_Pharmacologic_Management_of_Parkinsons_Disease_2_.ppt

To write a description on the pharmacological importance of Parkinson's disease, focus on key areas such as the role of medications in symptom management, disease progression, and the development of therapeutic strategies. Here's a brief outline to help:

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**Pharmacological Importance of Parkinson's Disease**

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by the progressive loss of dopamine-producing neurons in the brain, particularly in the substantia nigra. This dopamine deficiency leads to the hallmark motor symptoms of the disease, including tremors, rigidity, bradykinesia (slowness of movement), and postural instability. The pharmacological management of Parkinson's disease is crucial in improving patients' quality of life and managing symptoms.

1. **Dopamine Replacement Therapy**: The most common pharmacological treatment for Parkinson’s is levodopa, a precursor to dopamine. Levodopa is often combined with carbidopa to enhance its effectiveness and reduce peripheral side effects. Dopamine agonists, such as pramipexole and ropinirole, mimic dopamine’s effects and are also widely used.

2. **MAO-B Inhibitors and COMT Inhibitors**: These drugs prevent the breakdown of dopamine, extending its availability in the brain. MAO-B inhibitors (e.g., selegiline, rasagiline) and COMT inhibitors (e.g., entacapone) help to reduce "off" periods in which the medication's effects wear off.

3. **Symptom-Specific Drugs**: Pharmacological interventions are also tailored to address non-motor symptoms such as depression, anxiety, and sleep disturbances, which are common in PD. Anticholinergic drugs and amantadine can be used to treat tremors and dyskinesia, respectively.

4. **Neuroprotective Strategies**: Research is ongoing to develop drugs that not only treat symptoms but also slow the progression of neuronal degeneration. Such neuroprotective strategies focus on halting or reversing the disease process, potentially offering long-term relief to patients.

5. **Emerging Therapies**: Advances in pharmacology, including gene therapy, stem cell treatments, and the development of novel drug delivery systems, represent the future of Parkinson's treatment. These emerging therapies aim to offer more targeted and effective treatments with fewer side effects.

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This description emphasizes the current pharmacological approaches to Parkinson’s disease, highlighting their significance in managing symptoms and exploring potential future therapies.

1. Pharmacologic Management
of Parkinson’s Disease
Mikael Jones, Pharm.D., BCPS

2. Parkinson’s Disease
•Classic sign/symptoms
–Bradykinesia
–Tremor
•Resting Pill-rolling tremor
–Rigidity
•Cog-wheel movements of extremities
–Posture/gait abnormalities
•Shuffling, wide stance gait
•Other signs
–Cognitive slowing
•Some will progess to dementia
–Speech problems
–“emotionless” expression
•Mase facies
–Small handwriting

3. Pathophysiology
•Basal ganglia
–Modulates motor function
–Parts of the Basal ganglia include
•Striatum
•Globus pallidus
•Substantia nigra
•Subthalamic nucleus
•Thalamus
–Interacts with motor cortex

4. Pathophysiology
•The striatium receives excitatory input
from the cortex
–Mediated by the excitatory neurotransmitter,
glutamate
•The striatum also receives inhibitory input
from inhibitory neurons mediated by GABA
•Dopamine neurons from the substantia
nigra project to both of these exicitatory
and inhibitory neurons

5. Pathophysiology
•In PD Dopaminergic neurons that project
from the substantia nigra to the striatum
die
•The loss of the striatal dopamine neurons
produces an imbalance in striatum
•The overall consequence is reduction in
the thalamic-cortical pathway
–Which leads to suppression of the motor
cortex

6. CORTEX
Striatum
Globus pallidus
Substantia
nigra, pars
compacta
Thalamus
Subthalamic
Nucleus
Substantia nigra,
pars reticulate
GLutamate
GABA
Dopamine
Ach

7. Striatum
Globus pallidus
Substantia nigra,
pars compacta
Substantia nigra, pars
reticulate
D1D2
__
+
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M

8. CORTEX
Striatum
Globus pallidus
Substantia
nigra, pars
compacta
Thalamus
Subthalamic
Nucleus
Substantia nigra,
pars reticulate
GLutamate
GABA
Dopamine
Ach
Direct
Pathway
↓ activity
Indirect
Pathway

9. Treatment of PD
•Since Dopamine neurons are deteriorating
then replace dopamine to restore balance
–Increasing available dopamine
–Give dopamine agonists

10. How do you increase Dopamine?
Tyrosine DOPA Dopamine
3-methoxytyramine
Dihydroxyphenyl acetic acid
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Monoamine
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11. How do you increase Dopamine?
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Monoamine
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Levodopa
Selegiline
COMT inhibitors

12. Treatment Options
•Levodopa/carbidopa
•Dopamine Agonists
•Selegiine
•Anticholinergics
•Amantadine
•COMT inhibitors

13. Levodopa/carbidopa
•Clinical Pharmacology
–Levodopa is the amino acid precursor to
dopamine
•Cross blood brain barrier
•Elevates dopamine levels in the striatum
–Carbidopa
•Inhibits peripheral decarboxylation of levodopa so
that enough can cross the blood brain barrier
–Need 75mg/day to inhibit peripheral dopamine
decarboxylase
–A first line therapy (many Neurologist will
delay until symptoms are bothersome)

14. Levodopa/carbidopa
•Pharmacokinetics
–When given as immediate release product
•Half 1-1.5 hours
–Slow-release product allows for few daily doses
•Clinical effects
–Improves bradykinesia and rigidity
•Contraindications
–Psychosis
–Angle-closure glaucoma

15. Levodopa/carbidopa
•Adverse Effects
–Acute
•Nausea/voming
•Tachycardia
•Arrhythmias
•Orthostatic hypotension
•Agitation
•Hallucinations
–Long-term
•“Wearing off” phenomenon
•“on-off” phenomenon
•Dyskinensias

16. Levodopa/carbidopa
•Immediate Release
–TID dosing
•Delayed (or controlled release)
–BID-TID dosing
–Don’t crush or split tablets
•Titrate dose and may need combination of
Immediate release and delayed

17. Dopamine Agonists
•Available Agents
–Bromocriptine
–Pergolide
–Pramipexole (also used for restless leg)
–Ropinirole (also used for restless leg)
•Clinical Pharmacology
–Directly stimulate dopamine receptors
•D2 receptor agonists
•Bromocriptine and pergolide are also ergot derivatives and
also are D1 partial antagonists
–Used as initial therapy or adjunctive to
Levodopa

18. Dopamine Agonists
•Adverse Effects
–GI upset
–Constipation
–Postural hypotension
–Dyskinesias
–Confusion
–Hallucinations
–Hypersexulaity
•Bromocriptine and pergolide
–Retroperitoneal, pleuropulmonary, or cardiac fibrosis possible
–Pramipexole and Ropinirole are preferred

19. Anticholinergics
•Typical agents
–Trihexyphenidyl
–Benztropine
–others
•Clinical Pharmacology
–Block muscarininc receptors in the striatum
–Reduces striatal activity
•Modest effect on treating symptoms
–More beneficial for tremors

20. Anticholinergics
•Adverse effects
–Dry mouth
–Urinary retention
–Dry eyes
–Constipation
–Confusion
•Adverse effects limit utility especially in
elderly patients

21. Amantadine
•Clinical Pharmacology
–Enhances dopamine release
–Blocks reuptake
–Stimualtes receptors
•Clinical Effects
–Improves tremor, rigidity, and bradykinesia
–Adjunctive therapy in advanced disease
–Possible initial therapy for mild disease

22. Amantadine
•Adverse Effects
–Hallucinations
–Vivid nightmares
–Nausea/vomiting
–Orthostatic hypotension
•Renal Adjustment for patients with renal
impairment

23. COMT inhibitors
•Available agents
–Tolcapone
–Entacapone
•Clinical Pharmacology
–Blocks the metabolism of dopamine and
levodopa therefore can increase availability of
levodopa
•Improves half-live of levodopa
•Utilized with Levodopa/carbidopa
–Given with each dose (max 8 tabs/day)

24. COMT inhibitors
•Adverse effects
–Tolcapone not used because of hepatotoxicity
–Dyskinesias
–Nausea
–Orange colored urine
–Hallucinations
–Recent concerns that Entacapone may
increase CV risk

25. Selegiline
•Monamine Oxidase type B inhibitor
•Used in early treatment as monotherapy
–May slow progression of early disease
–May be neuroprotective
•Adjunctive use may improve motor complicatoions
associated with long-term levodopa therapy
•ADRs
–Nausea
–Hallucinations
–Orthostatic hypotension
–Insomnia (because metabolized to amphetamine)
•At doses >9mg/day becomes like a MOA type A inhibitor
–Tyramine-restricted diet
–Do not give with TCAs, SSRis

26. Rasagiline
•Monamine Oxidase type B inhibitor
–Similar to Selegiline
–Can be used first line or adjunctive to
levodopa therapy
•Dosing: 1mg po daily for monotherapy
–0.5mg po daily with levodopa (can ↑ to 1mg)
•May need to decrease levodopa dose by 10% to
prevent dyskinesias

27. Rasagiline
•Adverse effects similar to selegiline
•Drug Interactions
–Contraindicated with meperidine
–Avoid tramadol, methadone,
dextromethorphan, sympathomimetics,
fluoxetine and ciprofloxaci

28. Apomorphine
•Stimulates postsynaptic D2-type receptors
within the caudate putamen in the brain
•Treatment of hypomobility, “off” episodes
with Parkinson's disease
•SC injection give when patient
experiences off episode (~multiple
injections per day)
•Causes significant nausea and
hypotension

29. Apomorphine
•Patient’s must be started in clinician’s
office because of test dose procedure
•Must start the antiemetic
trimethobenzamide (Tigan) 3 days prior to
test dosing
–CANNOT USE 5HT3 antagonists as they
increase risk of hypotension
•Dosing depends on test dose tolerance
~2mg-6mg/dose 3 times per day

30. General Approach to Treatment
•Initial therapy added when sxs become
bothersome
–MAO-B inhibitors for mild sxs for some
patients
–Levodopa or dopamine agonists are typical 1
st

line therapy
•Levodopa provides better motor control than
dopamine agonists

31. General Approach to Treatment
•Adjunctive therapy
–If on Dopamine agonist add levodopa
–If on levodopa (800-1000mg/day) add next
agent based on patient’s characteristics
•Watch for symptoms of excess dopamine and
decrease levodopa as necessary

32. General Approach to Treatment
•“wearing off”
–Occur when last dose of Carbidopa/levodopa stops working
–Add dopamine agonist
–Add COMT
–Increase frequency/dose of levodopa
•“on-off”
–Fluctuation of response to drug
•Periods of improved symptoms alternating with poor symptom control
–Add COMT
–Examine protein intake as protein decrease absoprtion of levodopa
•Dyskinesias with levodopa/carbidopa
–Remove selegiline
–Decrease levodopa dose
–Add amantadine
•Hallucinations/psychosis
–D/c/reduce dose of PD medication
–Add antipsychotic with least amount of dopamine antagonism
•Quetiapine or clozapine