Parkinson PS 55

7/28/2019 Parkinson PS 55

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Assoc. Prof. Jintana [email protected]

Department of Pharmacology Faculty of Medicine

“Anti-PD”



1. Describe cardinal symptoms of PD2. Describe pathophysiology of PD

and principles of drug treatment 3. Describe the mechanisms of action and

important side effects of drugs used in PD

Objectives: Students are able to

1. หนังสอเภสัชวทยา เลม 2: ยาท ออกฤทธ ตอระบบประสาท

สวนกลาง, จนตนา สัตยาศัย บรรณาธการ 2555

2. Textbook ดานเภสัชวทยา

References

“Anti-PD”



1. The cardinal symptoms of PD2. Pathogenesis of PD3. Antiparkinson agents

-increase dopaminergic influences

Dopamine precursorDopamine agonistsInhibitors of dopamine degradationDopamine release enhancer

-decrease cholinergic influences

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“Anti-PD”



Parkinson’s Disease (PD) = Common chronic neuronal degenerative

disorder cause abnormal motor movement

Motor involvement

Resting tremor

Posture instability

Bradykinesia

Cogwheel rigidity

(อาการแสดงท สาคัญ)

“Anti-PD”



Resting tremor

2. Posture instability(การทรงตัวท ไมด)

1. Resting Tremor ( สั นขณะพัก) -rhythmic to & fro movement

at joint esp. at upper limbs - ~ pill rolling movement-prominent at rest

Posture instability

“Anti-PD”



3. Rigidity (แขงเกรง)

-increase of muscle tone(difficulty in movement) -having cogwheel rigidity

4. Bradykinesia (เคล อนไหวชา)

-a mask- like face,-monotonous speech-decrease of all reflexes

Bradykinesia Cogwheel rigidity

“Anti-PD”



INDIRECT PATHWAYS

(Glu) (Glu)

(Glu)

(Glu) (Glu)

(Glu)

(Glu)

(GABA Substance P)

(GABA enk)

(GABA)

(GABA)

(Glu)

(Glu)

(Glu)

Excitatory

Inhibitory

“Anti-PD”



(Glu) (Glu)

(Glu)

(Glu) (Glu)

(Glu)

(Glu)

(GABA Substance P)

INDIRECT PATHWAYS

(GABA enk)

(GABA)

(GABA)

(Glu)

(Glu)

(Glu)

Excitatory

Inhibitory

“Anti-PD”



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

ACh

“Anti-PD”



Disequilibrium among Dopamine

& Acetylcholine

Degeneration of DA neurons (in basal ganglia) -Neuronal metabolism (DA by MAO) -Genetics (mitochondria)-Toxins

Pathogenesis & the principles of treatment of PD

Reduce ACh

activity

Slow the loss of DA (neuroprotection)

Increase

availability

of DA

“Anti-PD”



STRIATUM

D2

receptor

DA DA

MAOB

Excitation Inhibition

COMT DA

DA

Dopa Dopa

decarboxylase

Metabolites

MAOB

inhibitor

Selegiline

ACh

COMT inhibitor

Entacapone

Muscarinic

receptor

ACh

P h a r m a c o l o g i c a l M a n a g e m e n t o f P D

Free

radicals

Metabo lites

Tyrosine

Levodopa +

carboxylase inhibitor

= Gold standard of PD

treatment

Anticholinergic drugs

Benzhexol

-

Dopamine precursor Levodopa

Release dopamine Amantadine Dopamine agonists

Piribedil Bromocriptine

Dopaminergic drugs

+

“Anti-PD”



Dopamine

A A D

B l o o - b r a

i n b a r r i e r

Blood & peri-pheral tissues

G u t W a l l

Gut lumen

Amino acid

tyrosine

tyrosine tyrosine Dopamine

Metabolites

Metabolites Free radicals

Neuronaldamage

COMT=catechol-O-methyl transferase

MAO-B=monoamine oxidase-B AAD=aromatic amino acid decarboxylase

Dopa

ตัวขนสงกรดอะม โน

Dopa

Brain

Receptorstimulation

1.1Dopamine precursor = Levodopa (L-Dopa)

“Anti-PD”



Brain

B l o o - b r a i n b a r r i e r

G u t W a l l

Levodopa Levodopa Levodopa Dopamine

AAD

A A D

Dopamine

Metabolites

Metabolites

Receptorstimulation

Benseraside, Carbidopa

MADOPAR =Levodopa+Benseraside

SINEMET =Levodopa+Carbidopa

R

R

1. levodopa(DA precursor)

+ AAD inhibitors

Free radicals

Neuronaldamage Side effects

Metabolites M

A O - B

C O M T

C O M

T

protein

food

Avoid protein

“Anti-PD”



Hypofunction of nigrostriatal DA neurons

Parkinson’s disease

Dopaminergic agents

(Antiparkinson agents)

Restore DA function

Hyperfunction of DA

CTZ

Nausea & vomiting

Levodopa & Side effects

Schizophrenia

Nucleus

accumbens

Sensitization

of receptor

Motor fluctuation

“Anti-PD”



Levodopa &

Motor fluctuation

Wearing off

On-Off phenomena

Dyskinesias Freezing /Motor blocks

“Anti-PD”



Basic management with Levodopa-induced

motor fluctuation

On-Off Phenomenon

(การออกฤทธ ไมแนนอน) -Levodopa before meals -redistribute protein

-dopamine agonists

Freezing/Motor Blocks (ตัวแขง เคล อนไหวลาบาก) -visual cues -antianxiety

Dyskinesias (ยกยอเหต ยา) Peak dose

-decrease levodopa

-dopamine agonist

Wearing off (หมดฤทธ เรว)

-smaller, more frequent doses -long-acting dosage form

-dopamine agonist -Amantadine

Dealing with motor fluctuation

“Anti-PD”



B B B

G u t W a l l

Levodopa

Levodopa

Metabolites C O M T

Metabolites

Levodopa

Dopamine

AAD

Metabolites M A O - B

C O M T

1.2. Inhibit DA metabolism: MOA-B

inhibitors & COMT inhibitors

Free radicals Neuronaldamage

Selegiline (JUMEX )

= neuroprotective

R

Entacapone

(COMTAN ),

Tolcapone

(TASMAR )

Tolcapone

R

R

*Tolcapone: hepatotoxic

“Anti-PD”



-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 Parkinson’s Disease Research Group)

Selegiline prescription rates have fallen > 50%

“Anti-PD”



-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)

“Anti-PD”



1.3 Dopamine agonists

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

•Ergot derivatives: as add-on therapy

-Bromocriptine (PARLODEL ), -Lisuride (DOPERGIN )-high incidence ofpsychiatric effects

-Pergolide (CELANCE );potency 10 times>

Bromocriptine

-Cabergoline; very long half-life (65 hrs)

R R

R

“Anti-PD”



Serious side effects of ergot deriv. (although rare):Pleural effusion (มของเหลวคั งในปอด),

Pulmonary and Retroperitoneal fibrosis (เกด fibrosis

ท ปอดและหลังเย อบ ชองทอง)

•Non-ergot dopamine agonists: as add-on therapy and

monotherapy in early Parkinson’s disease

-Piribedil (TRIVASTAL ) -Ropinirole (REQUIP ) -Pramipraxole (SIFROL®)

R R

Sudden unexpected falling asleep

during activities of daily living

“Anti-PD”



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



1.4 Dopamine releaser

Amantadine (SYMMETREL )

-Antiviral agent,

-Efficacy is poor -Tolerance develop with long-term treatment -Adverse effects: confusion, livedo reticularis

-Increase DA release

Rarely used in early disease,but used as

anti-dyskinesia agent (Glutamate antagonist)

in later disease

R

“Anti-PD”



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 ) Biperiden (AKINETON ) Diphenhydramine (BENADRYL ) Trihexyphenidyl (ARTANE )

Muscarinic antagonists

R

R

R

R

“Anti-PD”



Transplantation -Fetal cells -Adrenal gland -Stem cells

“Anti-PD”

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Parkinson PS 55