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Neurology > Pharmacological Management of Neurodegenerative Disorders > Flashcards

Pharmacological Management of Neurodegenerative Disorders Flashcards

1
Q

What is the average life expectancy of MND?

A

~3 years

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2
Q

What are the different types of MND?

A
  • Amyotrophic lateral sclerosis (UMN & LMN)
  • Progressive muscular atrophy (LMN)
  • Primary lateral sclerosis (UMN)
  • Spinal muscular atrophy
  • Lou Gehrig’s disease
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3
Q

Describe the trend in survival time of patients with MND using riluzole for amyotrophic lateral sclerosis (ALS).

A
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4
Q

What are the mechanisms of riluzole action?

A
  • Blocks TTX Na channels.
  • Reduces glutamate release (?calcium block).
  • Increases astrocyte glutamate uptake.
  • Enhances GABA activity.
  • Enhances BDNF action.
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5
Q

What is the ideal process for new drugs?

A
  • Likely target based on pathology with measurable surrogate (e.g. CSF / scan).
  • Animal models that are sensible, with well-designed experiments.
  • Look for target effects in phase 1 nd 2 studies.
  • Ensure clinical outcomes are relevant (valid) and sensitive to change (responsive).
  • Use modern methods to analyse results.
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6
Q

What is the ADAS-cog?

A
  • Measure of cognitive performance.
  • Developed early 1980s.
  • Widely used primary outcome measure in clinical trials (n>170AD).
  • Some modifications by adding componets (don’t overcome the key problems).
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7
Q

What is the striatum?

A

Dorsal and ventral striatum

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8
Q

What is the dorsal striatum?

A

Caudate nucleus and lentiform nucleus.

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9
Q

What is the ventral striatum?

A

Nucleus accumbens and olfactory tubercle.

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10
Q

What is the lentiform nucleus?

A

Putamen and globus pallidus.

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11
Q

Identify all the structures.

A
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12
Q

What are the functions of the basal ganglia?

A
  • Smooth movement
  • Switching behaviour
  • Reward systems
  • Closely linked to thalamus, cortex and limbic system.
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13
Q

Describe the direct pathway through the basal ganglia.

A
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14
Q

Describe the indirect pathway through the basal ganglia.

A
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15
Q

What excites and inhibits the basal ganglia?

A
  • Inhibition with GABA
  • Excitation with glutamate
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16
Q

Describe the substantia nigra dopaminergic pathway.

A
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17
Q

Describe the striatal interneurons cholinergic pathway.

A
18
Q

What are the clinical problems in the basal ganglia?

A
  • Parkinson’s disease (substantia nigra).
  • Huntington’s disease (caudate).
  • Wilson’s disease (lenticular).
  • Hemiballismus (subthalamic) - usually due to a stroke where you get flinging limb movements.
19
Q

Describe Huntington’s disease.

A
  • Autosomal dominant
  • CAG triplet repeat disease (>40 repeats)
  • Mutant huntingtin accumulates, toxic
  • Chorea, behavioural disorders, dementia
  • Caudate nucleus wasting.
20
Q

Describe Wilson’s disease.

A
  • Autosomal recessive
  • Abnormal copper accumulation
  • Hepato-lenticular degeneration (liver and brain)
  • Dystonia, ataxia, subcortical dementia
  • Copper transport protein abnormality
  • Low serum copper and caeruloplasmin
  • Kayser-Fleisher rings
  • Penicillamine Rx
21
Q

What are the features of Parkinson’s disease?

A
  • Tremor at rest
  • Rigidity - cogwheel, limbs > axial
  • Bradykinesia
  • Asymmetry
  • Loss of righting reflex
  • 30% cognitive decline
  • Hypomimia (lack of facial expression)
  • Glabellar tap
  • Quiet speech
  • Micrographia
22
Q

What happens to the direct and indirect pathways of the basal ganglia in Parkinson’s disease?

A
  • Turn down the direct pathway
  • Increase the indirect pathway
23
Q

What happens in the substantia nigra in Parkinson’s disease?

A
24
Q

Describe the drug treatment of Parkinson’s disease.

A
  • Main strategy is to counteract the deficiency in dopamine in the basal ganglia.
  • Levodopa (in combination with carbidopa or benserazide).
  • Dopamine agonists (e.g. pramipexole, ropinirole and bromocriptine).
  • Monoamine oxidase B (MAO-B_ inhibitors (e.g. selegiline and rasagiline).
  • Amantadine-releases dopamine.
  • Muscarinic ACh antagonist (benzhexol).
25
Q

What are the sites of action of common therapies for Parkinson’s disease?

A
26
Q

What is levodopa?

Describe its use.

A
  • First-line treatment for Parkinson’s Disease and combined with a dopa decarboxylase inhibitor (carbidopa or benserazide).
  • This combination lowers the dose needed and reduces peripheral system effects.
  • 80% of patients show initial improvement in rigidity and hypokinesia.
  • Limited in effectiveness with time as the neurodegeneration progresses.
  • Overall no evidence that L-dopa slows or accelerates neurodegeneration.
27
Q

What are the side-effects of Levodopa?

A
  • Involuntary writhin movements (dyskinesia) which may appear within 2 years. Affects face and limbs mainly. Occurs at peak therapeutic effect.
  • Rapid fluctuations in clinical state. Hypokinesia and rigidity may suddenly worsen and then improve again. This on-off effect is not seen in untreated Parkinson’s Disease patients or with other Parkinson’s disease drugs. Reflects fluctuating receptor dynamics.
28
Q

What are the different dopamine agonists?

A
  • Bromocriptine, cabergoline and pergolide (ergots) are orally active drugs that work on D1 and D2 receptors. They have limiting side effects - fibrotic reactions.
  • Pramipexole and roprinole are D2/D3 selective receptor agonists that are better tolerated. Short half-life in plasma could be a problem.
  • Rotigotine newer agent delivered by a transdermal patch.
  • Apomorphine given by injection; sometimes given to control the off effect of levodopa.
29
Q

Describe dopamine dysregulation syndrome.

A
  • Sudden onset sleep.
  • Impulse control disorders - gambling, binge eating, hypersexuality.
  • Neuroleptic malignant syndrome if stopped abruptly.
30
Q

What are MAO-inhibitors?

Give examples.

A
  • Selegiline is a selective MAO-B which lacks the unwanted peripheral effects of non-selective MAO-inhibitors.
  • Inhibition of MAO-B protects dopamine from extraneuronal degradation.
  • Combination with levodopa is more effective in relieving symptoms and prolonging life.
  • Rasagiline is an alternative and may retard the disease progression.
31
Q

What is amantadine?

A
  • Antiviral drug discovered to be beneficial in Parkinson’s Disease.
  • Increased dopamine release is primarily responsible for its therapeutic effect.
  • Less effective than levodopa or bromocriptine and action declines with time.
32
Q

Describe the use of acetylcholine antagonists in the treatment of Parkinson’s Disease.

A
  • Muscarinic acetylcholine receptors exert an inhibitory effect on dopaminergic nerves; suppression of which compensates for a lack of dopamine.
  • Benzhexol, Orphenadrine and procyclidine can all be used, with usual anti-cholinergic side effects.
33
Q

Give a summary of the drug treatment for neurodegenerative disorders.

A
  • Drugs acting by counteracting deficiency of dopamine in basal ganglia or by blocking acetylcholine receptors.
  • Dopamine precursor: levodopa.
  • Dopa decarboxylase inhibitor: carbidopa.
  • COMT inhibitor: entecapone.
  • Dopamine agonists: pramipexole, ropinirol, rotigotine, bromocriptine.
  • MAO-B inhibitors: selegine, rasagiline.
  • Dopamine release enhancer: amantadine.
  • Muscarinic antagonists: benzhexol (Trihexyphenidyl hydrochloride).
34
Q

What is an essential tremor?

A
  • Tremor on action - e.g. holding a cup of tea.
  • Present for years, gradually gets worse.
  • 30% familial.
  • 60% improve with alcohol.
  • Use Archimedes spiral to assess tremor.
  • No other features of Parkinson’s disease.
  • May improve with propanolol slow release.
35
Q

What are the different treatment groups in MS?

A
  • Immunosuppressive e.g. interferone, monoclonal antibodies etc.
  • Acute relapse treatment - high dose methyl prednisolone (500mg-1g daily for 3-5 days).
  • Symptomatic treatments - e.g. tremor, spesticity, bladder.
  • Neuroprotective strategies.
  • Repair strategies.
36
Q

What are the symptomatic treatments used in MS?

A
  • Bladder - anticholinergic drugs, botulinum toxin, SIC.
  • Pain - antiepileptic (commonly gabapentin), antidepressant (amitriptyline), NSAID, opiates.
  • Spasticity - baclofen, benzodiazepines, dantrolene, tizanidine, cannabis.
  • Tremor - betablockers, gabapentin, weights, surgery.
  • Depression
  • Seizures
  • Fatigue - amantadine, modafanil.
37
Q

What is the problem with trials for new drugs used to treat Multiple Sclerosis?

A
  • Too short.
  • Poor outcome measures - relapse rate or EDSS.
  • Not patient centred.
  • Commercial, bias and shorter duration (to reduce risk of patent running out).
  • Longer trials mean high drop out rate.
  • Too heavily MRI based.
  • Clinical effect vs statistical effect.
38
Q

What are the newer treatments for MS and what are their mechanisms of action and side effects?

A
39
Q

What are the oral treatments for MS? What are the mechanisms of action and side effects?

What is their general outcome?

A
  • 30-50% reduction in relapses.
40
Q

What are the more powerful treatments for MS?

What are the mechanisms of action and side effects?

A

Neurology (16 decks)

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