Transcript Treatments in Parkinson`s disease

Treatments in Parkinson’s
disease
Treatment in PD
• Complex because of
– Progressive nature of disease
– Motor and non-motor features
– Early and late side effects associated with the
treatments
Available Interventions
Goals of treatment in PD
• Prevention of disease progression
• Symptomatic treatment of motor symptoms
• Management of motor complications
– Wearing off/motor fluctuations
– Dyskinesias
• Symptomatic treatment of non-motor
symptoms
Prevention of disease progression
• “Neuroprotection is an unmet need in
Parkinson’s disease and no drug can be
recommended yet for this purpose in
practice.”
Motor symptoms
• Symptoms that are being targeted by
medications
– Tremor
– Rigidity
– Bradykinesia
– Gait/postural instability
Motor complications
• What are motor fluctuations/off time?
• Periods of alteration of symptom control
• On/off time – initially predictable, later unpredictable
• What are dyskinesias?
• Drug-induced involuntary movements that include
chorea and dystonia
• Risk factors for development
• Younger age at onset of PD, severity, higher L-dopa
dose and longer disease duration
Overview of topics
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Levodopa
Entocapone
Dopamine agonists
MAOB inhibitors
Amantadine
Anticholinergics
Deep brain stimulation
Treatment of non-motor symptoms
Question
• The mechanism of the antiparkinsonian effect
of rasagiline and selegiline is inhibition of:
– A. aromatic amino acid decarboxylase
– B. catechol-O-methyltransferase
– C. monoamine oxidase type A
– D. monoamine oxidase type B
– E. tyrosine hydroxylase
Question
• True or false?
• There is good evidence to support the use of
MAOB inhibitors as adjuncts to DA-agonists.
• MAOB inhibitors effectively reduce dyskinesias
in patients with PD.
MAO INHIBITORS
Monoamine Oxidase (MAO)
• Group of enzymes involved in monoamine
metabolism
– Dopamine, serotonin, norepinephrine
• Two enzyme subtypes
– Type A and type B
• In brain  Both A+B
• In GI tract  mostly A
Substrates of MAOs
MAO Inhibitors (MAOI)
• Serendipitously discovered group of drugs
with anti-depressant effect
• Despite effectiveness, second-line drug
– “Cheese reaction”
– Extensive side effect profile
What is the Cheese Reaction?
• Hypertensive crisis in patients on MAOIs who
ingest tyramine
• Tyramine is a monoamine present in aged
cheeses, red wine, sausages
• Usu. metabolised by MAO-A
• Gut, portal circulation, peripheral neurons
• With MAOI (non-selective or selective for A)
–  Tyramine stimulates peripheral adrenergic neurons
–  Hypertensive crisis
Why use MAOIs in PD?
• MAO is present in brain, including the BG
– Type B (80%) >> A
• If use selective MAO-B inhibitor:
– Will inhibit dopamine metabolism in the BG (80%
type B)
– Avoid cheese reaction (dependent on MAO-A)
– Avoid extensive side effect profile
• Selective MAO-B inhibitors
– Selegiline and rasagiline
Selegiline - Use
• What is the role of selegiline in the treatment
of PD for relief of motor symptoms?
• AAN Practice Parameters (2002):
– Can be used initially as monotherapy for mild
symptomatic relief
• Movement Disorder Society (2002)
– Effective as monotherapy
– Insufficient data to recommend use as as adjunct
in patients already on DA-ergic agents
Selegiline - Use
• What about its role in motor complications?
– Insufficient data for fluctuations
– Non-efficacious in preventing dyskinesias
• What about its role in neuroprotection?
– Insufficient evidence to suggest that it has a
neuroprotective effect (despite initial studies)
• Doses
– Start at 5mg daily
– Increase to 5mg bid (maximum dose)
Selegiline – Side effects
• Mortality
– One study showed excess mortality in selegiline
group
– Meta-analysis did not confirm this
• Headache, nausea, insomnia
• Confusion in the elderly
• Can enhance side effects of L-dopa
– (But no evidence to use together)
Rasagiline (Azilect)
• What is the role for rasagiline in mgmnt of
motor symptoms?
• Movement Disorder Society (2005)
– Effective as monotherapy
– Insufficient data to recommend use as adjunct in
patients already on DA-ergic agents
– Insufficient data regarding role in motor
complications (MDS)
Rasagiline (Azilect)
• Doses
– Start at 0.5mg daily
– Increase to 1mg daily (maximum dose)
• Side effects
– Same as selegiline
OTHER
Question
• In which group of PD patients would you
consider using anticholinergics?
– A. Younger patients with predominant rigidity
– B. Younger patients with predominant tremor
– C. Elderly patients with predominant motor
fluctuations
– D. Elderly patients with predominant non-motor
symptoms
Anticholinergics
• Mechanism of Action in PD
– Not clearly known
– Degeneration of DA-ergic nigrostriatal neurons 
imbalance between striatal dopamine and Ach
– Anticholinergics help counteract the imbalance
Anticholinergics - Use
• What is the role for anticholinergics in the
management of PD?
• 1993 AAN Practice parameters
– Can be considered as initial therapy esp. if tremor
predominant
• MDS (2002)
– Likely efficacious as monotherapy in early PD and as
adjunct in patients on L-dopa
– Insufficient data re: efficacy for prevention/treatment of
motor fluctuations
• Typically: young patients with predominant tremor
Anticholinergics – Side effects
• Main ones (start low, go slow):
– Trihexyphenidyl (Artane)
• Start 0.5-1mg bid, increase to 2mg tid
– Benztropine (Cogentin)
• Start 0.5-1 mg bid, increase to 2 bid
• Side effects
– Confusion, hallucinations, blurry vision, increased
intraocular pressure, dry mouth, urinary
retention, constipation
Amantadine
• Used in PD for over 40 years
• Antiparkinsonian MoA not fully known
– Partial NMDA receptor antagonist
– Partial dopamine agonist
Amantadine - Use
• What is the role for amantadine in the treatment
of motor symptoms?
– Safe and modestly effective (AAN)
– “Likely efficacious” as monotherapy in early PD (MDS)
• What about its role in motor complications?
– “Possibly efficacious” at reducing dyskinesias
– May be considered for pts with motor fluctuations
– Efficacious in pts on L-Dopa with motor complications
Amantadine - Use
• Role in motor complications ctn’d
– Effect on dyskinesias likely better than more frequent
dosing of L-Dopa
– Unknown efficacy in comparison to DA-agonist
(pramipexole, ropinirole)
• Dose
– 100 mg po daily to qid
• Side effects
– Livedo reticularis, leg edema,
– Same side effect profile as dopamine agonists
– Generally well-tolerated
NON-MOTOR SYMPTOMS
• A 78-year-old woman with a 15-year history of
PD has developed visual hallucinations. Her
medications include carbidopa/levodopa,
ropinirole, and rasagiline. Her hallucinations have
not diminished significantly with trials of
reductions of each of her medications. Which of
the following medications is most appropriate for
this patient?
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A. chlorpromazine
B. haloperidol
C. quetiapine
D. thioridazine
E. thiothixene
Non-motor symptoms
• “Non-motor symptoms dominate the clinical
picture of advanced Parkinson’s disease and
contribute to severe disability, impaired
quality of life, and shortened life expectancy”
Pathophysiology
• Non-dopaminergic-cell dysfunction thought to
play a major part in the development of the
non-motor symptoms
• However, neuroanatomy and neurochemistry
of non-motor symptoms are unknown
Non-motor symptoms
• Neuropsychiatric symptoms
– Depression, apathy, anxiety, hallucinations, dementia, impulsive
behavior (usu drug-induced)
• Sleep disorders
– Restless legs and period limb movements, REM-sleep behavior
disorder, excessive daytime somnolence
• Autonomic symptoms
– Bladder (urgency, nocturia, frequency), sweating, orthostatic
hypotension, sexual dysfunction
• GI symptoms (overlap with dysautonomia)
– Dribbling saliva, constipation, dysphagia, ageusia,
• Sensory symptoms
– Olfactory disturbance, pain, paresthesias
Management
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Depression
Anxiety
Psychosis
Orthostatic hypotension
Dementia
Sexual dysfunction
Sleep dysfunction
Management - Depression
• Can affect from 10-45% of patients
• Likely has a biological contribution
– May be a result of impaired 5HT transmission
• What is best pharmacological treatment? (AAN 2006)
– The highest level of evidence is for amitriptyline
– Although it may be considered, it is not necessarily the first
choice for treatment of depression associated with PD.
– Insufficient evidence to make recommendations regarding
other treatments for depression
• SSRIs and SNRIs are used but little published data in PD
Management – Anxiety and Apathy
• Anxiety disorder common
– Often coexists with depression
– Panic attacks, phobias, GAD, related to motor
fluctuations
• AAN practice parameters regarding treatment
– Insufficient evidence to make any
recommendations
Management - Psychosis
• What is the best treatment for patients with PD
and psychosis?
– Clozapine should be considered
• Remember: associated with agranulocytosis that may be
fatal. The absolute neutrophil count must be monitored.
– Quetiapine may be considered
– Olanzapine should not be routinely considered
• No proven efficacy and may worsen motor function
• Note that not FDA approved because of increased
risk of death in pts with dementia
Management - Dementia
• What are the most accurate screening tools in
PD?
– MMSE and CAMCog (Cambridge cognitive
assessment)
– MMSE as sensitive but not as specific
• What is the most effective treatment for
dementia in PD?
– Rivastigmine probably effective in improving cognitive
function. Modest effect and may exacerbate tremor
– Donepezil is probably effective in improving cognitive
function. Modest effect.
Management – Orthostatic
Hypotension
• Defined as a 20mmHg drop in systolic BP or a
10mmHg drop in diastolic BP
• Challenge in PD
– DA-ergic agents often worsen OH
– Reducing dose usually insufficient to treat
• What treatments are effective? (AAN 2006)
– Insufficient data to recommend to any particular
treatment
Management – Orthostatic
Hypotension
• Compression stockings
• Increasing water intake
• Fludrocortisone
• Dose: 0.1 – 0.3mg daily + high Na intake
• Supine hypertension, peripheral edema
• Midodrine
• Peripheral alpha1 receptor agonist
• Dose: 2.5 to 5mg tid
• Others: domperidone, pyridostigmine,
indomethacin
Management – Sexual Dysfunction
• Common in both men and women
• Multifactorial
– Motor dysfunction, medication side effects, mood
disorders, and dysautonomia
– Dysautonomia  erectile dysfunction
• One study looked at sildenafil in ED
– 12 patients with PD, BP > 90/50
– Sildenafil at 50mg significantly improved ED
Management – Sexual Dysfunction
• AAN Practice Parameter
– Sildenafil possibly efficacious
• Need to ensure that other treatable causes of
ED/sexual dysfctn have also been addressed
• Note: hypersexuality can be seen in PD
associated with DA-ergic agents
• A 48-year-old man with a 1-year history of PD
comes to the office with his wife. She states that
for the past 5 years he’s had episodes of kicking
and punching during sleep. This has resulted in
injuries to both. He is currently taking no
medications.
• What is the diagnosis?
• Which of the following is most likely to benefit
this patient’s nocturnal symptoms?
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A. amantadine
B. clonazepam
C. pramipexole
D. ropinirole
E. selegiline
Management – Sleep Dysfunction
• Range of sleep dysfunction
– REM sleep behavior disorder (RBD)
– Excessive daytime somnolence (EDS)
– Insomnia
– Restless legs syndrome and periodic limb
movement
Management – RBD
• A type of parasomnia characterized by
patients acting out dramatic or violent dreams
during the REM sleep stage.
• What treatments are effective in PD?
– Insufficient data
• What treatments are available for RBD?
– Clonazepam - 0.25 to 1mg po qhs
– Melatonin
Question
Management - EDS
• May be 2ary to disease process or medication
side effect
• Dopaminergic agents can cause mild to severe
somnolence
– Falling asleep at wheel of car
– Agonists > L-dopa
– FDA warnings for pramipexole and ropinirole
– Patients should be advised to d/c DA agonists if
marked increase in sleepiness
Management - EDS
• What treatments are available?
– Modafinil improves SUBJECTIVE feeling of
sleepiness but doesn’t change OBJECTIVE
measurements of somnolence
– Dose: 200mg daily in am
Management - Insomnia
• Etiology is multifactorial
– Mood disturbances, persistent tremor, nighttime PD
symptoms, nocturia, and reversal of sleep patterns
• Practice parameter: Insufficient data
• Available treatments
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Bedtime L-dopa – may improve nocturnal PD sx
Melatonin – Improves perception
Sedating antidepressants (trazodone)
Mild sedatives – zopiclone, zolpidem
Over-the-counter sleeping aids – beware of side
effects (anticholinergic effect)
Management - RLS
• Occurs in up to 20% of patients
• No evidence on how to treat of RLS in PD
• May use ropinirole and pramipexole
– FDA approved treatment in primary RLS
Summary
• MAOB Inhibitors
– Monotherapy, early PD
– Not for motor complications or neuroprotection
• Anticholinergics
– Young patients with predominant tremor
– Not for motor complications
• Amantadine
– Monotherapy for motor symptoms
– Adjunct if L-dopa induced motor complications
Summary
• Depression
– Consider amitryptilline
• Psychosis
– Clozapine > quetiapine
• Dementia
– Rivastigmine and donepezil
• Orthostatic hypotension
– Non-pharm; fludro, midodrine, domperidone
Summary
• RBD
– Clonazepam
• EDS
– Warn patients!
– Remove offending agent
• RLS
– Pramipexole and ropinirole
CASES
Case 1
• 44 y.o. woman. New left hand tremor and
shoulder stiffness. Not yet interfering with
work.
• On exam – left sided rigidity, bradykinesia and
tremor
• Assuming that your best diagnosis is IPD:
– Should you start the patient on treatment?
– What treatment would you start? What are the
benefits/disadvantages of the different options?
Case 1
• Should you start the patient on treatment?
– No evidence that starting treatment early is
harmful or worsens long-term outcome
– Therefore, generally decision to start treatment
should take into account degree of
symptoms/disability versus adverse effects of
medication
Case 1
• What treatment would you start? What are the
benefits/disadvantages of the different options?
– Levodopa –less sleepiness and psych Ses, but higher
rate of dyskinesias
– Dopamine agonists – longer duration of action, less
dyskinesias, but greater sleepiness and psychiatric SEs
– MAOB inhibitors
– Anticholinergics
– Amantadine
Case 2
• 65 y.o. man, PD x 5 yrs
• On Sinemet 100/25 qid and selegiline 5 bid
• For 1 yr: am off time before meds kick in and
pm dyskinesias
• How can you decrease morning off time?
• How can you decrease dyskinesias?
Case 2
• How can you decrease morning off time?
– Adding a COMT inhibitor  however, can increase
dyskinesias
– Adding pramipexole or ropinirole  may increase
dyskinesias
– Adding amantadine (less evidence for motor
fluctuations)
• How can you decrease dyskinesias?
– Adding DA- agonist and reducing L-Dopa dose slowly
– Adding Amantadine
Case 3
• 73 y.o. woman, PD x 10 years
• On Sinemet and pramipexole
– Mild dyskinesias and motor fluctuation
• Recent forgetfulness and apparent visual
hallucinations.
• On exam, MMSE 27/30 and mild choreatic
dyskinesias
Case 3
• What single intervention is most likely to
reduce hallucinations?
• If that fails to control hallucinations, what is
the next step?
• Would you treat her mild cognitive
impairment?
Case 3
• What single intervention is most likely to
reduce hallucinations?
– Remove the pramipexole
– This may lead to increased motor fluctuations and
dyskinesias and require Sinemet dose adjustment
• If that fails to control hallucinations, what is
the next step?
– Atypical antipsychotics: clozapine, quetiapine
Thank you
Review Question
• A 51 y.o. woman developed PD and was started
on treatment. Soon after, she began to spend
money on frivolous items and went to the casino
where she lost her life savings.
• What is the diagnosis?
• It is a side effect of which class of medication?
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MAOB inhibitors
Dopamine agonists
Anticholinergics
COMT inhibitors
Review Question
• Which of the following agents can be used as
monotherapy in PD (choose as many as apply)
– Pramipexole
– Ropinirole
– Rasagiline and selegiline
– Benztropine and trihexyphenidyl
– Amantadine
Figure 1. The mechanism of potentiation of cardiovascular effects of tyramine, the cheese
reaction, and NE release and metabolism after MAO-A inhibition.
Youdim M B , Riederer P F Neurology 2004;63:S32-S35
©2004 by Lippincott Williams & Wilkins
• Mechanism of action of MAOI (no pdf)
– http://www.neurology.org/content/63/7_suppl_2/S32
.full
• Treatment interventions in PD: and evidence
based assessment. Rascol et al. Lancet
2002;359:1589.
• Evidence-based medical review update:
Pharmacological and surgical treatments of PD:
2001-2004. Movement Disorders 2005;20(5):523
• Goetz CG, Koller WC, Poewe W, et al.
Management of Parkinson’s disease: an
evidence-based review. Mov Disord
2002;17(Suppl. 4)S1–S166.
• Update on the medical management of
parkinson disease. Continuum 2010;16:96-109
• Chaudhuri et al. Non-motor symptoms of
Parkinson’s disease: diagnosis and
management. Lancet Neurol 2006;5:235-45.
Figure 2. The pathway of dopamine (DA) synthesis from levodopa (l-dopa) and its metabolism
by intraneuronal MAO-A and by MAO-A and B extraneuronally by glia and astrocytes and the
inhibition of MAO by various selective (moclobemide, selegiline, rasagiline) ...
Youdim M B , Riederer P F Neurology 2004;63:S32-S35
©2004 by Lippincott Williams & Wilkins
• Which of the following sleep disorders is most
common in patients with Parkinson disease?
• A. central sleep apnea
• B. delayed sleep phase syndrome
• C. narcolepsy
• D. REM sleep behavior disorder