1. Objectives Description of Parkinson's disease
The neurotransmitter model
Use of levodopa
Agents which enhance dopaminergic activity
Anticholinergic agents
New approaches..

2. Description Signs of the disease muscular rigidity (cog-wheel)
bradykinesia
resting tremor (pill-rolling)
characteristic flexed posture and shuffling gait
loss of normal associated movement
little spontaneous movement
slow initiation of voluntary movement..

3. Historical evidence - a great story - the first piece
Biogenic amines - amphetamine
originally given for excess sleepiness
found to relieve symptoms
Clue ==> enhanced biogenic amine activity is a positive factor
Atropine
given for excess salivation
anticholinergic agents relieved symptoms
Clue ==> enhanced cholinergic activity is a negative factor..

4. The second piece - drug-induced extra-pyramidal disorders
Drugs which deplete dopamine (reserpine) or block receptors (antipsychotics: chlorpromazine, haloperidol, etc.) cause Parkinson effects
A decrease in dopamine in the basal ganglia
MPTP - may be related to cell damage caused by excitatory amino acids at NMDA receptors..

5. Neurotransmitter model
Disorder

6. Treatment approaches Dopaminergic drugs Anticholinergic agents
augment defective inhibitory systems: l-DOPA
probably involves D2 receptors
D2 agonists: Pramipexole, Ropinirole and Bromocriptine, are used for effective treatment
potent D2 blockers, butyrophenones (other anti-schizophrenic drugs), cause the syndrome
Anticholinergic agents
may be used for mild cases
used as adjunctive therapy with dopaminergic drugs
for drug-induced extrapyramidal effects
Treatment does not reverse the disease process..

7. The dopamine picture
Rotigotine

8. The use of levodopa Stimulating dopamine synthesis
Therapy with levodopa
Side/toxic effects
Combination of a peripheral dopa-decarboxylase inhibitor - Carbidopa
Interactions/precautions..

9. Rate-limiting step in dopamine synthesis( )
Tyrosine hydroxylase is the rate-limiting step in the synthesis dopamine
By-pass the bottleneck in the remaining healthy neurons by giving dopa to synthesize more dopamine..

10. Therapy with levodopa
Goal: low doses at small intervals - side-effects are then reduced
Improvement may take several weeks
70% respond well
90% obtain relief for 5 years
neuronal deterioration occurs
levodopa can no longer be converted to dopamine
new dopaminergic agonists are important agents
Fluctuations in therapeutic response may occur..

11. Side/toxic effects
Gastrointestinal - nausea, vomiting (Chemoreceptor Trigger Zone)
Cardiovascular/autonomic
orthostatic hypotension in 30% - tolerance occurs
ß-adrenergic stimulation of the heart in patients with pre-existing problems
Endocrine - growth hormone increases, prolactin decreases..

12. Side/toxic effects Abnormal involuntary movements
choreiform or faciolingual problems
after 5-8 years, many patients have dose-related dyskinesias (chorea, dystonia)
Psychiatric/behavioral problems - about 15%
the dopamine hypothesis for schizophrenia
reports of increased compulsive behavior
cognitive defects may be related to decreased cholinergic activity..

13. Addition of carbidopa
Much of the l-dopa is converted to dopamine in the periphery which doesn't cross the blood-brain-barrier>>
Carbidopa

14. Addition of carbidopa
Without carbidopa, large doses are administered to obtain small amounts in the CNS which are converted to the necessary dopamine
With cabidopa, smaller overall doses are effective
half-life is min.
daily amount is divided into 3-6 doses to reduce side effects
Prevention of peripheral conversion allows for lower doses>>

15. Addition of carbidopa

16. Cost/benefit ratio to the combination
Advantages
Can reduce the effective dose of levodopa by 75%
Nausea and vomiting are reduced
Effective dose levels are achieved more rapidly
Control is more even - diurnal variation is reduced
Per cent of patients helped is greater..

17. Benefit/cost ratio to the combination
Disadvantages
Orthostatic hypotension is not helped
Involuntary movements may occur earlier, be more severe, and last longer
Adverse mental effects occur earlier
Combination of levodopa and carbidopa is SINEMET..

18. Interactions/precautions
Acute psychosis, psychoneurosis
Caution with other adrenergic agents in asthma or emphysema
MAO-A inhibitors
act primarily on norepinephrine and serotonin
effects of dopamine (converted to norepinephrine) may be exaggerated or unpredictable - hypertension, hyperpyrexia..

19. Peripheral enhancers of dopaminergic activity
COMT inhibitors (similar approach to Carbidopa)
Entacapone (COMTAN) prevents the conversion of dopa to 3-O-methyl DOPA peripherally
thereby prolonging its half-life and enhancing entry into the CNS
other COMT-metabolized drugs will have an increased duration of activity
a useful adjunct especially in patients with an "end of dose" fluctuating response to treatment >>

20. Peripheral enhancers of dopaminergic activity

21. Peripheral enhancers of dopaminergic activity
Tolcapone (TASMAR), a similar more potent agent is more hepatotoxic is reserved for patients not responding to entacapone
There is now a combination product available
Stalevo is a combination of levodopa, carbidopa and entacapone

22. Central enhancers of dopaminergic activity
Dopaminergic agonists
Pramipexole (MIRAPEX) and Ropinirole (REQUIP) are agonists at D2 and D3 receptors
may be used as initial treatment, fewer on/off issues, longer duration of action, less likely to induce dyskinesias (movement difficulties)
can reach therapeutic levels more rapidly
reduces levodopa requirement and smoothes the response
Both drugs have been approved for “restless leg syndrome”..

23. Central enhancers of dopaminergic activity
Dopaminergic agonists
Rotigotine (NEUPRO) is a D3/D2/D1 dopamine agonist
Used in a once daily patch
Side effects include irritation at the site of application
CNS - dizziness, headache, somnolence
GI - nausea, vomiting
poor impulse control - pathologic gambling, excessive shopping, binge eating or hypersexuality (previously reported with levodopa)..

24. Central enhancers of dopaminergic activity
These have largely replaced Bromocriptine (PARLODEL) - D2 agonist (ergot derivative)..
DOPA induction of free radicals may contribute to cell death; agonists do not change the course of the disease..

25. Central enhancers of dopaminergic activity
Amantidine
antiviral agent - NMDA -antagonist
the exact mechanism in PD is unknown
usual CNS dopaminergic side-effects, psychosis..

26. Central enhancers of dopaminergic activity
Deprenyl/selegiline - an MAO-B inhibitor - affects predominately dopamine at the doses used
preserves dopamine in the basal ganglia
allows for lower doses of l-dopa and more even drug effect
probably does not slow the disease progression as originally thought..

27. Enhancers of dopaminergic activity
Rasagiline (AZILECT) - another MAO-B inhibitor that is completing clinical trials
may not be as selective for dopamine, as there are major precautions against use with antidepressants that raise serotonin - serotonin syndrome (tachycardia, hypertension, hyperthermia, muscular rigidity)
should not be used with meperidine, propoxyphene, tramaol, methadone, mirtazapine, cyclobenzaprine, dextromethorphan and St. John’s Wort because their breakdown is slowed
should not be used with sympathomimetics..

28. Central enhancers of dopaminergic activity
About MAO-B inhibitors
early thoughts were that they were neuroprotective and slow the advancement of PD
this was later dispelled, particularly because selegiline is metabolized to amphetamine derivatives that may be neurotoxic
Rasagiline may have neuroprotective and anti-apoptotic effects on dopaminergic neurons
distinctive benefits remain to be seen..

29. Central enhancers of dopaminergic activity
Apomorphine has been introduced in advanced Parkinson patients with significant “off” periods
A specific dopamine agonist at the CTZ causing nausea
Other typical dopaminergic side effects occur
orthostatic hypotension
confusion and other CNS effects..

30. Anticholinergic agents
Historical background - the use of atropine
Effective anticholinergic agents
trihexyphenidyl (ARTANE)
benztropine (atropine/diphenhydramine)
others: antihistamines, phenothiazines..

31. Anticholinergic agents
Only approach for drug-induced Parkinson effects>>
Benztropine
Trihexyphenidyl

32. Anticholinergic agents
Effectiveness - 25%
begun with small doses until side-effects are too severe
may be used with dopaminergic agents
Side/toxic effects
dry mouth, failure to accommodate
constipation, urinary retention
heat stroke (no sweating)
elderly: delirium, confusion
Precautions/interactions
glaucoma, prostatic hypertrophy..

33. New approaches Lesions/microstimulators Tissue implants
a return to an older approach, now more precise for relieving tremor and rigidity
Tissue implants
adrenal medullary tissue
fetal brain tissue - MPTP patients..

34. Review of Rotigotine therapy

35. Initial therapy - NEJM ‘05, Treatment Guidelines ‘07
First-line dopaminergic agents
Carbidopa plus levodopa
Carbidopa plus levodopa plus entacapone
Dopamine agonists
Non-ergot: pramipexole, ropinirole, rotigotine
Ergot: pergolide
Second-line agents
Anticholinergic: trihexyphenidyl, benztropine
Selective MAO-B antagoinist - selegiline
NMDA antagonist: amantadine..

36. Considerations on management
Effectiveness of levodopa diminishes with time
Adverse l-DOPA effects increase
Some suggest avoiding treatment until symptoms or disability affect lifestyle
Suggest using dopamine agonists instead of levodopa in younger patients..

37. Considerations on management
With disease progression, begin dopaminergic therapy
levodopa/carbidopa/entacapone and an agonist
a peripheral COMT inhibitor can be added as levodopa control is difficult or wanes
consider adding selegiline as control becomes more difficult
apomorphine may be added to deal with “off” drug periods in advanced patients..

38. Costs