Parkinson's Disease Treatment

Question 1

What is the order of drugs to try in PD?

Answer 1

1) Muscarinic antagonist (if just have bit of tremor)
2) MAO-B inhibitor - works on remaining endogenous dopamine, 2-3 years more of good movement
3) Dopamine agonist
4) Levodopa
5) If bad dyskinesia maybe amantadine

Question 2

What drug would you prescribe a PD patient who is v old and may not have long left?

Answer 2

Levodopa - takes time to develop side effects and best drug available

Question 3

What are the two aims of PD drug treatments to restore dopamine/ACh imbalance?

Answer 3

1) Reduce cholinergic transmission

2) Boost dopaminergic transmission

Question 4

What drugs are used to reduce the increased cholinergic transmission?

Answer 4

Muscarinic antagonists e.g. benzhexol, benztropine

Question 5

What symptom do muscarinic antagonists treat?

Answer 5

Tremor (minimal effect against bradykinesia and rigidity)

Question 6

How does loss of dopamine lead to increased ACh and tremor?

Answer 6

1) Loss of dopamine disinhibits striatal cholinergic interneurons
2) Increase in striatal ACh levels due to lack of D2 receptor activation
3) Activation of Gq-coupled muscarinic ACh receptors in striatum
4) This further increases overactivity of the indirect pathway
5) Contributes to symptoms of tremor

Question 7

What are the side effects of muscarinic antagonists due to blocking muscarinic receptors elsewhere?

Answer 7

1) Central - confusion and mood changes due to less septohippocampal firing from blocked muscarinic receptors in hippocampus
2) Peripheral e.g. constipation, blurred vision, dry mouth

Question 8

What non-motor symptom might muscarinic antagonists be good at treating as a result of a side effect?

Answer 8

The side effect of dry mouth may be useful if sialorrhoea (drooling or excessive salvation) is a problem

Question 9

What is levodopa (L-DOPA)?

Answer 9

• L-3,4-dihydroxyphenylalanine
• Natural dopamine precursor which unlike dopamine can cross the BBB
• It is converted to dopamine by dopa decarboxylase (DCC) in the brain inside monoaminergic neurones (DA and 5-HT neurons)
• V effective

Question 10

For what two reasons may levodopa have to be administered with other drugs and which drugs are they?

Answer 10

1) ~90% of levodopa is converted by DCC in the intestinal wall which prevents it getting into the brain and peripheral dopamine causes nausea and vomiting - so co-administered with carbidopa/benserazide (peripherally acting DCC inhibitors) and domperidone (peripheral DA receptor antagonist) which can’t cross the BBB
2) ~5% of levodopa is metabolised by plasma catechol O-methyl transferase so if really need to all levodopa in brain, can co-administer entacapone (COMT inhibitor) to ensure the majority of levodopa enters the brain unchanged

Question 11

What are the therapeutic effects of levodopa?

Answer 11

• Levodopa with carbidopa/benserazide raises striatal dopamine levels
• Activity is normalised in direct (D1) and indirect (D2) pathways, normalising firing patterns of circuitry in the basal ganglia
• Improves rigidity, bradykinesia, facial expression, speech and handwriting
• Levodopa can improve cognition in early stages and insomnia if related to pain due to akinesia

Question 12

What are the acute side effects if levodopa?

Answer 12

1) Nausea due to remaining peripheral dopamine receptor activation (but helped by co-administering the other drugs)
2) Postural hypotension esp. in patients on anti-hypertensive drugs
3) Psychological - hallucinations, confusion, insomnia, nightmares, psychosis (too much dopamine, more like schizophrenia)

Question 13

What are the two chronic side effects of chronic levodopa that ⅓ patients develop within 3 years of starting levodopa?

Answer 13

1) Motor fluctuations

2) Levodopa-induced dyskinesia (LID) - dyskinesia = excess/too much movement

Question 14

Describe motor fluctuations as a chronic side effect of levodopa

Answer 14

• ‘On-off effect and wearing off
• Rapid fluctuations in clinical state - freezing may last minutes or hours
• Related to plasma fluctuations in levodopa
• Related to limited storage of dopamine as generation progresses - due to fewer dopamine nerves

Question 15

Describe dyskinesia as a chronic side effect of levodopa

Answer 15

• Excess, hyperkinetic involuntary movements
• Very disabling
• Can be v painful
• Face and limbs mostly affected but trunk and neck susceptible too

Question 16

What causes dyskinesia in levodopa treatment?

Answer 16

• Thalamocortical feedback is increased above normal (underactive in PD)
• Mechanism uncertain but plasticity across corticostriatal synapse involved

Question 17

What movements occur in dyskinesia?

Answer 17

1) Choreic (dancing)
2) Dystonic - people get stuck in twisted postures that are very painful
3) Ballistic (shooting ballisms) -repetitive, but constantly varying, large amplitude involuntary movements of the proximal parts of the limbs

Question 18

What is the only drug that can provide relief from dyskinesia?

Answer 18

Amantadine

• NMDA-type glutamte receptor blocker/antagonist
• So maybe also increasing firing/activity of NMDA glutamate receptors has something to do with dyskinesia
• Doesn’t really have a role to play in releasing dopamine

Question 19

What is the problem with taking levodopa?

Answer 19

• It doesn’t work for a very long time (3-4 hours)
• Therefore have to take another tablet after 3-4 hours so usually people start with ~3 tablets a day which then increases to 5-6 times a day
• This high amount of medication and taking it several times a day leads to development of dyskinesia

Question 20

Describe how pulsatile treatment and intermittent dosing of levodopa causes motor fluctuations and dyskinesia

Answer 20

1) If don’t take levodopa for a while you are v stiff and slow
2) Then when you take the medication after ½-1 hour, due to the high amount of levodopa coming into the neuron which is converted to dopamine and released into the synaptic cleft, this causes excess stimulation of the post-synaptic cleft and dyskinesia
3) After about 3-4 hours levodopa stops working so then you go into a stiff, rigid and slow ‘off state’
4) Then you get another dose and the same process repeats

Question 21

When does motor fluctuation and dyskinesia start happening?

Answer 21

After a few years of levodopa treatment

Question 22

How does the degenerative nature of PD cause dyskinesia and motor fluctuations to develop with levodopa?

Answer 22

1) In early PD, there are still enough striatal neurones and residual dopamine terminals to store the dopamine converted from levodopa and release it when needed to control fluctuations in plasma levodopa concentration
2) This allows relatively continuous and physiological release of dopamine and stimulation of dopamine receptors
3) However as PD progresses and short-acting levodopa are administered intermittently, intrasynaptic dopamine levels begin to vary
4) The large shifts in levodopa lead to large variation in dopamine levels and activity
5) When levodopa is taken up into degenerating neurons the release of dopamine is accelerated
6) As the number of surviving dopaminergic terminals decreases, regulatory mechanisms are lost and dopamine levels fluctuate wildly

Question 23

What is the effect of increasing frequency of dosing of levodopa to minimise the wearing off that develops between doses?

Answer 23

It is successful to some extent at first, but does not address the pulsatile delivery of levodopa, and large fluctuations in plasma drug levels remain

Question 24

How does pulsatile activation of dopamine receptors lead to chronic motor complications?

Answer 24

1) Multiple daily dosing with dopaminergic therapy (levodopa or short acting dopamine agonists) is directly translated into fluctuations in striatal dopamine levels
2) This pulsatile activation of dopamine receptors results in marked oscillations in synaptic and striatal dopamine levels and further destabilises the dopamine-depleted dysfunctional basal ganglia network
3) Therefore intermittent dosing with dopaminergic therapy and pulsatile activation of dopamine receptors results in long term motor side effects

Question 25

Describe the link between dyskinesia and disease duration

Answer 25

- Even if someone is started on levodopa later than someone else they will generally develop dyskinesia at the same time so it is more to do with the neurodegeneration/disease - As PD progresses, dyskinesia threshold decreases so becomes easier to induce dyskinesia even with the same dose of levodopa given before - So as dyskinesia is linked to disease duration there is not much point delaying treatment to avoid dyskinesia - Medication also lasts a shorter time

Question 26

What happens in moderate PD with levodopa treatment?

Answer 26

- The duration of response to levodopa and clinical benefit diminishes and begins to more closely reflect its short half life (~1.5 hours) - Symptom control becomes increasingly governed by fluctuations in plasma levodopa levels - Increased incidence of dyskinesias due to lower threshold

Question 27

What happens in advanced PD with levodopa treatment?

Answer 27

- The short duration response to levodopa predominates - The therapeutic window narrows, and adequate control of symptoms becomes increasingly difficult - Clinical response mirrors levodopa plasma pharmacokinetic profile - Initially this is manifested by an end-of-dose deterioration, where PD symptoms return before the next scheduled medication dose - Patients are often either 'off' or 'on' with dyskinesia and other complications - 'On' time associated with dyskinesias

Question 28

Describe the response to levodopa in early PD

Answer 28

- Response to levodopa is excellent - smooth long duration of clinical benefit - At this stage, the anti-parkinsonian benefits are associated with a low incidence of dyskinesia - Need to give a certain amount of levodopa to turn the patient 'on' to address symptoms so that the stiffness and slowness is gone - V difficult to overdose bc the threshold for developing dyskinesia is high

Question 29

What are the two key factors that interact to lead to the development of motor complications?

Answer 29

1) Pulsatile stimulation usually with levodopa | 2) Progressive degeneration of PD, lowering the threshold for dyskinesia

Question 30

How do dopamine receptor agonists work?

Answer 30

- Produce effects mainly through the activation of striatal D2 receptors (D2 receptor agonists) - Therefore they are largely working to correct the abnormal excessive firing of the indirect pathway (not affected by progressive neurodegeneration)

Question 31

What are the side effects of dopamine agonists?

Answer 31

1) Acute side effects same as levodopa - nausea, vomiting, hypotension 2) Chronic side effects - lessened, long half life (8-10h or even 24h) so less plasma fluctuations, less 'on-off' effect and reduced incidence of dyskinesia bc less potent 3) Possible side effect can be obsessive hobbies e.g. shopping or gambling, so wouldn't prescribe these in someone who already has these problems

Question 32

What are dopamine agonists used?

Answer 32

1) First line in younger patients (bc bad side effects of levodopa) - but less effective than levodopa in relieving symptoms, so levodopa is needed eventually, effective in early disease 2) Used as adjuncts to lower levodopa dose when levodopa required 3) Used also to treat early cognitive problems and restless legs syndrome

Question 33

What are examples of dopamine agonists?

Answer 33

1) Bromocriptine 2) Lysuride 3) Ropinirole 4) Pramipexole 5) Apomorphine (mixed D1 and D2 receptor agonist) - s/c injection 6) Rotigotine (patch)

Question 34

What are 3 alternative routes of drug administration to circumvent dyskinesia?

Answer 34

1) Transdermal rotigotine 2) Subcutaneous apomorphine infusion 3) Intra jejunal/duodenal levodopa infusion (duo-dopa) - These provide less fluctuation and dyskinesia but at some point they will occur bc neurodegenerative process progresses

Question 35

Describe use of transdermal rotigotine

Answer 35

- Effective as monotherapy in early PD - Leave transdermal patch on skin for 24h - Works for 24h, producing/releasing a v stable level of dopamine (agonist) in the bloodstream - This is associated with less dyskinesia (motor complications)

Question 36

Describe use of subcutaneous apomorphine infusion

Answer 36

- Apomorphine fluid is pumped under the skin via a small needle and pump - It is absorbed by the skin - Therefore you get a v steady level of medication, preventing dyskinesias but also addressing motor symptoms

Question 37

Describe use of intra jejunal or duodenal levodopa infusion (duo-dopa)

Answer 37

- Levodopa fluid (same as tablet) is pumped into the intestine through a lead inserted into a small hole made in the abdominal wall - This gives a v steady level bc it continuously pumps a certain amount - Similar to s/c apomorphine but levodopa doesn't have s/c formulation

Question 38

How do MAO-B inhibitors work?

Answer 38

- Monoamine oxidase B (MAO-B) is a principal route of dopamine metabolism in dopamine rich brain regions - MAO-B inhibitors block dopamine metabolism and breakdown, keeping dopamine in the neuron - Works on endogenous dopamine, keeping pt's own dopamine levels for longer - e.g. if have just been diagnosed and starting to show symptoms can boost remaining dopamine (still have e.g. 40% of neurons), keeping it around for longer and making the most out of it - Maybe will push pt back below threshold of symptoms and might get another 2-3 years of good movement without needing to have something that is really pushing the dopamine system

Question 39

How are MAO-B inhibitors used?

Answer 39

- May be used as monotherapy in early PD - Often used as an adjunct to lower levodopa dose required - MAO-B/COMT inhibitors improve motor side effects in the long term, might give if having motor fluctuations or gaps where levodopa isn't working to avoid having to give more levodopa - Would give on top of other medications if motor side effects have started

Question 40

What are side effects of MAO-B inhibitors?

Answer 40

Unlike non-selective MAO inhibitors, these do not inhibit peripheral tyramine metabolism (does not inhibit MAO-A) so NO cheese reaction

Question 41

What are examples of MAO-B inhibitors?

Answer 41

Selegiline, rasagiline

Question 42

What are types of surgical treatments for PD?

Answer 42

1) Neuroablative surgery (otomy) - used as last resort, blast hole (thermolytic lesion) into part of basal ganglia motor loop to restore normal thalamocortical feedback, blast hole in overactive nuclei stop it functioning (irreversible) 2) Deep brain stimulation (DBS) - used when levodopa doesn't work

Question 43

What are the types and risks of neuroablative surgery?

Answer 43

1) Thalamotomy - tremor dominant cases (if tremor worst in DBS aim for thalamus) 2) Pallidotomy - improves rigidity and bradykinesia 3) Subthalamotomy - improves rigidity, bradykinesia and LIDs - Risks = visual impairment (if damage to optic tract), intracerebral haemorrhage, mild speech and cognitive impairment

Question 44

Describe deep brain stimulation (DBS)

Answer 44

- Sends electrical pulses to the brain to interfere with neural activity at the target site - Switches off/normalises firing of motor loop nuclei by depolarising and keeping the membrane potential there and next time impulse comes can't generate AP so electrically silences region - Reversible (take electrode out and move), graded and patient has control over when to switch on and off (stimulation) using pacemaker implanted under skin attached to indwelling electrode - Preferred region is subthalamic nucleus (STN) (or GPi) which becomes overactive in PD so switching it off works well - Imaging used to check they are in right region rather than waiting on patient to say they can do certain movements

Question 45

Why are most non-motor symptoms not improved with dopaminergic treatments?

Answer 45

Bc their underlying basis is nothing to do with the nigrostriatal degeneration, but to degeneration in other brain regions e.g. raphe nuclei, locus coeruleus

Question 46

What are the failings of current PD treatments?

Answer 46

1) Only treat some symptoms e.g. postural balance left untreated, physiotherapy helps to improve balance but atm this is untackled by treatment and no treatment for many non-motor symptoms 2) Side effects - can be very disabling e.g. LID, hyperkinetic involuntary uncontrolled movements 3) Do not address progressive degeneration that occurs in the brain (loss of nigrostriatal neurons) - no cure, doesn't address the disease, can't stop it or make it any better

Question 47

What can be used to monitor disease modifying strategies in clinical trials longitudinally to see if interventions slow down progression?

Answer 47

SPECT images of progressive striatal DaT loss in PD patients

Question 48

What are side effects of amantadine (NMDA antagonist)?

Answer 48

- Nausea - Dizziness - Sleeping problems - Worsens the acute side effects of the other drugs - Lots

Question 49

What should you remember about levodopa and dyskinesia?

Answer 49

Not everyone develops dyskinesia

Question 50

What are the goals of PD therapy?

Answer 50

1) Effective symptom control (no cure) 2) Effective motor fluctuation control (preventing dyskinesia) 3) Continuous control of symptoms throughout day and night - stable levels of medication without the peaks and troughs which sometimes get with levodopa 4) Maintenance of independence and QoL through symptom control

Question 51

What is the role of the physiotherapist in PD?

Answer 51

To address balance issues and falls

Question 52

What is the role of SALT in PD?

Answer 52

To address dysarthria (slow or slurred speech that can be difficult to understand) or v soft voice that can be typical of PD

Question 53

What is the aim of dopamine therapy in PD?

Answer 53

1) To replace dopamine that gets lost in the substantia nigra (in pigmented neurones) 2) Try to mimic the normal action of dopamine - it regulates certain parts of the brain e.g. the striatum which you need to have normal, smooth movement

Question 54

When is treatment initiated and what is the effect of treatment?

Answer 54

- At diagnosis - Instead of following the no symptomatic treatment line of increasingly worse motor symptoms we can improve them a little bit and stabilise them towards the end

Question 55

How do you treat depression in PD?

Answer 55

Bupropion and sertraline

Question 56

How do you treat anxiety in PD?

Answer 56

DBS

Question 57

How do you treat RBD in PD?

Answer 57

Clonazepam (sedative)