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Clinical Pharmacology > 12.2 Neuro Pharmocology > Flashcards

12.2 Neuro Pharmocology Flashcards

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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
What are the side effects associated with levodopa?
Nausea/anorexia Hypotension Psychosis (hallucinations/delusions/paranoia) Tachycardia
26
What are the disadvantages of using levodopa?
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
What are the drug drug interactions of levodopa?
• 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
What drug class is pramipexole?
Dopamine receptor agonist (non ergot derived)
29
What are the different types of dopamine receptor agonists?
* Non Ergot (tablet) - Ropinirole, Pramipexole * Patch - Rotigotine * Subcutaneous - Apomorphine
30
When are dopamine receptor agonists indicated?
De novo therapy (first line) Add on therapy Apomorphine only used in patients with severe motor fluctuations
31
What are the advantages of dopamine receptor agonists?
* Direct acting * Less dyskinesias/ motor complications * Possible neuroprotection
32
What are the disadvantages of dopamine receptor agonists
Less efficacy than L-DOPA Impulse control disorders More psychiatric side effects - dose limiting Expensive
33
What are the side effects of impulse control disorders?
``` Pathological gambling Hyper sexuality Compulsive shopping Desire to increase dose Punding ```
34
What are the side effects of dopamine receptor agonists?
``` Impulse control disorder Sedation Hallucinations Confusion Nausea Hypotension ```
35
What are the 6 drug classes used to treat Parkinson’s disease?
``` Levodopa Dopamine receptor agonists MOOI type B inhibitors COMT inhibitors Anticholinergics Amantidine ```
36
What are the indications for MAOI type B inhibitors?
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
What is the mechanism of action of monoamines oxidase B inhibitors?
Inhibits monoamine oxidase B which usually metabolises dopamine, predominantly in dopamine containing regions of the brain, enhancing the amount of dopamine available
38
Give examples of monoamine oxidase B inhibitors ?
Selegiline Rasagaline Safinamide
39
What is the mechanism of action of catechol-O-methyl Transferase (COMT) inhibitors?
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
What are the common indications of COMT inhibitors?
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
How is COMT inhibitors prescribed ?
In a combination tablet with levodopa and usually a peripheral dopa decarboxylase inhibitor.
42
Give examples of COMT inhibitors?
-Capone Entacapone Opicapone
43
Why are anticholinergics used to treat Parkinson’s?
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
Give examples of anticholinergics?
• Trihexyphenidydyl • Orphenadrine • Procyclidine
45
What are the advantages of anticholinergics in Parkinson’s?
Treat tremor | Not acting via dopamine systems
46
What are the disadvantages of using dopamine to treat Parkinson’s?
No effect of bradykinesia | Significant side effects : confusion/drowsiness/usual anticholinergics symptoms
47
What is the role of amantidine in treating Parkinson’s disease?
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
What are indications for neurosurgery for Parkinson’s?
Must be dopamine responsive Unable to take large enough doses of levodopa due to significant side effects No psychiatric illness
49
What neurosurgery is used in parakinsons?
Usually deep brain stimulation of the sub thalamic nucleus Or Destructive lesions - thalamus for tremor or globus pallidus interna for dyskinesias
50
What is myasthenia gravis?
An autoimmune condition | Development of autoantibodies against Ach receptors on the post synaptic membrane
51
What are the symptoms of myasthenia gravis?
Fluctuating, fatiguable, weakness skeletal muscle – Extraocular muscles – commonest presentation (diplopia, Ptosis) – Bulbar involvement – dysphagia, dysphonia, dysarthria – Limb weakness – proximal symmetric – Respiratory muscle involvement
52
What things worsen myasthenia gravis symptoms?
Stress Infection Surgery Drugs : Aminoglycosides/Beta-blockers, CCBs, quinidine, procainamide/ Chloroquine, penicillamine/ Succinylcholine/ Magnesium/ACE inhibitors
53
What are the complications in treating myasthenia gravis?
1. Acute exacerbation - myasthenic crisis | 2. Overtreatment - cholinergic crisis
54
What is the main treatment used to manage symptoms of myasthenia gravis?
Pyridostigmine -orally
55
What is the main drug type used to treat myasthenia gravis?
Acetylcholinesterase inhibitors
56
What is the function of acetylcholinesterase inhibitors?
Enhance neuromuscular transmission by allowing more ACh to remain in the neuromuscular junction. Allows increase in power of smooth and skeletal muscle
57
What acetylcholinesterase inhibitor is used in ITU?
Neostigmine – oral and IV preparations (ITU) • Quicker action, duration up to 4 hours • Significant antimuscarinic side effect
58
What is a cholinergic crisis?
When acetylcholinesterase inhibitors are given in excess dose, causing a depolarising dose
59
What are the pharmokinetics of pyridostigmine?
Onset 30min; peak 60-120min; duration 3-6hr
60
What are the side effects of pyridostigmine?
Muscarinic side effects - dry mouth - mydriasis - Tachycardia - agitation - urinary retention - constipation
61
How is a cholinergic crisis treated?
Administering antimuscarinics
62
What are the side effects for antimuscainics?
Antimuscarinic side effect – – miosis and the SSLUDGE syndrome: » Salivation, » Sweating, » Lacrimation » Urinary incontinence » Diarrhea, » GI upset and hypermotility » Emesis
63
What are the 5 lines of treatment of myasthenia gravis?
``` • 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 ```

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