Antiparkinsonian Drugs — Levodopa-Carbidopa, Dopamine Agonists, MAO-B and COMT Inhibitors, Anticholinergics

Parkinson disease (PD) is a progressive neurodegenerative disorder in which dopaminergic neurons of the substantia nigra degenerate and alpha-synuclein accumulates in Lewy bodies. By the time of clinical diagnosis, more than half — and up to 80% — of these neurons have already been lost. The cardinal motor features are bradykinesia, resting tremor and rigidity, with postural instability appearing later. No therapy currently slows the disease; every drug is symptomatic.

Because motor symptoms come from too little dopamine and a relative excess of cholinergic activity in the striatum, the drugs work in four ways: replace dopamine (levodopa), mimic dopamine (dopamine agonists), prolong dopamine by blocking its breakdown (MAO-B and COMT inhibitors) and reduce cholinergic tone (anticholinergics). Amantadine acts through dopamine release and NMDA antagonism.

Levodopa is the precursor of dopamine and, unlike dopamine, crosses the blood-brain barrier. About 70% of an oral dose is absorbed from the small intestine, where much of it is converted to dopamine by aromatic L-amino acid decarboxylase (AADC), and only about 1% reaches the brain. Carbidopa is a peripheral AADC inhibitor that does not cross the blood-brain barrier: it lets far lower levodopa doses be used, reduces peripheral dopamine effects such as nausea, and extends the levodopa half-life to about 90 minutes. Levodopa is most effective for bradykinesia.

• Short duration of action — about 3 to 4 hours. In early disease the 'on' time is long because surviving neurons store dopamine; as the disease advances the 'on' time shortens and motor fluctuations (wearing-off) appear. Most drugs give good control for 3 to 6 years.
• Common adverse effects — nausea, vomiting, dizziness, headache and somnolence; dyskinesia and hallucinations or psychosis; orthostatic hypotension. Extra carbidopa relieves nausea, and domperidone can help if it does not.
• Food interaction — take levodopa about 1 hour before or 2 hours after protein meals; high-protein diets reduce absorption by competing for amino acid transporters.
• Contraindications (levodopa/carbidopa/entacapone label) — non-selective MAO inhibitors (stop at least 14 days before starting) and narrow-angle glaucoma; caution with a history of melanoma.
• Formulations — immediate-release, controlled-release, extended-release capsules, a combination with entacapone, an enteral gel infused into the small intestine for advanced fluctuations, and a continuous subcutaneous infusion.

When carbidopa blocks decarboxylation, peripheral levodopa is broken down mainly by catechol-O-methyltransferase (COMT). Entacapone selectively inhibits COMT in peripheral tissues, prolonging the levodopa half-life by up to 75% and giving steadier dopamine delivery. It is indicated for patients showing wearing-off on levodopa/carbidopa and is also available as a fixed triple combination (levodopa/carbidopa/entacapone). The risk of CNS adverse effects, especially dyskinesia, is higher with the triple combination, but dyskinesia usually improves if the levodopa dose is reduced.

• Entacapone — a harmless dark reddish or orange urine discolouration is a common adverse effect; diarrhoea may occur.
• Tolcapone — an adjunct for patients with motor fluctuations or who cannot tolerate other therapies; it carries a black box warning for liver toxicity (rare but serious acute liver failure) and should not be started in clinical liver disease.
• Caution with other COMT-metabolised drugs such as epinephrine, norepinephrine, apomorphine, dopamine and dobutamine (tachycardia and arrhythmias).

Dopamine agonists are classed as ergot-derived (for example bromocriptine) and non-ergot-derived (pramipexole, ropinirole). Pramipexole is a selective agonist with the highest affinity for D3, about eight times higher than for D2, and negligible D1 affinity. Ropinirole binds D2 receptors and treats both early and advanced PD and restless legs syndrome. Bromocriptine is a D2 agonist with partial D1 antagonist activity, also used for type 2 diabetes, acromegaly and prolactinoma.

Younger patients are more prone to levodopa motor fluctuations, so pramipexole can be started as monotherapy in young patients, while elderly patients are more susceptible to its adverse effects and are given it mainly for fluctuations on levodopa. Characteristic adverse effects are sudden onset of sleep ('sleep attacks') — leading to road traffic accidents — orthostatic hypotension, hallucinations, dyskinesia and impulse control disorders (gambling, excessive shopping, hypersexuality, punding).

Dopamine and tyramine are metabolised by both MAO-A and MAO-B; phenylethylamine is a substrate of MAO-B. Selegiline and rasagiline are irreversible, selective MAO-B inhibitors, whereas safinamide is a reversible selective MAO-B inhibitor. By blocking dopamine breakdown they raise synaptic dopamine. Selegiline loses selectivity at higher doses, and oral selegiline for PD is an adjunct to levodopa/carbidopa; the transdermal patch is approved for depression, and it inhibits both MAO-A and MAO-B because it bypasses first-pass metabolism.

• Tyramine reaction — non-selective MAOIs (phenelzine, tranylcypromine) cause hypertensive crisis with tyramine-rich food; selective MAO-B inhibitors carry a lower risk, but selegiline can still cause one with tyramine-rich food, drink or supplements.
• Other adverse effects of selegiline — sudden sleep episodes, orthostatic hypotension, arrhythmias, hallucinations, dyskinesia, dry mouth, constipation and serotonin syndrome with serotonergic drugs.
• The levodopa/carbidopa/entacapone combination is contraindicated with non-selective MAO inhibitors (a 14-day gap is needed).

Trihexyphenidyl (benzhexol) and benztropine are anticholinergics that block muscarinic receptors and reduce central cholinergic effects. Trihexyphenidyl is used for the tremor, spasms, stiffness and weak muscle control of Parkinson disease, as an adjunct with levodopa, and for antipsychotic-induced parkinsonism and extrapyramidal side effects; it is also used off-label for dystonia and to reduce drooling in children with developmental disabilities. Adverse effects are the anticholinergic set: dry mouth, blurred vision from mydriasis, confusion and delirium (especially in older patients), urinary retention and constipation.

• Contraindication — narrow-angle glaucoma (mydriasis closes the angle and raises intraocular pressure).
• Do not stop abruptly — worsening of parkinsonism and reports of neuroleptic malignant syndrome-like reactions after sudden withdrawal.
• Misuse potential — trihexyphenidyl has a short-acting euphoric effect; it can also lower the seizure threshold.
• Benztropine — a synthetic muscarinic antagonist approved as adjunct therapy for idiopathic and post-encephalitic parkinsonism; its adverse effects include dry mouth, mydriasis, heat intolerance and hyperthermia, delirium and hallucinations.

Amantadine is an antiviral agent with mild antiparkinsonian activity. In PD it acts on dopamine neurons as a weak, non-competitive NMDA receptor antagonist that increases dopamine release and blocks reuptake. It has a low side effect profile: livedo reticularis (reversible on stopping), peripheral oedema, orthostatic hypotension, dizziness, hallucinations and constipation, with rare neuroleptic malignant syndrome and psychosis. Amantadine is no longer recommended for influenza A because of high resistance.

• Levodopa/carbidopa remains the most effective oral therapy for motor symptoms and the standard when function is impaired.
• Younger patients are managed more aggressively and can start on a dopamine agonist such as pramipexole as monotherapy because they are more prone to levodopa fluctuations; older patients are more susceptible to agonist adverse effects.
• Wearing-off → add a COMT inhibitor (entacapone) or an MAO-B inhibitor; consider advanced formulations.
• Tremor, stiffness or drug-induced parkinsonism → an anticholinergic (trihexyphenidyl, benztropine) is an option; watch for confusion in older patients and avoid it in narrow-angle glaucoma.
• Refractory motor fluctuations → deep brain stimulation of the subthalamic nucleus, globus pallidus interna or thalamus; it adds at least 3 to 4 hours of 'on' time a day and lets the average drug dose fall by about 50%.
• Non-motor symptoms: constipation (polyethylene glycol), depression and anxiety (SSRIs), dementia (cholinesterase inhibitors), psychosis (antipsychotics such as pimavanserin), somnolence (modafinil).