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Pharmacology (Semester 6) > 4.2 Movement disorders > Flashcards

4.2 Movement disorders Flashcards

1
Q

What is Idiopathic Parkinsons disease (IPD)?

A

A progressive neurodegenerative disorder which affects motor function. (95% of cases of PD)

PD (incl IPD) is due to low dopamine and disturbance to other neurotransmitter levels

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2
Q

Motor symptoms of IPD improve with what medication?

A

Levodopa

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3
Q

Parkinsonism is an umbrella term for symptoms of Parkinson’s

List the 4 key symptoms (TRAP)

A

Tremor, Rigidity, Akinesia (bradykinesia), Postural instability

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4
Q

Give 4 non motor manifestations PD

A
  1. mood changes, anxiety, depression
  2. pain
  3. cognitive change
  4. hyposmia (reduced sense of smell)
  5. urinary symptoms
  6. sleep disorder
  7. sweating
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5
Q

Give the Prognosis/ progression of PD across 15 years

A
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6
Q

How is Parkinsons diagnosed?

A

Clinical – history and examination (differential diagnosis)

Exclude other forms of PD

Early referral to neurologist

Rarely SPECT

MRI for DD between Parkinsonian syndromes

Response to Treatment

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7
Q

What is SPECT and how is it used in the diagnosis of PD

A

Single photon emission computed tomography

Uses a labelled tracer - Ioflupane (123I), a dopamine analogue and view its presynaptic uptake in the brain. This would be abnormal in PD

  • Left: normal brain showing strong dopamine uptake
  • Right: PD fewer dopinergic neurons
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8
Q

What is the pathology of IPD?

A

A degenerative disorder of dopaminergic neurotransmission in the basal ganglia.

Results in dopamine depletion causing altered patterns of inhibition in the basal ganglia:

  • strengthens indirect pathway
  • increases inhibitory output

+ Other neurotransmitters involved

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9
Q

What would be seen in a brain scan of a patient with IPD

A

Loss of pigmentation in the substantia nigra and cell death in other deep cortical and brainstem nuclei + lewy bodies

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10
Q

How/why do Lewy bodies form?

A

α-synuclein protein misfolds and accumulates in the dopaminergic neurons ➞ synucleinopathy ➞ leads to cell death

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11
Q

Explain the direct vs indirect pathway

A

Direct = excitatory ➞ release neurons from inhibition

Indirect = inhibitory ➞ supress neurons further ‘a brake on the system’

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12
Q

What % of dopaminergic neuron loss is required before motor symptoms arise?

A

50%

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13
Q

Explain the synthesis of Epinephrin (adrenaline) from L-Tyrosine

(Incl intermediates and enzymes)

A
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14
Q

Dopamine is a ________ which is synthesised from ________ to L-Dopa via the enzyme ________.

L-Dopa is then converted into dopamine via the enzyme ________.

This occurs within ________ neurons.

A

Catecholamine, L-Tyrosine, Tyrosine Hydroxylase, DOPA decarboxylase, dopaminergic

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15
Q

In noradrenergic neurons dopamine is converted to Noradrenaline via the enzyme _______.

This can be furthur converted to Adrenaline within the cytosol of the adrenal gland via the enzyme _______.

A

Dopamine B-hydroxylase, Phenylethanolamine n-methyltransferase

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16
Q

Explain the 2 pathways in which dopamine can be degraded

(Incl intermediates and enzymes)

A

1) Dopamine ➞ 3,4 dihyrophenyl-acetic acid ➞ Homovanillic acid enzymes: monoamine oxidase, catechol-O-methyl transferase (COMT)
2) Dopamine ➞ Methoxytyramine (3MT) ➞ Homovanillic acid enzymes: COMT, monoamine oxidase

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17
Q

Give the 7 drug classes used in IPD

A
  1. Levodopa (L-DOPA)
  2. DOPA decarboxylase inhibitors
  3. Dopamine receptor agonists
  4. MAO type B inhibitors
  5. COMT inhibitors
  6. Anticholinergics
  7. Amantidine
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18
Q

Why can we not use dopamine itself to treat PD?

A

Cannot cross the BBB, use L-dopa (precursor) instead

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19
Q

Levodopa must be taken up by ________ cells in the ___________ to be converted to dopamine.

In PD we have _________ remaining cells, meaning there is a less reliable effect of levodopa. This can result in __________.

Once dopamine is produced the 2 enzymes _______ and ______ begin process of dopamine degredation.

A

dopaminergic, substantia nigra, fewer, motor fluctuations, MAO, COMT

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20
Q

State the following PK information about L-DOPA

  1. administration
  2. absorption mechanism
  3. T1/2
A

1) administration - ORAL
2) absorption mechanism - ACTIVE transport
3) T1/2 - 2 hrs

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21
Q

How much L-DOPA actually reaches the CNS and why?

A

90% inactivated in intestinal wall

9% converted to dopamine in peripheral tissues

<1% enters CNS

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22
Q

What is the implication of L-dopas administration AND transport mechanism?

A

Administration: as it is absorbed orally it must enter the GI system. Here 90% is inactivated within the intestinal wall by monoamine oxidase and DOPA decarboxylase

Transport: because it requires active transport, it competes with other large amino acids within the GI tract for space on transporters. This means high protein meals can reduce effectivness of L-DOPA.

23
Q

What is the implication of L-DOPAs T1/2

A

As its half life is only 2 hours it requires short dose intervals (regular administration). This can result in fluctuations in blood levels producing motor symptoms.

24
Q

What are the 2 types of movement produced by physiological dopamine and what is the effect of L-DOPA on these?

A

Physiologically dopamine is produces phasic relief (in response to an AP) and also tonic control (background level).

L-DOPA aims to mimic these actions by entering neurones however, it prodcues a certain amount of tonic movement due to its pre-mature beakdown before it is taken up into neurons.

25
Q

Once L-DOPA reaches the BBB, what challenge does it face?

How can we overcome this pharmacologically?

A

Competition with other amino acids for active transport across blood brain barrier

Use L-DOPA in combination with a peripheral DOPA decarboxylase inhibitor

26
Q

Give an example of a DOPA decarboxylase inhibitor

Give 2 examples of co-drug formulations of L-DOPA + the drug you have mentioned

A

DOPA decarboxylase inhibitor: carbidopa

L-DOPA + carbidopa:

  • co-careldopa Sinemet
  • co-beneldopa Madopar
27
Q

Give 3 benefits of combining L-DOPA with a peripheral DOPA decarboxylase inhibitor

A

1) reduced dose required: because more is crossing the BBB
2) reduced side effects: less breakown of L-DOPA in the peripheries
3) Increased L-DOPA reaching brain

28
Q

Give 3 tablet formations of L-DOPA

A

1) standard dosage – variable strengths
2) controlled release preparations (CR)
3) dispersible madopar (not soluble)

29
Q

Give 2 advantages of L-DOPA

A

1) Highly efficacious
2) Low side effects

30
Q

Give 4 potential side effects of L-Dopa

A

1) Nausea/ anorexia: vomiting centres
2) Hypotension: central and peripheral
3) Psychosis: schizophrenia-like effects: hallucination/delusion/ paranoia
4) Tachycardia

(But side effects are low)

31
Q

Give 4 disadvantges of L-DOPA

A
32
Q

Give 3 DDI’s with L-DOPA and the effect each has

A

1) Pyridoxine (Vit B6) ⬆ peripheral breakdown of L- DOPA
2) MAOIs risk hypertensive crisis (not MOABIs at normal dose-lose specificity at high dose)
3) many antipsychotic drugs block dopamine receptors: parkinsonism is a side effect

33
Q

Why are Ergot derived dopamine receptor agonists no longer used?

A

Tendancy towards fibrosis of cardiac valves and lungs

34
Q

Give 2 non-Ergot dopamine receptor agonists

A

Ropinirole and Pramipexole

35
Q

Give an example of a dopamine receptor agonist that can be used as a patch

A

Rotigotine

36
Q

Give an example of a dopamine receptor agonist that can be given subcutaneously

A

Apomorphine

37
Q

Dopamine receptor agonists are usually used in what 2 ways?

A

Either De Novo therapy (starting therapy) or as add on therapy

38
Q

What is Apomorphine?

A

A dopamine receptor agonist usually only used for patients with severe motor fluctuations

39
Q

Give 3 advantages of Dopamine receptor agonists

A
40
Q

Give 4 disadvantages of Dopamine receptor agonists

A
41
Q

A side effect of dopamine receptor agonists is Impulse control disorders, give 4 examples of what this may include

A

Also known as Dopamine Dysregulation Syndrome

  • Pathological Gambling
  • Hypersexuality
  • Compulsive Shopping
  • Desire to increase dosage
  • Punding
42
Q

Give 4 symptomatic side effects of dopamine receptor agonists

A
  • Sedation
  • Hallucinations
  • Confusion
  • Nausea
  • Hypotension
43
Q

What is the role of Monoamine oxidase B?

A

Metabolises dopamine and Pre-dominates in dopamine containing regions in brain

44
Q

What are the 2 enzymes which metabolise L-DOPA in the peripheries?

Incl the products of their metabolism

A

Dopa decarboxylase: L-DOPA ➞ dopamine

COMT: L-DOPA ➞ 3 O Methyldopa (competes with L-DOPA for transport across the BBB)

45
Q

What is the function of MAOB inhibitors and give 2 examples

A

Function to enhance dopamine by prolonging the action of L-DOPA. Acts to smooth out motor response and can be used alone or as a adjunct therapy.

Eg. Selegiline and Rasagaline

(may be neuroprotective)

46
Q

What does COMT stand for?

A

Catechol-O-methyl Transferase

47
Q

What is the function of COMT inhibitors

A

Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa ➞ as 3-O-methyldopa competes with L-DOPA for transport across the BBB, reducing its breakdownmeans less competition)

48
Q

COMT inhibtors has no therapeutic effect alone so are used in combination tablets

What drugs are contained within these tablets, and give an example

A

COMT inhibitor, L-DOPA and peripheral dopa decarboxylase inhibitor

Eg. Stalevo

49
Q

Give 2 benefits of COMT inhibtors

A

1) Have L-DOPA ‘sparing’ effect
2) As it prolongs the motor response to L-DOPA it reduces symptoms of ‘wearing off’

50
Q

What is the use of Anticholinergics in PD

Give 2 examples

A

Acetyl Choline may have antagonistic effects to dopamine, has a minor role in treatment of PD

Eg.

  • Trihexyphenidydyl
  • Orphenadrine
  • Procyclidine
51
Q

Give 2 advantages of anti-cholinergics

A

1) Treat tremor
2) Not acting via dopamine systems

52
Q

Give 2 disadvantages of anticholinergics

A

1) No effect on bradykinesia
2) Side effects (confusion, drowsiness, usual anticholinergic s/e)

53
Q

What is the role of Amantidine is PD

A

It is a glutamate antagonist, hence will compete for binding with glutaminergic neurons.

However, there are no benefits or harms in the treatment of PD (but it is mentioned in NICE guidlines)

54
Q

Watch this video if you get confused again

A

https://www.youtube.com/watch?v=Z84iypHdftQ

Pharmacology (Semester 6) (17 decks)

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