Transcript Drugs of Anti-Parkinson`s disease

Drugs of Anti-Parkinson’s disease
Department of Pharmacology
Zhang Yan-mei
Pathogenesis of Parkinson’s disease
• Parkinson’s disease (PD) is a progressive
disorder of movement that occurs mainly
in the elderly. The chief symptoms are:
– Tremor at rest, usually starting in the hands
(‘pill- rolling’ tremor), which tend to
diminish during voluntary activity
Pathogenesis of Parkinson’s disease
– Muscle rigidity, detectable as an increased
resistance in passive limb movement
--Bradykinesia
– Suppression of voluntary movements
(hypokinesis), due partly to an inherent
inertia of the motor system, which means
that motor activity is difficult to stop as well
as to initiate.
Action of MPTP
• 1-methyl 4-phenyl 1,2,3,6tetrahydropyridine (MPTP) causes
irreversible destruction of nigrostriatal
dopaminergic neurons in various species,
and produces a PD-like state in primates.
MPTP
MAO-B
inhibit
Selegiline
MPP+
MPP+ is taken up by the
dopaminergic neurons,
selective in destroying
nigrostriatal neurons. It
inhibits mitochondrial
oxidation reactions,
producing oxidative stress.
Parkinson’s Disease
• Degenerative disease of the basal ganglia
causing tremor at rest, muscle rigidity
hypokinesia, often with dementia.
• Often idiopathic, but may follow stroke,
virus infection, can be drug-induced
(neuroleptic drugs).
Parkinson’s Disease
• Associated with marked loss of dopamine
from basal ganglia.
• Can be induced by MPTP, a neurotoxin
affecting dopamine neurons in the corpus
striatum.
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
• Mechanism:
(1) Because dopamine does not cross the
blood-brain barrier levodopa, the precursor
of dopamine, is given instead.
(2) Levodopa is formed 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.
• Therapy with MAO inhibitors must be stopped
14 days prior to the initiation of levodopa
therapy.
• 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
concomitantly.
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 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)