Pharmacology of the Basal Ganglia disorders Flashcards
What is dystonia?
Lasting muscle spasms; repeated twisting movements or altered posture.
Occurs in Parkinson’s
If a patient has writhing movements, what is it called?
Athetosis
Occurs in Huntington’s
If a patient has twitching or jerking of a group of muscles, what do they have?
Chorea
Occurs in Huntington’s
And too much Levodopa - e.g. Parkinson’s patient on too high a dose
What is Ballismus?
Large, flinging, limb movements (Hemiballismus - unilateral)
Caused by any damage to subthalamic nuclei
What regions of the brain are involved in Parkinson’s, Huntington’s and Hemiballismus?
Parkinson’s - Substantia nigra (loss of dopamine)
Huntington’s - Striatum (Caudate and Putamen - loss of GABA cells and ACh)
Hemiballismus - Subthalamic nuclei
What is Wilson’s disease?
Pseudoparkinsonism - due to toxic copper buildup.
What type of parkinsonism is Progressive Supranuclear Palsy disease?
Parkinsonism with extras
Name the 4 main DOPAMINE pathways
Nigrostriatal/Mesostriatal (SN to Striatum)
Mesolimbic (ventral tegmental area in the midbrain, to the ventral striatum of the basal ganglia)
Mesocortical (connects the ventral tegmentum to the prefrontal cortex)
Tubero-hypophyseal (hypothalamus to pituitary gland - dopamine antagonist means more prolactin produced)
What are the three main groups that Parkinsonism can be divided into and name some examples of each?
Pure Parkinsonism:
Idiopathic – Parkinson’s disease
Iatrogenic
Post-encephalitic
Parkinsonism with extras:
Multiple systems atrophy (3-types: MSA-A*, -P, -C)
Progressive supranuclear palsy
Pseudoparkinsonism:
Wilson’s disease
Essential Tremor
Trauma and vascular-related
What are the four cardinal features of parkinsons (TRAP)?
Tremor (resting)
Rigidity (lead pipe, cogwheel)
Akinesia (bradykinesia)
Postural instability
What are the three main pharmacological treatments for Parkinsonism?
Levodopa Dopamine agonists (if motor not affection QOL) MAOB inhibitor (if motor not affection QOL)
Why can you not use dopamine for treatment of parkinsonism?
Dopamine does not cross the blood brain barrier. Therefore you use the precursor (Levadopa)
What is the name of the enzyme which converts L-Dopa to Dopamine?
Dopa-decarboxylase
What do you have to give a patient with parkinsonism, along with Levadopa?
DDIs (Dopa-decarboxylase inhibitors):
Carbidopa
Benserazide
Combined with L-Dopa:
Co-careldopa
Co-beneldopa
How will giving a dopmaine antagonist to a patient, affect lactation?
One of the main regulators of the production of prolactin from the pituitary gland is the hormone called dopamine, which is produced by the hypothalamus. Dopamine restrains prolactin production, so the more dopamine there is, the less prolactin is released. Therefore, a dopamine antagonist will increase the levels of prolactic and so activate lactation.
What can you give to prevent breakdown of Dopamine?
Monoamineoxidase inhibitors (MAOB)
Use alone in early stage or as adjuvant with L-dopa:
Selegiline
Rasagiline
Catechol-O-methyltransferase (COMT) inhibitors
At later stages if L-Dopa and MAOB insufficient can include as an adjunct:Entacapone
Tolcapone
Name some dopamine synthetic agonists.
Pramipexole - most important!
Ropinirole
Rotigotine
Which dopamine pathways cause psychiatric effects?
Mesolimibic (emotions, memory, learning) and Mesocorticol (pre-frontal cortex - decision making)
What can be advantages and disadvantages of dopamine agonists?
Can be useful in younger patients and initial treatment of PD
Fewer motor complications long-term, but less improvement overall. More psychiatric side-effects.
What are some side effects associated with dopamine based treatments?
Nausea, vomiting, sudden onset of sleep and 'on-off' effects Anorexia Drowsiness Hypomania Psychosis Hypotension Tachycardia Arrythmias
What are apomorphine and domperidone used for and how is domperidone administered?
Are used to treat on-off side effects of dopamine treatment. They are used to ‘fill in the gaps’ and domperidone is always administered prophylactically (to prevent) before apomorphine use
What is Duodopa used for?
An implanted gel form of L-dopa and carbidopa (DDI) (basically co-careldopa), useful for severe on-off effects. It’s implanted and basically releases itself.
What are anticholinergics and how do they work?
Useful for iatrogenic (drug-induced) Parkinsonism
Decrease in dopamine leads to an increase in acetylcholine concentration*
Only have mild anti-Parkinsonism effects (tremor) and may reduce absorption of Levodopa
Name the three anticholinergics used to treat parkinsonism.
Procyclidine
Trihexphenidyl (Benhexol, Broflex)
Orphenadrine
How do anticholinergics work?
The striatum contains cholinergic cells that modulate activity in the GABAergic cells projecting to the globus pallidus
They basically do the opposite of dopamine, reducing activity in the direct pathway, increasing it in the indirect pathway
What is Amantadine used for?
Amantadine can be used as an adjunct in Parkinsonism for treatment of dyskinesias. It is a glutamate antagonist. Acts as a glutamate (NMDA) receptor antagonist and is a weak DA agonist
Name some adenosine antagonists
Caffeine
What type of genetic disorder in Huntington’s?
Autosomal dominant
Degeneration of GABAergic cells in the striatum, particularly the caudate nucleus
Cholinergic dysfunction
What are the four main treatments for Huntington’s?
Dopamine depleting drugs: Tetrabenazine* – reduces involuntary movement
Antipsychotics: risperidone, quetiapine and haloperidol, reduce chorea and tics; help control delusions, hallucinations and violent outbursts.
Benzodiazepines: clonazepam and diazepam, general relaxants
Depression and Mood disorders associated with HD are treated with antidepressants (SSRIs/TCAs).
What is the MoA of Tetrabenazine?
Dopamine depleting drug:
Block VMAT2 (vesicular monoamine transporter), prevents transport of dopamine into vesicles, therefore less released into synaptic cleft
Affects all monoamines, not just dopamine!
Similar to Reserpine which causes depression by decreasing 5HT and NA levels
What can be described as involuntary, irregular, random and dance-like, flowing movements which flit from one part of the body to another?
Chorea
What are the treatments for Chorea (and Athetosis and Ballismus)?
2nd Generation antipsychotics. (Risperidone and Clozapine) Use is limited by side-effects, e.g. tardive dyskinesia and Parkinsonism.
Dopamine-depleting drugs - tetrabenazine
GABAergic drugs, e.g. anti-epileptics, gabapentin and benzodiazepines
Post-surgical Chorea may to respond to steroids
Name the 1st, 2nd and 3rd generation of antipsychotics.
1st Generation - Dopamine (DA) antagonists
Haloperidol
Chlorpromazine
2nd Generation - Serotonin (5HT) and DA antagonists
Risperidone
Clozapine
3rd Generation - Partial agonist at 5HT and DA
Aripiprazole
What causes Ballismus?
Caused by neurodegeneration of subthalamic nuclei
How is Ballismus treated?
Treated as for Chorea
Intravenous diazepam and oral haloperidol.
Which diseases are tics most commonly associated with?
Tourettes, Wilson’s disease and Huntington’s
How can tics be treated?
Patient education
2nd generation antipsychotics
1st generation antipsychotics
How can you treat dystonia?
Botulinum toxin injections (Botox) and diazepam
What is Wilson’s disease and what is it caused by?
Wilson’s disease is a genetic disorder in which excess copper builds up in the body. Hepatolenticular Degeneration caused by copper accumulation
What are the three forms of Wilson’s disease?
Dystonic Pseudoparkinsonism Cerebellar (pseudosclerotic)
How do you treat wilson’s disease?
Reduce levels of copped using copper chelators or zinc
What is essential tremor?
A familial progressive disorder characterized by intention tremor, not present at rest
Rhythmic tremor 4-12Hz frequency
Essential tremor generally first appears in the arms, spreading to other regions of the body, particularly the head, neck, jaw and voice.
Head tremor (titubation) is more common in women
What is the treatment of essential tremor?
β-Blocker – Propanolol
Antiepileptic (AED) – Primidone (Barbiturate)
Botulinumn toxin type A (botox)* – head and voice
1-2 units of alcohol
