24 - Neurological Disorders Flashcards
What are some clinical features of Parkinsonism?
Motor: resting/pill rolling tremor, bradykinesia, rigidity, postural instability, shuffling gait
Non-motor: mood changes (depression), cognitive change, urinary symptoms, sleep disorders, sweating, pain
After 15 years, what clinical features will patients with PD have during follow up?
- Dyskinesia (94%) (secondary to LDopa treatment)
- Falls (81%)
- Cognitive decline (84%)
- Somnolence (80%)
- Swallowing difficulties (50%)
- Severe speech problems (27%)
How do you make a diagnosis of idiopathic Parkinson’s Disease?
- Clinical features
- Exclude other causes of Parkinsonism
- Response to treatment
- Normal structural neuro-imaging e.g PET
What are some non-idiopathic causes of Parkinsonism?
- Drug induced
- Vascular
- Progressive supranuclear
- Corticobasal degeneration
What is the pathology of idiopathic parkinson’s disease?
- When over 50% loss of pigment this is when symptoms occur
- Lewy body deposition in pars compacta of substantia nigra causes neurodegeneration
How is the basal ganglia circuit affected in Parkinson’s disease?
How is dopamine synthesised and degraded?
What are the six different classes of drugs used to treat IPD?
- Levodopa (L-DOPA)
- Dopamine receptor agonists
- MAOI type B inhibitors
- COMT inhibitors
- Anticholinergics
- Amantidine
Why is L-DOPA used to treat IPD instead of Dopamine?
- Dopamine receptor agonists
- It is given orally and must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine
- Given up to 5 times a day as short half life of 2 hours
How is L-Dopa absorbed when taken orally?
Don’t eat big protein meals with Levodopa as there will be more competition for absorption
What is L-Dopa administered with?
- Peripheral DOPA decarboxylase inhibitor (co-careldopa/co-beneldopa)
- Reduces the dose required, reduces side effects and increases amount of L-Dopa reaching the brain
What are the advantages and disadvantages of using L-Dopa in IPD?
+ Highly efficacious
+ Low side effects (e.g nausea, vomiting, hypotension, tachycardia, psychosis)
- Needs enzyme conversion
- Involunrary movements
- Loses efficacy as disease progresses as loss of neurones
- Motor complications e.g freezing, dystonia
What DDIs does L-Dopa have?
- Pyridoxine (Vit B6): increases peripheral breakdown of L-DOPA
- MAOIs: risk hypertensive crisis
- Antipsychotic drugs: lead to parkinsonism (block dopamine receptors)
What are some different subtypes of dopamine receptor agonists and give some examples in each subtype?
What are the advantages and disadvantages of using dopamine receptor agonists as treatment for IPD?
+ direct acting
+ less motor complications/dyskinesias
+ possible neuroprotection
- less efficacy than L-Dopa
- impulse control disorders
- more psychiatric side effects
- expensive
What are some impulse control disorders? (a.k.a dopaine dysregulation syndrome)
- Pathological gambling
- Hypersexuality
- Compulsive shopping
- Desire to increase dosage
- Punding
What are some of the side effects of dopamine receptor agonists?
- Impulse control disorders
- Hallucinations
- Confusion
- Hypotension
- Sedation
- Nausea
What is the mechanism of action of monoamine oxidase B inhibitors and give some examples of this class of drugs?
- Inhibits metabolism of dopamine* by MAO
- Prolongs action of L-DOPA
- Smooths out motor response
- Selegiline
- Rasagaline
How do COMT inhibitors work to treat IPD and what is an example of this class of drug?
- Entacapone
- Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa (3-O-methyldopa competes with L-DOPA for active transport into CNS)
- Prolongs motor response to L-DOPA so reduces symptoms of wearing off
- No therapeutic effect alone, need to be given as Stalevo with carbidopa and levodopa
How are anticholinergics used to treat IPD and what are some examples of these types of drugs?
- Acetyl choline may have antagonistics effects on dopamine
- Minor role in treatment of PD
- Orphenadrine
- Procyclidine
What are the advantages and disadvantages of using anti-cholinergics to treat Parkinson’s disease?
+ Treats tremor
+ Not acting via dopamine systems
- No effect on bradykinesia
- Side effects like confusion, drowsiness, usual anticholinergic side effects (urinary retention, dry mouth etc)
What is the MOA of Amantadine in the treatment of IPD?
Unknown but possibly:
- Enhanced dopamine release
- Anticholinergic NMDA inhibition
DOPAMINE RECEPTOR AGONIST
What are the disadvantages of amantadine?
- Poorly effective
- Few side effects
- Little effect on tremor
Apart from pharmacology, what else can we do to help the treatment of IPD?
Deep brain stimulation stereotactically in the subthalamic nucleus
What are the differences in the post synaptic membrane of a normal neuromuscular junction with that of one in myasthenia gravis?
Autoimmune disease not neurodegenerative
How does myasthenia gravis present?
- Extraocular muscles – commonest presentation
- Bulbar involvement – dysphagia, dysphonia, dysarthria
- Limb weakness – proximal symmetric
- Respiratory muscle involvement - e.g tired when walking stairs
FLUCTUATING FATIGUABLE WEAKNESS OF SKELETAL MUSCLE
What are some classes of drugs that can exacerbate a patient’s myasthenia gravis?
- Aminoglycosides
- Beta-blockers
- CCBs
- Quinidine
- ACE inhibitors
BE CAREFUL WHEN PRESCRIBING TO MG PATIENTS
What are the complications of Myasthenia gravis?
- Acute exacerbation – Myasthenic crisis
- Overtreatment – cholinergic crisis
What is the acute therapeutic management of Myasthenia gravis?
Acetylcholinesterase inhibitors – enhance neuromuscular transmission at skeletal and smooth muscle by stopping breakdown of Ach at NMJ
- Pyridostigmine (oral)
- Neostigmine (oral/IV)
Why may pyridostigmine be used over neostigmine?
- Although has quicker action and duration of 4 hours it has more significant cholinergic side effects
What are cholinergic side effects?
- Miosis
- SSLUDGE syndrome: salivation, sweating, lacrimation, urinary incontinence, diarrhea, GI upset and hypermotility, emesis
What are the three parts of treating a patient with PD?
- Neuroprotection e.g L-Dopa
- Symptomatic treatment
- Surgery
Apart from AchEi’s, how can myasthenia gravis be pharmacologically treated?
- Immunoglobulins IV to help a crisis
- Azathioprine to be steroid sparing
- Corticosteroids to decrease immune response
- Plasmapheresis
What antiemetic would you not give to a patient with Parkinson’s?
- Metoclopramide as it is a dopamine d2 antagonist working all over the body so will affect the CNS
- Give domperidone instead as only acts on D2 receptors in the gut, not the CTZ as cannot cross BBB
