2.

1-05
July 24, 2013
Angeline D. Alabastro, M.D. CNS Pharmacology I:
"Everyday, I'm shuff-ff-fling. Shuffling, shuffling."
Antiparkinsonians

SECTION PAGE ANTIPARKINSONIANS

I. Overview of Parkinsonism (Paralysis Agitans) 1 1. Dopamine precursors
II. Antiparkinsonians 2. Dopamine agonists
A. Levodopa a. Ergot derivatives
1. Chemistry 1 b. Non-ergot derivatives
2. Pharmacokinetics 1 3. Monoamine oxidase inhibitors
3. Clinical Pharmacology 2 4. Catechol-O-methyltransferase inhibitors
5. Anticholinergics
4. Adverse Effects 2
5. Drug Holiday 2
6. Drug Interactions 2
7. Contraindications 2
B. Dopamine Receptor Agonists
1. Ergot Derivatives 2-3
2. Non-Ergot Derivatives 3
3. Adverse Effects 3
4. Contraindications 3
C. MAO Inhibitors 3
D. COMT Inhibitors 4
E. Apomorphine 4
F. Amantadine 4
G. Anticholinergic Antiparkinsonians 4
H. Other Treatment Modalities 5
III. Review Questions 5

TRANSMASTER'S NOTE
*Lecture-based content, side comments, or transmaster notes

OVERVIEW OF PARKINSONISM (PARALYSIS AGITANS)

 Multiple etiologies but usually idiopathic
 Loss of dopaminergic cells in substantia nigra  dopamine
concentration in basal ganglia  motor manifestations

LEVODOPA (L-DOPA)

CHEMISTRY
 L-3,4-dihydroxyphenylalanine
 Levorotatory stereoisomer of dopa
 Metabolic precursor of dopamine
 Largely inert
 Therapeutic and adverse effects – result from
decarboxylation of L-dopa to dopamine
 Entry of the drug into the central nervous system (CNS)
across the blood–brain barrier, mediated by a membrane
transporter for aromatic amino acids, and competition
 Clinical findings: between dietary protein
o Bradykinesia – slowness and poverty of movement
(moves like a robot) PHARMACOKINETICS
o Muscular rigidity  CNS entry across blood-brain barrier via L-amino acid
o Resting tremor – usually abates during voluntary transporter (LAT)  decarboxylated to dopamine
movement  Rapidly absorbed from the small intestine
o Impairment of postural balance  Amino acids  slows down GIT absorption of levodopa
o Akinesia – difficulty in initiating movement  Peak plasma concentration – 1-2 hours after oral dose
o Mask-like facies or expressionless face  Plasma half-life – usually 1-3 hours
o Shuffling gait  Main metabolic products:
 Pathologic findings: o 3-methoxy-4-hydroxyphenyl acetic acid (homovanillic
o Loss of pigmented dopaminergic neurons of acid or HVA)
substantia nigra pars compacta o Dihydroxyphenylacetic acid (DOPAC)
o Lewy bodies – intracellular inclusions containing α-  1–3% of L-dopa  enters the brain
synuclein in fetal dopaminergic cells  Remainder of L-dopa  extracerebral metabolism

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 CNS Pharmacology I: Antiparkinsonians

4. BEHAVIORAL
 More common in patients taking L-dopa + dopa
decarboxylase inhibitor than levodopa only

5. FLUCTUATIONS IN RESPONSE
 Occurs in prolonged treatment
 Wearing-off reactions (end-of-dose akinesia) –
fluctuations consistent with timing of L-dopa intake
 On-off phenomenon
o Fluctuations NOT related to timing of intake
o Off-periods of marked akinesia + on-periods of
improved mobility with marked dyskinesia

6. MISCELLANEOUS
a. Mydriasis  precipitation of acute glaucoma
b. Blood dyscrasias
c. Positive Coombs' test with evidence of hemolysis
d. Hot flushes
e. Precipitation of gout
f. Smell or taste abnormalities
g. Brownish discoloration of secretions
h. Priapism
i. Mild, transient elevations of some analytes:
1. Blood urea nitrogen
2. Serum transaminases
3. Alkaline phosphatase
4. Bilirubin

DRUG HOLIDAY
 Discontinuance of levodopa for 3-21 days
 Temporarily improves responsiveness to levodopa
 Not helpful in management of on-off phenomenon
 No longer recommended because of the following risks:
o Aspiration pneumonia
o Venous thrombosis
o Pulmonary embolism
o Depression
CLINICAL PHARMACOLOGY
 Treatment of Parkinson's disease
DRUG INTERACTIONS
 Sinemet
 Pyridoxine (therapeutic doses)  enhanced cerebral
o Preparation of L-dopa + carbidopa
metabolism of levodopa
 Carbidopa
 Levodopa + MAOA inhibitors  hypertensive crisis
‒ Peripheral dopa decarboxylase inhibitor
‒  peripheral conversion of L-dopa to dopamine
o  plasma L-dopa   available L-dopa for CNS entry CONTRAINDICATIONS
o  L-dopa needed   adverse effects  Psychosis  exacerbation of mental disturbance
 Stalevo (under COMT inhibitors)  Angle-closure glaucoma
 Caution with cardiac disease and active peptic ulcer disease
ADVERSE EFFECTS  Melanoma
1. GASTROINTESTINAL
 L-dopa only  anorexia, nausea, vomiting DOPAMINE RECEPTOR AGONISTS
o Chemoreceptor trigger zone activation  vomiting  Imitates dopamine
 May be used alone in early stages in younger patients
2. CARDIOVASCULAR  No enzymatic conversion to active metabolites
 Cardiac arrhyhthmias:  No toxic metabolites
o Tachycardia  Does not compete with other substances
o Ventricular extrasystoles  Limited adverse effects
o Atrial fibrillation   incidence of fluctuations
 Postural hypotension – common  Given to patients with fluctuations resistant to L-dopa
 Hypertension – in the presence of nonselective MAOI
or sympathomimetics or massive doses of L-dopa ERGOT DERIVATIVES
1. BROMOCRIPTINE (Parlodel)
3. DYSKINESIAS  D2 agonist
 Dose-related  Widely used in treatment of Parkinson's disease
 Choreoathetosis of face and distal extremities – most  Pharmacokinetics
common presentation o Peak plasma levels within 1-2 hours after oral dose
o Biliary and fecal elimination
 More toxic than non-ergot derivatives

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2. PERGOLIDE MONOAMINE OXIDASE INHIBITORS (MAOI)

 D1 and D2 agonist
  "on-time" among response fluctuators  permits  in
MONOAMINE OXIDASE
L-dopa dose
 MAOA – degrades norepinephrine, serotonin, and dopamine
 Replaced with non-ergot derivatives because of
 MAOB – degrades dopamine in the brain
association with valvular heart disease
1. SELEGILINE (Eldepryl)
NON-ERGOT DERIVATIVES
 Selective MAOB inhibitor
1. PRAMIPEXOLE (Mirapex) o Inhibits MAOA as well at high doses
 D3 agonist  Retards dopamine breakdown   antiparkinsonism
 Clinical uses effect of L-dopa (permits  in L-dopa dose)
o Monotherapy for mild parkinsonism   mild on-off or wearing-off phenomena
o Permits  of L-dopa dose in advanced disease o Used as adjunctive therapy for patients with
 Can be used as initial therapy and also effective in declining or fluctuating response to L-dopa
on-off phenomenon  Mildly effective by itself; often given as supplement
 Neuroprotective  Insomnia (adverse effect)
 Pharmacokinetics  Degraded into metabolites
o Rapidly absorbed after oral administration o Desmethylselegiline
o Peak plasma concentrations within 2 hours  Presumably responsible for neuroprotective
effects (involving antiapoptotic mechanisms)
2. ROPINIROLE (Requip) o Amphetamine and metamphetamine
 Pure D2 agonist  Responsible for adverse effects of selegiline
 Same clinical uses as with pramipexole (anxiety, insomnia)
 CYP1A2 metabolism
2. RASAGILINE (Azilect)
3. ROTIGOTINE (Neupro)  Selective MAOB inhibitor
 Treatment of early Parkinson's disease  Clinical uses
 Delivered daily through a skin patch o Early symptomatic treatment of parkinsonism
 Provides more continuous dopaminergic stimulation o Neuroprotective agent
than oral medication in early disease  More potent than selegiline in preventing MPTP-induced
 Recalled in 2008 because of crystal formation on the parkinsonism
patches, affecting its availability and efficacy
DRUG-DRUG INTERACTIONS
ADVERSE EFFECTS OF DOPAMINE AGONISTS
 MAOI + L-dopa
1. GASTROINTESTINAL o  adverse effects of L-dopa
 Anorexia, nausea, vomiting – minimized by taking o Hypertensive crisis
medications with meals  MAOI + meperidine, tricyclic antidepressants, or
 GI bleeding from peptic ulcers serotonin reuptake inhibitors   risk of acute toxic
interactions of serotonin syndrome
2. CARDIOVASCULAR
 Painless digital vasospasm (in ergot derivatives)
TRANSMASTER'S NOTE
 Arrhythmia
In therapeutic doses, selective MAOB inhibitors
 Peripheral edema
(selegiline and rasagiline), compared to selective MAOA or
nonselective inhibitors, do not usually require restrictions
3. DYSKINESIAS
in tyramine-rich food (cheese or wine) which, if combined
with MAOI, may induce hypertensive crisis.
4. MENTAL DISTURBANCES
 Confusion
 Hallucination TRANSMASTER'S NOTE
 Delusions Serotonin syndrome is a life-threatening reaction
 Disorders of impulse control occurring within minutes after adminstering MAOI with
serotonin agonists (SSRI) to cause excessive buildup of
5. MISCELLANEOUS serotonin in the CNS. Clinical findings can range from
 Headache diaphoresis, mydriasis, and hyperreflexia to more severe
 Nasal congestion symptoms like hyperthermia, tachycardia, and hypertension.
 Pulmonary infiltrates
 Erythromelalgia CONTRAINDICATIONS
 Cardiac valvulopathies (in pergolide)  Analgesics
 Uncontrolled tendency to fall asleep at inappropriate o Meperidine
time (in non-ergot derivatives) o Tramadol
o Methadone
CONTRAINDICATIONS o Propoxyphene
 Psychotic illness  Cyclobenzaprine
 Recent myocardial infarction  St. John's wort
 Peptic ulcer disease  OTC cold medications (dextromethorphan)

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CATECHOL-O-METHYLTRANSFERASE INHIBITORS o Antagonizes effects of adenosine at adenosine A2A

  L-dopa metabolism by COMT  prolongs action of L-dopa receptors which may inhibit D2 receptor function
  L-dopa clearance  Less potent than L-dopa
  relative bioavailability of L-dopa  Short-lived benefits
 Helpful in patients on L-dopa with response fluctuations;  Improves tremor and rigidity
not useful when taken alone  May be helpful in reducing iatrogenic dyskinesias
 Pharmacokinetics
o Rapidly absorbed PHARMACOKINETICS
o Half-life – 2 hours  Peak plasma concentration of 1-4 hours
 Plasma half-life of 2-4 hours
CATECHOL-O-METHYLTRANSFERASE (COMT)  Drug unchanged in the urine
 Metabolizes levodopa to 3-O-methyldopa (3OMD)
which competes with L-dopa itself for an active carrier ADVERSE EFFECTS
mechanism that governs its transport across the intestinal 1. CNS
mucosa and the blood-brain barrier  Restlessness
 Depression
1. ENTACAPONE (Comtan)  Irritability
 Peripheral COMT inhibition   metabolism of L-  Insomnia
dopa  prolonged action  Agitation
 No CNS entry  Excitement
 More potent than tolcapone  Hallucinations
 + levodopa-carbidopa = Stalevo  Confusion
 Generally preferred (non-hepatotoxic)
2. DERMATOLOGIC
2. TOLCAPONE (Tasmar)  Livedo reticularis
 Capable of CNS entry unlike entacapone
 Centrally and peripherally-acting 3. PERIPHERAL EDEMA
 Evidence of hepatotoxicity   liver enzymes
 Longer duration of action than entacapone CONTRAINDICATIONS
 Patients with a history of:
TOLCAPONE ENTACAPONE o Seizures
Central and o Heart failure
Effects Peripheral only
peripheral
Potency and ANTICHOLINERGIC ANTIPARKINSONIANS
More Less
duration of action  Centrally-acting antimuscarinic agents
Dosing TID 4-5X with L-dopa  Improves tremors and rigidity
Hepatotoxicity + -  Little effect on bradykinesia

1. BENZTROPIN (Cogentin)
APOMORPHINE (APOKYN)  Muscarinic receptor antagonist
 Non-ergot derivative o Acts on M receptors in basal ganglia
 Potent dopamine agonist   tremor and rigidity
 Effective for temporary relief ("rescue") of off-periods  Little effect on bradykinesia
of akinesia in patients on optimized dopaminergic therapy  Typical antimuscarinic effects:
 ROA – subcutaneous injection o Sedation
 Rapidly taken up in the blood and then the brain o Mydriasis
 Clinical benefit within about 10 minutes of injection o Urinary retention
and persists for up to 2 hours o Constipation
 Adequate benefit achieved at maximum of 10 mg o Dry mouth
 Trimethobenzamanide (antiemetic) given 3 days before
apomorphine administration and continued for a month 2. BIPERIDEN (Akineton), ORPHENADRINE,
PROCYCLIDINE, TRIHEXYPHENIDYL (Artane)
ADVERSE EFFECTS  Similar antimuscarinic agents with CNS effects
 Persistent nausea (TX: trimethobenzamanide)
 Dyskinesia CLINICAL USES
 Drowsiness  Treatment starts with a low dose of anticholinergic
 Chest pain o Gradual  in dose until benefit occurs or until adverse
 Sweating effects limit further increment
 Hypotension
 Bruising at injection site CONTRAINDICATIONS
 Angle-closure glaucoma
AMANTADINE (SYMMETREL)  Benign prostatic hyperplasia
 Antiviral agent with antiparkinsonism properties  GI obstruction
 Mechanism of action
o Potentiates dopaminergic functions by influencing DRUG INTERACTION
synthesis, release, or reuptake of dopamine
 Tricyclic antidepressants
 Antihistamines

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d. Vanillylmandelic acid is a metabolite

OTHER TREATMENT MODALITIES
3. Fluctuation NOT related to timing of L-dopa intake:
a. End-of-dose akinesia
SURGICAL PROCEDURES
b. On-off phenomenon
 Patients with advanced disease that is poorly c. Wearing-off reaction
responsive to pharmacotherapy d. None of the above
 Procedures:
o Thalamotomy for conspicuous tremor 4. Sinemet is a combination of:
o Posteroventral pallidotomy a. L-dopa + carbidopa + entacapone
o High-frequency deep brain stimulation to induce b. L-dopa + dopa decarboxylase inhibitor
functional, reversible lesions c. L-dopa + entacapone
o Implanted electrode and stimulator to stimulate d. L-dopa + MAO inhibitor
subthalamic nucleus or globus pallidus
o Transplantation of dopaminergic tissue 5. All are non-ergot dopamine agonists except:
a. Apomorphine
NEUROPROTECTIVE THERAPY b. Bromocriptine
 Antioxidants c. Pramipexole
 Antiapoptotic agents d. Ropinirole
 Glutamate antagonists
 Intraparenchymal glial-derived neurotrophic factor 6. Serotonin syndrome is a life-threatening drug-drug
 Coenzyme Q10 interaction of all of the following except:
 Creatine a. MAOI + meperidine
 Anti-inflammatory drugs b. MAOI + SSRI
c. MAOI + TCAD
GENE THERAPY d. MAOI + tyramine
 Infusion of adeno-associated virus type 2 into striatum
o Genes for: 7. Tolcapone, a catechol-O-methyltransferase inhibitor, has
 Glutamic acid decarboxylase all of the following properties except:
 Aromatic acid decarboxylase –  metabolism of a. Central and peripheral action
L-dopa to dopamine b. Hepatotoxic potential
 Neurturin – growth factor that may enhance the c. High potency
survival of dopaminergic neurons d. Long-acting

8. Apomorphine, a dopamine agonist, has all of the

THERAPY FOR NON-MOTOR MANIFESTATIONS
following properties except:
 Cognitive decline a. Ergot derivative
o Rivastigmine b. Given as subcutaneous injection
o Memantine c. Pro-emetic
o Donepezil d. Useful in off-periods of akinesia
 Affective disorders
o Antidepressants 9. Amantadine has all of the following properties except:
o Anxiolytic agents (barbiturates, benzodiazepines) a. Adenosine antagonist
 Excessive daytime sleepiness b. Helpful in reduction of iatrogenic dyskinesias
o Modafinil c. Livedo reticularis included in adverse effects
d. Originally an antibacterial agent
RECOMMENDATIONS IN MANAGEMENT
 Mild parkinsonism 10. Benztropin, an anticholinergic antiparkinsonian agent,
o Symptomatic treatment best avoided until there is has all of the following properties except:
some degree of disability a. Acts on basal ganglia M receptors
 Progression b. Ineffective in relieving tremors and rigidity
o Start with dopamine agonists or in combination with c. Little effect in bradykinesia
low-dose Sinemet d. Muscarinic receptor antagonist
 Severe parkinsonism or on-off phenomenon
o Trial with COMT inhibitor
 Young patients or mild parkinsonism
o Selegiline or rasagiline

REVIEW QUESTIONS
1. Characteristic of Parkinson's disease:
a. Intention tremor
b. Postural tremor
c. Resting tremor
d. None of the above

2. All are pharmacokinetic properties of L-dopa except:

a. Crosses blood-brain barrier Masked (mask-like facies), robotic (bradykinesia), loves to
b. Peripheral metabolism > CNS entry shuffle (shuffling gait). Yep. He has Parkinson's.
c. Rapid enteric absorption

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