Week 1- Pharmacology of basal ganglia disorders Flashcards
1
Q
What is a movement disorder?
What is it characterised by?
A
- A movement disorder is a disorder caused by neuronal damage to circuits that modify motor output- the extrapyramidal tracts
- Characterised by uncontrollable movement: 1) hyperkinetic (too much) 2) hypokinetic (too little).
- Characterised by changes in muscle tone 1) hypertonia 2) hypotonia
2
Q
List the hyperkinetic disorders
A
CHEW Dont Hack:
Chorea
Hemiballism
Essential tremor
Wilson’s disease (dystonic)
Dystonia
Huntington’s disease
3
Q
List the hypokinetic disorders
A
WE Push My Pram
Wilson’s disease
Essential tremor
Progressive supranuclear palsy
Multiple systems atrophy
Parkinson’s disease
4
Q
How do we classify movement disorders?
A
- Movement disorders classified according to 1) rhythm 2) speed 3) control
- Rythmic - tremor
- Non rhythmic further broken down into rapid/ slow/ sustained
- Slow non rhythmic - athetosis
- Sustained non rhythmic - dystonia
- Rapid further broken down into supressible or non supressible
- Supressible = tic
- non supressible = hemiballismus, chorea or myoclonus
5
Q
Define:
Tremor
Dystonia
Athetosis
Chorea
Ballismus
Tic
A
- Tremor = shaking movements
- Dystonia - sustained twisting and repetitive movements or abnormal posture
- Athetosis- writhing movements
- Chorea- twitching or jerking of a group of muscle
- Ballismum- large, flinging limb movements
- Tics- small involuntary movements
6
Q
What are the regions involved in parkinsons, huntingtons and hemiballismus?
What brain area is associated with tremor?
A
- Parkinson’s disease = loss of dopaminergic neurones in the substantia nigra leading to loss of activation of direct pathway (movement) and loss of inhibition of the indirect pathway (which prevents movement).
- Huntington’s disease= loss of GABAergic transmission in the striatum, caudate nucleus degenerates first then the putamen. Loss of inhibition of the GPe which now inhibits the subthalamic nuclei from activating inhibition of the thalamus by GPi/SNPR.
- Hemiballismus= loss of subthalamic stimulation of GPi/SNPR which inhibits the thalamus- therefore excessive flinging movements.
- The Globus Pallidus = focal centre for tremor, has intrinsic rhythmic activity.
7
Q
List the three categories of parkinsonism and what conditions are included
A
- Pure parkinsonism:
- Symptoms purely due to degeneration of the substantia nigra
- Idiopathic- pure parkinson’s disease
- Iatrogenic- due to treatment of hyperkinetic disorders with antidopaminergic drugs, induces parkinsonism
- Post- encephalitic
- Parkinsonism with extras:
- Parkinsonism due to degeneration of the substantia nigra and other brain regions- often autonomic or cerebellum
- Progressive supranuclear palsy- degeneration of the SN and midbrain regions, especially nuclei involved in vision- get visual disturbance, speech and thought disturbance, mood/ behaviour as well as disordered movement
- Multiple systems atrophy- classified as MSA- A (autonmic region degenerate), MSA-C (cerebellum) and MSA-P (extrapyramidal tracts degenerate).
- Pseudoparkinsonism:
- Parkinsonism like symptoms but no degeneration of the substantia nigra
- Essential tremor
- Wilson’s disease
- Trauma and vascular related
8
Q
What are the symptoms of parkinson’s disease?
A
TRAP
- Tremor
- Rigidity
- Akinesia- actually HYPOkinesia
- Postural instability
MASk Man
- Mask like face
- Aprosodia - monotonous voice, unable to shoe emotional tone
- Sleep disturbance
- Micrographia
9
Q
What causes Parkinson’s disease?
A
- Loss of 80-90% of the dopaminergic neurones in the substantia nigra
- By the time a patient presents with symptoms already lost 60% of the neurones w/in Substantia nigra, treatment is focussed on maintaining the patient/s QOL for as long as possible.
- Also associated with the formation of LEWY bodies and increased/abnormal levels of synuclein (major consitituent of lewy bodies) and parkin proteins (parkin involved in protein breakdown.
10
Q
What are the 4 dopaminergic pathways that exist in the brain?
A
- Nigrostriatal pathway= from the substantia nigra to the striatum
- Tuberohypophyseal pathway = from the hypothalamus to the pituitary, where DA neurones inhibit the release of prolactin from the anterior pituitary
- Mesolimbic pathway- from the ventral tegmental area to the limbic system
- Mesocortical pathway- from the ventral tegmental area to the prefrontal cortex. Involved in memory/emotion/thoughts/higher cognitive functioning- therefore antidopaminergic treatment can have psychotic effects on this p/w.
11
Q
Discuss the treatment strategy for parkinsonism and the rationale behind it
A
- Pharmacological treatment of parkinsonism is not commenced until symptoms severly affect their quality of life
- Treatment gradually titrated against symptoms
- This is due to the fact that once the higher doses of pharmacological treatment have been reached, nothing further can be done
- Also due to unwanted side effects that can occur- therefore treatment left until as late as possible
- Combined with a multidisciplinary approach- occupational therapist, speech therapist, dietary assessment.
12
Q
What is the main treatment for parkinsonism?
A
- Dopamine has degenerated- need to replace dopamine levels within the CNS
- Problem: dopamine does not cross BBB of its own accord
- Use precursor- L-Dopa/Levadopa, will cross BBB barrier, get into CNS and breakdown into dopamine to aid movement
- Once max dose reached no more movement can occur after that point therefore leave until as late as possible
13
Q
What is the problem with just administering L-Dopa/Levadopa in parkinsonism treatment?
A
- Second problem occurs with L-Dopa/Levadopa in that it is broken down quickly in the periphery by the enzyme L-Dopa Decarboxylase
- Therefore need to use L-Dopa Decarboxylase inhibitors in conjunction w L-Dopa:
-
Ben sir had to hide the carbs and dope:
- Benserazide
- Carbidopa
- Often comes in combination with L-Dopa to lessen the no of pills patients have to take and increase compliance:
- Co-careldopa
- Co-beneldopa
14
Q
What is a further problem that can occur with L-Dopa/Levadopa even if given in conjunction with a Dopa-decarboxylase inhibitor?
A
- Further problem is that L-Dopa is still broken down by two routes in the CNS (as well as in the periphery).
- Broken down by:
- COMT: catechol-O-methyl transferase
- MAO: Monoamine oxidase (which itself comes in two forms A and B, MAO-A involved in treatment of depression, inhibit the breakdown of monoamines DA/NA/5-HT)
- MAO-B form involved in parkinsonism, prevent the breakdown of DA.
-
COMT-Inhibitors: “MT- motorway- EnterCarpone, pass the TOLpone”
- ENTACAPONE
- TOLCAPONE (specialist)
-
MAOB-I: “Ma! O Blimey! See the leg lean and the RA Sag and lean!”
- SELEGILINE
- RASAGILINE
15
Q
What is another class of drugs used to treat parkinsonism?
A
- Dopamine Receptor Agonists- Primarily D2 receptors
- Particularly useful for younger patients and for the initial treatment of parkinsonism where you’re trying to delay treatment with L-Dopa for as long as possible.
- L-Dopa can be added at a later stage
- Fewer motor complications initially but less improvement overall
- Can be psychiatric side effects due to action in the mesolimbic and mesocortical pathways.
- Examples:
- Pramipexole - 1st line (parkinson’s receptor agonist, movement is pretty excellent. good for the sole”.
- Ropinirole
- Rotigotine
16
Q
What are the side effects of dopamine based treatment?
A
- Nausea/ Vomiting/ Anorexia
- Drowsiness/ Sudden Onset Sleep
- Hypomania/ Psychosis
- Hypotension
- Arrythmias/ Tachycardia
- On - Off effects (as you reach maximal doses of L-Dopa there is nowhere else to go, start to see periods where treatment fails).
17
Q
What treatments are useful for combating the On-Off effects seen in parkinsonism treatment?
A
- In a significant number of patients (50-90% of patients after 2 years of L-Dopa treatment) as they begin to reach maximal doses, begin to see on off effects.
- Severe fluctation in motor ability despite having taken treatment.
-
Apomorphine –> used to bridge the gap, thought to stimulate D2 receptors:
- but can cause severe nausea and vomiting.
- always administer prophylactic Domperidone before apomorphine.
- Duo-Dopa: intestinal gel form of levodopa/ carbidopa for continual administering of drug. V. useful for patients with severe on/off effects.
18
Q
What other treatment targets are there for parkinsonism (other than dopaminergics, Dopa- decarboxylase inhibitors, MAOB-I’s, COMT-I’s, duodopa, apomorphine) (not dopamine pathway).
A
- Anticholinergic treatments are also useful in parkinsonism treatment- for IATROGENIC Parkinsonism
- Psychosis often thought to be due to too much DA, treated with antidopaminergics but can induce drug-induced parkinsonism.
- Anticholinergics have only a mild effect on idiopathic (true) parkinson’s disease, and may reduce the absorption of L-Dopa.
- Thought that depletion of DA leads to an increase in ACh.
- Treated with anticholinergics: (mAch R)
- “The orphan adrian was looked after by his Auntie Chloe, his best friend Dean, loves cycling. His other friend Sphen loves triathalons and hexathalons he thinks they’re ideal”
- Orphenadrine
- Procyclidine
- Trihexphenidyl
19
Q
What are two other targets for the treatment of parkinsonism?
(excluding standard dopaminergic pathway drugs and anticholingergic drugs).
A
-
Glutamate antagonists:
- Inhibit NMDA glutamate receptor, and are weak DA receptor agonists
- Glutamate transmission linked to no. of neurodegenerative diseases, antagonism reduces dyskinesia
- Amantidine used in parkinsons treatment - treat tremor/rigidity/bradykinesia
-
Adenosine Antagonists:
- may interact with glutamatergic transmission
- adenosine antagonists decrease receptor sensitivity of adenosine A2A Receptor
- Adenosine may have a neuroprotective role
20
Q
What are the hyperkinetic disorders?
A
- Hunting Dogs get WET, TICS And Cant catch BALLs.
- Huntington’s disease
- Dystonia
- Wilson’s disease
- Essential Tremor
- Tics
- Athetosis
- Chorea
- Ballismus
21
Q
What is Wilson’s disease?
How can we treat it?
A
- Wilson’s disease is caused by an excessive accumulation of copper in the body due to defective excretion.
- Three forms: 1) dystonic 2) pesudoparkinsonism 3) Cerebellar (pseudosclerotic).
- Leads to degeneration of both the liver and lentiform nucleus (hepatolenticular degeneration).
- Causes copper ring around the iris- shown as classic kayser- fleischer ring
- Treated with copper chelators and zinc:
- Copper chelators increase excretion of copper, but needs to monitored as it can over-excrete, kept at maintenance dose after initial excretion
- Zinc reduces copper absorption by the gut and has fewer side effects that other treatments.
22
Q
What is Essential tremor?
How may it present?
What are the treatments?
A
- Essential tremor = familial progressive disorder
- Characterised by intention tremor
- Rythmic tremor (4-12 hz)
- Tends to present first bilaterally in the arms before moving on to other body regions such as the head/ neck/ jaw/ voice
- Treated by:
- Beta blockers- Propanolol to reduce symptoms
- Antiepileptics - Primidone
- Botunlinum Toxin Type A/BOTOX: used to paralyse focal muscle spasms (but can develop later spasm as new nerve routes attempt to grow and innervate muscle)
- 1-2 units of alcohol - acts on the cerebellum to reduce the tremor.
23
Q
What is Huntington’s disease?
How can we treat it?
A
- Huntington’s disease is an autosomal dominant inherited neurodegenerative disorder
- characterised by abnormal movement such as chorea and gait disturbance
- cognitive slowing
- psychiatric symptoms- depression/apathy/social disinhibition
- Hyperkinetic disorder- therefore there is too much Dopamine in the system
Treatment:
- Dopamine depleting drugs - Tetrabenazine - BLOCKS VMAT preventing uptake of DA into vesicles.
- Antipsychotics: dopamine receptor antagonists: risperidone, and haloperidol
- Benzodiazepines: Clonazepam, diazepam- general relaxants
- Depression and mood disorders treated with antidepressants (SSRI’S/ TCA’s).
24
Q
What is the mechanism of action of tetrabenazine?
A
- Tetrabenazine is a dopamine- depleting drug
- inhibits the enzyme VMAT (vesicular monoamine transporter) from recycling the monoamines (DA, 5-HT, NA) into vesicles prior to release.
- By inhibiting this there is less for release at the synaptic cleft
- Doesnt just act on DA but 5HT and NA too
- Similar to resperpine that can cause depression by decreasing 5HT and NA levels.
25
Q
What is dystonia?
How do we treat it pharmacologically?
How do we treat it non-pharmacologically?
A
- Dystonia = sustained muscular contraction/spasms resulting in repeated twisting movements or abnormal posture
- Two groups 1) primary/ genetic 2) acquired
- Pharmacological treatment is focussed on muscle relaxation:
- Botulinum toxin A injections - 3 monthly
- Anticholinergics: Procyclidine and trihexphenidyl
- GABA agonist- Baclofen - antispasm medication
- GABA Coagonist- Diazepam - muscle relaxant
- Non pharm:
- physio
- deep brain stimulation
- denervation (avoid).
26
Q
What is chorea?
What is primary and secondary?
What are the treatments?
A
- Chorea describes involuntary, irregular, random, flowing, dance like movements that flit from one body part to another.
- Can be primary/genetic - i.e hungtingtons
- or secondary/acquired - i.e drugs and toxin induced
Treatment:
1) Dopamine antagonists- 2nd generation antipsychotics
inhibit both 5HT and DA, limited by side effects, dyskinesia and parkinsonism
2) Dopamine depleting drugs - 4 bens ave zine DAn Do Drugs
Tetrabenazine
3) GABAergic drugs- antiepileptics/ gabapentin/benzodiazepines
4) Post surgical chorea may respond to steroids
27
Q
What is athetosis?
A
- Slow, irregulat sinuous writhing movements often of the fingers
- if it occurs with chorea it is called choreoathetosis
- treatment is the same for chorea:
- 1) antidopaminergics- 2nd generation antipsychotics
- 2) dopamine depleting drugs - tetrabenazine
- 3) GABAergic drugs- antiepileptics/gabapentin/benzodiazepine
- 4) for surgical, choreoathetosis -steroids
28
Q
What is ballismus?
A
- Ballismus= large, violent, proximal, flinging movements of the limbs ( can be unilateral- hemiballismus)
- Caused be neurogenerations of the subthalamic nuclei
- Treatment is the same as for chorea: 1) dopamine antagonists- 2ns generation antipsychotics 2) dopamine depleting tetrabenazine 3) GABAergic drugs 4) steroids post surgical
- Intravenous diazepam and oral haloperidol (1st generation antipsychotic).
