Pharmacotherapy of Parkinsonism

Parkinsonism, a progressive neurodegenerative disorder, is primarily managed through a

multi-faceted pharmacological approach aimed at restoring the delicate balance of
neurotransmitters in the brain, principally dopamine. The mainstay of treatment revolves around
enhancing dopaminergic activity or reducing cholinergic influence within the basal ganglia.

The Cornerstone of Treatment: Restoring Dopaminergic Function

The core pathology of Parkinson's disease lies in the degeneration of dopaminergic neurons in
the substantia nigra pars compacta, leading to a profound deficiency of dopamine in the
striatum. Consequently, the primary goal of pharmacotherapy is to replenish or mimic the effects
of dopamine.

Levodopa: The Gold Standard

Levodopa (L-dopa) remains the most effective drug for the symptomatic treatment of
Parkinson's disease. As a precursor of dopamine, levodopa can cross the blood-brain barrier,
which dopamine itself cannot. Once in the brain, it is converted to dopamine by the enzyme
L-aromatic amino acid decarboxylase (AADC), thereby replenishing the deficient
neurotransmitter.
Mechanism of Action: Levodopa's therapeutic effect is a direct consequence of its conversion
to dopamine in the striatum, which then stimulates D2 receptors, improving the cardinal motor
symptoms of bradykinesia and rigidity.
Pharmacokinetics: Levodopa is rapidly absorbed from the small intestine, but its peripheral
metabolism to dopamine by AADC in the gut wall, liver, and other tissues significantly reduces
its bioavailability and leads to peripheral side effects. To overcome this, levodopa is almost
always co-administered with a peripheral decarboxylase inhibitor such as carbidopa or
benserazide. These inhibitors do not cross the blood-brain barrier and thus prevent the
peripheral conversion of levodopa, allowing a higher concentration to reach the brain. This
combination significantly reduces the required dose of levodopa and minimizes peripheral
adverse effects like nausea and vomiting.
Adverse Effects:
●​ Peripheral: Nausea, vomiting, orthostatic hypotension, and cardiac arrhythmias. These
are largely mitigated by the addition of a peripheral decarboxylase inhibitor.
●​ Central: The long-term use of levodopa is associated with significant motor
complications, including:
○​ "Wearing-off" phenomenon: A predictable decline in motor function towards the
end of a dose interval.
○​ "On-off" phenomenon: Unpredictable, abrupt fluctuations between periods of
good motor control ("on") and severe parkinsonian symptoms ("off").
○​ Dyskinesias: Involuntary, choreiform, or dystonic movements that often occur at
peak levodopa concentrations.
●​ Behavioral effects: Confusion, hallucinations, delusions, and sleep disturbances can
also occur, particularly in elderly patients.
Augmenting Dopaminergic Activity: Other Key Drug Classes
To complement levodopa therapy, delay its initiation, or manage its long-term complications,
several other classes of drugs are employed.

Dopamine Agonists

These drugs directly stimulate dopamine receptors in the brain, bypassing the need for
conversion from levodopa. They have a longer duration of action than levodopa and are less
likely to cause motor fluctuations in the early stages of the disease. They are often used as
initial therapy in younger patients to postpone the need for levodopa.
●​ Ergot derivatives: Bromocriptine (a D2 agonist)
●​ Non-ergot derivatives: Ropinirole and Pramipexole (primarily D2/D3 agonists) are now
more commonly used due to a better side-effect profile, particularly a lower risk of fibrotic
reactions. Apomorphine, a potent dopamine agonist, is administered subcutaneously for
the rapid relief of "off" episodes.
Adverse Effects: Similar to levodopa, they can cause nausea, vomiting, and orthostatic
hypotension. However, they have a higher propensity to cause hallucinations, somnolence
(sudden sleep attacks), and impulse control disorders (e.g., compulsive gambling,
hypersexuality).

Monoamine Oxidase-B (MAO-B) Inhibitors

Selegiline and Rasagiline are selective, irreversible inhibitors of MAO-B, the enzyme primarily
responsible for the breakdown of dopamine in the brain. By inhibiting this enzyme, they increase
the synaptic concentration and prolong the action of dopamine.
●​ Therapeutic Use: They provide modest symptomatic relief in early disease and are used
as an adjunct to levodopa to reduce "wearing-off" phenomena. There is some evidence
suggesting a potential neuroprotective effect, though this remains a subject of debate.
Adverse Effects: When used alone, they are generally well-tolerated. Nausea and headache
are the most common side effects. When combined with levodopa, they can potentiate its
dopaminergic side effects. The risk of a hypertensive crisis ("cheese reaction") associated with
non-selective MAO inhibitors is minimal with selective MAO-B inhibitors at standard doses.

Catechol-O-Methyltransferase (COMT) Inhibitors

Entacapone and Tolcapone are inhibitors of COMT, an enzyme that peripherally metabolizes
levodopa to 3-O-methyldopa (3-OMD). By inhibiting COMT, they increase the plasma half-life of
levodopa, enhancing its bioavailability and prolonging its therapeutic effect.
●​ Therapeutic Use: They are always used as an adjunct to levodopa-carbidopa therapy to
manage "wearing-off" fluctuations. Entacapone acts only peripherally, while tolcapone has
both central and peripheral actions.
Adverse Effects: They primarily enhance the adverse effects of levodopa. Diarrhea is a
common side effect. Tolcapone carries a risk of hepatotoxicity, requiring regular monitoring of
liver function, which has limited its use. Entacapone does not share this toxicity. A harmless
orange discoloration of the urine may occur.
Dopamine Facilitator

Amantadine, an antiviral agent, was fortuitously found to have anti-parkinsonian properties. Its
exact mechanism is not fully understood but is thought to involve enhancing the release of
dopamine from presynaptic terminals, inhibiting its reuptake, and possessing some
anticholinergic and NMDA receptor antagonist properties.
●​ Therapeutic Use: It provides mild symptomatic relief in the early stages of the disease
and is particularly useful in reducing levodopa-induced dyskinesias.
Adverse Effects: Ankle edema, livedo reticularis (a purplish, mottled skin discoloration),
confusion, and hallucinations are notable side effects.

Addressing the Cholinergic Imbalance

In the striatum, there is a physiological balance between dopamine (inhibitory) and acetylcholine
(excitatory). The deficiency of dopamine in Parkinson's disease leads to a relative overactivity of
the cholinergic system, contributing to tremor and rigidity.

Central Anticholinergics

Drugs like Trihexyphenidyl (Benzhexol), Procyclidine, and Biperiden block muscarinic

receptors in the basal ganglia, thereby reducing the excitatory effect of acetylcholine.
●​ Therapeutic Use: They are most effective in controlling tremor and are generally used in
younger patients in the early stages of the disease where tremor is the predominant
symptom. Their use in older adults is limited due to significant cognitive side effects.
Adverse Effects: Dry mouth, blurred vision, constipation, urinary retention, and cognitive
impairment (confusion, memory loss) are common.

Therapeutic Strategies and Management of Complications

The choice of initial therapy in Parkinson's disease depends on the patient's age, the severity of
symptoms, and the degree of functional impairment.
●​ Early Disease: In younger patients (< 60-65 years), dopamine agonists or MAO-B
inhibitors are often preferred as initial monotherapy to delay the need for levodopa and its
associated motor complications. In older patients or those with more significant functional
disability, levodopa-carbidopa is the treatment of choice.
●​ Advanced Disease: As the disease progresses, most patients will require levodopa
therapy. Management focuses on optimizing the levodopa dose and using adjunct
therapies to control motor fluctuations.
○​ "Wearing-off": This can be managed by increasing the frequency of levodopa
doses, adding a COMT inhibitor or a MAO-B inhibitor, or incorporating a dopamine
agonist.
○​ "On-off": This is more challenging to manage. Strategies include redistributing
dietary protein (as large neutral amino acids can compete with levodopa for
absorption), using controlled-release levodopa formulations, or utilizing
subcutaneous apomorphine for rapid rescue from "off" states.
○​ Dyskinesias: Reducing the individual doses of levodopa, adding amantadine, or in
severe cases, considering deep brain stimulation (DBS) are the primary
management options.