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PH3.7 | PH3.7 | Antiparkinsonian and Neurodegenerative Disorder Drugs — SDL Guide — SDL Guide (Part 2)

Levodopa and Dopaminergic Agents — PK, PD, Uses, and ADRs

Levodopa/Carbidopa: Levodopa is the most effective drug for PD and the gold standard for moderate-severe PD. It is a prodrug — after crossing the BBB it is converted to dopamine by DOPA-decarboxylase (DDC) in residual nigrostriatal neurons and glial cells. When given alone, >95% of levodopa is converted to dopamine peripherally by DDC before reaching the brain — causing systemic dopaminergic ADRs (nausea, vomiting, hypotension). Carbidopa is a peripheral DDC inhibitor (does not cross BBB) — combined with levodopa (carbidopa:levodopa = 1:4, e.g., 25:100 mg), it reduces peripheral conversion, approximately doubles CNS levodopa bioavailability, and dramatically reduces nausea.

Long-term levodopa complications:
- Motor fluctuations (on-off phenomenon): after 5-10 years, smooth motor control is replaced by unpredictable switches between 'on' (functional) and 'off' (akinetic) states, correlating with plasma levodopa oscillations. Managed with COMT inhibitors, MAO-B inhibitors (extend effective duration of each dose), or dopamine agonist infusion.
- Peak-dose dyskinesias: involuntary writhing movements at peak plasma levodopa concentration. Managed with amantadine (NMDA antagonism) and dose reduction strategies.

Dopamine agonists (pramipexole, ropinirole): Direct D2/D3 receptor agonists. Advantages: longer duration of action than levodopa (smoother motor control), less dyskinesia. Preferred as initial monotherapy in younger PD patients. ADRs: nausea, postural hypotension, impulse control disorders (compulsive gambling, hypersexuality, binge eating — class effect, important to warn patients and families), sudden onset sleep ('sleep attacks' — particularly dangerous while driving), psychosis.

Selegiline/Rasagiline (MAO-B inhibitors): Selectively inhibit MAO-B in the striatum, reducing dopamine catabolism and increasing synaptic dopamine duration. Used as monotherapy in early PD or as levodopa adjuncts. Selegiline is metabolised to l-amphetamine and l-methamphetamine (minor metabolites — mild stimulant effect, insomnia). At standard doses, selectivity for MAO-B means MAO-A in the gut is preserved — no tyramine reaction, no cheese effect. This distinguishes selegiline from the non-selective MAOIs (phenelzine, tranylcypromine) used in psychiatry.

COMT inhibitors (entacapone): Block peripheral COMT-mediated L-DOPA catabolism → increase L-DOPA half-life and reduce 'wearing-off'. Used as adjuncts to levodopa/carbidopa. ADRs: dyskinesia (exacerbated by increased L-DOPA effect), urine discolouration (orange), diarrhoea.

Anticholinergics and Drug-Induced Parkinsonism

Drug-induced parkinsonism (DIP) is caused by blockade of D2 receptors in the nigrostriatal pathway by antipsychotics (haloperidol, chlorpromazine, risperidone) or by antiemetics (metoclopramide). Clinical features are identical to idiopathic PD: resting tremor, rigidity, bradykinesia, masked facies, shuffling gait — but in the context of recent antipsychotic or antiemetic exposure. DIP is completely reversible if the offending drug is stopped or reduced, unlike idiopathic PD (which is progressive).

Treatment of DIP: Anticholinergic drugs — trihexyphenidyl (benzhexol) 1-2 mg TDS (typical dose) or benztropine — are first-line. They reduce the relative cholinergic excess in the striatum (ACh overactivity when dopaminergic tone is suppressed by D2 blockade) and are effective for tremor and rigidity.

Why levodopa is NOT used for DIP:
1. Mechanistic incompatibility: DIP is caused by D2 receptor blockade — the receptor is present but occupied by the antipsychotic. Levodopa increases dopamine availability, but extra dopamine cannot displace the antipsychotic from the D2 receptor (antipsychotics bind with higher affinity). The therapeutic target (D2 receptor) is pharmacologically inaccessible.
2. Worsening psychosis: if haloperidol is the cause of DIP (the most common scenario), increasing dopaminergic tone by adding levodopa would directly antagonise the antipsychotic's mesolimbic D2 blockade, worsening psychosis.
3. Anticholinergics are mechanistically correct: DIP causes relative ACh excess (not absolute DA deficiency) — anticholinergics directly address this imbalance.

Writing the prescription for DIP:
- Primary intervention: review the need for the offending drug; reduce dose if possible
- Pharmacological: Trihexyphenidyl (Benzhexol) 1 mg oral BD, increasing to 2 mg TDS as tolerated
- Monitor for anticholinergic ADRs: dry mouth, urinary retention, constipation, confusion (especially in elderly)

Anticholinergics in idiopathic PD: Used mainly for tremor-dominant PD in younger patients. Less useful for bradykinesia. Avoided in elderly (cognitive impairment, constipation, urinary retention worsened).

Prescribing for Drug-Induced Parkinsonism and Clinical Decision-Making

The clinical decision framework for a patient presenting with parkinsonism begins with determining whether it is idiopathic or drug-induced — the drug history is the single most important clinical discriminator. Recent exposure to antipsychotics, metoclopramide, prochlorperazine, or cinnarizine in a patient with parkinsonism-like features should prompt suspicion of DIP.

Management decision tree:
- Drug exposure identified → DIP → (1) Review whether the offending drug can be stopped or reduced; if antipsychotic: consider switching to an atypical with lower EPS risk (quetiapine, clozapine); if metoclopramide: use domperidone instead (does not cross BBB); (2) Prescribe trihexyphenidyl orally; (3) Do NOT prescribe levodopa.
- No drug exposure → evaluate for idiopathic PD → refer to neurologist for confirmation; initiate levodopa/carbidopa or dopamine agonist depending on age and severity.

Neurodegenerative disorders — Alzheimer's dementia:
For completeness, the pharmacological management of Alzheimer's dementia rests on two drug classes:
1. Acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, galantamine — inhibit the enzyme that breaks down acetylcholine in the synapse, increasing cholinergic transmission in the hippocampus and cortex. These are symptomatic treatments (reduce cognitive decline rate, improve daily function), not disease-modifying. Used in mild-moderate Alzheimer's. ADRs: GI (nausea, diarrhoea, bradycardia via vagal stimulation).
2. Memantine: NMDA receptor antagonist — reduces glutamate excitotoxicity, protecting remaining neurons. Used in moderate-severe Alzheimer's, often combined with donepezil. ADRs: mild (dizziness, constipation).

Drug	Mechanism	Indication	Key ADR
Levodopa/Carbidopa	DA precursor + peripheral DDC inhibitor	Idiopathic PD (moderate-severe)	On-off, dyskinesias
Pramipexole/Ropinirole	D2/D3 agonist	Early PD monotherapy, adjunct	Impulse control disorder, sleep attacks
Selegiline	MAO-B inhibitor	Early PD, levodopa adjunct	L-amphetamine metabolite (insomnia)
Trihexyphenidyl	Muscarinic antagonist	Drug-induced parkinsonism, tremor	Anticholinergic (dry mouth, confusion in elderly)
Donepezil	AChEI	Alzheimer's (mild-moderate)	GI, bradycardia
Memantine	NMDA antagonist	Alzheimer's (moderate-severe)	Dizziness