Download Levodopa

PARKINSONISM
Parkinsonism is characterized by a combination of rigidity, bradykinesia, tremor,
and postural instability that can occur for a variety of reasons but is usually
idiopathic. Cognitive decline occurs in many patients as the disease advances.
DRUGS USED IN PARKINSON DISEASE
Currently available drugs offer temporary relief from the symptoms of the
disorder, but they do not arrest or reverse the neuronal degeneration caused by the
disease.
One . Levodopa and carbidopa
Levodopa is a metabolic precursor of dopamine. It restores dopaminergic
neurotransmission in the corpus striatum by enhancing the synthesis of dopamine
in the surviving neurons of the substantia nigra. In patients with early disease, the
number of residual dopaminergic neurons in the substantia nigra (typically about
20 percent of normal) is adequate for conversion of levodopa to dopamine. Thus,
in new patients, the therapeutic response to levodopa is consistent, and the patient
rarely complains that the drug effects“wear off .” Unfortunately, with time, the
number of neurons decreases, and fewer cells are capable of taking up exogenously
administered levodopa and converting it to dopamine for subsequent storage and
release. Consequently, motor control fluctuation develops.
1. Mechanism of action:
a. Levodopa: Because parkinsonism results from insufficient dopamine in specific
regions of the brain, attempts have been made to replenish the dopamine defi
ciency. Large doses of levodopa are required, because much of the drug is
decarboxylated to dopamine in the periphery, resulting in side effects that include
nausea, vomiting, cardiac arrhythmias, and hypotension.
b. Carbidopa: Carbidopa, a dopa decarboxylase inhibitor, diminishes the
metabolism of levodopa in the gastrointestinal tract and peripheral tissues, thereby
increasing the availability of levodopa to the CNS. The addition of carbidopa
lowers the dose of levodopa needed by four- to fivefold and, consequently,
decreases the severity of the side effects arising from peripherally formed
dopamine.
2. Actions: Levodopa decreases the rigidity, tremors, and other symptoms of
parkinsonism.
3. Absorption and metabolism: The drug is absorbed rapidly from the small
intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2
hours), which causes fluctuations in plasma concentration. This may produce
fluctuations in motor response, which generally correlate with the plasma
concentrations of levodopa, or perhaps give rise to the more troublesome “on-off
” phenomenon. Ingestion of meals, particularly if high in protein, interferes with
the transport of levodopa into the CNS. Large, neutral amino acids (for example,
leucine and isoleucine) compete with levodopa for absorption from the gut and for
transport across the blood-brain barrier. Thus, levodopa should be taken on an
empty stomach, typically 45 minutes before a meal. Withdrawal from the drug
must be gradual.
Adverse effects:
a. Peripheral eff ects: Anorexia, nausea, and vomiting occur because of
stimulation of the chemoreceptor trigger zone of the medulla. Tachycardia and
ventricular extrasystoles result from dopaminergic action on the heart.
Hypotension may also develop.
b. CNS eff ects: Visual and auditory hallucinations and abnormal involuntary
movements (dyskinesias) may occur. Levodopa can also cause mood changes,
depression, psychosis, and anxiety.
6. Interactions:
 The vitamin pyridoxine (B6) increases the peripheral breakdown of
levodopa and diminishes its effectiveness.
 Concomitant administration of levodopa and monoamine oxidase inhibitors
(MAOIs), such as phenelzine, can produce a hypertensive crisis.
 In many psychotic patients, levodopa exacerbates symptoms.
 In patients with glaucoma, the drug can cause an increase in intraocular
pressure.
 Antipsychotic drugs are generally contraindicated in parkinsonian patients.
However low doses of certain “atypical” antipsychotic agents are
sometimes used to treat levodopa-induced psychiatric symptoms.
Two. DOPAMINE RECEPTOR AGONISTS
Drugs acting directly on postsynaptic dopamine receptors may have a beneficial
effect in addition to that of levodopa. Unlike levodopa, they do not require
enzymatic conversion to an active metabolite, act directly on the postsynaptic
dopamine receptors, have no potentially toxic metabolites, and do not compete
with other substances for active transport into the blood and across the blood-brain
barrier. Moreover, drugs selectively affecting certain (but not all) dopamine
receptors may have more limited adverse effects than levodopa.
Dopamine agonists have an important role as first-line therapy for Parkinson’s
disease, and their use is associated with a lower incidence of the response
fluctuations and dyskinesias that occur with long-term levodopa therapy. In
consequence, dopaminergic therapy is often initiated with a dopamine agonist.
Alternatively, a low dose of carbidopa plus levodopa (eg, Sinemet-25/100 three
times daily) is introduced, and a dopamine agonist is then added. The response to a
dopamine agonist is generally disappointing in patients who have never responded
to levodopa.
Bromocriptine
Bromocriptine is a D2 agonist. This drug has been widely used to treat Parkinson
’sndisease in the past but is now rarely used for this purpose, having been
superseded by the newer dopamine agonists.
Pergolide
Pergolide, another ergot derivative, directly stimulates both D1 and D2 receptors.
It too has been widely used for parkinsonism but is no longer available in the
United States because its use has been associated with the development of valvular
heart disease. It is nevertheless still used in certain countries.
Pramipexole
Pramipexole is not an ergot derivative, but it has preferential affinity for the D3
family of receptors. It is effective as monotherapy for mild parkinsonism and is
also helpful in patients with advanced disease, permitting the dose of levodopa to
be reduced and smoothing out response fluctuations. Pramipexole may ameliorate
affective symptoms. Pramipexole is rapidly absorbed after oral administration,
reaching peak plasma concentrations in approximately 2 hours, and is excreted
largely unchanged in the urine.
Ropinirole
Another nonergoline derivative, ropinirole (now available in a generic preparation)
is a relatively pure D2 receptor agonist that is effective as monotherapy in patients
with mild disease and as a means of smoothing the response to levodopa in patients
with more advanced disease and response fluctuations
Rotigotine The dopamine agonist rotigotine, delivered daily through a skin patch,
is approved for treatment of early Parkinson’s disease. It supposedly provides
more continuous dopaminergic stimulation than oral medication in early disease
Adverse Effects of Dopamine Agonists
A. Gastrointestinal Effects
Anorexia and nausea and vomiting may occur when a dopamine agonist is
introduced and can be minimized by taking the medication with meals.
Constipation, dyspepsia, and symptoms of reflux esophagitis may also occur.
Bleeding from peptic ulceration has been reported.
B. Cardiovascular Effects
Postural hypotension may occur, particularly at the initiation of therapy. Painless
digital vasospasm is a dose-related complication of long-term treatment with the
ergot derivatives (bromocriptine or pergolide).
C. Dyskinesias
Abnormal movements similar to those introduced by levodopa may occur and are
reversed by reducing the total dose of dopaminergic drugs being taken.
D. Mental Disturbances
Confusion, hallucinations, delusions, and other psychiatric reactions are potential
complications of dopaminergic treatment and are more common and severe with
dopamine receptor agonists than with levodopa.
Three. MONOAMINE OXIDASE
INHIBITORS – TYPE B
Selegiline and rasagiline
Selegiline selectively inhibits MAO Type B (which metabolizes dopamine) at low
to moderate doses but does not inhibit MAO Type A (which metabolizes
norepinephrine and serotonin) unless given at above recommended doses, where it
loses its selectivity. By, thus, decreasing the metabolism of dopamine, selegiline
has been found to increase dopamine levels in the brain. Therefore, it enhances the
actions of levodopa when these drugs are administered together. Selegiline
substantially reduces the required dose of levodopa. Unlike nonselective MAOIs,
selegiline at recommended doses has little potential for causing hypertensive
crises. However, if selegiline is administered at high doses, the selectivity of the
drug is lost, and the patient is at risk for severe hypertension. Selegiline is
metabolized to methamphetamine and amphetamine, whose stimulating properties
may produce insomnia if the drug is administered later than midafternoon.
Rasagiline an irreversible and selective inhibitor of brain monoamine oxidase Type
B, has five times the potency of selegiline. Unlike selegiline, rasagiline is not
metabolized to an amphetamine like substance
Four. CATECHOL-O-METHYL
TRANSFERASE INHIBITORS
Mechanism of action: Inhibition of dopa decarboxylase is associated with
compensatory activation of other pathways of levodopa metabolism, especially
catechol-O-methyl transferase (COMT), and this increases plasma levels of 3-Omethyldopa (3-OMD). Elevated levels of 3-OMD have been associated with a poor
therapeutic response to levodopa. Selective COMT inhibitors such as tolcapone
and entacapone also prolong the action of levodopa by diminishing its peripheral
metabolism. Levodopa clearance is decreased and relative bioavailability of
levodopa is thus increased.
Uses: Tolcapone and entacapone are used for adjunctive therapy in patients who
are already taking L-dopa/dopa decarboxylaseinhibitor combinations with
unsatisfactory control (e.g. end-ofdose deterioration). These agents improve
symptoms with less on–off fluctuations, as well as reducing the levodopa dose
requirement by 20–30%.
Adverse effects
These include the following:
• Nausea, vomiting, diarrhoea and constipation;
• increased levodopa-related side effects;
• Dizziness
• Hepatitis – rare with entacapone, but potentially lifethreatening with tolcapone
(liver function testing is mandatory before and during treatment)
• Urine discoloration.
Five. APOMORPHINE
Subcutaneous injection of apomorphine hydrochloride (Apokyn), a potent
nonergoline dopamine agonist that interacts with postsynaptic D2 receptors is
effective for the temporary relief (“rescue”) of off-periods of akinesia in patients
on optimized dopaminergic therapy. It is rapidly taken up in the blood and then the
brain, leading to clinical benefit that begins within about 10 minutes of injection
and persists for up to 2 hours. Nausea is often troublesome, especially at the
initiation of apomorphine treatment; accordingly, pretreatment with the antiemetic
trimethobenzamide or domperidone for 3 days is recommended before
apomorphine is introduced and is then continued for at least 1 month. Other
adverse effects include dyskinesias, drowsiness, insomnia, chest pain, sweating,
hypotension, syncope, constipation, diarrhea, and mental or behavioral
disturbances
Six: AMANTADINE
Use: Amantadine has limited efficacy, but approximately 60% of patients
experience some benefit. Severe toxicity is rare.
Mechanism of action: Endogenous dopamine release is stimulated by amantadine,
which also inhibits reuptake of dopamine into nerve terminals.
Seven: MUSCARINIC RECEPTOR
ANTAGONISTS
Muscarinic antagonists (e.g. trihexyphenidyl, benzatropine, orphenadrine,
procyclidine) are effective in the treatment of parkinsonian tremor and to a lesser
extent rigidity, but produce only a slight improvement in bradykinesia. They are
usually given in divided doses, which are increased every two to five days until
optimum benefit is achieved or until adverse effects occur. Their main use is in
patients with Parkinsonism caused by antipsychotic agents.
Adverse effects
These include the following:
• Dry mouth, blurred vision, constipation;
• Precipitation of glaucoma or urinary retention
• Cognitive impairment, confusion, excitement or psychosis, especially in the
elderly.