Antiparkinsonian

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J. Parkinson
Antiparkinsonian drugs (Abstract)
Assoc. Prof. Iv. Lambev E-mail
itlambev_at_mail.bg www.medpharm-sofia.eu
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Parkinsons disease (PD) is a progressive
neurodegenerative disorder. It is caused by
degeneration of substantia nigra in the midbrain,
and consequent loss of DA-containing neurons in
the nigrostrial pathway. Two balanced systems are
important in the extrapyramidal control of motor
activity at the level of the corpus striatum and
substantia nigra in the first the
neurotransmitter is ACh, in the second DA. The
symptoms of PD are connected with loss of
nigrostrial neurons and DA depletion. The
symptomatic triad includes bradykinesia, rigidity
and tremor with secondary manifestations like
defective posture and gait, mask-like face and
sialorrhoea dementia may accompany.
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Parkinsonism
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Clinical Pharmacology 9th Ed. (2003)
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Rang et al. Pharmacology 5st Ed. (2003)
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Distribution and characteristics of DA receptors
in the central nervous system
Goodman Gilman's The Pharmacologic Basis of
Therapeutics - 11th Ed. (2006)
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The normally high concentration of DA in the
basal ganglia of the brain is reduced in PD, and
pharmacologic attempts to restore DA-ergic
activity with levodopa and DA agonists have
been successful in alleviating many of the
clinical features of the disorder. An alternative
but complementary approach has been to restore
the normal balance of cholinergic and
dopaminergic influences on the basal ganglia with
antimuscarinic drugs. The pathophysiologic
basis for this therapy is that in idiopathic
parkinsonism, dopaminergic neurons in the
substantia nigra that normally inhibit the output
of GABA-ergic cells in the corpus striatum are
lost. In contrast, Huntington's chorea involves
the loss of some cholin- ergic neurons and an
even greater loss of the GABA-ergic cells
that exit the corpus striatum. Drugs that induce
parkinsonian syndromes are DA receptor
antagonists (e.g., antipsychotic agents) which
lead to the destruction of the DA-ergic
nigrostriatal neurons.
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The cause of selective degeneration of
nigrostrial neurones in PD is not precisely
known. It appears to be multifactorial. Oxidation
of DA by MAO-B and aldehyde dehydrogenase
generate hydroxyl free radicals (?OH) in the
presence of ferrous iron (basal ganglia are rich
in iron). Normally these radicals are quenched by
gluta- thione and other endogenous antioxidants.
Age-related (e.g. in atherosclerosis) and/or
otherwise acquired defect in protective antioxidan
t mechanisms allows the free radicals to damage
lipid membranes and DNA resulting in neuronal
degenerations. Gene- tic predisposition may
contribute to high vulnerability of
substantia nigra neurons. Environmental toxins or
some infections (grippe) may accentuate these
defects. A synthetic toxin N-methyl-4-phenyl tetra
hydropyridine (MPTP), which occurs as a
contaminant of some illicit drugs, produces
nigrostrial degenerations similar to
PD. Neuroleptics and other DA blockers may cause
temporary PD too.
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Production of free radical by the metabolism of
dopamine (DA). DA is converted by MAO and
aldehyde dehydrogenase (AD) in 3,4-dihydroxypheny
lacetic acid (DOPAC), producing hydrogen peroxide
(H2O2). In the presence of ferrous ion hydrogen
per- oxide undergoes spontaneous conversion,
forming a hydroxyl free radical (The Fenton
reaction).
Goodman Gilman's The Pharmacologic Basis of
Therapeutics - 11th Ed. (2006)
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?
Grippe
Essential of Medical Pharmacology 5st Ed.
(2003)
Factors contributing to degeneration of
nigrostrial DA-ergic neurones causing PD
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The key steps in the synthesis and degradation of
dopamine and the sites of action of various
psychoactive substances at the dopaminergic
synapse
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• Objectives of antiparkinsonian pharmacotherapy
• The dopaminergic/cholinergic balance may be
• restored by two mechanisms.
• 1. Enhancement of DA-ergic activity by drugs
  which may
• replenish neuronal DA by supplying levodopa,
  which
• is its natural precursor administration of DA
  itself is
• ineffective as it does not cross the BBB
• (b) act as DA agonists (bromocriptine, pergolide,
  cabergoline, etc.)
• (c) prolong the action of DA through selective
  inhibition of its
• metabolism (selegiline)
• (d) release DA from stores and inhibit reuptake
  (amantadine).
• 2. Reduction of cholinergic activity by
  antimuscarinic
• drugs this approach is most effective against
  tremor and rigidity,
• and less effective in the treatment of
  bradykinesia.

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Central DA-ergic Drugs
Levodopa
Levodopa
Dopamine
(-)
Selegiline
MAO-B
(-)
Amantadine
Reuptake
Amantadine
()
Bromocriptine Pergolide
()
D2-receptors
The Principles of Medical Pharmacology (1994)
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?LEVODOPA (DOPA DihydroOxy- PhenylAlanine
(t1/2 1,5 h) is a natural amino acid precursor
of DA. The major disadvantage is the extensive
decarboxylation of levodopa to DA in periferal
tissues. So that only 13 of an oral
dose reaches the brain.

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Basic Clinical Pharmacology 10th Ed. (2007)
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• Thus large quantities of levodopa would have to
  be given.
• Levodopa and its metabolites cause significant
  adverse reactions
• (ARs) by peripheral actions, notably nausea,
  arrhythmia, postural
• hypotension. This problem has been largely
  circumvented by
• decarboxylase inhibitors (benserazide,
  carbidopa), which do
• not enter the CNS they prevent only the
  extracerebral metabolism
• of levodopa. The inhibitors are given in
  combination with
• levodopa but in this case only 25 of the dose
  of levodopa is
• required and ARs diminish significantly. Levodopa
  alone and in
• combination is introduced gradually and titrated
  according to
• clinical response the dose being altered every
  two weeks.
• Co-careldopa (carbidopa and levodopa in
  proportions
• 12.5/50 mg, 25/100 mg, 25/250 mg) Sinemet.
• Co-beneldopa (benserazide and levodopa in
  proportions
• 12.5/50 mg, 25/100 mg, 50/200 mg) Madopar.

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Basic Clinical Pharmacology 10th Ed. (2007)
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?BROMOCRIPTINE (t1/2 5 h) a derivative of
ergot (Ergot de savle, Secale cornutum). It is
a D2-receptor agonist, but also a weak
alpha-adrenoceptor anatagonist. Bromocriptine is
com- monly used with levodopa. It should be
started at very low doses (11,25 mg p.o. at
night), increasing at weekly interval and
according to clinical response. It is also used
for treatment of prolactin-secreting adenomas,
amenorrhea/galactorrhea to hyperprolactinemia, to
stop lactation, acromegaly. ADRs Nausea and
vomiting, which may be prevented
with domperidone postural hypotension (may cause
dizziness or syncope) after prolonged use
pleural effusion and retroperitoneal fibrosis.
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?CABERGOLINE, also an ergot derivative, has a
t1/2 gt80 h. This allows it to be used in a
single daily (or even twice weekly) dose.
Cabergoline alleviates night-time problems in
parkinso- nian patients due to lack of levodopa.
?PRAMIPEXOLE is a non-ergot D2-receptor agonist
it is more effective against tremor than the
others. ?ROPINIROLE (Requip) is a new non-ergot
direct D2-receptor agonist. There are
insufficient data to allow an informed choice
between pramipexole and ropinirole. ?ENTACAPONE
inhibits COMT (Catechol-Ortho-MethylTrans- pherase
), one of the main enzymes responsible for the
metabolism of DA the action of levodopa is thus
prolonged. Entacapone is most effective for
patients with early end-of-dose deterioration.
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?SELEGILINE. The problem with nonselective MAO
inhibitors is that they prevent degradation of
dietary adrenomimetic amines, especially
tyramine, by MAO-A inhibition which
causes hypertensive cheese reaction. Selegiline
does not cause the cheese reaction, because
MAO-A is still presented in the liver to
metabolize tyramine. MAO-A also metabolizes
tyramine in the sympathetic nerve endings in
periphery. Selegiline inhibits selectively
and irreversibly only MAO-B in the CNS and
protects DA from intraneuronal degradation. It
is used as an adjunct drug in PD if
levodopa/carbidopa or levodopa/benserazide
therapy is deteriorating. In a transdermal patch
selegiline is used as a treatment for major
depression.
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?AMANTADINE is an antivirus drug which, given for
influenza to a parkinsonian patient, was noted to
be beneficial. Antiviral and antiparkinsonian
effects of amantadine are probably unrelated.
Antiparkinsonian effect is due to increase
synthesis and release of DA, and diminish
neuronal reuptake too. Amantadine also has
slight antimuscarinic effect. It is used for oral
adjunct treatment of PD and influenza A virus
infection. Amantadine is relatively free from
ARs, which, however, includes ankle edema
(probably a local effect on blood vessels),
orthostatic hypotension, insomnia,
hallucinations, rarely fits.
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Central antimuscarinic drugs
Atropa belladonna L. (Deadly night shade) Radix
Belladonnae (cura bulgara) atropine
Belladonna roots have been empirically used
for treatment of PD in 1920s in Bulgaria by
healer Ivan Raev (Sopot 18761938).
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?BIPERIDEN, TRIHEXYPHENIDYL, TRIPERIDEN are
synthetic compounds (central M-cholinolytics).
They benefit parkinsonism by blocking ACh
receptors in the CNS, thereby partially
redressing the imbalance created by decreased
DA-ergic activity. They also produce modest
improvement in tremor, rigidity, sialorrhoea
(hypersalivation), muscular stiffness and
leg cramp, but little in bradykinesia, which is
the most disabling symptom of Parkinsons
disease. ARs of antimuscarinic drugs include dry
mouth (xerostomia), blurred vision,
constipation, urine retention, glaucoma,
hallucinations, memory defects, toxic confusional
states and psychoses (which should be distinguish
from presenile dementia).
Trihexyphenidyl
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Pharmacotherapy of PD (Clinical Pharmacology
9th Ed., 2003) The main features that require
alleviation are tremor, rigidity and
bradykinesia. Drug therapy has the most important
role in symptom relief, but it does not alter the
progressive course of PD. Treatment should begin
only when it is judged necessary in each
individual case. Two conflicting objectives have
to be balanced the desire for satisfactory
relief of current symptoms and the avoidance of
ARs as a result of long-continued
treatment. There is a debate as to whether the
treatment should commence with levodopa or a
synthetic DA agonist. Levodopa provides the
biggest improvement in motor activity but its use
is associated with the development of dyskinesia
(involuntary movement of the face and limbs)
after 510 years, and sometimes sooner.
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DA agonists have a much less powerful motor
effect but are less likely to produce
dyskinesias. The treatment usually begins
with levodopa in low doses to get a good motor
response and adds a DA agonist when the initial
benefit begins to wane. A typical course is that
for about 24 years on treatment with levodopa or
DA agonist, the patients disability and
motor performance remains near normal despite
progression of the underlying disease. After some
5 years about 50 of patients exhibit problems of
long-term treatment, namely, dyskinesia and
end-of-dose deterioration with the on-off
phenomenon. After 10 years virtually 100 of
patients are affected.
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End-of-dose deterioration is managed by
increasing the frequency of dosing with levodopa
(e.g. to 2 or 3-hourly), but this tends to worsen
the dyskinesia. The motor response then becomes
more brittle with abrupt swings between hyper-
and hypomobility (the on-off phenomenon). In this
case a more effective approach is to use a COMT
inhibitor, e.g. entacapone, which can sometimes
allay early end-of-dose deterioration without
causing dyskinesia. Some 20 of the patients
with Parkinsons disease, notably the Elderly
ones, develop impairment of memory and speech
with a fluctuating confusional state and
hallucinations. As these symptoms are often
aggravated by medication, it is
preferable gradually to reduce the
antiparkinsonian treatment.
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Antimuscarinic drugs are suitable only for
younger patients predo- minantly troubled with
tremor and rigidity. They do not benefit
bra- dyskinesia, the main disability symptom. The
ARs of acute angle glaucoma, retention of urine,
constipation and psychiatric distur- bance are
general contraindications to their use in the
elderly. Drug-induced Parkinsonism is
alleviated by antimuscarinics, but not by
levodopa or DA agonist, because antipsychotics
block D2-receptors by which these drugs act. The
piperazine phenothiazines (e.g. trifluoperazine)
and butyrophenones (e.g. haloperidol) often
cause Parkinsonism because they
block D2-receptors.
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Treatment approaches to newly diagnosed
idiopathic PD
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Comparison of levodopa benserazide, levodopa
benserazide selegiline and bromocriptine on
progression of PD symptoms
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