medical therapy of parkinsons disease.pptx

1. MEDICAL THERAPY OF PARKINSONS DISEASE
Dr. N. Vinay kumar
DM Neurology resident
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2. 2

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
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4. • 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
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5. • 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
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6. CORTEX
Striatum
Globus pallidus
Substantia
nigra, pars
compacta
Thalamus
Subthalamic
Nucleus
Substantia nigra,
pars reticulate
GLutamate
GABA
Dopamine
Ach
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7. Striatum
Globus pallidus
Substantia nigra,
pars compacta
Substantia nigra, pars
reticulate
D1
D2
__ +
__
M
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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
Neuronal imbalance in this brain region and
alterations of striatal outflow pathways (called
direct pathway and indirect pathway)
The direct pathway of the striatum to the
substantia nigra pars compacta becomes less
active
The indirect pathway (striatum to
globus pallidus to subthalamic
nucleus to substantia nigra pars
reticulate increase in activity
The consequence is an enhanced activation of the
par reticulate neurons which exert an overall
reduction of the thalamic-cortical pathway
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9. Treatment
• Pharmacologic- motor and non motor symptoms
• Nonpharmacologic
• Surgical therapy
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10. Pharmacological management Parkinson's
disease
• Medications restore dopaminergic activity → reduce symptoms,
improve quality of life
• Therapeutic options:
• Levodopa (increases dopamine supply)
• Dopamine agonists (increase activation of D2 and D3 receptors)
• N-methyl-D-aspartate (NMDA) receptor antagonists
• Monoamine oxidase(MAO) type B inhibitors
• Catechol O-methyltransferase (COMT) inhibitors
• Anticholinergics
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11. COMT: catechol O-methyltransferase
3-MT: 3-Methoxytyramine
3-OMD: 3-O-methyldopa
DOPAC: 3,4-dihydroxy-phenylacetic
acid
L-DOPA: levodopa
MAO-B: monoamine oxidase type B
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12. Levodopa
• Structure:
• Amino acid precursor of dopamine
• Levo rotatory stereoisomer of dopa (L-dopa)
• Mechanism of action:
• Levodopa crosses (BBB ); dopamine itself cannot cross the BBB .
• Converted to dopamine in the brain , even if the dopaminergic neurons are dying.
• Protected in the plasma from decarboxylation by concomitant administration of
carbidopa
• In the brain parenchyma, levodopa is decarboxylated to dopamine .
• Dopamine supply is restored → stimulates dopaminergic receptors
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13. Pharmacokinetics
• Absorption:
• Absorbed in 30–60 minutes, increased with high-fat/high-protein meals
• Oral preparations include carbidopa to prevent decarboxylation in the plasma.
• Distribution:
• Crosses the BBB
• Peak plasma concentration: 20–30 minutes
• Half-life: 30 minutes to 4 hours
• Metabolism: in the brain parenchyma → metabolized into dopamine
• Excretion: urine
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14. Adverse effects
• Nausea ,dizziness, headache, somnolence
• Arrhythmias:
• Ventricular extrasystole
• Atrial fibrillation
• Orthostatic hypotension
• Neuroleptic malignant syndrome(NMS)–like symptoms can be seen
with the sudden withdrawal of levodopa:
• Hyperthermia, confusion, muscle rigidity, diaphoresis, tachycardia
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15. Drug–drug interactions
• Dopamine antagonists may reduce therapeutic effects.
• Pyridoxine increases extracerebral metabolism → decreased bioavailability
Contraindications
• Pre existing neuropathy
• Combination with (MAOIs) → hypertensive crisis
• Requires 14 day washout period between either drug (MAOI or levodopa–
carbidopa)
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16. Dopamine Agonists
Chemistry and pharmacodynamics
• Dopamine agonists:
• Greater affinity for D2 and D3 receptors
• Inhibit anterior pituitary prolactin secretion
• Drugs include-Bromocriptine, Pramipexole, Ropinirole, Rotigotine
(transdermal patch), apomorphine
• Mechanism of action:
• Bind to dopamine receptors directly on the postsynaptic terminal
• The D2, D3, and D4 receptors couple to the Gi/o family of G proteins,
and dopamine agonists inhibit adenylyl cyclase and thus cAMP synthesis.
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17. Pharmacokinetics
• Absorption:
• Absorbed quickly, with peak plasma concentration in 30 minutes to 6 hours
• Available in immediate-acting or extended-release forms
• Distribution:
• Crosses the BBB
• Half-life: 5–12 hours
• Metabolism: hepatic cytochrome P450system (CYP1A2 and CYP3A4)
• Excretion: renal and fecal
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18. Indications
• Mild to moderate symptoms of PD
non-Parkinson indications for dopamine agonists:
• Pramipexole, ropinirole, and rotigotine: restless legs syndrome
• Bromocriptine: Hyperprolactinemia due to prolactin-
secreting pituitary adenoma and Acromegaly
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19. Adverse effects
• Sleep attacks, particularly with pramipexole and ropinirole
• Nausea/vomiting, Dizziness, Orthostatic hypotension, Headache,
Cardiac arrhythmia, Dyskinesias
• Long-term use may cause:
• Choreiform and dystonic movements
• Psychiatric symptoms: Mania or depression, Hallucinations/psychosis,
Delusions
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20. Drug–drug interactions
• MAOIs ,Dopamine antagonists (1st- and 2nd-generation antipsychotics)
• Other drugs that are metabolized by cytochrome P450 enzymes
Contraindications
• History of psychotic illness
• Severe cardiovascular disease
• Postpartum or breastfeeding
• Type 1 diabetes
• Sleep disorder
• Alcohol use
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21. Amantadine (N-methyl-D-aspartate
Antagonist)
Chemistry and pharmacodynamics
• Structure: synthetic tricyclic amine
• Mechanism of action:
• Antagonist of the NMDA-type glutamate receptor → antidyskinetic effect
• May influence synthesis, release, or reuptake of dopamine
• Antagonizes the effects of adenosine at adenosine alpha-2-adrenergic
(A2A) receptors
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22. Pharmacokinetics
• Absorption: oral
• Distribution:
• Cross the BBB
• Onset of action: within 48 hours
• Peak plasma concentration: 2–12 hours, depending on the dosage form
• Half-life: 9–31 hours
• Metabolism: conjugation, other unknown mechanisms
• Excretion: urine (up to 90% unchanged)
Indications
• Originally used as a treatment for influenza A
• Recommended for mild Parkinsonian symptoms, specifically dyskinesia and rigidity:
• May be used in combination with other agents
• Therapeutic effect lasts only 1st few weeks.
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23. • Adverse effects- restlessness, depression, suicidal ideation, somnolence,
insomnia, agitation, hallucinations/psychosis.
Drug–drug interactions
• Clozapine: may cause severe constipation or ileus
• Trimethoprim: may increase amantadine levels and risk of psychosis
• Bupropion: may increase risk of adverse CNS effects
Contraindications
• Pregnancy and breastfeeding
• End-stage renal disease
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24. Monoamine Oxidase (MAO) Inhibitors
Chemistry and pharmacodynamics
• Classified as:
• Irreversible inhibitors: selegiline and rasagiline
• Reversible inhibitors: safinamide
• Mechanism of action:
• Types of MAO:
• Type A metabolizes norepinephrine, serotonin, and dopamine (used for depression).
• Type B metabolizes dopamine selectively (used for PD).
• In the brain parenchyma, MAO type B (MAO-B) is selectively inhibited →
increased intracerebral concentration of dopamine
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25. Pharmacokinetics
• Absorption: oral or transdermal
• Distribution:
• Crosses the BBB
• Peak plasma concentration: 1–3 hours, depending on the agent
• Onset of action: 2–3 weeks
• Half-life: 3–26 hours, depending on the agent
• Metabolism: hepatic (substrate of CYP1A2, CYP2D6, and other
CYP450 enzymes
• Excretion: renal and fecal, in different proportions, depending on the agent
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26. Indications
• Recommended as an adjunct therapy for individuals with PD
• taking levodopa–carbidopa who exhibit a deterioration in response to it.
• Transdermal form has also been used in individuals with major depressive
disorder.
Adverse effects
• Drug–food interactions can lead to a hypertensive crisis:
• Avoid foods with high tyramine levels
• Xerostomia
• NauseaDiarrhea or constipation
• Drowsiness or insomnia
• Dizziness
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27. Drug–drug interactions and
contraindications
• drugs that use the cytochrome P450 enzymesfor metabolism interact with MAO-
B inhibitors:
• CYP2B6 substrates NSAIDs: naproxen
• beta-blockers (bisoprolol) → additive hypotension
• Antidepressant bupropion → increased risk of hypertension
• Opioid pain medications
• Risk of serotonin syndrome with:
• SSRIs- fluoxetine, paroxetine
• SNRIs- duloxetine
• TCAs-amitriptyline
• Triptans
• Symptoms include altered mental status, autonomic instability, tremors, myoclonus, and
seizures
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29. Catechol O-methyltransferase (COMT)
Inhibitors
Chemistry and pharmacodynamics
• Structure: parent compound is 3-nitrobenzene-1,2-diol, also called
nitrocatechol.
• Drug names:Entacapone,tolcapone, opicapone
• Mechanism of action:
• COMT peripherally metabolizes levodopa into 3-O-methyldopa.
• COMT is selectively inhibited → increased bioavailability of levodopa →
prolonged action of levodopa
• Clearance of levodopa is also decreased → greater bioavailability
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30. Pharmacokinetics
• Absorption: oral
• Distribution:
• Act peripherally
• Peak plasma concentration:
1–2 hours
• Half-life: 1–3 hours
• Metabolism: hepatic
• Excretion: renal and fecal
Adverse effects
•Dyskinesia
•Hallucinations/psychosis
•Orthostatic hypotension
•Abdominal pain
•Sleep disturbances
•Orange discoloration of the urine
•Hepatotoxicity
•Abrupt discontinuation can cause
NMS-like symptoms
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31. • Drug–drug interactions
Codeine, metoclopramide, selegiline, promethazine, CCB, BZD
Contraindications
• History of neuroleptic malignant syndrome
• Liver disease
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32. 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
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33. • Adverse effects
• Dry mouth
• Urinary retention
• Dry eyes
• Constipation
• Confusion
• Adverse effects limit utility especially in elderly patients
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34. 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 1st line therapy
• Levodopa provides better motor control than dopamine agonists
• 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
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36. Changes in motor response associated with chronic levodopa treatment. Levodopa-induced
motor complications. Schematic illustration of the gradual shortening of the duration of a beneficial
motor response to levodopa (wearing off) and the appearance of dyskinesias complicating “on” time.
PD, Parkinson’s disease
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37. • “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
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39. Management of nonmotor symptoms in Parkinson disease
• Depression
• Apathy
• Anxiety
• Cognitive impairment
• Psychosis
• Insomnia and other sleep disorders
• Daytime sleepiness
• Fatigue
• Dysphagia
• Autonomic dysfunction-
Constipation, Sialorrhea,
Rhinorrhea, Sexual dysfunction,
Orthostatic hypotension
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40. Depression
• most common psychiatric disturbance and associated with suicidal
ideation and thoughts of death are common.
• Treatment — Patients with depression should be offered
antidepressants , CBT, or both
• AAN reviewed six small, RCT of pharmacologic treatment for
depression in patients with PD.
• SNRI or SSRI can be prescribed because of less adverse events than
TCA
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41. Safety considerations with SSRI use
• QT prolongation
• Exacerbation of motor symptoms – induce or worsen dystonia,
akathisia, tremor.
• Exacerbation of comorbid sleep disorders – worsens RLS and rapid
eye movement sleep behavior disorder (RBD).
• Serotonin syndrome-uncommon but serious adverse event on
combination of MAO B inhibitor with antidepressant.
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42. ANXIETY
• occur alone, or with depression.
• may be a symptom of wearing off of dopaminergic medication
• SSRIs such as citalopam, sertraline and SNRIs such as venlafaxine, mirtazapine
• Psychotherapy is also an option
• cannabinoids like nabilone is under trial
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43. PSYCHOSIS
• characterized mainly by visual hallucinations and delusions
• dopamine agonists are the important cause of psychosis.
• Also triggered by infection, delirium, dementia.
• Treatment includes PD medication adjustments.
pharmacologic treatment include
• Pimavanserin-. 34 mg daily
• Quetiapine-12.5 mg to100 mg
• Clozapine-12.5 mg to 50 mg
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45. FATIGUE
• Excessive daytime sleepiness (EDS) and depression are most common
and the most treatable identifiable causes
• empiric treatment amantadine and stimulants such
as methylphenidate and pemoline, are options.
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46. DYSPHAGIA
• All phases of swallow are impacted due to abnormalities in both
striated and smooth muscle function, ineffective tongue movements,
delayed swallow responses, and weak cough-expectoration response.
• contributes to sialorrhea and increases risk of aspiration and
pneumonia.
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47. Constipation
• related to autonomic dysfunction and slowed colonic transit time
• patient education, behavior modification and dietary changes and laxative
therapy.
• Polyethylene glycol , Probiotics.
• Lubiprostone, a locally acting chloride channel activator .
• alpha-synuclein deposited in the enteric nervous system, and therapies
targeting gut pathologic alpha-synuclein are under investigation
• ENT-01 (squalamine phosphate) is an oral steroid-polyamine conjugate that
displaces alpha-synuclein from enteric nerve cell membranes in preclinical
models.
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48. Sialorrhea
• Due to reduced oro motor control and autonomic dysfunction
• anticholinergic medications- glycopyrrolate, atropine, hyoscine,
sublingual ipratropium
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49. Sexual dysfunction
• Range from underactivity to hypersexuality
• Hypersexuality occur more in younger men and patients treated with
dopamine agonist therapy or DBS
• Erectile dysfunction may benefit from treatment
with sildenafil , tadalafil and vardenafil .
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50. Orthostatic hypotension —
• Caused by disease itself or the PD medications including levodopa,
dopamine agonists, and (MAO B) inhibitors
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54. Nonpharmacologic management of Parkinson disease
• Education
• Social prescribing- promote social engagement and lifestyle modifications
• EXERCISE AND PHYSICAL THERAPY- improve balance, flexibility, and strength.
Brisk walks, tai chi, swimming, and water aerobic exercises may be useful
• SPEECH and OCCUPATIONAL THERAPY
• Nutrition – high-fiber diet, adequate hydration, and regular exercise and MIND
diet may be associated with a lower risk of cognitive impairment.
Nutt JG, Carter JH. Dietary issues in the treatment of Parkinson's disease. In: Therapy of
Parkinson's Disease, Koller WC, Paulson G (Eds), Marcel Dekker, New York 1990. p.531.
Metcalfe-Roach A, Yu AC, Golz E, et al. MIND and Mediterranean Diets Associated with
Later Onset of Parkinson's Disease. Mov Disord 2021; 36:977. 54

55. 55

56. Immunosuppressant
Azathioprine ISRCTN14616801,
EudraCT-2018-
003089-14 (AZA-PD)
2 Early PD MDS-UPDRS part III
Statin
Simvastatin NCT02787590,
ISRCTN16108482,
EudraCT-2015-
000148-40,
PDSTAT2015
2 PD with wearing-off
phenomenon
MDS-UPDRS part III
Lovastatin NCT03242499,
NCTRC201702
2 Early PD MDS-UPDRS part III
Mitochondrial enhancer
Ursodeoxycholic
acid
NCT03840005, STH1
8493,
EudraCT-2018-
001887-46 (UP
study)
2 Early PD Number of adverse
treatment reactions
Number of serious
adverse events
Number of patients
completing the
study
Murakami H, Shiraishi T, Umehara T, Omoto S, Iguchi Y. Recent Advances in Drug Therapy for Parkinson's
Disease. Intern Med. 2023 Jan 1;62(1):33-42. doi: 10.2169/internalmedicine.8940-21. Epub 2022 Feb 1. PMID:
35110492; PMCID: PMC9876715.
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57. SUMMARY AND RECOMMENDATIONS
• When to initiate therapy – Treatment should generally begin when motor
symptoms are affecting function and quality of life.
• Preferred therapy for most patients –levodopa has superior effects on motor
function, activities of daily life, and quality of life and is often the best tolerated,
especially in older adults.
• Alternatives in select patients- DA, MAO B inhibitor, or amantadine is a
reasonable alternative. significant tremor despite levodopa may benefit from
add-on therapy with amantadine or an anticholinergic.
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Thank you