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

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

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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

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 O-methyldopa (3-OMD)
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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

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

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 pharmacology.

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

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 pharmacology.

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 pharmacology.

30. Other treatment modalities for parkinsonismV.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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

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 pharmacology.

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

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 pharmacology.

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 pharmacology.

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

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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