Drugs of Anti-Parkinson’s disease

Department of Pharmacology

Zhang Xiaojie

What is Parkinson’s disease?

A progressive nervous disease occurring most often after the age of 50, associated with the destruction of brain cells that produce dopamine, and characterized by muscular tremor, slowing of movement, partial facial paralysis, peculiarity of gait and posture, and weakness.

one of the “neurodegenerative diseases”

Characterized symptoms

resting tremor

muscle rigidity

bradykinesia

abnormal postural reflexes

Pathogenesis of Parkinson’s disease

Associated with marked loss of dopaminergic neurons of the substantia nigra and a reduction in the striatal dopamine content in excess of 80%

正常人中脑有一条狭长的黑色素沉着部位，那便是正常数量的黑质神经元聚集的部位。而在帕金森病人中脑的相应部位则颜色浅淡，这是黑质神经元减少的缘故。

striatumnigraSpinal cordmotor neuron

coordinated movement

DADA

ACh

(-)

(+)

Pathogenesis of Parkinson’s disease

DA ACh

normal

DA

ACh

parkinsonism

Therapy methodsreestablish the dopamine/acetylcholine balance.(1) To increase function of dopaminergic neur

ons in nigrostriatum.(2) To decrease function of cholinergic neurons. Clinical effect: reliefing symptoms, not stopi

ng progress

Drugs Treatment of Parkinson’s Disease

• Drugs that replace dopamine (e.g. levodopa, usually used concomitantly with peripherally acting dopa decarboxylase inhibitor, e.g. carbidopa)

• Drugs that mimic the action of dopamine (e.g. bromocriptine, pergolide and others in development)

Drugs Treatment of Parkinson’s Disease

• MAO-B inhibitors (e.g. selegiline)

• Drugs that release dopamine (e.g. amantadine)

• Acetylcholine antagonists (e.g. artane)

Levodopa (L-dopa)

• Mechanism:(1) Because dopamine can not cross the bloo

d-brain barrier ,levodopa, the precursor of dopamine, is given instead.

(2) Levodopa is formed from L-tyrosine and is an intermediate in the synthesis of catecholamines.

Levodopa

• Mechanism:(3) Levodopa itself has minimal pharmacologic ac

tivity, in contrast to its decarboxylated product, dopamine.

(4) Levodopa is rapidly decarboxylated in the gastrointestinal tract. Prior to the advent of decarboxylase inhibitors (carbidopa), large oral doses of levodopa were required; thus, toxicity from dopamine was a limiting factor.

Levodopa

• Pharmacokinetics:(1) Levodopa is well absorbed from the small bo

wel; however, 95% is rapidly decarboxylated in periphery.

(2) Peripheral dopamine is metabolized in the liver to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), which are then excreted in urine.

Levodopa

• Pharmacologic effects:

(1) The effects on bradykinesia and rigidity are more rapid and complete than the effects on tremor. Other motor defects in PD improve. The psychological well-being of patient is also improved.

Levodopa

• Pharmacologic effects:

(2) Tolerance to both beneficial and adverse effects occurs with time. Levodopa is most effective in the first 2-5 years of treatment. After 5 years of therapy, patients have dose-related dyskinesia, inadequate response, or toxicity.

Levodopa• Adverse effect:Principal adverse effects include:

(1) Anorexia, nausea, and vomiting upon initial administration, which often limit the initial dosage.

(2) Cardiovascular effects, including tachycardia, arrhythmias, and orthostatic hypotension.

Levodopa• Adverse effect:(3) Mental disturbances, including vivid drea

ms, delusions, and hallucination.

(4) Hyperkinesia

(5) On-off phenomena

Levodopa

• Adverse effect:

Sudden discontinuation can result in fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 days.

LevodopaDrug interactions:

• Vit B6 reduces the beneficial effects of Levodopa by enhancing its extracerebral metabolism.

• Phenothiazines, reserpine, and butyrophenones antagonize the effects of levodopa because they lead to a junctional blockade of dopamine action.

Carbidopa

• Carbidopa is an inhibitor of dopa decarboxylase. Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. As a result, when carbidopa and levodopa are given together, the amount of levodopa into brain increase

Carbidopa

Virtue:

a. It can decrease the dosage of levodopa.

b. It can reduce toxic side effects of levodopa.

c. A shorter latency period precedes the occurrence of beneficial effects.

Selegiline

• A selective inhibitor of MAO-B, which predominates in DA-containing regions of the CNS and lacks unwanted peripheral effects of non-selective MAO inhibitors.

• It enhances and prolongs the antiparkinsonism effect of levodopa.

• It may reduce mild on-off or wearing-off phenomena.

Selegiline

• Long-term trials showed that the combination of selegiline and levodopa was more effective than levodopa along in relieving symptoms and prolonging life.

Amantadine

Therapeutic uses and mechanism of action• Amantadine is an antiviral agent used in the proph

ylaxis of influenza A2 . It was found to improve parkinsonian symptoms by stimulating the synthesis and release of dopamine from dopaminergic nerve terminals in the nigrostriatum and delaying its reuptake.

Amantadine

Therapeutic uses and mechanism of action• Amantadine may be more efficacious in Parkinson

ism than the anticholinergic atropine derivatives but is less effective than levodopa. It has been used alone to treat early PD and as an adjunct in later stages.

Anticholinergic agents: artane

Mechanism:• Since the deficiency of dopamine in the triatum

augments the excitatory cholinergic system in the striatum, the blockade of this system by anticholinergic agents, such as artane, helps to alleviate the motor dysfunction.

• Improvement in the parkinsonian tremor is more pronounced than improvement in bradykinesia and rigidity.

Artane

Therapeutic uses: • Although not as effectives as levodopa or brom

ocriptine, it may have an additive therapeutic effect at any stage of the disease when taken concurrently.

Adverse effects:• Mental confusion and hallucinations.• It can occur as can peripheral atropine-like toxi

city (e.g. cycloplegia, urinary retention, constipation)

Summary for this chapter

1. mechanisms of action of levodopa

2. main adverse reactions of L-dopa.

3. combination of levodopa and carbidopa.