1. Pharmacologic Management of Parkinson disease (PD)
Chapter 28
Pharmacologic Management of Parkinson disease (PD)

2. Overview of Parkinson's Disease
PD is a progressive neurological disorder of muscle movement, characterized by combination of rigidity, bradykinesia, resting tremor, and postural instability
It generally affects the elderly and is estimated to afflict more than 1% of individuals over the age of 65
PD is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum-parts of the brain's basal ganglia system that are involved in motor control

3. Overview of Parkinson's Disease
Thus, the normal modulating inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly diminished, resulting in overproduction or a relative over-activity of acetylcholine by the stimulatory neurons
This triggers a chain of abnormal signaling, resulting in loss of the control of muscle movements

4. + _ _ NEOSTRIATUM SUBSTANTIA NIGRA STIMULATORY Ach NEURONE
Connection to muscle through motor cortex and spinal cord
STIMULATORY Ach NEURONE + _
NEOSTRIATUM
Cell death results in less dopamine release in the neostriatum
SUBSTANTIA
NIGRA _

5. Strategy of treatment
Since there is no cure for PD, the aim of pharmacological therapy is to provide symptomatic relief
This is obtained re-establishing the correct dopamine/acetylcholine balance through the use of drugs that either increase dopaminergic actions or antagonizing the excitatory effect of cholinergic neurons

6. Drugs Used in Parkinson's Disease
Drugs used in Parkinson’s disease include:
Levodopa
Dopamine agonists
Monoamine oxidase (MAO) inhibitors
Cathechol-O-methyl transferase (COMT( inhibitors
Anticholinergic agents
Amantadine

7. Levodopa
Levodopa is the single most effective agent in the treatment of PD
It is immediate metabolic precursor of DA
Levodopa is itself largely inert
levodopa, as an a.a, is transported into the brain by a.a transport systems
Therapeutic and adverse effects of levodopa result from its decarboxylation to dopamine
Oral levodopa is absorbed rapidly from the small intestine by the transport system for aromatic amino acids

8. Aromatic Amino Acid Decarboxylase
Na+
DOPA
Aromatic Amino Acid Decarboxylase
Tyrosine
Hydroxylase
Dopamine
Tyrosine
MAO H+ DA
DOPAC
COMT
Uptake 1
HVA
HVA DA
Uptake 2
Dopamine receptor
HVA DA
MAO
COMT
3MT

9. Levodopa
Certain a.as from ingested food can compete with levodopa for absorption from gut & for transport from blood to brain
About 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the BBB
It is combined with a peripheral dopa decarboxylase inhibitor (e.g .carbidopa)

10. Carbidopa A dopa decarboxylase inhibitor that does not cross the BBB
Carbidopa diminishes the metabolism of levodopa in the GIT and peripheral tissues:
Increases the availability of levodopa to the CNS
Lowers the dose of levodopa needed by about 10-fold
Decreases the severity of the side effects arising from peripherally formed dopamine

11. Levodopa Clinical use
Levodopa is widely used for treatment of all types of PD except those associated with antipsychotic drug therapy
Levodopa substantially reduces the severity of all the signs and symptoms of PD in the first few years of treatment
Patients then typically experience a decline in response during the third to fifth year of therapy (progression of the disease and the loss of striatal dopamine nerve terminals)

12. Levodopa ADRs Gastrointestinal tract (GIT)
Anorexia, nausea, and vomiting (likely due to dopamine’s stimulation of the CTZ)
Minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly
When levodopa is given in combination with carbidopa, adverse GIT effects are much less frequent & patients can tolerate proportionately higher doses

13. Levodopa ADRs Cardiovascular effects
Cardiac arrhythmias: caused by increased catecholamine formation peripherally
Postural hypotension as a result of the peripheral decarboxylation of levodopa and release of dopamine into the circulation
Incidence can be reduced if levodopa is taken in combination with Carbidopa

14. Levodopa ADRs Dyskinesias
Occur in up to 80% of patients receiving levodopa within 2 years of starting levodopa therapy
Are excessive and abnormal choreiform/ involuntary movements of the limbs, hands, trunk, and tongue
The development of dyskinesias is dose-related that occur most often when the plasma levodopa concentration is high
There is considerable individual variation in the dose required to produce them

15. Levodopa ADRs Fluctuations in Response
Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues
Wearing-off phenomenon/ end-of-dose akinesia:
Related to the timing of levodopa intake
Each dose of levodopa effectively improves mobility for a period of time (1–2 hrs), but rigidity and akinesia return rapidly at the end of the dosing interval
Increasing the dose and frequency of administration can improve this situation

16. Levodopa ADRs Fluctuations in Response On-off phenomenon
Fluctuations in response are unrelated to timing of doses
Patients fluctuate rapidly between being “off,” having no beneficial effects from their medications, and being “on” but with disabling dyskinesias
Can be reduced by: using a sustained-release formulation, division of the total daily dose into more frequently administered portions, coadministration of COMT inhibitors or selegline, and regulation of dietary protein intake

17. Levodopa ADRs Behavioral Effects
Depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality
More common in patients taking levodopa in combination with carbidopa
The use the “atypical” antipsychotic agents (e.g., clozapine), which are effective in the treatment of psychosis but do not cause or worsen parkinsonism

18. Levodopa Careful management in patients with: Contraindications
Psychotic patients
Angle-closure glaucoma1
Careful management in patients with:
History of cardiac arrhythmias or recent cardiac infarction
Active peptic ulcer must be managed carefully
History of melanoma or with suspicious undiagnosed skin lesions2
1 Levodopa can cause severe mydriasis that would markedly aggravate the glaucoma
2 Levodopa is precursor of skin melanin

19. Monoamine Oxidase Inhibitors
Two types of monoamine oxidase have been distinguished in the nervous system (MAO-A and MAO-B)
The isoenzyme MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of dopamine in the brain
Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors
Selective MAO-B Inhibitors: Selegiline & Rasagiline

20. Monoamine Oxidase Inhibitors
Neither selegiline nor rasagiline should be taken by patients receiving meperidine (stupor, rigidity, agitation, and hyperthermia)
They should be used with care in patients receiving TCAs or SSRIs b/c of the theoretical risk of acute toxic interactions of the serotonin syndrome type
ADEs:
Most related to the increased levels of dopamine
Anxiety, insomnia (selegline)
Metabolites of selegiline include amphetamine and methamphetamine

21. Catechol-O-Methyltransferase Inhibitors
Normally, the methylation of levodopa by catechol-O-methyltransferase (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism
However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS
Selective COMT inhibitors: tolcapone & entacapone

22. Effect of entacapone on dopa concentration in the central nervous system (CNS). COMT = catechol-O-methyltransferase

23. Catechol-O-Methyltransferase Inhibitors
Entacapone is generally preferred: tolcapone has both central & peripheral effects, whereas effect of entacapone is peripheral
ADRs:
Increased levodopa exposure
Orange discoloration of urine
Hepatoxicity (tolcapone)

24. Dopamine Receptor Agonists
Dopamine agonists may delay the need to employ levodopa therapy in early PD and may decrease the dose of levodopa in advanced Parkinson's disease
Dopamine receptor agonists:
Ergot derivatives e.g. bromocriptine
Non-ergot derivatives e.g. apomorphine, pramipexole, ropinirole, and rotigotine
The differences between the ergot derivatives and the newer/ non-ergot agents reside primarily in their adverse effects, tolerability, and speed of titration

25. Dopamine Receptor Agonists ADRs
Gastrointestinal tract effects:
Anorexia, N & V: can be minimized by taking the medication with meals
Constipation, dyspepsia, and symptoms of reflux
Bleeding from peptic ulceration

26. Dopamine Receptor Agonists ADRs
Cardiovascular effects:
Postural hypotension common at the initiation of therapy especially with the ergot derivatives
Dose-related painless digital vasospasm with the ergot derivatives
Cardiac arrhythmias (discontinuation)
Peripheral edema

27. Dopamine Receptor Agonists ADRs
Dyskinesias: reversed by reducing the total dose of dopaminergic drugs
Mental Disturbances
Include confusion, hallucinations, delusions, and other psychiatric reactions which are more common and severe with dopamine receptor agonists than with levodopa
Disappear on withdrawal

28. Dopamine Receptor Agonists Contraindications
History of psychotic illness
Recent myocardial infarction
Active peptic ulceration
Peripheral vascular disease (ergot derivatives)

29. Acetylcholine-Blocking Drugs
Centrally acting antimuscarinic drugs include: benzotropine mesylate, biperiden, orphenadrine, procyclidine, & trihexphenidyl
Their efficacy in PD is likely due to the ability to block muscarinic receptors in the striatum
Are much less efficacious than levodopa and thus are most commonly used during the early stages of the disease or as an adjunct to levodopa therapy

30. Acetylcholine-Blocking Drugs ADRs
The adverse effects of these drugs are a result of their anticholinergic properties (CNS & peripheral effects)
CNS: mental confusion, delirium, and hallucinations
Peripheral: constipation, urinary retention, and blurred vision through cycloplegia, sinus tachycardia, & dry mouth
Are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis