Pharmacological Management of Neurodegenerative Disorders Flashcards
What is the average life expectancy of MND?
~3 years
What are the different types of MND?
- Amyotrophic lateral sclerosis (UMN & LMN)
- Progressive muscular atrophy (LMN)
- Primary lateral sclerosis (UMN)
- Spinal muscular atrophy
- Lou Gehrig’s disease
Describe the trend in survival time of patients with MND using riluzole for amyotrophic lateral sclerosis (ALS).
What are the mechanisms of riluzole action?
- Blocks TTX Na channels.
- Reduces glutamate release (?calcium block).
- Increases astrocyte glutamate uptake.
- Enhances GABA activity.
- Enhances BDNF action.
What is the ideal process for new drugs?
- 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.
What is the ADAS-cog?
- 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).
What is the striatum?
Dorsal and ventral striatum
What is the dorsal striatum?
Caudate nucleus and lentiform nucleus.
What is the ventral striatum?
Nucleus accumbens and olfactory tubercle.
What is the lentiform nucleus?
Putamen and globus pallidus.
Identify all the structures.
What are the functions of the basal ganglia?
- Smooth movement
- Switching behaviour
- Reward systems
- Closely linked to thalamus, cortex and limbic system.
Describe the direct pathway through the basal ganglia.
Describe the indirect pathway through the basal ganglia.
What excites and inhibits the basal ganglia?
- Inhibition with GABA
- Excitation with glutamate
Describe the substantia nigra dopaminergic pathway.
Describe the striatal interneurons cholinergic pathway.
What are the clinical problems in the basal ganglia?
- 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.
Describe Huntington’s disease.
- Autosomal dominant
- CAG triplet repeat disease (>40 repeats)
- Mutant huntingtin accumulates, toxic
- Chorea, behavioural disorders, dementia
- Caudate nucleus wasting.
Describe Wilson’s disease.
- 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
What are the features of Parkinson’s disease?
- 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
What happens to the direct and indirect pathways of the basal ganglia in Parkinson’s disease?
- Turn down the direct pathway
- Increase the indirect pathway
What happens in the substantia nigra in Parkinson’s disease?
Describe the drug treatment of Parkinson’s disease.
- 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).
What are the sites of action of common therapies for Parkinson’s disease?
What is levodopa?
Describe its use.
- 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.
What are the side-effects of Levodopa?
- 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.
What are the different dopamine agonists?
- 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.
Describe dopamine dysregulation syndrome.
- Sudden onset sleep.
- Impulse control disorders - gambling, binge eating, hypersexuality.
- Neuroleptic malignant syndrome if stopped abruptly.
What are MAO-inhibitors?
Give examples.
- 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.
What is amantadine?
- 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.
Describe the use of acetylcholine antagonists in the treatment of Parkinson’s Disease.
- 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.
Give a summary of the drug treatment for neurodegenerative disorders.
- 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).
What is an essential tremor?
- 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.
What are the different treatment groups in MS?
- 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.
What are the symptomatic treatments used in MS?
- 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.
What is the problem with trials for new drugs used to treat Multiple Sclerosis?
- 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.
What are the newer treatments for MS and what are their mechanisms of action and side effects?
What are the oral treatments for MS? What are the mechanisms of action and side effects?
What is their general outcome?
- 30-50% reduction in relapses.
What are the more powerful treatments for MS?
What are the mechanisms of action and side effects?
