Drugs of Anti-Parkinsons disease

Department of Pharmacology
Zhang Xiaojie

What is Parkinsons 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 Parkinsons disease

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

Pathogenesis of Parkinsons disease

nigra

DA

DA (-)

striatum

Spinal cord
motor neuron

ACh (+)

coordinated movement

DA

ACh

DA

ACh

normal

parkinsonism

Therapy methods
reestablish the dopamine/acetylcholine balance.
(1) To increase function of dopaminergic neurons
in nigrostriatum.
(2) To decrease function of cholinergic neurons.
Clinical effect: reliefing symptoms, not stoping
progress

Drugs Treatment of Parkinsons 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 Parkinsons 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
blood-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
activity, 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
bowel; 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 wellbeing 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
dreams, 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.

Levodopa
Drug 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
prophylaxis 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
Parkinsonism 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
bromocriptine, 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
toxicity (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.