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Antiparkinson Agents Art Hupka, Ph.D.
2009
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A neurodegenerative disordercharacterized by progressive motordysfunction which includes:Tremor
Rigidity
Bradykinesia (slow movement )
disturbance of posture
Affects ~ 1% of over age 65
Parkinson’s Disease
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Parkinson’s Disease
Signs and symptoms of parkinsonism aredue to the degeneration of dopaminergic neurons projecting from the substantia
nigra to the striatum• Individuals with parkinsonism have a deficiency of
dopamine
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Parkinson’s Disease
there are many hypotheses, the causes ofthe neuronal degeneration in Parkinson‟s
disease remain largely unknown
Oxidative stress theory• Oxidation of DA yields highly reactive free radicals that are
toxic to DA neurons and lead to degeneration
• Agents that prevent DA oxidation may be neuroprotective(selegiline)
Environmental toxins theory• MPTP -- MPP+ interacts with mitochondria cell death
• Selegiline neuroprotective
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D1
D2
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Parkinsonism
SymptomsTremor
• pill rolling contractions – Often present at rest but disappear during purposeful
movement
Bradykinesia• decreased spontaneous movement, loss of normal
associated movement, slow initiation of movement
Rigidity• due to increased muscle tone
• Cog-wheel like movements
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Parkinsonism
Symptoms (cont.)Posture
• progressive stooped position
Psychological changes such as depressionand dementia
Others• Masked facies
• Hallucinations (~ ¼ of patients)
• Oily skin urinary incontinence constipation
• Loss of smell neuropathic pain dizziness
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Parkinsonism
Neurochemical defectNormal voluntary movement is controlled by a
balance of dopaminergic and cholinergic nervousactivity
In parkinsonism, there is a deficiency of dopamine,allowing relative cholinergic dominance
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Parkinsonism
Parkinson variants
It has become apparent that what has beencalled Parkinson‟s Disease is not a single
disorder
Consequently, symptoms and response todrugs will vary
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Pharmacological Intervention
Pharmacological approaches
1. Decrease functional cholinergic component
2. Increase function of nigrostriataldopaminergic component (major approach )
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Drugs Used in the Treatment ofParkinsonism
Levodopa – single most effective agent
immediate precursor of dopamine
crosses the blood brain barrier by means oftransporter for aromatic amino acids
Pharmacological properties
• Levodopa itself is fairly inert
• activity is due to conversion to dopamine in CNS,thus increasing dopamine in the basal ganglia(replacement therapy )
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AADC or LAAD= aromatic aminoacid decarboxylaseCOMT = catechol-O-methyltransferaseMAO = monoamine oxidasteBBB = blood brain barrier
Metabolism of levodopa
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l- dopa kinetics and drug targets
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Levodopa
Pharmacological properties• No change in muscle tone or movement innormal individuals
• Bradykinesia and rigidity are reversed
quickly• reversal of tremor requires continued
therapy
• Changes in mood associated with
parkinsonism are reversed – patients more alert and interested in
environment
– dementia may not reverse
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LDopa
Pharmacological properties (cont.)Cardiovascular
– Asymptomatic (usually ) orthostatic hypotension – Dopamine stimulates both alpha and beta
receptors – Cardiac stimulation
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LDopa
Endocrine• Dopamine important in physiological regulationof anterior pituitary function
• Prolactin secretion inhibited
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LDopa
Disposition
• Well absorbed orally via aromatic aminoacid transporter but can be altered by
–Rate of gastric emptying
–pH of gastric fluids (acidity interferes with
absorption )
–Degradation by enzymes in intestinalmucosa
–Dietary protein (aa compete for transport )
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L-Dopa
Pharmacokinetics (cont.)
~ 95% of l-dopa is metabolized in theperiphery to dopamine; metabolism may be
increased with prolonged therapyExtensive first pass effect as passes from gut
lumen through liver
Only a small portion entering the brain
Metabolites excreted in urine
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ORAL DISPOSITION OF LEVODOPA
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L-Dopa
Adverse effects (caused mostly by DA)Most patients treated with l-dopa develop side
effects.
Intensity and type vary at different stages oftherapy
Early side effects
• Dose dependent; tolerance may develop – GI – nausea, vomiting (80%)
– CVS – orthostatic hypotension (30%), cardiacarrhythmias
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L-Dopa
Adverse effects (cont.)Long term effects
• severity correlates with the degree of clinical improvement,duration of therapy and dose. No tolerance develops
• Abnormal involuntary movements
– Levodopa-induced dyskinesia (80% after 1 year)
– Most commonly jerky, dance-like movements of armsand/or head
– Reduction in dosage required
• Psychiatric and behavioral disturbances (15%) – Depression anxiety agitation insomnia delusions
– Hallucinations euphoria nightmares
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L-dopa
Long term adverse effects
On-Off” syndrome – oscillations inperformance involving rapid changes from
akinesia to dyskinesia• different from „end of dose‟ or „wearing off effect‟
• Mechanism of On-Off syndrome unclear
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Wearing off effect
„end of dose‟ or „wearing off effect‟ – Early in PD, still some intact DA neurons
– Treatment elevates levels in striatum and some takeninto DA neurons
– As end of levodopa dose interval, levels of DA fall instriatum but some DA in neuron buffers and keepsneurons functional
– Late in PD, DA neurons are gone and so is bufferingeffect resulting in loss of effectiveness near end of dose
– Can increase dose or frequency of dosing but run risk ofdyskinesias
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L-Dopa
Drug interactionsPyridoxine (vitamin B6) increases peripheral
conversion of dopa to dopamine (co-factor for LAAD)
Antipsychotic drugs are dopaminergic antagonists
and thus counteract the effects of dopaMAO inhibitors increase the effects of dopa, may
lead to hypertensive crises
Anticholinergic drugs may slow gastric emptying
time and decrease absorption of l-dopaTricyclic antidepressants – may aggravate
hypotensive symptoms
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Drugs Used in the Treatment ofParkinsonism
CarbidopaL-aromatic amino acid decarboxylase (LAAD) is
responsible for the conversion of dopa to dopamine
LAAD activity causes 95% of a dose of dopa to be
converted to dopamine before entering the CNS.
Carbidopa is an inhibitor of this peripheraldecarboxylase and allows greater amounts ofdopa to enter the CNS (carbidopa doesn’t cross
BBB ) – Only available in combination with l-dopa (Sinemet )
– Highly effective in first 2 – 5 years
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Carbidopainhibits
peripheralLAAD topreventconversion oflevodopa toDA
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Carbidopa
Advantages
• Allows reduction in dopa dose
• Nausea and vomiting are decreased
• Cardiac side effects decreased
• Pyridoxine (vitamin B6) antagonism oflevodopa prevented
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Adverse effects – increased central side effectsof dopa
Earlier development of long term side effects possible
Slow release form (SINEMET CR) is availablewhich may help manage „wearing off‟ effect
New on the market is a formulation (Parcopa)which dissolves on the tongue
This may be useful since Parkinsons patients oftenhave trouble swallowing tablets
Carbidopa
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Other Drugs Used in theTreatment of Parkinsonism
COMT Inhibitors
Tolcapone (Tasmar)
Entacapone (Comtan)
(Remember Al Capone and Chicago Organized Mob )
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tolcapone
COMT inhibitors
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COMT Inhibitors
Pharmacological properties – drugsinhibit COMT, thereby increasing theduration of action of l-dopa and dopamine
(remember COMT inactivates l-dopa and dopamine ).
There is a kinetic difference in these drugs in
that tolcapone is highly lipid soluble andreaches CNS. Entacapone does not.
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COMT Inhibitors
Adverse reactions – diarrhea, brightorange discoloration of urine, increased l-dopa side effects (dyskinesias, nausea, confusion )
Increased amino-transferase activity(indication of hepatotoxicity ) with tolcaponewhich may require discontinuation
• Apparently not a problem with entacapone.
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COMT Inhibitors
Clinical uses – adjunct to l-dopa inpatients with stable PD and in patientswith end of dose (“wearing off”) problems
with l-dopa/carbidopa therapy.A combination of carbidopa + l-dopa +
entacapone is available (Stalevo)
• Simplifies regimen• Less tablets consumed
• Costs less than individual drugs
• Especially useful for pts with wearing off problems
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Dopamine agonists used in theTreatment of Parkinsonism
Ergot derivativesBromocryptine (Parlodel) is the prototype
but now rarely used.
• Pergolide (Permax) no longer available because of valularheart disease.
directly stimulate dopamine receptor (D2)
• Not dependent on uptake into DA neurons
Rapidly absorbed, effective levels reachedquickly and persists 3-4 times longer than l-dopa
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Non-ergot DA Agonists
ropinirole (Requip) and pramipexole(Mirapex) – non-ergot DA agonists
• Ropinirole relatively pure D2 agonist
• Pramipexole prefers D3
They also alter cellular metabolism so thatprogression of disease appears to beslowed somewhat
Effective as monotherapy in mild PD alsohelpful in pts with advanced disease
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Dopamine agonists
Kinetics
Pramipexole -Largely eliminated unchangedby kidneys
Ropinirol – metabolized by CYP1A2 andother drugs may slow its elimination
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Non-ergot DA agonists
Adverse effects• Anorexia, nausea, vomiting
• Confusion, hallucinations, delusions and otherpsychiatric reactions are more common and
severe than with levodopa• Orthostatic hypotension can occur early in
treatment. Occasional cardiac arrhythmias
• Pramipexole and ropinirole may cause sudden onset of sleep with no warning
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Dopamine agonists
ContraindicationsDA agonists are contraindicated in pts with ahistory of:
• Psychotic illness
• Recent myocardial infarct
• Active peptic ulceration
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Dopamine agonists
Clinical use• Useful doses usually established within week or
two
• Often used as initial PD treatment rather than otheradjuncts
• Used as initial therapy (without l-dopa ) that maydelay need for levodopa Rx
• adjunctive therapy with l-dopa (lower the dose
requirement of levodopa )• May be effective in restless leg syndrome
h d d h
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Other drugs Used in theTreatment of Parkinsonism
Amantadine (Symmetrel)antiviral agent found to be effective against
parkinsonism
Apparently acts by increasing dopaminerelease from intact dopaminergic neurons• Also blocks NMDA glutamate receptors
• Some anticholinergic effects
• Block reuptake of DA into presynaptic terminal
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Amantadineeffective quickly but for short time (6-8 weeks)
Adjunct used early in treatment
Adverse effects – are mild and reversibleand include:
Hallucinations, confusion, and nightmares
Insomnia, dizziness, lethargy, slurred speech
Long term use may result in livido reticularis
O h d d i h
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Other drugs used in theTreatment of Parkinsonism
Antimuscarinic drugs – used as adjunctto l-dopa therapy and generally lesseffective than dopaminergic drugs
Central acting agents block the unopposedcholinergic effects in the basal ganglia ofparkinsonism patients
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Antimuscarinic drugs for PD
trihexyphenidyl (Artane) and benztropine (Cogentin)• Decrease tremor
• less effect on rigidity and bradykinesia
• Generally have little peripheral effect, but mayreduce some autonomic symptoms
Useful adjunct early and advanced PD alsouseful to reduce parkinson symptoms causedby DA receptor antagonists such ashaloperidol
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Antimuscarinic drugs for PD
Adverse reactions
CNS – confusion, delirium, somnolence,hallucinations
Peripheral – may produce cycloplegia,constipation, and urinary retention in certainpatients
MAO inhibitors
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MAO inhibitors
MAO i hibit d i th
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MAO inhibitors used in theTreatment of Parkinsonism
Selegiline (Eldepryl)selegiline selectively and irreversibly inhibits
MAOB to decrease catabolism of DA (mostly
MAO B in striatum )• Prolongs and enhances the effects of levodopa(allows dosage reduction )
• Does not inhibit peripheral catabolism ofcatecholamines
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Selegiline
Used in early or mild PD alone or as anadjunct in advanced disease
Reduces levodopa dose requirement and mayimprove motor function in pts who experience„wearing off‟ or „on-off‟ difficulties with ldopa
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Selegiline
Adverse effects• Some metabolites are methamphetamine and
amphetamine which produce some of the adverseeffects
• Nausea (10%), dizziness (7%), hallucinations,confusion, depression
• Insomnia if taken late in the day
• Dose must be kept at 10 mg/day or less to
selectively inhibit MAOB, otherwise adversereactions associated with non-specific MAOs occur – Hypertension with tyramine
– Potential serotonin syndrome (e.g. SSRIs, meperidine)
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Therapy for Parkinsonism
Goal
No cure of underlying pathology (although gene
therapy is being tested )
Drug + physiotherapy + exercise +psychological support → provide maximal
symptomatic relief and permits a near normallifespan.
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Some Anesthetic implications
Abrupt withdrawal of levodopa can lead toskeletal muscle rigidity which can interferewith adequate ventilation
Continue levodopa therapy duringperioperative period including usual morningdose
Consider possibility of orthostatichypotension, cardiac dysrhythmias, andmaybe hypertension in pts Rx withlevodopa
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