Pharmacology of Movement Flashcards
What are the 3 characteristics of neurodegnerative disorders?
- Loss of neurones
- progressive
- irreversible
What is an alternative name for Parkinson’s disease
What type of syndrome / disorder is it?
“Shaking palsy”
it is common worldwide and incidence increases over 70
it is an akinetic-rigid syndrome involving loss of movement and increased muscle tone
it is an extrapyramidal disorder
What is the progression of Parkinson’s disease like?
- It is slow and progressive
- causes mild inconvenience at first but becomes intrusive
- remission is rare
- it usually lasts 10-15 years, but can last decades
- death is usually from bronchopneumonia
What are the characteristics of tremor, rigidity and speech in Parkinson’s disease?
Tremor:
- 4 - 7 Hz
- “pill rolling”
- sometimes unilateral
Rigidity:
- limb stiffness - “lead piping”
speech:
- slurred and monotone
- dribbles
- dysphagia occurs later
What is akinesia and postural changes in Parkinson’s disease?
Akinesia:
- difficulty in initiating movement
- facial immobility
- blinking reduced - “serpentine stare”
Postural changes:
- stoop
- shuffling
- poor arm swinging
- balance impaired
- “telegraph pole” falls
What is the pathology involved in Parkinson’s disease?
- Loss of neurones in substantia nigra
- Lewy bodies - spherical, eosinophilic, contain cellular proteins
- DA-ergic neurones affected
- loss of nigro-striatal inhibitory / excitatory pathway
- midbrain nuclei
What are the causes of Parkinson’s disease?
- Unknown - idiopathic
- Associated disorders
- drug-induced (iatrogenic)
- MPTP-induced
- post-encephalic
What are the components involved in the Parkinson’s disease pathway?
How much of the pathway involved in Parkinson’s needs to disappear for there to be loss of symptoms?
50% loss for symptoms
80%+ loss at autopsy
What are the 2 general approaches to Parkinson’s disease treatment?
Increase DA activity
Decrease ACh activity
How can DA activity be increased?
Which drugs are used?
- Replace DA - L-DOPA
- reduced DA breakdown - MAO inhibitors, COMT inhibitors
- increase DA release - amantidine
- DA agonists - bromocriptine, pergolide
What type of drugs are used to decrease ACh activity?
Antimuscarinics - benzhexol, orphenadrine
How does L-DOPA work?
It replaces DA to increase DA activity
L-DOPA is converted to dopamine by DOPA decarboxylase
Increase in brain dopamine concentrations improves nerve conduction and assists in movement disorders
What is MOA?
How does it work and interact with neurones?
It is a dopamine precursor
it crosses the blood-brain barrier and enters neurones via carrier mechanism
it is converted to DA in neurones and glia
it is retained mainly by neurones and leads to increased DA release from remaining neurones
What are the problems associated with L-DOPA?
- Metabolism in the periphery
- 90% metabolism in the intestinal wall by DOPA decarboxylase / MAO
- 9% metabolism in other peripheral sites
- 1% reaches the brain
What is L-DOPA usually given alongside and why?
It is usually given with carbidopa which doesn’t pass the blood-brain barrier
carbidopa inhibits DOPA decarboxylase
What are the most common adverse effects of L-DOPA?
- “On-off” effect - worsening of PD symptoms as dopamine concentration drops
- nausea, vomiting, anorexia
- dyskinesias
- tachycardia, extrasystoles - (peripheral - block with domperidone)
What are more adverse effects of L-DOPA?
How does this change with time?
- Hypotension
- insomina, confusion, schizophrenic effects - (block with clozapine - neuroleptic with no D2 action)
- side effects are greater with time
- the effect wears off as neurones die - final therapy
What is selegiline?
How does it work and when is it given?
It is a MAOB selective inhibitor
it is effective alone in early stages
it is ineffective alone in later stages and is usually given to prolong L-DOPA action
What are the side effects of selegiline?
What is it also known as?
- Also known as deprenyl
- it may have neuroprotective effects
- it has few side effects but potentiates central side effects of L-DOPA
What is the main COMT inhibitor?
How does it work?
Entacapone is an adjunct to L-DOPA / carbidopa combinations
it is used for patients with “on-off” problems
it is a drug which inhibits catechol-O-methyltransferase - an enzyme which methylates catecholamines such as dopamine
What are the adverse effects of COMT inhibitors?
- Aggravate L-DOPA dyskinesias
- nausea
- diarrhoea
- abdominal pain
- dry mouth
What is amatidine?
Is it still in use?
It increases dopamine release
it is useful in early stages and generally well tolerated
it is no longer recommended in the UK as it causes confusion and hallucinations in the elderly
What are bromocriptine and pergolide?
What is the difference and what is their half life like?
They are dopamine agonists
bromocriptine works on D1 & D2, but pergolide is D2 selective
they are given alone or with L-DOPA
half life is 6-8 hours but the peak is between 1-3 hours
What are the adverse effects of bromocriptine and pergolide?
Adverse effects are similar to L-DOPA
- dyskinesias
- nause & vomiting
- severe hypotensive effects
- hallucinations
What are examples of antimuscarinics?
Which type of patients are they used in?
They block muscarinic receptors
e.g. benzhexol and orphenadrine
they are most effective on tremor and drooling
they are ONLY used in the young with severe tremor
What are the adverse effects of antimuscarinics?
Peripheral anticholinergic uncommon
central effects are SEVERE
- confusion
- delusions
- hallucinations
- drowsiness
- mood changes
What are the different types of surgery used to treat Parkinson’s disease?
Lesions:
- motor thalamus - thalamotomy
- globus pallidus - pallidotomy
- subthalamus - subthalamotomy
implantable stimulators
grafts:
- adrenal medulla
- foetal nigral tissue
- GM fibroblasts
- stem cells
- xenografts
What is the onset of Huntingdon’s disease like?
When does someone tend to die?
What are the main symptoms?
- Gradual onset with progressive development
- typically starts at 30-50 years but juvenile onset is more severe
- death in 10-20 years after onset
- main symptoms are chorea and dementia
What are the symptoms of Huntingdon’s disease?
What tests can be used to identify it?
Dementia:
- irritability
- moodiness
- antisocial behaviour
gross choreiform movements:
- fidgeting
- restlessness
diagnosed through genetic testing
CT / MRI shows cerebellar atrophy
what is the pathology involved in Huntingdon’s disease?
Selective cell loss in the corpus striatum of the cerebral cortex
first affected are the medium-sized spiny neurones containing GABA and enkephalin
What causes Huntingdon’s disease?
What is the chance of the child developing it if 1 parent has it?
- It is a hereditary autosomal dominant disorder
- there is a gene defect on the short arm of chromosome 4
- locus 4p16.3 - codes for a protein called “Huntingdin”
- gives rise to an expanded and repeated CAG repeat
What is involved in the treatment for Huntingdon’s disease?
- There is no cure and death is inevitable
- drugs to increase GABA or ACh activity don’t work
- drugs can control movement disorders:
- D2 agonists - haloperidol, chlorpromazine
- Dopamine depletion - reserpine, tetrabenzine
What are the adverse effects of the drugs used to treat Huntingdon’s disease?
D2 antagonists:
- Parkinsonism
- restlessness
DA depletion:
- hypotension
- depression
- sedation
- GI disturbances
What are the drugs used to treat dystonias?
Dystonia is a movement Disorder in which a person’s muscles contract uncontrollably
- DOPA replacement
- anticholinergics
- benzodiazepines
- baclofen
- botulinum toxin
