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Clinical Pharmacology > 12.2 Neuro Pharmocology > Flashcards

12.2 Neuro Pharmocology Flashcards

1
Q

What is idiopathic Parkinson’s disease?

A

Neurodegenerative disorder

Progressive clinical course resulting in loss of dopaminergic neurones in the substantia nigra

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2
Q

What is the treatment of idiopathic Parkinson’s disease?

A

No treatment to prevent of reduce loss of damage. Can only control symptoms:

  • Motor symptoms improve with levodopa
  • Non motor symptoms can be treated (e.g. depression)
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3
Q

Describe the pathophysiology of Parkinson’s?

A

Reduced dopamine
Inhibitory dopaminergic neurones in the substantia nigra project to the neostriatum
Loss of these neurones results in loss of inhibition in the neostriatum and increased production of acetyl choline
Chain of abnormal signalling occurs leading to increased stimulation of the cortex and spinal cord

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4
Q

What is the histological hallmark of idiopathic Parkinson’s disease?

A

Lewy bodies - abnormal deposits of protein (alphasinucleins)

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5
Q

How does the substantia nigra change in appearance in Parkinson’s?

A

Loss of pigmentation

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6
Q

When does the movement disorder of IPD start to manifest? Why?

A

After 50% of the neurones in the substantia nigra have been lost. Due to local adaptations such as increased local turnover and upregulation of receptors allowing normal function to continue for a long time

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7
Q

What are the clinical features of Parkinson’s?

A 
Tremor
Rigidity
Bradykinesia
Postural instability 
Forward flexed shuffling gait with reduced asymmetric arm swing
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8
Q

What is Bradykinesia?

A

Abnormal slowness of movement
Ask to do small repetitive motor movements such as finger tapping - reduced amplitude and inability to maintain good rhythm, slowness and tremulous ness of the movements

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9
Q

How is Parkinson’s diagnosed?

A
  • Clinical Features
  • Exclude other causes of Parkinsonism
  • Response to Treatment (levodopa)
  • Structural neuro imaging is normal
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10
Q

What diagnostic criteria are used in Parkinson’s?

A

UK Parkinson’s disease society brain bank clinical diagnostic criteria

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11
Q

What are the non motor manifestations of Parkinson’s disease?

A 
Mood changes
Pain
Cognitive change
Urinary symptoms
Sleep disorder
Sweating 
Low blood pressure 
Restless leg
Fatigue
Hallucinations
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12
Q

What are the long term implications of Parkinson’s?

A
  • 94% Dyskinesia
  • 81% Falls
  • 84% Cognitive decline(50% hallucinations)
  • 80% Somnolence (drowsiness/sleepiness)n
  • 50% Swallowing difficulty
  • 27% Severe speech problems
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13
Q

what enzymes can be targeted to prevent dopamine degradation?

A

Monoamine dehydrogenase

Catechol-O-methyl transferase COMT

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14
Q

Describe the mechanism of action of dopamine at the synaptic cleft from production to action

A
  1. Synthesised in the cell body and packaged into vesicles
  2. Transported down the axon to the presynaptic membrane
  3. AP causes calcium to enter
  4. Calcium evokes the vesicles to fuse with the membrane of the presynaptic terminal and release dopamine into the synaptic cleft
  5. Dopamine attaches to post synaptic receptors to have its inhibitory effect
  6. Dopamine is then reabsorbed into the pre synaptic neurone and recycled and repackaged
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15
Q

Why is Levodopa, a dopamine precursor used in treatment instead of dopamine itself?

A

Dopamine cannot cross the blood brain barrier but Levodopa can
Dopamine also causes a lot of peripheral side effects such as irregular heart beat, N+V, anxiety, headache, chills SoB

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16
Q

Describe the mechanism of action of levodopa in treating parkinsonian features?

A

Levodopa crosses the BBB
Taken up by dopaminergic cells in the substantia nigra
Converted to dopamine to have clinical affect

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17
Q

Why is levodopa less effective in advanced Parkinson’s?

A

Fewer remaining cells - less reliable effect of levodopa as less taken up and converted to dopamine - motor fluctuations

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18
Q

Describe the mechanism of

A

F

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19
Q

How is levodopa administered? Why?

A

Administered orally
Combined with DOPA decarboxylase inhibitors to reduce the amount of levodopa converted into dopamine in the peripheral tissues by DOPA decarboxylase, which cause pathological side effects

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20
Q

How might diet impact levodopa absorption?

A

As absorbed by active transport in the gut, it is in competition with amino acids if a patient eats a high protein meal within an hour or so of the medication

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21
Q

What is the half life of levodopa? What are the clinical manifestations of this?

A

Very short half life of T1/2 = 2 hours
Short does interval - problem in hospital to get medications at appropriate times
Fluctuations in blood levels and symptoms

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22
Q

What are the 2 different types of levodopa medications and how do they vary?

A 
Co-careldopa = sinemet (levodopa/carbidopa)
Co-beneldopa = madopar (levodopa/benserazide)
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23
Q

Why is it beneficial to give a DOPA decarboxylase inhibitor with levodopa?

A
  • Reduced dose required
  • Reduced side effects
  • Increased L-DOPA reaching brain
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24
Q

What are the advantages of using levodopa?

A

Highly efficacious

Low side effects

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25
Q

What are the side effects associated with levodopa?

A

Nausea/anorexia
Hypotension
Psychosis (hallucinations/delusions/paranoia)
Tachycardia

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26
Q

What are the disadvantages of using levodopa?

A

Precursor drug requiring enzyme conversion - needs some cells left in the substantia nigra
Long term = loss of efficacy
Choreoathetosis = involuntary movements
Motor complications = on/off, wearing off, dyskinesia, dystonias, freezing

27
Q

What are the drug drug interactions of levodopa?

A

• Pyridoxine (vitamin B6) increases peripheral
breakdown of L-DOPA
• MAOIs monoamine oxidase inhibitors - risk hypertensive crisis (not MOABIs at normal dose-lose specificity at high dose)
• Many antipsychotic drugs block dopamine receptors and parkinsonism is a side effect (newer, ‘atypical’ antipsychotics less so)

28
Q

What drug class is pramipexole?

A

Dopamine receptor agonist (non ergot derived)

29
Q

What are the different types of dopamine receptor agonists?

A
  • Non Ergot (tablet) - Ropinirole, Pramipexole
  • Patch - Rotigotine
  • Subcutaneous - Apomorphine
30
Q

When are dopamine receptor agonists indicated?

A

De novo therapy (first line)
Add on therapy
Apomorphine only used in patients with severe motor fluctuations

31
Q

What are the advantages of dopamine receptor agonists?

A
  • Direct acting
  • Less dyskinesias/ motor complications
  • Possible neuroprotection
32
Q

What are the disadvantages of dopamine receptor agonists

A

Less efficacy than L-DOPA
Impulse control disorders
More psychiatric side effects - dose limiting
Expensive

33
Q

What are the side effects of impulse control disorders?

A 
Pathological gambling
Hyper sexuality
Compulsive shopping
Desire to increase dose
Punding
34
Q

What are the side effects of dopamine receptor agonists?

A 
Impulse control disorder
Sedation
Hallucinations
Confusion
Nausea
Hypotension
35
Q

What are the 6 drug classes used to treat Parkinson’s disease?

A 
Levodopa
Dopamine receptor agonists
MOOI type B inhibitors 
COMT inhibitors
Anticholinergics
Amantidine
36
Q

What are the indications for MAOI type B inhibitors?

A

First line or add on medication for the motor symptoms of Parkinson’s disease
(Prolongs action of L-DOPA, smooths out motor response and may be neuroprotective)

37
Q

What is the mechanism of action of monoamines oxidase B inhibitors?

A

Inhibits monoamine oxidase B which usually metabolises dopamine, predominantly in dopamine containing regions of the brain, enhancing the amount of dopamine available

38
Q

Give examples of monoamine oxidase B inhibitors ?

A

Selegiline
Rasagaline
Safinamide

39
Q

What is the mechanism of action of catechol-O-methyl Transferase (COMT) inhibitors?

A

Reduce peripheral breakdown of levodopa to 3-O-methyldopa
3-O-methyldopa competes with L-DOPA active transport into CNS
Increases the amount of levodopa crossing into the brain

40
Q

What are the common indications of COMT inhibitors?

A

Used in combination with levodopa as have no therapeutic effect in isolation. Have a levodopa sparing effect, prolonging the motor response to L-DOPA, reducing symptoms of wearing off.

41
Q

How is COMT inhibitors prescribed ?

A

In a combination tablet with levodopa and usually a peripheral dopa decarboxylase inhibitor.

42
Q

Give examples of COMT inhibitors?

A

-Capone
Entacapone
Opicapone

43
Q

Why are anticholinergics used to treat Parkinson’s?

A

As decreased dopamine causes an increase in acetylcholine production in the neostriatum. Anticholinergics are used to reduce the levels of the ACh and rebalance the relative levels of the neurotransmitters in the hope this would help the motor symptoms

44
Q

Give examples of anticholinergics?

A

• Trihexyphenidydyl • Orphenadrine • Procyclidine

45
Q

What are the advantages of anticholinergics in Parkinson’s?

A

Treat tremor

Not acting via dopamine systems

46
Q

What are the disadvantages of using dopamine to treat Parkinson’s?

A

No effect of bradykinesia

Significant side effects : confusion/drowsiness/usual anticholinergics symptoms

47
Q

What is the role of amantidine in treating Parkinson’s disease?

A

Can treat dyskinesia through NMDAR inhibition. Doesn’t work for the other side effects of Parkinson’s so poorly effective. Few side effects but does include hallucinations. Little to no effect on tremor

48
Q

What are indications for neurosurgery for Parkinson’s?

A

Must be dopamine responsive
Unable to take large enough doses of levodopa due to significant side effects
No psychiatric illness

49
Q

What neurosurgery is used in parakinsons?

A

Usually deep brain stimulation of the sub thalamic nucleus
Or
Destructive lesions - thalamus for tremor or globus pallidus interna for dyskinesias

50
Q

What is myasthenia gravis?

A

An autoimmune condition

Development of autoantibodies against Ach receptors on the post synaptic membrane

51
Q

What are the symptoms of myasthenia gravis?

A

Fluctuating, fatiguable, weakness skeletal
muscle
– Extraocular muscles – commonest presentation (diplopia, Ptosis)
– Bulbar involvement – dysphagia, dysphonia, dysarthria
– Limb weakness – proximal symmetric
– Respiratory muscle involvement

52
Q

What things worsen myasthenia gravis symptoms?

A

Stress
Infection
Surgery
Drugs : Aminoglycosides/Beta-blockers, CCBs, quinidine,
procainamide/ Chloroquine, penicillamine/ Succinylcholine/ Magnesium/ACE inhibitors

53
Q

What are the complications in treating myasthenia gravis?

A
  1. Acute exacerbation - myasthenic crisis

2. Overtreatment - cholinergic crisis

54
Q

What is the main treatment used to manage symptoms of myasthenia gravis?

A

Pyridostigmine -orally

55
Q

What is the main drug type used to treat myasthenia gravis?

A

Acetylcholinesterase inhibitors

56
Q

What is the function of acetylcholinesterase inhibitors?

A

Enhance neuromuscular transmission by allowing more ACh to remain in the neuromuscular junction. Allows increase in power of smooth and skeletal muscle

57
Q

What acetylcholinesterase inhibitor is used in ITU?

A

Neostigmine – oral and IV preparations (ITU)
• Quicker action, duration up to 4 hours
• Significant antimuscarinic side effect

58
Q

What is a cholinergic crisis?

A

When acetylcholinesterase inhibitors are given in excess dose, causing a depolarising dose

59
Q

What are the pharmokinetics of pyridostigmine?

A

Onset 30min; peak 60-120min; duration 3-6hr

60
Q

What are the side effects of pyridostigmine?

A

Muscarinic side effects

  • dry mouth
  • mydriasis
  • Tachycardia
  • agitation
  • urinary retention
  • constipation
61
Q

How is a cholinergic crisis treated?

A

Administering antimuscarinics

62
Q

What are the side effects for antimuscainics?

A

Antimuscarinic side effect –
– miosis and the SSLUDGE syndrome:
» Salivation, » Sweating, » Lacrimation » Urinary incontinence » Diarrhea, » GI upset and hypermotility » Emesis

63
Q

What are the 5 lines of treatment of myasthenia gravis?

A 
• Acetylcholinesterase inhibitors 
• Corticosteroids
– Decrease immune response 
• Steroid sparing
– Azathioprine 
• IV immunoglobulin - Acute decline or crisis – 60% will respond after 7-10 days 
• Plasmapheresis
– Removes AChR antibodies and  short-term improvement

Clinical Pharmacology (26 decks)

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