Other treatment modalities for parkinsonism: monoamine oxidase inhibitors, COMT inhibitors, amantadine, surgical procedures...

1. Parkinsonism: MAO-i,
COMT-i and other
Domina Petric, MD

2. Monoamine oxidase inhibitors
I.
Katzung, Masters, Trevor.
Basic and clinical

3. Monoamine oxidase inhibitors
• Monoamine oxidase A metabolizes
norepinephrine, serotonin and dopamine.
• Monoamine oxidase B metabolizes
dopamine selectively.
• Selegiline (deprenyl) is a selective
irreversible inhibitor of monoamine oxidase
B at normal doses, but at higher doses it
inhibits monoamine oxidase A as well.
Katzung, Masters, Trevor.
Basic and clinical

4. Monoamine oxidase inhibitors
• Selegiline retards the breakdown of dopamine.
• It enhances and prolongs the antiparkinsonism
effect of levodopa and may reduce mild on-off
or wearing-off phenomena.
• Selegiline is used as adjunctive therapy for
patients with a declining or fluctuating
response to levodopa.
• Standard dose is 5 mg with breakfast and 5 mg
with lunch.
Katzung, Masters, Trevor.
Basic and clinical

5. Monoamine oxidase inhibitors
Selegiline may cause insomnia when
taken later during the day.
Selegiline has only a minor
therapeutic effect on parkinsonism
when given alone.
Katzung, Masters, Trevor.
Basic and clinical

6. Rasagiline
• It is monoamine oxidase B inhibitor.
• It is more potent than selegiline in preventing
MPTP-induced parkinsonism.
• It is being used for early symptomatic treatment.
• The standard dosage is 1 mg/day.
• Rasagiline is also used as adjunctive therapy at a
dosage of 0,5 or 1 mg/day to prolong the effects of
levodopa-carbidopa in advanced disease.
Katzung, Masters, Trevor.
Basic and clinical

7. Monoamine oxidase inhibitors
• Neither selegiline nor rasagiline should be taken
by patients receiving meperidine, tramadol,
methadone, propoxyphene, cyclobenzaprine or
St. John´s wort.
• The antitussive dextromethorphan should be
also avoided.
• It is wise to advise patients to avoid all
over-the-counter cold preparations.
Katzung, Masters, Trevor.
Basic and clinical

8. Monoamine oxidase inhibitors
• Rasagiline or selegiline should be used with
care in patients receiving tricyclic
antidepressants or SSRIs: SEROTONIN
SYNDROME.
• The combined administration of levodopa and
nonselective monoamine oxidase inhibitor
must be avoided: HYPERTENSIVE CRISES
(peripheral accumulation of norepinephrine).
Katzung, Masters, Trevor.
Basic and clinical

9. Catechol-O-methyltransferase
inhibitors (COMT-i)
II.
Katzung, Masters, Trevor.
Basic and clinical

10. COMT-i
Inhibition of dopa decarboxylase is
associated with compensatory activation of
other pathways of levodopa metabolism:
• catechol-O-methyltransferase (COMT)
• increase of plasma levels of
3-O-methyldopa (3-OMD)
Katzung, Masters, Trevor.
Basic and clinical

11. COMT-i
• Elevated levels of 3-OMD have been
associated with a poor therapeutic
response to levodopa.
• 3-OMD competes with levodopa for an
active carrier mechanism that governs its
transport across the intestinal mucosa
and the blood-brain barrier.
Katzung, Masters, Trevor.
Basic and clinical

12. COMT-i
• Selective COMT inhibitors (COMT-i) tolcapone
and entacapone prolong the action of levodopa
by diminishing its peripheral metabolism.
• Levodopa clearance is decreased: relative
bioavailability of levodopa is increased.
• COMT-i may be helpful in patients receiving
levodopa who have response fluctuations:
smoother response, more prolonged on-time,
reduction of total daily levodopa dose.
Katzung, Masters, Trevor.
Basic and clinical

13. COMT-i
• Entacapone is preferred because it has
not been associated with hepatotoxicity.
• COMT-i are rapidly absorbed, bound to
plasma proteins and metabolized before
excretion.
• Tolcapone has both central and peripheral
effects.
• The effect of entacapone is peripheral.
Katzung, Masters, Trevor.
Basic and clinical

14. COMT-i
• The half-life of COMT-i is approximately 2
hours.
• Tolcapone is slightly more potent and has a
longer duration of action.
• It is taken in a standard dosage of 100 mg three
times daily.
• Entacapone 200 mg needs to be taken with
each dose of levodopa up to five times daily.
Katzung, Masters, Trevor.
Basic and clinical

15. COMT-i
• Adverse effects that relate to increased
levodopa exposure are dyskinesias, nausea and
confusion.
• It is often necessary to lower the daily dose of
levodopa by about 30% in the first 48 hours.
• Other adverse effects: diarrhea, abdominal
pain, orthostatic hypotension, sleep
disturbances, orange discoloration of the urine.
Katzung, Masters, Trevor.
Basic and clinical

16. COMT-i
Tolcapone may cause an
increase in liver enzyme
levels and has been
associated rarely with death
from acute hepatic failure.
Katzung, Masters, Trevor.
Basic and clinical

17. Stalevo
• Levodopa-carbidopa-entacapone!
• Stalevo 50: 50 mg-12,5 mg-200 mg.
• Stalevo 100: 100 mg-25 mg-200 mg.
• Stalevo 150: 150 mg-37,5 mg-200 mg.
• Use of Stalevo rather than levodopa-
carbidopa has been associated with
earlier occurrence and increased
frequency of dyskinesia.
Katzung, Masters, Trevor.
Basic and clinical

18. Amantadine
III.
Katzung, Masters, Trevor.
Basic and clinical

19. Amantadine-antiviral agent
Its mode of action in parkinsonism may include some
of the following mechanisms:
• Potentiation of dopaminergic function by
influencing the synthesis, release or reuptake of
dopamine.
• Antagonization of the effects of adenosine at
adenosine A2A receptors: these receptors may
inhibit D2 receptor function.
• Release of catecholamines from peripheral stores.
Katzung, Masters, Trevor.
Basic and clinical

20. Amantadine
Peak plasma concentrations of
amantadine are reached 1-4 hours after an
oral dose.
The plasma half-life is between 2 and 4
hours.
Most of the drug is being excreted
unchanged in the urine.
Katzung, Masters, Trevor.
Basic and clinical

21. Amantadine
• Amantadine is less efficacious than levodopa.
• Its benefits may be short-lived, often disappearing
after only a few weeks of treatment.
• During that time it may favorably influence the
bradykinesia, rigidity and tremor of parkinsonism.
• Dosage: 100 mg orally two or three times daily.
• It may help in reducing iatrogenic dyskinesias in
patients with advanced disease.
Katzung, Masters, Trevor.
Basic and clinical

22. Amantadine
• CNS adverse effects: restlessness, depression,
irritability, insomnia, agitation, excitement,
hallucinations and confusion.
• Overdosage may produce an acute toxic
psychosis.
• Very high doses may produce convulsions.
• Livedo reticularis clears within 1 month after
the drug withdrawal.
Katzung, Masters, Trevor.
Basic and clinical

23. Amantadine
• Peripheral edema is not accompanied by signs
of cardiac, hepatic or renal disease.
• Amantadine-caused edema responds to
diuretics.
• Other adverse reactions: headache, heart
failure, postural hypotension, urinary retention
and gastrointestinal disturbances (anorexia,
nausea, constipation, dry mouth).
Katzung, Masters, Trevor.
Basic and clinical

24. Amantadine
Amantadine should be
used with caution in
patients with a history of
seizures or heart failure.
Katzung, Masters, Trevor.
Basic and clinical

25. Acetylcholine-blocking drugs
IV.
Katzung, Masters, Trevor.
Basic and clinical

26. Acetylcholine-blocking drugs
Centrally acting antimuscarinic
preparations may improve the
tremor and rigidity of
parkinsonism, but have little
effect on bradykinesia.
Katzung, Masters, Trevor.
Basic and clinical

27. Acetylcholine-blocking drugs
Drug Usual daily dose (mg)
Benztropine
mesylate
1-6
Biperiden 2-12
Orphenadrine 150-400
Procyclidine 7,5-30
Trihexyphenidyl 6-20
Katzung, Masters, Trevor.
Basic and clinical

28. Acetylcholine-blocking drugs
Treatment is started with a low dose of
one of the drugs in this category.
The dosage is gradually being increased
until benefit occurs or until adverse
effects limit further increments.
Katzung, Masters, Trevor.
Basic and clinical

29. Acetylcholine-blocking drugs
These drugs are poorly tolerated by the
elderly.
If medication has to be withdrawn, this
should be accomplished gradually.
Abrupt cessation of drug may cause acute
exacerbation of parkinsonism.
Katzung, Masters, Trevor.
Basic and clinical

30. Other treatment modalities for
parkinsonism
V.
Katzung, Masters, Trevor.
Basic and clinical

31. Surgical procedures
Thalamotomy for conspicuous tremor
Posteroventral pallidotomy
High-frequency deep brain
stimulation
Katzung, Masters, Trevor.
Basic and clinical

32. Surgical procedures
High-frequency deep brain stimulation:
stimulation of the subthalamic nucleus or globus
pallidus by an implanted electrode.
Such procedures are contraindicated in patients
with secondary or atypical parkinsonism,
dementia or failure to respond to dopaminergic
medication.
Katzung, Masters, Trevor.
Basic and clinical

33. Surgical procedures
Transplantation of
dopaminergic tissue (fetal
substantia nigra tissue):
symptomatic benefit in
younger patients.
Katzung, Masters, Trevor.
Basic and clinical

34. Neuroprotective therapy
• antioxidants
• antiapoptotic agents
• glutamate
antagonists
• intraparenchymally
administered glial-
derived neurotrophic
factor
• coenyzme Q10
• creatine
• anti-
inflammatory
drugs
• rasagiline
Katzung, Masters, Trevor.
Basic and clinical

35. Gene therapy
• Infusion into the striatum of adeno-associated virus
type 2 as the vector for the gene.
• Gene for glutamic acid decarboxylase (GAD, to
facilitate synthesis of GABA) infused into the
subthalamic nucleus to cause inhibition.
• Gene for aromatic acid decarboxylase (AADC)
infused into the putamen to increase metabolism
of levodopa to dopamine.
• Gene for neurturin (growth factor that may
enhance survival of dopaminergic neurons) infused
into the putamen.
Katzung, Masters, Trevor.
Basic and clinical

36. Therapy for nonmotor manifestations
Cognitive
decline
• Rivastigmine
1,5-6 mg twice
daily
• Memantine 5-
10 mg daily
• Donepezil
5-10 mg daily
Affective
disorders
• Antidepressants
• Anxiolytic
agents
Excessive
daytime
sleepiness
• Modafinil 100-
400 mg in the
morning
Bladder and
bowel
disorders:
appropriate
symptomatic
therapy
Katzung, Masters, Trevor.
Basic and clinical

37. Conclusion
• Symptomatic treatment of mild parkinsonism is
probably best avoided until there is some
degree of disability or until symptoms begin to
have a significant impact on the patient´s
lifestyle.
• When symptomatic treatment becomes
necessary, a trial of rasagiline, amantadine or
an antimuscarinic drug (in young patients) may
be worthwhile.
Katzung, Masters, Trevor.
Basic and clinical

38. Conclusion
• With disease progression, dopaminergic
therapy becomes necessary: dopamine
agonist alone or in combination with low-
dose carbidopa-levodopa therapy.
• Dopamine agonist can be omitted and the
patient can start immediately on
carbidopa-levodopa therapy (older
patients).
Katzung, Masters, Trevor.
Basic and clinical

39. Conclusion
• Physical therapy is helpful in improving
mobility.
• In patients with severe parkinsonism and long-
term complications of levodopa therapy (on-off
phenomenon), a trial of treatment with a
COMT-i or rasagiline may help.
• Regulation of dietary protein intake may also
improve response fluctuations.
Katzung, Masters, Trevor.
Basic and clinical

40. Conclusion
• Deep brain stimulation is often helpful
in patients who fail to respond
adequately to these measures.
• Treating young patients or those who
have mild parkinsonism with rasagiline
may delay disease progression.
Katzung, Masters, Trevor.
Basic and clinical

41. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
Katzung, Masters, Trevor.
Basic and clinical