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Aim

  • Provide students with the opportunity to observe clinical manifestations of Parkinson’s disease (PD) and the effects of symptomatic treatment with L-DOPA
  • Build on knowledge of the pathophysiology of PD to develop an understanding of the mechanism of action and rationale for current L-DOPA and adjunctive therapy for PD
  • Encourage students to think critically about L-DOPA as a long term treatment strategy for PD

Key concept

  • Pharmacological treatment of PD

L-Dopa and adjunct therapy

  • Problems with L-Dopa
    • L-DOPA is converted to dopamine in the periphery and not in the CNS where it is needed
      • Thus we need high doses
      • Side effects: nausea, vomiting
  • Catechol-O-methyl transferase (COMT) inhibitor
    • COMT breaks down L-DOP A when DDC is inhibited
    • Thus an inhibitor prolongs the plasma half life of l-dopa and prevents motor symptoms of PD
  • Dopa decarboxylase (DDC) inhibitor
    • Inhibits of the break down of L-dopa in the periphery
    • If the administered L-Dopa were to be metabolised by this enzyme in the periphery, you'd get side effects, and no beneficial effects (which occur only with dopamine in the CNS)
  • Monoaminoxidase inhibitor
    • Stops the break down of L-dopa into DOPAC, the inactive form and thus prolongs the effects
    • Crosses the BBB

Characteristics of Parkinson's disease

Basal ganglia in health and disease
  • Parkinson's treatment
    • Non pharmacological e.g. DBS
    • Pharmacological e.g. L-Dopa
    • Supportive e.g. physiotherapy, OT, speech therapy
  • Clinical manifestations
    • Akinesia/bradykinesia
      • Festinating gait (shuffling)
      • Initiation failure (for movement)
      • Rigidity - cogwheel
      • Speech problems
    • Resting tremor - pill-rolling
    • Mask facies
    • Micrographia
    • Stooped posture
    • Non-motor
      • Depression/neuropsychiatric problems
      • Sensory complaints
    • Autonomic dysfunction
    • Cognitive impairment
    • Affective disturbances
    • Sleep disorders
  • Pathology
    • Basal ganglia circuit disruption
    • Substantia nigra pars compacta - dopaminergic neurone death, deposition of alpha-synuclein (Lewy bodies); lack of striatal dopamine, resulting in overactive indirect pathway and underactive direct pathway

Researching L-DOPA and adjunct therapies for the treatment of Parkinson’s Disease

  • Outline the Pharmacological rationale and associated problems with treating PD with L-DOPA therapy alone
    • In the absence of inhibitors L-Dopa administered alone is quickly converted in the periphery to dopamine. As dopamine does not cross the blood brain barrier (BBB) up to 99% of the original L-dopa dose is metabolised with only 1% L-dopa crossing into the CNS for clinical effect.
    • ARx: orthostatic hypotension, euphoria, hallucinations, psychosis, weight loss, insomnia, tiredness, dizziness, syncope
  • What is the Pharmacological rationale for adjunctive therapy with a Catechol-O-methyl transferase (COMT) inhibitor in PD?
    • Catechol O-methyl transferase (COMT) is one of the major enzymes that metabolises L-dopa in the periphery contributing to reduced CNS availability of L-dopa. (NOTE: COMT inhibitors do not generally cross the BBB)
  • What is the Pharmacological rationale for adjunctive therapy with a Dopa decarboxylase (DDC) inhibitor in PD?
    • Dopamine decarboxylase (DDC) is another major enzyme that also metabolises L-dopa in the periphery, again contributing to reduced CNS availability of L-dopa. (NOTE: DDC inhibitors do not generally cross the BBB)
    • E.g. carbidopa. When you administer L-Dopa, give carbidopa with it
  • What is the Pharmacological rationale for adjunctive therapy with a monoamine oxidase (MAO) inhibitor in PD?
    • Monoamine oxidase inhibitors do cross the BBB and therefore can reduce the conversion of dopamine formed form L-dopa into biologically inactive DOPAC and thus prolong the clinical effect of L-dopa
  • Overview of pharmacological treatments for PD and class discussion

PDTreatmentFlowChart.png


Note just by looking at it which drugs should/shouldn't cross the BBB

Parkinson's Disease video

  • Early in the day, patient's movements are slow, feet stick to floor, and he freezes when negotiating doorways
  • With medication, involuntary movements are common
    • Patient himself is barely aware of involuntary movements they're performing
  • Loss of facial expression, overactivity of some facial muscles (e.g. frontalis), shuffling, leaning-forward gate, eyes close involuntarily. Sometimes touching the cheek will allow them to open their eyes
  • Speech becomes weaker/sped up and is lost eventually.
  • Tremor mainly occurs when the limb is supported and when no voluntary action is being performed
  • Writing becomes smaller the longer you write, due to akinesia (the most disabling aspect of the disease)
    • Makes the simplest task very difficult
    • Patients become increasingly dependent on others
  • Eventually every part of the body is affected
  • Involuntary movements = dyskinesia
  • In a few patients, tremor is a major source of disability - embarrassing and in social isolation.
  • PD = commonest disorder of the extrapyramidal cells
  • Neurons of the SN degenerate, meaning a lack of dopamine in basal ganglia. L-Dopa can help.
  • Patients tire easily
  • Some patients have very effective treatment and only withdrawal of L-Dopa can reveal symptoms
  • Patients who have been on L-Dopa for some years exhibit fluctuations (end of dose deterioration).
    • End of dose akinesia: For a couple of hours after each dose of L-Dopa they're fine, but then they deteriorate toward the end of the dose.
    • Early morning akinesia:Another type of fluctuation is early morning akinesia - difficulty getting out of bed (legs won't work)
    • Peak dose dyskinesia: 1-2 hours after each dose they have involuntary movements
  • These are all due to the loss of the brain's ability to store the dopamine
  • Most patients prefer dyskinesias to akinesias
  • Early in the disease, the brain seems to be able to store dopamine, so it can be given intermittently
    • Later on, the intermittent dosing causes massive variation in the functionality of the patient (fluctuations - see above)
  • Long term complication of PD is dementia (treat with cholinesterase inhibitors)
  • Treating PD patient, ask about how they function during the day (they may have timed their fluctuations etc to appear good to the doctor)
    • Anticholinergics and bromopriptine exacerbate hallucinations associated with dementia. You should aim to give the lowest dose of L-dopa possible for the patient to function normally (to reduce the dementia complications)
  • Loss of balance in PD doesn't respond to drug treatment
  • When stimulated appropriately (e.g. good music), some patients who can barely walk are able to dance quite coordinatedly

Parkinson’s Disease quiz

  • 1. What characteristic symptoms of Parkinson’s disease (PD) is associated with facial expression?
    • 1) Loss of facial expression
    • 2) Excessive contraction of facial (frontalis) muscles)
  • 2. What is the most obvious feature of Parkinson’s disease and how is it affected by voluntary use?
    • 1) Tremor, especially of the extremities
    • 2) The tremor subsides once the limb is used
    • Vascular dementia - mainly appears to be gait
  • 3. What is the most disabling aspect of PD?
    • Akinesia (i.e. inability or reduced ability to move)
    • Most disabling as they're unable to do things for themselves
    • When they start to move, it's like running (shuffling)
    • Risks of falling - fractures, subdural/epidural haemorrhages
  • 4. What area of the brain is affected in PD?
    • The substantia nigra pars compacta
  • 5. What is the principle pharmacotherapy (drug) used to treat PD?
    • Levodopa
  • 6. What is the most common form of ‘fluctuation’ in PD?
    • End of dose deterioration
  • 7. Why are PD treatments less effective with time?
    • In the early stage of the disease the brain appears to be able to store dopamine and therefore it is able to draw form this ‘reservoir’. Toward the later stages of the disease this ‘reservoir’ no longer appears to be present and the patient becomes dependent on each dose of levodopa given.
  • 8. Is the gait disturbance and “loss of balance”, in late disease responsive to drug therapy?
    • No
    • Need carers, family support
  • 9. What is dyskinesia in PD?
    • Dyskinesia is the jerky, involuntary movements experienced by patients on long term levodopa therapy
    • Dyskinesia is because administering too much dopamine gives too much facilitation of movement (note that in hemiballismus, the indirect pathway is disinhibited, and this is a similar neurological syndrome to the dyskinesias of PD treatment)
  • 10. Some patients with PD suffer from cognitive dysfunction, especially late in the disease, and their anti-parkinsonian treatments such as anticholinergics, can make these symptoms worse. Why is this?
    • Dementia is likely due to a dopamine deficiency caused by nigral degeneration compounded by the loss of inputs from noradrenergic and cholinergic nuclei (locus coeruleus and nucleus basalis of Meynert, respectively).
    • Normal cognition is dependent, at least in part, on maintaining a balance between the cholinergic and dopaminergic systems in the brain. Creating an imbalance in this system can result in an altered perception of reality.
  • 11. What are some of the common side effects produced with drug treatments for PD?
    • Short term: Nausea, increased dreams, dizziness, hallucinations, compulsive behaviours (stimulation of brain 'reward' system). Treatment with ergot-derived dopamine agonists is associated with heart problems.
    • Long term: dyskinesias
  • 12. What are some of the less common and non-motor symptoms that may occur in PD patients?
    • Gait disturbances, restless legs, cramps, loss of fine motor skills, bowel and bladder problems, fatigue, freezing when initiating and ending movements, depression, disturbed sleep, micrographia (small writing), sensory disturbances,
  • 13. What can PD patients do to better manage their disease
    • Controlled release or slow release L-Dopa
    • Exercise, diet (managing protein intake), adjunct therapy (speech therapy, OT), medical treatments of associated symptoms e.g. use of SSRIs for depression, be an active participant in the medical treatment of their PD with their neurologist or PD nurse
    • Drug has better effect if you reduce the protein
  • Note that current treatment strategies address the symptoms but do not alter the course of the disease

Quiz summary

  • In Parkinson’s disease, there is a loss official expression or an excessive contraction of facial muscles
  • The most obvious feature of PD is the pill-rolling tremor
    • Subsides with voluntary movement
  • Most disabling aspect of PD – akinesia (inability to move)
    • Makes simple tasks harder
  • PD affects the substantia nigra pars compacta
  • The principle pharmacotherapy is levo-dopa
  • The most common fluctuation in PD is the end of dose deterioration
  • PD treatments are less effective with time
    • In early stage disease, dopamine can be stored in a ‘reservoir’
    • In late stage, the ‘reservoir’ is no longer present, and the patient is dependent on the L-dopa dose
  • In gait disturbances and loss of balance in late disease, drug therapy can have no effect
  • Dyskinesia – jerk, involuntary movements experienced when patients are on long term levo-dopa therapy
  • Dementia (cognitive dysfunction) is often due to a dopamine deficiency
    • This is caused by nigral degeneration and a loss of inputs from adrenergic and cholinergic nuclei
      • Ie the locus caeruleus and the nucleus of Meynert
    • Cognition depends on a cholinergic, dopaminergic balance
      • Imbalance (due to a lack of cholinergic nuclei input ) results in an altered perception of reality

Homework

  • Stem cell based therapy for PD or something - q2/3