Drug Treatments of Movement Disorders Flashcards
What are the main features of neurodegenerative disorders? (3)
- Loss of neurons
- Progressive
- Irreversible (cannot regenerate neurons)
When was Parkinson’s first described, and what were the main features?
1817.
- ‘shaking palsy
- akinetic-rigid syndrome
- extrapyramidal disorder
How does Parkinson’s progress?
Slowly; usually die within 10-15 years.
-death usually due to bronchopneumonia / sepsis
What is remission, and how common is it in Parkinson’s?
Disappearance of signs.
-rare, and only lasts for seconds/minutes
What are the main symptoms of Parkinson’s? (6)
- Tremor (4-7Hz)
- Rigidity (increased tone)
- Slurred speech
- Akinesia
- Decreased blinking
- Postural changes (stoop, shuffling)
What are the unusual ways to describe some of the symptoms of Parkinson’s?
TREMOR – ‘pill rolling’
RIGIDITY - ‘lead piping limbs’
DECREASED BLINKING – ‘serpentine stare’
POSTURAL CHANGES – ‘telegraph pole falls’
What is akinesia?
Difficulty initiating voluntary movements.
What is the general pathology of Parkinson’s?
- Loss of neruones in substantia nigra
- Lewy body accumulation (eosinophilic proteins in cells)
- Loss of nigro-subtantia inhibitory-excitatory pathway
What type of neurones are affected by Parkinson’s?
Dopaminergic neurones.
What causes Parkinson’s?
Unknown cause.
-idiopathic
What disorders are associated with Parkinson’s? (3)
- Drug-induced (iatrogenic)
- MPTP-induced (amphetamine-related)
- Post-encephalitic
What are the 2 pathways affected by Parkinson’s?
Indirect and direct.
-both involve dopamine (D1/D2)
What is the direct pathway?
D1-mediated.
-signals from striatum
What is the indirect pathway?
D2-mediated.
-signals from striatum
What is the abbreviation of dopamine?
DA.
What are the general mechanisms of Parkinson’s treatment? (2)
- Increase DA activity
- Decrease Ach activity
How is DA activity increased? (4)
- Replace DA
- Decrease DA breakdown
- Increase DA release
- DA agonists
What drug is used to replace DA?
L-DOPA.
What drugs are used to decrease DA breakdown? (2)
- MAO inhibitors
- COMT inhibitors
What drug is used to increase DA release?
Amantidine.
What drugs are used as DA agonists? (2)
- Bromocriptine
- Pergolide
What class of drugs decrease Ach activity?
Antimuscarinics.
-benzhexol, orphenadrine
What is the 1st line treatment for Parkinson’s?
- L-DOPA
- MAO / COMT inhibitors
How does L-DOPA increase dopamine levels?
L-DOPA is a precursor for dopamine.
-DOPA decarboxylase converts it
How does L-DOPA act?
- L-DOPA crosses the BBB»_space; neurones.
- converted to DA in neurones and glia
What is the main problem with L-DOPA?
Metabolised in the periphery»_space; only 1% reaches brain.
-90% in intestine
What is given with L-DOPA to prevent it being broken down, and how does it work?
Carbidopa.
- inhibits DOPA decarboxylase
- doesn’t pass BBB
What are the main side effects of L-DOPA?
- ‘On-off’ effect (worsening symptoms)
- Nausea / anorexia
- Dysknesias
- Tachycardia
- Hypotension
- Insomnia
What happens to the side effects of L-DOPA with time?
Increased side effects with time.
-partly due to increased dose
How do MAO inhibitors reduce DA breakdown?
Mono-amine oxidase (MAO) breaks down DA to homovanillinic acid.
-inhibitors prevent this
What is a commonly used MAO inhibitor?
Selegiline.
How does Selegiline act?
- MAOb inhibitor (CNS specific)
- Increase DA in brain
- Effective alone in early stages, ineffective later on
Where are MAOa and MAOb located?
MAOa – periphery
MAOb – CNS
How do COMT inhibitors reduce DA breakdown?
COMT breaks down L-DOPA (»3-O-methyl DOPA) and DA (»homovanillinic acid)
-inhibitors prevent this
What are COMT inhibitors used for?
Patients with on-off symptoms.
What COMT inhibitor was withdrawn due to adverse effects?
Tolcapone.
How does amatidine act and when is it used?
Increases DA release.
-useful in early stages, but not generally used
What are bromocriptine and peroglide?
Dopamine agonists.
-usually given towards end of disorder
What are the selectivities of bromocriptine and peroglide?
Bromocriptine – D1 and D2.
Peroglide – D2 selective.
What is the action of antimuscarinics?
Block muscarinic receptors.
- most effective on tremor and drooling
- used only in young with severe tremor
How can surgery be used to treat Parkinson’s? (3)
- Lesions
- Implantable stimuli
- Grafts
What lesions can be used to treat Parkinson’s?
- Motor thalamus (thalamotomy)
- Globus pallidus (pallidotomy)
- Subthalamus (subthalamotomy)
Why are lesions used in Parkinson’s?
Can reduce motor symptoms; usually last resort.
How does Huntington’s progress?
Gradual onset.
-death within 10-20 years
What is the typical age of onset of Huntington’s?
30-50 years.
-younger»_space; more severe
What are the main symptoms of Huntington’s? (2)
- Fidgeting / restlessness»_space; chorea
- Irritability / moodiness»_space; dementia
What is chorea?
Jerky, involuntary movements.
What is the general pathology of Huntington’s?
Selective cell loss in cerebral cortex and corpus striatum.
- medium spiny neurones containing GABA and encephalin = 1st affected
- altered NT levels
What causes Huntington’s?
HEREDITARY – autosomal dominant
- gene defect on chromosome 4 (4p16.3)
- CAG repeate (polyglutamine)
How is Huntington’s treated?
No cure.
-can control movement disorder: D2 antagonists, DA depletion
