adjust body position)
  • rigidity
  • postural instability
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22
Q

What are the non-motor symptoms associated with Parkinson’s Disease?

A
  • cognitive decline leading into dementia
  • autonomic dysfunction (constipation + hypotension)
  • depression and anxiety
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23
Q

What is the goal for the treatment of Parkinson’s disease?

A

increase dopamine receptor activation in the striatum

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24
Q

What is the ‘gold standard’ treatment option for Parkinson’s Disease?

A

Levodopa (L-dopa)

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25
Q

Why is dopamine not given as a treatment for Parkinson’s disease? What is given instead?

A
  • cannot give dopamine because it can’t cross the BBB and has systemic effects
  • give metabolic precursor of dopamine
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26
Q

How is Levodopa given?

A
  • given alone but with low bioavailability

- given with dopa decarboxylase inhibitor for increased effect

27
Q

What is drug is a dopa decarboxylase inhibitor?

A

Carbidopa

28
Q

What is the effect of Carbidopa?

A
  • inhibits the conversion of L-dopa into dopamine in the systemic circulation (it can’t cross BBB)
  • this causes reduces peripheral side effects (cardiovascular + GI)
  • more L-dopa to the brain where it is converted to dopamine
29
Q

What are the problems associated with chronic L-dopa treatment?

A
  • psychological effects (delusion/hallucination)
  • decreased effectiveness over time due to cells death
  • dyskinesia (hyperkinetic, purposeless movement)
  • on-off phenomenon (sudden unpredictable changes in mobility)
30
Q

What is the second like treatment for Parkinson’s Disease?

A

dopamine agonist

31
Q

How is apomorphine (dopamine agonist) given?

A
  • orally

- subcutaneous injection

32
Q

What drug is a dopamine agonist?

A

apomorphine

33
Q

What are the benefits of using a dopamine agonist cf. L-dopa?

A
  • last longer
  • lower risk of dyskinesia
  • when used in combination with L-dopa able to smooth on/off phenomenon
  • however is less effective
34
Q

What is the onset of action and half-life of apomorphine?

A
  • effects in ~ 5min
  • peak plasma conc. ~3min after injection
  • half-life of 30min
35
Q

What is a good use of apomorphine in combination with L-dopa?

A

good way to manage off-period symptoms before L-dopa has effect

36
Q

What are the problems associated with L-dopa use in combination with dopamine receptor agonists?

A
  • require functioning neurons = less effective in later stages of disease
  • side effects
37
Q

What are the side effects of L-dopa and dopamine receptor agonist combination use?

A
  • hallucinations
  • nausea and vomiting because triggers dopamine receptors in chemoreceptor trigger zone
    NOTE: above side effects can be managed by dose
  • impulse control disorder (because dopamine pathways associated with reward) = impulse shoppers and gamblers
38
Q

What is the last treatment option for Parkinson’s Disease?

A

enzyme inhibitors:

  • monoamine oxidase (MAOb) inhibitor
  • COMT inhibitor
39
Q

How do enzyme inhibitors work in Parkinson’s Disease?

A
  • reduce the breakdown of dopamine

- increase the duration of action of dopamine in the brain by increasing at synapse

40
Q

When are enzymes inhibitors used in Parkinson’s Disease?

A
  • used alone in early stages
  • treat anti-depressant effects in later stages (increased serotonin - monoamine)
  • can be used in combination with L-dopa to increase effectiveness
41
Q

DONT NEED TO KNOW DRUG NAMES: What drugs are enzyme inhibitors used in Parkinson’s disease treatment?

A
  • MOAb inhibitor: selegiline

- COMT inhibitor: entacapone

42
Q

What is Schizophrenia?

A

neurological disorder characterised by abnormal social behavious and failure to understand what is real
- too much dopamine receptor activation in prefrontal cortex and nucleus accumbens

43
Q

What are the causes of Schizophrenia?

A

cause remains unclear

  • genetic predisposition
  • maternal viral infection increases risk
44
Q

What is the life expectancy of people with schizophrenia and why?

A

20-30 years shorter

  • unhealthy lifestyle
  • smoking
  • increased suicide risk
45
Q

What are the symptoms associated with the condition schizophrenia?

A
  • positive symptoms: delusions and hallucinations
  • negative symptoms: withdrawal, lack of emotions and social functioning
  • mood disorders: depression and anxiety
  • cognitive defects: difficulty concentrating and following instructions
46
Q

What are the positive symptoms of schizophrenia?

A
  • delusions
  • hallucinations
  • thought disorder: wild train of though, irrational conclusions
  • abnormal behaviours: stereotyped movements, aggressive behaviour
47
Q

What are the negative symptoms of schizophrenia?

A
  • withdrawal from social contact
  • poor social functioning
  • apathy
  • flattening of emotional responses
48
Q

What are the cognitive symptoms of schizophrenia?

A
  • attention
  • memory
  • executive functioning (following instructions)
49
Q

What are the mood disorder symptoms of schizophrenia?

A
  • anxiety
  • depression
  • aggression
  • 10% patients commit suicide
50
Q

What is the cause for the positive symptoms experienced in schizophrenia?

A

increased dopamine in the nucleus accumbens

= delusions + hallucinations

51
Q

What is the cause for negative symptoms of schizophrenia?

A

decreased dopamine in the prefrontal cortex

52
Q

What brain pathways are involved in schizophrenia and what is occurring?

A
  • nucleus accumbens: increased dopamine

- prefrontal cortex: decreased dopamine (due to receptor desensitisation in the nucleus accumbens ??????)

53
Q

What are the types of drug treatments for schizophrenia?

A
  • typical antipsychotics

- atypical antipsychotics

54
Q

What is the mechanism of action of typical antipsychotics?

A

they are antagonists or inverse agonists for dopamine D2 type receptors

55
Q

What is a drug that is a typical antipsychotic?

A

haloperidol

56
Q

What are the side effects of typical antipsychotics?

A
  • can induce negative symptoms
  • Parkinson’s like symptoms
  • antihistamine side effects
  • anticholinergic side effects
  • antiadrenergic side effects
57
Q

Why are there wide spread side effects associated with typical antipsychotic use?

A

because they are non-selective and also block other receptors in the body:

  • muscarinic receptors
  • histamine receptors
  • alpha adrenergic receptors
58
Q

What are the wide spread side effects?

A 
antihistamine side effects:
- weight gain
- drowsiness
anticholinergic:
- constipation
- blurred vision
- dry mouth
- drowsiness
antiadrenergic side effects:
- decreased blood pressure
- drowsiness
- dizziness
59
Q

What is the mechanism of action for atypical antipsychotics?

A
  • act as an antagonist for both dopamine D1 and D2 receptor types
  • block serotonin (5-HT) receptors
60
Q

What is the benefit in atypical antipsychotics to block serotonin receptors?

A

serotonin modulates dopamine activity by:
- increasing dopamine D2 type receptors
- increasing dopamine release
= blocking these receptors causes a decrease in dopamine in the brain

61
Q

What is an atypical antipsychotic drug?

A

clozapine

62
Q

What are the side effects of atypical antipsychotics?

A 
- Parkinson's-like side effects
also blocks other receptors:
- muscarinic receptors
- histamine receptors
- alpha adrenergic receptors
63
Q

Atypical antipsychotics are more commonly used now than typical antipsychotics. Why?

A
  • lower risk of Parkinson-like side effects

- less affinity for other receptors so less side effects

64
Q

What are the treatment options for the different symptoms of schizophrenia?

A

positive symptoms: antipsychotics
negative symptoms: antidepressants
negative symptoms: no proven treatment
cognitive defects: no proven treatment

262B Pharmacology (18 decks)

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