Pharmacology of the basal ganglia disorders Flashcards
What are the 2 classes of movement disorders?
Hyperkinetic
Hypokinetic
What disorders are classed as hyperkinetic?
Hemiballismus Huntingdon's Disease Dystonias Wilson's disease (dystonic) Essential tremor Chorea Athetosis
What disorders are classed as hypokinetic?
Parkinson's Multiple systems atrophy Progressive supranuclear palsy Wilson's Disease (psuedoparkinsonism) Essential tremor
How are movement disorders classified?
By activities, assessing rhythm, speed and control
What is dystonia?
Twisting and repetitive movements or abnormal postures
What is athetosis?
Writhing movements
What is chorea?
Twitching or jerking of a group of muscles
What is ballismus?
Large, flinging limb movements
What key region is associated with Parkinson’s Disease?
Substantia Nigra (degeneration of dopaminergic neurons)
What key region is associated with Huntingdon’s Disease?
Striatum (degeneration of GABAergic cells)
What key region is associated with Hemiballismus?
Subthalamic Nuclei
What area of the brain is thought to be responsible for generation of tremors?
Globus Pallidus
What are the 3 main groups of Parkinsonism?
Pure Parkinsonism
Parkinsonism with extras
Pseudoparkinsonism
What is Pure Parkinsonism?
Damage to substantia nigra with classic Parkinson’s Disease, including:
Idiopathic (Parkinson’s Disease)
Iatrogenic (induced Parkinson’s e.g. through drug use)
Post-encephalitic
What is Parkinsonism with extras?
Classic Parkinson’s Disease plus additional symptoms due to damage to additional sites:
Multiple Systems Atrophy (e.g. classic + ANS symptoms)
Progressive supranuclear palsy (classic + damage to midbrain)
What is Pseudoparkinsonism?
Parkinson-like symptoms without degeneration to substantia nigra due to:
Wilson’s Disease
Benign Essential Tremor
Trauma and vascular-related
What are the 4 cardinal symptoms of Parkinson’s Disease?
Tremor (resting)
Rigidity (smooth movements that are difficult to do)
Akinesia (bradykinesia)
Postural instability
What additional symptoms can be present in Parkinson’s Disease?
Micrographia (small, cramped writing)
Mask-like face (lack of expression)
Sleep disturbances
Aprosodia (change in rhythm, speed etc. of speech)
What dopamine pathway is involved in Parkinson’s Disease?
Nigrostriatal (Substantia nigra to Striatum)
What are the treatment principles for Parkinson’s?
Don’t start treatment until quality of life is significantly disrupted
Multi-disciplinary (input from SLT, OT, Physio etc.)
Gradual treatment (to avoid reaching maximum doses)
Why can dopamine not be used as a treatment for Parkinson’s and how can this be overcome?
Can not cross blood brain barrier
Use of dopamine precursor which can cross BBB (L-Dopa)
What is the problem with using L-Dopa to treat Parkinson’s and how can this be overcome?
Levodopa is metabolised quickly (before it gets into the CNS).
Use of dopa-decarboxylase inhibitors (Carbidopa or Benserazide) in combination with L-Dopa
What 2 routes break down Dopamine within the CNS?
Catechol-O Methyltransferase
Monoamineoxidase
What drugs can be given to prevent breakdown of Dopamine within the CNS?
COMT inhibitor - Entacapone or Tolcapone
MAOI-B inhibitor - Selegiline or Rasagiline
When would COMT and MAOI-B inhibitors be used?
Can be used as a first line treatment before use of a dopamine agonist or L-Dopa
When are Dopamine agonists useful?
Younger patients and initial treatment of Parkinson’s
What is the main Dopamine agonist?
Pramipexole
Also Rotigotene + Ropinirole
What side affects are associated with Dopamine based treatments?
Nausea/ vomiting Sudden onset sleeping Anorexia Drowsiness On-off effects Tachycardia/ arrhythmias Psychosis
What are on-off effects?
On phase - when medication is working well to control symptoms
Off phase - when medication has worn off and symptoms much more pronounced
How can on-off effects be treated?
Use of Apomorphine to ‘fill gaps’ during off phases - Domperidone must always be administered prophylactically prior to Apomorphine use
What neurological disorder are anticholinergics used to treat?
Iatrogenic (drug-induced) Parkinson’s
What are the disadvantages of using anticholinergics to treat Iatrogenic Parkinson’s?
Only have mild anti-Parkinsonism effects (e.g. reducing tremor)
May reduce absorption of Levodopa
What anticholinergics are used to treat Iatrogenic Parkinson’s?
Orphenadrine
Procyclidine
Trihexphenidyl
What glutamate antagonist can be used to treat Parkinson’s?
Amantadine
What symptoms does Amantadine help to reduce in Parkinson’s?
Tremor
Rigidity
Bradykinesia
What is a Kayser-Fleischer ring?
Build up of copper around the iris of the eye
Indicative of Wilson’s Disease
What are the 3 forms of Wilson’s Disease?
Dystonic Pseudoparkinsonism Cerebellar (pseudosclerotic)
How can Wilson’s Disease be treated?
By reducing copper levels using a Copper chelator or Zinc
How do Copper Chelators work to reduce copper levels?
Cause excretion of excess copper
Used as maintenance after initial excretion of copper
Examples: Penicillamine or Trientine
How does Zinc work to reduce copper levels?
Blocks absorption of copper in the gut to prevent further build up
Fewer side effects than alternative therapeutics
What is Essential Tremor?
Familial progressive disorder characterised by intention tremor (not present at rest)
Tends to first appear in arms before spreading to rest of body (particularly the head, neck, jaw and voice)
Generally bilateral
What is titubation?
Head tremor
More common in females
What is the treatment for Essential Tremor?
Beta-blocker (Propanolol)
Anti-epileptic (Primedone)
Botox (Botulinumn toxin type A) - used for head and voice mainly
1-2 units of alcohol (for tremor)
What is Huntingdon’s Disease?
Inherited neurodegenerative disorder
Autosomal dominant
Degeneration of GABAergic cells in the striatum (generally starts in caudate nucleus before progressing to putamen) - causes cholinergic dysfunction
What is the treatment for Huntingdon’s Disease?
Dopamine depleting drugs (Tetrabenazine) - reduces involuntary movements
Antipsychotics (Risperidone, Haloperidol) - reduces chorea and tics; controls delusions, hallucinations and violent outbursts
Benzodiazepines (Diazepam)
Antidepressants
What is the MoA for Tetrabenazine?
Dopamine depleting drug: Blocks VMAT2 (vesicular monoamine transporter) Prevents transport of Dopamine into vesicles thus preventing release of Dopamine into synaptic cleft
What is the disadvantage of Tetrabenazine?
Prevents release of all monoamines rather than selectively inhibiting Dopamine release - this causes depression due to decreased levels of 5HT and NA
What is a tic?
Small, involuntary movement
Seen in Tourettes, Wilson’s Disease and Huntingdon’s Disease
How can tics be managed?
Patient education (tic management)
2nd gen antipsychotics
1st gen antipsychotics
What is dystonia?
Lasting muscle spasms causing repeated twisting movements or altered posture
Can be primary (genetic) or secondary (acquired)
How is dystonia managed?
Botox injections (Botulinum toxin A) Anticholinergics GABA agonist (Baclofen) - antispasm BDZ GABA co-agonist (Diazepam) - muscle relaxant Physiotherapy Deep brain stimulation Denervation
What is chorea?
Involuntary, irregular, flowing movements
Can be primary (inherited e.g. HD) or secondary (acquired e.g. medication side effect or toxins)
What is the treatment for chorea?
2nd gen antipsychotics
Dopamine depleting drugs (Tetrabenazine)
GABAergic drugs (e.g. antiepileptics, benzodiazepines)
Steroids (for post op chorea)
What is athetosis?
Slow, irregular, writhing movements - often in fingers
Athetosis + Chorea = choreoathetosis
Same treatment as for chorea
What is ballismus?
Large, violent, proximal, flinging movements
Often in limbs
Hemiballismus = unilateral
What causes ballismus?
Degeneration of subthalamic nuclei
Lesion
How is ballismus treated?
Same as chorea (2nd gen antipsychotics, dopamine depleting drugs, GABAergic drugs)
IV Diazepam
Oral Haloperidol
