Pharmacology Of Basal Ganglia Disorders Flashcards
What are movement disorders?
Disorders resulting from neuronal damage to the circuits modifying motor outflow, the extrapyramidal pathways characterised by uncontrollable movements (hyper/hypokinesis) and changes in tone (hyper/hypotonia)
What are some examples of hypokinetic disorders?
PD MS atrophy Progressive supranuclear palsy Wilson's disease (pseudoparkinsonism) Essential tremor
What are some examples of hyperkinetic?
Hemiballismus HD (baseline level of hypokinetic activity alongside hyperkinetic periods of hyperkinesis) Wilson's disease (dystonic) Essential tremor Chorea Athetosis
How are movement disorders classified?
- Rhythm
- Speed
- Control
What is dystonia?
Twisting, repetitive, nonrhythmic and sustained/lasting spasm movements or altered posture (includes Writer’s cramp) and has 2 types:
- Primary (genetic)
- Secondary (acquired/unclear)
What is athetosis?
Writhing, nonrhythmic, sinuous and slow movements (snake-like)often of the fingers (can occur with chorea = choreoathetosis) caused by striatal degeneration
What is chorea?
Twitching or jerking rapid, random + dance-like flowing nonsupressible involuntary movements of a group of muscles (distal) flitting from one part of the body to another and has 2 types:
- Primary (inherited e.g. HD or benign hereditary chorea)
- Secondary (acquired e.g. drugs/toxins like antipsychotics, AEDs, CO + cyanide)
What is ballismus?
Large, violent, flinging rapid and nonsupressible limb movements (proximal) which can be uni/bi-lateral caused by neurodegeneration of subthalamic nuclei (STN) most commonly due to vascular causes
What are tics?
Small involuntary suppressible movements(larger ones called spasms) most commonly associated with Tourettes but also Wilson’s disease + HD
Define tremor.
Shaking rhythmic movements characterised as resting, kinetic or postural
Define myoclonus.
Spasmodic jerky contractions in multiple muscle groups
What is the primary problem in Parkinson’s Disease (PD)?
Dopaminergic degeneration in Substantia Nigra (SN)
Lewy body formation + presence of abnormal levels of parkin and synuclein proteins are associated too
What is supposedly the focal centre for generation of tremors?
Globus Pallidus (GP)
What are the 3 main groups of parkinsonism?
- Pure: idiopathic (PD), iatrogenic + post-encephalitic
- With extras: MS atrophy (MSA-A*, -P + -C) + professive supranuclear palsy
- Pseudoparkinsonism (no SN degeneration): Wilson’s disease, benign essential tremor, trauma + vascular-related
What are the symptoms of Parkinsons Disease (PD)?
Cardinal: T: tremor (resting) R: rigidity (lead pipe, cogwheel) A: akinesia (bradykinesia) P: postural instability
Other: Festinating gait Micrographia Mask-like face (lack of facial expression) Sleep disturbances Aprosodia
What are the 4 dopamine (DA) pathways?
- Nigrostriatal
- Mesolimbic
- Mesocortical
- Tubero-hypophyseal
What is the treatment of parkinsonism?
Not commenced until symptoms significantly disrupt quality of life as treatments have unwanted effects and titrated gradually/slowly against symptoms
Combine with physiotherapy, speech + occupational therapy, dietary consults etc.
What is the best available treatment for Parkinson’s Disease (PD)?
Levodopa (L-Dopa) but once max dose is reached there is nothing more you can do so leave it as late as possible
Why can you not get Parkinson’s Disease (PD) patients pure dopamine (DA)?
DA does not cross the BBB so the precursor of DA must be used
What is the problem with the drug Levodopa (L-Dopa) and how can this be dealt with?
It is metabolised quickly even before it gets to CNS so combine with Dopa-decarboxylase inhibitors e.g. Carbidopa + Benserazide
Combos of both = Cocareldopa + Co-beneldopa
What 2 routes breakdown dopamine (DA) in the CNS?
- Catechol-O-methyltransferase (COMT) inhibitors e.g. Entacapone + Tolcapone (specialist use only)
- Monoamineoxidase inhibitors (MAOI-B) e.g. Selegiline + Rasagiline
What drug can be used as 1st line for Parkinson’s Disease (PD)?
MAOI-B preventing DA breakdown
What are dopamine (DA) agonists?
Synthetic agonists replacing DA loss acting on DA receptors (primarily D2)
What are dopamine (DA) agonists?
Synthetic agonists replacing DA loss acting on DA receptors (primarily D2) e.g. Pramipexole, Ropinirole + Rotigotine (may be combined with L-dopa at later stages)
What are the advantages and disadvantages of dopamine (DA) agonists?
Adv: useful in young patients + initial PD treatment and fewer motor complications long-term
Disadv: less improvement overall + more psychiatric side-effects (via mesolimbic/mesocortical activity)
What are side effects associated with dopamine (DA)-based treatments?
Peripheral effects cause nausea/vomiting Anorexia Drowsiness Hypomania Psychosis Hypotension Tachycardia Arrhythmias On-off effects
How can you treat on-off effects?
Apomorphine to fill in gaps in combination with Domperidone prophylactically to prevent nausea/sickness
Duodopa (implanted gel form of L-dopa + carbidopa) useful for severe on-off effects
How do anticholinergics treat Parkinsonism?
The striatum contains cholinergic cells that modulate activity in the GABAergic cells projecting to the GP doing the opposite of DA reducing activity in the direct pathway reducing movement so blocking them will promote movement
What are the advantages and disadvantages of anticholinergic drug use in Parkinsonism?
Adv: useful for iatrogenic cause + only have mild anti-Parkinsonism effects (tremor)
Disadv: reduce absorption of L-dopa
Give some examples of anticholinergics used in Parkinsonism.
Orphenadrine
Procyclidine
Trihexphenidyl (Benhexol, Broflex)
How are glutamate antagonists used to treat Parkinsonism?
Glutamate transmission linked to no. of neurodegenerative diseases and antagonists may reduce dyskinesias - Amantadine (NMDA receptor antagonist/weak DA agonist) used for treatment of tremor, rigidity + bradykinesia in PD
What was Amantidine originally developed as?
Anti-viral
How do adenosine antagonists used in the treatment of Parkinsonism?
May interact with glutamatergic transmission with possible neuro-protectant role
Adenosine2A antagonists (e.g. Caffeine (A1/A2 antagonist)) decrease receptor sensitivity
What is Wilson’s disease?
Genetic condition causing hepatolenticular degeneration caused by copper accumulation in lentiform nucleus of striatum causing choreoathetotic symptoms, dementia + liver cirrhosis
What are the 3 forms of Wilson’s disease?
- Dystonic
- Pseudoparkinsonism
- Cerebellar (pseudosclerotir)
What treatment is there for Wilson’s disease?
Reduce levels of copper using copper chelators (e.g. Penicillamine or Trietine) or zinc which blocks copper absorption in the gut preventing further build-up
What is essential tremor?
A familial progressive disorder characterized by intention tremor (rhythmic), not present at rest
Essential tremor generally first appears bilaterally in arms, spreading to other regions of body, particularly head (titubation - more common in women), neck, jaw + voice
What is the treatment for essential tremor?
- B-blocker e.g. propranolol
- Antiepileptic e.g. primidone (barbiturate)
- Botulinumn toxin type A (botox) for head + voice
- 1-2 units of alcohol
What is Huntington’s disease (HD)?
Inherited/genetic neurodegenerative disorder that is autosomal dominant characterized by degeneration of GABAergic cells in the striatum (caudate nucleus + putamen), particularly caudate nucleus + cholinergic dysfunction causing choreiform movements, clumsy/unsteady gait, difficulty with speech/swallowing + cognitive changes
What are the treatments for Huntington’s Disease (HD)?
- DA depleting drugs e.g. Tetrabenazine: reduce involuntary movement
- Antipsychotics e.g. risperidone, quetiapine + haloperidol: reduce chorea/tics + help control delusions, hallucinations + violent outbursts
- BZDs e.g. clonazepam + diazepam: general relaxants
- SSRIs/TCAs: treat depression/mood disorder
Why is Tetrabenazine a better drug than Reserpine?
Both antipsychotics but Tetrabenazine has the advantage of little peripheral effect
How does Tetrabenazine work?
DA-depleting drug: block Vesicular Monoamine Transport (VMAT2) preventing transport of DA into vesicles therefore less is released into synaptic cleft
Depletes 5-HT/NA too
How do you treat tics?
- Patient education
- 2nd generation antipsychotics
- 1st generation antipsychotics
How do you treat dystonia?
- Botulinum toxic (A) injections every 3 months
- Anticholinergics e.g. Trihexyphenidyl + Procyclidine
- Baclofen e.g. GABA agonist
- Diazepam e.g. BDZ GABA co-agonist
- Physiotherapy
- Deep brain stimulation
- Denervation
How do you treat chorea and athetosis?
- Dopaminergic antagonists - 2nd generation antipsychotics (limited use due to side movement side effects)
- DA-depleting drugs e.g. Tetrabenazine
- GABAergic drugs e.g. AEDs, Gabapentin + BZDs
- Steroids for post-surgical chorea
How do you treat ballismus?
Same as chorea but also IV Diazepam + oral Haloperidol
What is Syndenham’s chorea?
An infection that affects the striatum causing choreiform movements generally affecting limbs, face + trunk but self resolving
How can the tremor aspect of Parkinson’s Disease (PD) be treated?
Pallidotomy or DBS targeting the GP as damage to this area is associated with the onset of tremors
What are the different types of dopamine (DA) agonists for hypokinetic disorders?
Synthetic e.g. pramipexole + ropinirole
Natural: L-dopa
Plus:
- Carbidopa (blocks dopa-decarb)
- Entacapone (blocks COMT)
- Rasagiline (block MAOI-B)
What are the general treatments for hypokinetic disorders?
- DA agonists
2. Anticholinergics (e.g. Orphenadrine, Procyclidine)
What are the general treatments for hyperkinetic disorders?
DA antagonist
Antipsychotics (e.g. Risperidone, Quetiapine)
DA-depleting drugs (e.g. Tetrabenazine)
