Anti-PD

Department of Pharmacology Faculty of Medicine

Assoc. Prof. Jintana Sattayasai sjinta@kku.ac.th

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Objectives: Students are able to

1. Describe cardinal symptoms of PD 2. Describe pathophysiology of PD and principles of drug treatment 3. Describe the mechanisms of action and important side effects of drugs used in PD

References

1. 2: , 2555 2. Textbook

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1. The cardinal symptoms of PD 2. Pathogenesis of PD 3. Antiparkinson agents -increase dopaminergic influences Dopamine precursor Dopamine agonists Inhibitors of dopamine degradation Dopamine release enhancer -decrease cholinergic influences

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Parkinsons Disease (PD)

= Common chronic neuronal degenerative disorder cause abnormal motor movement Motor involvement

( )
Resting tremor Posture instability Bradykinesia Cogwheel rigidity

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1. Resting Tremor ( ) -rhythmic to & fro movement at joint esp. at upper limbs - ~ pill rolling movement -prominent at rest Resting tremor

2. Posture instability

()
Posture instability

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3. Rigidity () -increase of muscle tone (difficulty in movement) -having cogwheel rigidity Cogwheel rigidity

4. Bradykinesia () -a mask- like face, -monotonous speech -decrease of all reflexes Bradykinesia

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(Glu) (Glu)

(Glu)

(Glu) (Glu)

INDIRECT (GABA (Glu)

PATHWAYS enk)

(GABA Substance P)

(Glu)

(GABA)

(Glu) (GABA) (Glu) (Glu) Excitatory Inhibitory

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(Glu) (Glu)

(Glu)

(Glu) (Glu)

INDIRECT (GABA (Glu)

PATHWAYS enk)

(GABA Substance P)

(Glu)

(GABA)

(Glu) (GABA)

(Glu)
(Glu) Excitatory Inhibitory

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ACh

(Schapira, J Neurol Neurosurg Psychiatry 2005; Olanow et al., Neurology 2009)

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Pathogenesis & the principles of treatment of PD

Disequilibrium among Dopamine & Acetylcholine Degeneration of DA neurons (in basal ganglia) -Neuronal metabolism
(DA by MAO) -Genetics (mitochondria)

Increase availability of DA

Reduce ACh activity

-Toxins

Slow the loss of DA (neuroprotection)

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Pharmacological Management of PD

STRIATUM

Free radicals

MAOB inhibitor Selegiline

COMT inhibitor Metabolites Entacapone

MAOB

Anticholinergic drugs Benzhexol

ACh Metabo lites ACh COMT

DA

Dopa decarboxylase

Tyrosine Dopa DA

DA

DA + Muscarinic D2 receptor receptor Excitation Inhibition

Dopaminergic drugs Dopamine precursor Levodopa Release dopamine Amantadine Dopamine agonists Piribedil Bromocriptine

carboxylase inhibitor

Levodopa +

= Gold standard of PD treatment

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1.1 Dopamine precursor = Levodopa (L-Dopa)

Gut lumen
Gut Wall Bloo-brain barrier

Blood & peripheral tissues

Brain

Metabolites tyrosine

Amino acid tyrosine

Receptor stimulation
Dopamine

tyrosine
AAD

Dopa

Dopa
Metabolites

Dopamine

COMT=catechol-O-methyl transferase MAO-B=monoamine oxidase-B

Free radicals

Neuronal damage
AAD=aromatic amino acid decarboxylase

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1. levodopa(DA precursor) + AAD inhibitors

Gut Wall

MADOPAR =Levodopa+Benseraside R SINEMET =Levodopa+Carbidopa

R

COMT

Benseraside, Carbidopa

Bloo-brain barrier

Brain
Metabolites
AAD

Levodopa

Levodopa
MAO-B
COMT

Levodopa

Dopamine

Receptor stimulation

protein food
Avoid protein

AAD

Dopamine

Metabolites Side effects

Neuronal damage

Metabolites Free radicals

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Levodopa & Side effects Hypofunction of nigrostriatal DA neurons Restore DA function Parkinsons disease

Dopaminergic agents (Antiparkinson agents)

Hyperfunction of DA CTZ Nucleus accumbens Schizophrenia Sensitization of receptor

Nausea & vomiting

Motor fluctuation

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Levodopa & Motor fluctuation

Wearing off On-Off phenomena Freezing/Motor blocks Dyskinesias

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Basic management with Levodopa-induced motor fluctuation

Dealing with motor fluctuation
Wearing off () -smaller, more frequent doses -long-acting dosage form -dopamine agonist -Amantadine

Freezing/Motor Blocks

( )
-visual cues -antianxiety

On-Off Phenomenon

( )

-Levodopa before meals -redistribute protein -dopamine agonists

Dyskinesias () Peak dose -decrease levodopa -dopamine agonist

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1.2. Inhibit DA metabolism: MOA-B inhibitors & COMT inhibitors

Gut Wall BBB

Metabolites
COMT

Tolcapone

Levodopa
COMT

Levodopa
MAO-B

Levodopa

AAD

Dopamine

Entacapone R (COMTAN ), Tolcapone R (TASMAR )

Metabolites

Metabolites

Free radicals Neuronal damage

Selegiline (JUMEX )
R

*Tolcapone: hepatotoxic

= neuroprotective

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-MAO-B Inhibitor: Selegiline (JUMEX)

with tyramine-containing food hypertensive crisis-Rare With SSRI antidepressants serotonin syndrome
Selegiline

Metabolized to amphetamine & metamphetamine Sleep problems: insomnia

*significant increase in mortality after 6 years (UK Parkinsons Disease Research Group) Selegiline prescription rates have fallen > 50%

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-COMT Inhibitors (reversible): Entacarpone (COMTAN) Tolcapone (TASMAR) Entacapone+Levodopa+Carbidopa (STALEVO)

Smoothing out the peaks and troughs of levodopa response Tolcapone Fulminant hepatic failure (consent form, liver function test, discontinue if no benefit within 3 weeks)

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1.3 Dopamine agonists

Free radical from dopamine turnover Direct antioxidant effect Incidence of dyskinesia, antidepressant effect

Ergot derivatives: as add-on therapy

-Bromocriptine (PARLODELR ), -Lisuride (DOPERGIN R )-high incidence of psychiatric effects -Pergolide (CELANCE R );potency 10 times> Bromocriptine -Cabergoline; very long half-life (65 hrs)

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Non-ergot dopamine agonists: as add-on therapy and monotherapy in early Parkinsons disease
-Piribedil (TRIVASTAL R )
-Ropinirole (REQUIP R ) -Pramipraxole (SIFROL)

Serious side effects of ergot deriv. (although rare): Pleural effusion ( ), Pulmonary and Retroperitoneal fibrosis ( fibrosis )

Sudden unexpected falling asleep during activities of daily living

(Eiseneggeret al., Biological Psychaitry 2010; Ray et al., Neurobiology of Disease 2012)

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1.4 Dopamine releaser

Amantadine (SYMMETREL R )
-Antiviral agent, -Increase DA release -Efficacy is poor -Tolerance develop with long-term treatment -Adverse effects: confusion, livedo reticularis Rarely used in early disease, but used as anti-dyskinesia agent (Glutamate antagonist) in later disease

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2. Decreasing cholinergic influence

-effective for tremor: mostly used in early onset PD

-confusion & hallucination esp. in elderly

-disturb learning & memory -cause dry mouth, urinary retention & sedation Benztropine (COGENTIN ) R Biperiden (AKINETON ) R Diphenhydramine (BENADRYL ) R Trihexyphenidyl (ARTANE )
R

Muscarinic antagonists

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Transplantation -Fetal cells -Adrenal gland -Stem cells