Anti-Parkinson Drugs
By: Sara Tufer (B.Pharm, MSc pharmacology)
Introduction
• PD is slowly progressive degenerative diseases of the
brain that affects dopaminergic neurons in the
Substantia Nigra(SN).
• Affects the nerve cells in the areas of the brain called,
basal ganglia, which are important in determining
how the body moves.
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Introduction …
• The nerve cells in the SN produces dopamine(D)
– D is important for planning and controlling movement
• The
action of D is balanced with another
neurotransmitter(NT) called Acetylcholine(Ach)
Both
NT
ensures
smooth
,coordinated
movement .
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Classification
I. Drugs affecting brain dopaminergic system
a. Dopamine precursor : Levodopa (I-dopa)
Peripheral decarboxylase inhibitors: Carbidopa,
Benserazide.
b. MAO-B inhibitor: Selegiline
c. COMT inhibitors: Entacapone, Tolcapone
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Classification…
d. Dopaminergic agonists: Bromocriptine, Ropinirole,
Pramipexole
e. Dopamine facilitator: Amantadine.
II. Drugs affecting brain cholinergic system
 Central anti-cholinergics
– Trihexyphenidyl, Procydidine, Biperiden.
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Strategy of treatment
• In addition to an abundance of inhibitory
dopaminergic neurons, the striatum is also rich in
excitatory cholinergic neurons that oppose the
action of D.
• Many of the symptoms of parkinsonism reflect an
imbalance between this two neurons
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Strategy of treatment…
Aim of therapy:
• To restore dopamine in the basal ganglia and
antagonizing the excitatory effect of cholinergic
neurons
– Thereby reestablishing the correct D/Ach balance
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Dopamine Precursor : Levodopa (l-dopa)
Mechanism of action
• D does not cross the BBB but its immediate precursor
levodopa does.
o After its actively transported into the CNS and it will be
converted to D in the surviving neurons of the SN
• Thereby restoring dopaminergic neurotransmission in the
neostriatum.
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Dopamine Precursor : Levodopa (ldopa)...
• In the SNc, levodopa is converted to dopamine by the
enzyme l-amino acid decarboxylase(L-AAD) and inactivated
by the enzymes MAO and COMT.
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Why Levodopa Must Be
Administered With Carbidopa ?
 Carbidopa: a dopamine decarboxylase inhibitor
• ↓ the metabolism of levodopa in the periphery, thereby ↑ing
the availability of levodopa to the CNS.
• The addition of carbidopa lowers the dose of levodopa
needed by 4-to 5 fold
• Thus, ↓es the severity of adverse effects arising from
peripherally formed D.
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Dopamine Precursor : Levodopa (ldopa)...
Therapeutic uses
• Levodopa + carbidopa :Parkinson disease.
• In approximately 2/3 of patients, the combination
markedly ↓ the severity of symptoms for the 1st few
years of treatment.
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Dopamine Precursor : Levodopa (ldopa)...
 Pharmacokinetics
• Levodopa is rapidly absorbed from the small intestines ;
o by utilizing the active transport process meant for aromatic
amino acids.
• Bioavailability of levodopa is affected by:
I.
Gastric emptying
II. Amino acids present in food compete for the same carrier
for absorption
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Dopamine Precursor : Levodopa (ldopa)...
 Blood levels are lower when taken with meals
 Thus, levodopa should be taken on an empty stomach,
typically 30 minutes before a meal.
• Levodopa undergoes high 1st pass metabolism in GI mucosa
and liver.
• The plasma half-life of levodopa is 1-2 hours.
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Dopamine Precursor : Levodopa (ldopa)...
 Adverse effects: anorexia, nausea,
and vomiting
 CNS effects: Visual and auditory
hallucinations ,dyskinesias, mood
changes, depression, psychosis, and
anxiety.
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Dopamine Precursor : Levodopa (ldopa)...
• Long-term levodopa therapy is associated with a variety of
motor complications.
• This complications can occur as early as 6 months after
starting levodopa therapy, especially if excessive doses are
used initially
– End-of-dose “wearing off ” (motor fluctuations)
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Dopamine Precursor : Levodopa (ldopa)...
Interactions
• Pyridoxine ( Vitamin-B6) ↑ the peripheral
breakdown of levodopa and diminishes its effectiveness
• Levodopa and Nonselective MAOIs
– Because they bring hypertensive crisis caused by enhanced
catecholamine production.
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Dopamine Precursor : Levodopa (ldopa)...
• In many psychotic patients, levodopa exacerbates
symptoms, possibly through the buildup of central
catecholamines.
• Antipsychotic drugs are generally contraindicated in
PD.
– Because they potently block dopamine receptors and may
augment parkinsonian symptoms.
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MAO-B inhibitor
• Include :Selegiline, rasagiline, and safinamide
 Selegiline, selectively inhibits MAO type B, the enzyme
that metabolizes dopamine.
• By ↓ing the metabolism of dopamine, it ↑ dopamine
levels in the brain.
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MAO-B inhibitor…
• When given with levodopa, it enhances the actions of
levodopa and markedly ↓ the required dose.
 At therapeutic doses
• Preferentially inhibit MAO-B over MAO-A.
• Has little potential for causing hypertensive crises
– But ,it loses its selectivity when given above recommended
doses(at high doses)
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Catechol-O-methyl-transferase (COMT)
inhibitors
• Methylation of levodopa by COMT to 3-O-methyldopa is
a minor pathway for levodopa metabolism.
• Inhibition of peripheral dopamine decarboxylase by
carbidopa causes formation of significant concentration
of 3-O-methyldopa.
– 3-O-methyldopa :competes with levodopa for active transport
into the CNS and reduce central uptake of levodopa.
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Catechol-O-methyl-transferase (COMT)
inhibitors…
• Two selectively and reversibly COMT inhibitors
– Entacapone and Tolcapone
• Inhibition of COMT leads to
– ↓ plasma concentrations of 3-O-methyldopa
– ↑ed central uptake of levodopa, and greater concentrations of
brain dopamine.
• Indicated for managing wearing off
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Catechol-O-methyl-transferase (COMT)
inhibitors…
 Pharmacokinetics
• Oral absorption of both drugs occurs readily and is not
influenced by food.
• Tolcapone has a relatively long duration of action compared
to entacapone, which requires more frequent dosing.
• Both drugs are extensively metabolized and eliminated in
feces and urine.
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Catechol-O-methyl-transferase (COMT)
inhibitors…
 Adverse effects
• Both causes diarrhea, postural hypotension, nausea,
anorexia, dyskinesias, hallucinations, and sleep disorders.
• Intense hepatic necrosis(most seriously), is associated
with tolcapone use.
– Its use is limited by reports of fatal hepatotoxicity
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Dopamine Receptor Agonists
• Includes : Bromocriptine ,Ropinirole , Pramipexole ,
Rotigotine , and Apomorphine.
• They have a longer duration of action than that of levodopa
• Are effective in patients exhibiting fluctuations in
response to levodopa.
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Dopamine Receptor Agonists…
• Bromocriptine, pramipexole, and ropinirole are effective in
patients with PD complicated by motor fluctuations and
dyskinesias.
• Apomorphine is an injectable dopamine agonist that is used in
severe and advanced stages of the disease.
• Adverse effects severely limit the utility of the
dopamine agonists
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Dopamine Receptor Agonists…
Pharmacokinetic
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Dopamine Facilitator: Amantadine
• Amantadine has several effects on a number of
NTs implicated in parkinsonism
– ↑ing the release of dopamine
– Blocking cholinergic receptors
– Inhibiting the N-methyl-D-aspartate (NMDA) type of
glutamate receptors.
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Dopamine Facilitator: Amantadine…
• It is less efficacious than levodopa, and tolerance develops
more readily.
• The drug may cause restlessness, agitation, confusion, and
hallucinations
• At high doses, it may induce acute toxic psychosis.
• Orthostatic hypotension, urinary retention, peripheral edema,
and dry mouth also may occur.
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Drugs Affecting Brain Cholinergic
System
• Include: Trihexyphenidyl, Procydidine,
Biperiden
• They are much less efficacious than levodopa
• Play only an adjuvant role in anti-parkinsonism
therapy.
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Drugs Affecting Brain Cholinergic
System…
• The actions of benztropine and trihexyphenidyl are similar;
– Blockade of cholinergic transmission produces effects similar to
augmentation of dopaminergic transmission
o Since it helps to correct the imbalance in the D/Ach activity
• They induce mood changes and confusion, and produce xerostomia,
constipation, and visual problems typical of muscarinic blockers
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Thank you
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