Antiparkinson Agents

Art Hupka, Ph.D. 2009

Parkinsons Disease
A neurodegenerative disorder characterized by progressive motor dysfunction which includes:
Tremor Rigidity Bradykinesia (slow movement) disturbance of posture

Affects ~ 1% of over age 65

Parkinsons Disease
Signs and symptoms of parkinsonism are due to the degeneration of dopaminergic neurons projecting from the substantia nigra to the striatum
Individuals with parkinsonism have a deficiency of dopamine

Parkinsons Disease
there are many hypotheses, the causes of the neuronal degeneration in Parkinsons 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

D2

D1

Parkinsonism
Symptoms
Tremor
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

Parkinsonism
Symptoms (cont.)
Posture
progressive stooped position

Psychological changes such as depression and dementia Others

Masked facies Hallucinations (~ of patients) Oily skin urinary incontinence constipation Loss of smell neuropathic pain dizziness

Parkinsonism
Neurochemical defect
Normal voluntary movement is controlled by a balance of dopaminergic and cholinergic nervous activity

In parkinsonism, there is a deficiency of dopamine, allowing relative cholinergic dominance

Parkinsonism
Parkinson variants
It has become apparent that what has been called Parkinsons Disease is not a single disorder Consequently, symptoms and response to drugs will vary

Pharmacological Intervention
Pharmacological approaches
1. Decrease functional cholinergic component 2. Increase function of nigrostriatal dopaminergic component (major approach)

Drugs Used in the Treatment of Parkinsonism

Levodopa single most effective agent
immediate precursor of dopamine crosses the blood brain barrier by means of transporter 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)

Metabolism of levodopa

AADC or LAAD= aromatic aminoacid decarboxylase COMT = catechol-O-methyltransferase MAO = monoamine oxidaste BBB = blood brain barrier

l- dopa kinetics and drug targets

Levodopa
Pharmacological properties
No change in muscle tone or movement in normal 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

LDopa
Pharmacological properties (cont.) Cardiovascular
Asymptomatic (usually) orthostatic hypotension Dopamine stimulates both alpha and beta receptors Cardiac stimulation

LDopa
Endocrine
Dopamine important in physiological regulation of anterior pituitary function Prolactin secretion inhibited

LDopa
Disposition
Well absorbed orally via aromatic amino acid transporter but can be altered by Rate of gastric emptying pH of gastric fluids (acidity interferes with absorption) Degradation by enzymes in intestinal mucosa Dietary protein (aa compete for transport)

L-Dopa
Pharmacokinetics (cont.)
~ 95% of l-dopa is metabolized in the periphery to dopamine; metabolism may be increased with prolonged therapy Extensive first pass effect as passes from gut lumen through liver Only a small portion entering the brain
Metabolites excreted in urine

ORAL DISPOSITION OF LEVODOPA

L-Dopa
Adverse effects (caused mostly by DA)
Most patients treated with l-dopa develop side effects. Intensity and type vary at different stages of therapy

Early side effects

Dose dependent; tolerance may develop
GI nausea, vomiting (80%) CVS orthostatic hypotension (30%), cardiac arrhythmias

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 arms and/or head Reduction in dosage required

Psychiatric and behavioral disturbances (15%)

Depression anxiety agitation insomnia delusions Hallucinations euphoria nightmares

L-dopa
Long term adverse effects
On-Off syndrome oscillations in performance involving rapid changes from akinesia to dyskinesia
different from end of dose or wearing off effect Mechanism of On-Off syndrome unclear

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 taken into DA neurons As end of levodopa dose interval, levels of DA fall in striatum but some DA in neuron buffers and keeps neurons functional Late in PD, DA neurons are gone and so is buffering effect resulting in loss of effectiveness near end of dose Can increase dose or frequency of dosing but run risk of dyskinesias

L-Dopa
Drug interactions
Pyridoxine (vitamin B6) increases peripheral conversion of dopa to dopamine (co-factor for LAAD) Antipsychotic drugs are dopaminergic antagonists and thus counteract the effects of dopa MAO inhibitors increase the effects of dopa, may lead to hypertensive crises Anticholinergic drugs may slow gastric emptying time and decrease absorption of l-dopa Tricyclic antidepressants may aggravate hypotensive symptoms

Drugs Used in the Treatment of Parkinsonism

Carbidopa
L-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 peripheral decarboxylase and allows greater amounts of dopa to enter the CNS (carbidopa doesnt cross BBB)
Only available in combination with l-dopa (Sinemet) Highly effective in first 2 5 years

Carbidopa inhibits peripheral LAAD to prevent conversion of levodopa to DA

Carbidopa
Advantages
Allows reduction in dopa dose Nausea and vomiting are decreased Cardiac side effects decreased Pyridoxine (vitamin B6) antagonism of levodopa prevented

Carbidopa
Adverse effects increased central side effects of dopa
Earlier development of long term side effects possible

Slow release form (SINEMET CR) is available which 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 often have trouble swallowing tablets

Other Drugs Used in the Treatment of Parkinsonism

COMT Inhibitors
Tolcapone (Tasmar) Entacapone (Comtan) (Remember Al Capone and Chicago Organized Mob)

COMT inhibitors
tolcapone

COMT Inhibitors
Pharmacological properties drugs inhibit COMT, thereby increasing the duration 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 and reaches CNS. Entacapone does not.

COMT Inhibitors
Adverse reactions diarrhea, bright orange discoloration of urine, increased ldopa side effects (dyskinesias, nausea, confusion)
Increased amino-transferase activity (indication of hepatotoxicity) with tolcapone which may require discontinuation
Apparently not a problem with entacapone.

COMT Inhibitors
Clinical uses adjunct to l-dopa in patients with stable PD and in patients with 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

Dopamine agonists used in the Treatment of Parkinsonism

Ergot derivatives
Bromocryptine (Parlodel) is the prototype but now rarely used.
Pergolide (Permax) no longer available because of valular heart disease.

directly stimulate dopamine receptor (D2)

Not dependent on uptake into DA neurons

Rapidly absorbed, effective levels reached quickly and persists 3-4 times longer than ldopa

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 that progression of disease appears to be slowed somewhat Effective as monotherapy in mild PD also helpful in pts with advanced disease

Dopamine agonists
Kinetics
Pramipexole -Largely eliminated unchanged by kidneys Ropinirol metabolized by CYP1A2 and other drugs may slow its elimination

Non-ergot DA agonists
Adverse effects
Anorexia, nausea, vomiting Confusion, hallucinations, delusions and other psychiatric 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

Dopamine agonists
Contraindications
DA agonists are contraindicated in pts with a history of:
Psychotic illness Recent myocardial infarct Active peptic ulceration

Dopamine agonists
Clinical use
Useful doses usually established within week or two Often used as initial PD treatment rather than other adjuncts Used as initial therapy (without l-dopa) that may delay need for levodopa Rx adjunctive therapy with l-dopa (lower the dose requirement of levodopa) May be effective in restless leg syndrome

Other drugs Used in the Treatment of Parkinsonism

Amantadine (Symmetrel)
antiviral agent found to be effective against parkinsonism Apparently acts by increasing dopamine release from intact dopaminergic neurons
Also blocks NMDA glutamate receptors Some anticholinergic effects Block reuptake of DA into presynaptic terminal

Amantadine
effective quickly but for short time (6-8 weeks) Adjunct used early in treatment

Adverse effects are mild and reversible and include:

Hallucinations, confusion, and nightmares Insomnia, dizziness, lethargy, slurred speech Long term use may result in livido reticularis

Other drugs used in the Treatment of Parkinsonism

Antimuscarinic drugs used as adjunct to l-dopa therapy and generally less effective than dopaminergic drugs
Central acting agents block the unopposed cholinergic effects in the basal ganglia of parkinsonism patients

Antimuscarinic drugs for PD

trihexyphenidyl (Artane) and benztropine (Cogentin)
Decrease tremor less effect on rigidity and bradykinesia Generally have little peripheral effect, but may reduce some autonomic symptoms

Useful adjunct early and advanced PD also useful to reduce parkinson symptoms caused by DA receptor antagonists such as haloperidol

Antimuscarinic drugs for PD

Adverse reactions
CNS confusion, delirium, somnolence, hallucinations Peripheral may produce cycloplegia, constipation, and urinary retention in certain patients

MAO inhibitors

MAO inhibitors used in the Treatment of Parkinsonism

Selegiline (Eldepryl)
selegiline selectively and irreversibly inhibits MAOB to decrease catabolism of DA (mostly MAOB in striatum)
Prolongs and enhances the effects of levodopa (allows dosage reduction) Does not inhibit peripheral catabolism of catecholamines

Selegiline
Used in early or mild PD alone or as an adjunct in advanced disease Reduces levodopa dose requirement and may improve motor function in pts who experience wearing off or on-off difficulties with ldopa

Selegiline
Adverse effects
Some metabolites are methamphetamine and amphetamine which produce some of the adverse effects 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 adverse reactions associated with non-specific MAOs occur
Hypertension with tyramine Potential serotonin syndrome (e.g. SSRIs, meperidine)

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 normal lifespan.

Some Anesthetic implications

Abrupt withdrawal of levodopa can lead to skeletal muscle rigidity which can interfere with adequate ventilation
Continue levodopa therapy during perioperative period including usual morning dose

Consider possibility of orthostatic hypotension, cardiac dysrhythmias, and maybe hypertension in pts Rx with levodopa