Regulating Dopamine Levels Flashcards Preview

MD1 Neuroscience > Regulating Dopamine Levels > Flashcards

Flashcards in Regulating Dopamine Levels Deck (81):
1

Describe the extrapyramidal motor system?

Dopaminergic neurons in substantia nigra give tonic inhibition to cholinergic neurons in corpus striatum
Cholinergic neurons in corpus striatum give excitatory input to inhibitory interneurons
Inhibitory interneurons give inhibitory input to spinal cord
Inhibition of output to skeletal muscle

2

What happens in Parkinson's disease (PD)?

Death of dopaminergic neurons in substantia nigra

3

Describe the time course of PD

Chronic
Progressive

4

What is PD a disorder of?

Muscle movement

5

What are the motor signs and symptoms of PD?

Tremor
Rigidity of limbs
Bradykinesia
Impairment of postural reflexes
Facial
- Impassive
- No blinking
Speech
- Monotonous
- Hypophonic
Movement
- Decreased manual dexterity

6

What are the non-motor signs and symptoms of PD?

Cognitive deficiencies
Depression
Raised anxiety levels
Olfactory deficiencies
Sleep disturbances
Fatigue
Pain
Bowel and bladder problems
Sexual dysfunction

7

What is one of the first symptoms of PD?

Lack of smell

8

How many dopaminergic neurons are destroyed by the time motor deficits emerge?

80%

9

What is diagnostic of PD?

Reduced dopamine levels
Lewy bodies present at post-morten

10

How many cases of PD are genetic?

10%

11

When do genetic cases of PD tend to develop?

At younger age

12

How many people have no known genetic mutations?

90%

13

What is the biggest risk factor for developing PD?

Age

14

What do drugs do in PD?

Provide symptomatic relief

15

How can dopamine deficiency be restored?

Increase dopamine synthesis
Increase dopamine release
Dopamine receptor agonists
Reduce dopamine metabolism

16

What is necessary to balance if you're exogenously increasing dopamine levels?

Decrease ACh levels to keep balance
- Via cholinergic antagonists

17

Does dopamine cross the BBB?

No

18

What is L-DOPA converted to in the body?

Dopamine

19

What is the effect of ingesting dopamine?

Emetic

20

How is dopamine stored in the neuron?

Packaged into vesicles

21

What is reserpine?

Depletes dopamine

22

What is the gold standard therapy of PD?

L-DOPA

23

How do you increase dopamine synthesis?

Give levodopa

24

What is levodopa?

Amino acid isomer

25

How much levodopa is metabolised in the periphery?

Over 90%

26

What is done to increase levodopa bioavailability?

Block dopadecarboxylases (DDC) in peripheral tissues

27

What are the peripheral effects of levodopa because of its conversion to dopamine and noradrenaline?

Nausea
Vomiting
Orthostatic hypotension
Cardiac dysrhythmias

28

What is levodopa formulated with?

Peripheral DDC inhibitor
- Carbidopa
- Benserazide

29

What is needed for levodopa to work?

Some functional dopaminergic neurons

30

What are the beneficial effects of levodopa?

Reduces rigidity
Reduces tremors
Reduces other symptoms

31

When is levodopa given?

First line of treatment

32

When is levodopa rapidly absorbed from the stomach?

When it's empty

33

What does levodopa compete with for uptake?

Other neutral amino acids

34

What is the half life of levodopa?

1-2 hours

35

What is the plasma concentration of levodopa?

Variable

36

How does the effectiveness of levodopa change over time?

Declines

37

Why does the effectiveness of levodopa change over time?

Continued degeneration of dopaminergic nerves

38

What is done when levodopa starts to become ineffective?

Increase dose
Incorporate other drugs

39

What are the peripheral adverse effects of levodopa?

Anorexia
Nausea
Vomiting
Tachycardia
Ventricular dysrhythmias
Orthostatic hypotension
Pupil dilation

40

What are the central adverse effects of levodopa?

Visual and auditory hallucinations
Abnormal motor movements
Mood changes
Depression
Anxiety

41

What are the drug interactions of levodopa?

Vitamin B6
Monamine (MAO) type A inhibitors
Inhalational anaesthetics
Anticonvulsants
Neuroleptics

42

What are bromocriptine and cabergoline?

Dopamine agonists

43

How are bromocriptine and cabergoline used?

Can be used as monotherapy

44

What are the beneficial effects of bromocriptine and cabergoline?

Improve bradykinesia and rigidity

45

Why may bromocriptine and cabergoline be preferred in young patients?

Some evidence suggests that giving L-DOPA accelerates progression of PD by increasing IC dopamine levels > causes oxidative stress in neuron > damage > death of dopaminergic neurons

46

What is pergolide?

Dopamine agonist

47

How is pergolide used?

Adjunct to levodopa

48

Why aren't dopamine agonists as good as levodopa?

Because they bind indiscriminately to dopamine receptors, whereas levodopa is taken up selectively by dopaminergic neurons for synthesis of dopamine, and subsequent release

49

What are the side effects of dopamine agonists?

Similar to levodopa, but some more common:
- Hallucinations
- Confusion
- Delirium
- Nausea
- Hypotension
Dyskinesias less prominent
Arrhythmias
Myocardial infarction

50

What does it mean for dosage of levodopa if there is a titration effect?

Different doses for morning and evening
Different doses for different people because don't know how many neurons degenerated with each person

51

What is selegiline?

MAO type B inhibitor

52

How do MAO type B inhibitors work?

Reduce metabolism of dopamine

53

What are the benefits of using MAO type B inhibitors?

No hypertensive crises like with MAO type A inhibitors
Early use may delay disease progression
- Reduced formation of free radicals

54

What is entacapone?

Catechol-O-methyltransferase (COMT) inhibitor

55

What do COMT inhibitors do?

Reduce metabolism of L-DOPA

56

How are COMT inhibitors used?

Adjunct to L-DOPA > increase CNS levels

57

What are MOA and COMT?

Enzymes involved in the metabolism of dopamine

58

What is amantadine?

Antiviral in influenza
Observed to reduce rigidity and bradykinesia

59

How does amantadine work?

Enhances release of dopamine

60

What are the drawbacks of amantadine?

Less efficacious than L-DOPA
More rapid tolerance

61

What are the adverse effects of amantadine?

Restlessness
Agitation
Confusion
Hallucinations
Orthostatic hypotension
Urinary retention
Dry mouth

62

What is the cholinergic activity of amantadine?

Anticholinergic > don't need to give extra anticholinergic

63

Why are muscarinic receptor antagonists used in the treatment of PD?

Restore dopaminergic-cholinergic imbalance

64

How are muscarinic receptor antagonists used?

Adjunct to L-DOPA

65

What are the effects of muscarinic receptor antagonists?

Modest effect on
- Tremor
Little effect on
- Rigidity
- Bradykinesia

66

What are some examples of muscarinic receptor antagonists?

Bezhexol
Benztropine
Biperiden
Orphenadrine

67

What are the classic anti-muscarinic side effects?

Reduced
- Salivation
- Lacrimation
- Urination
- Defacation
(SLUD)

68

What are the peripheral adverse effects of muscarinic receptor antagonists?

Dry mouth
Dry skin
Blurred vision
Constipation
Urinary hesitancy
Nausea
Vomiting

69

What are the central adverse effects of muscarinic receptor antagonists?

Memory impairment
Confusion
Worsening of dyskinesias

70

Does deep brain stimulation work in all patients with PD?

No

71

What is required for deep brain stimulation to work in PD?

Relatively high levels of dopaminergic neurons

72

What is alph-synuclein?

Protein monomer of Lewy bodies

73

What are Lewy bodies made of?

Alpha-synuclein fibrils

74

Where are Lewy bodies found?

Deposits inside neurons in affected brain areas in PD

75

What can cause PD?

Mutating/overproducing alpha-synuclein
Several mitochondria-related genes when mutated

76

What is believed to be the toxic drivers of PD?

Small oligomers of alpha-synuclein

77

Does smoking increase or decrease your risk of developing PD?

Decrease

78

Which pesticides have been linked to high incidence of PD?

Rotenone
Paraquat

79

Which areas are first affected in PD?

Loss of smell
Loss of gut motility

80

What does some evidence suggest stabilises alpha-synuclein oligomers?

Oxidised dopamine

81

What is the average age of onset of PD?

60

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