Medicine – Drugs Used in Parkinsonism

Drug treatment of Parkinson disease aims mainly to restore the imbalance between dopaminergic and cholinergic activity within the basal ganglia. The major motor manifestations—bradykinesia, rigidity, resting tremor, and later postural instability—result largely from degeneration of dopaminergic neurons in the substantia nigra pars compacta, causing reduced dopamine within the striatum.

The drugs in your table can be organised into five important groups: levodopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, and anticholinergic drugs. Some details in the older table need updating because modern Parkinson treatment has changed considerably.

1. Levodopa

Levodopa (L-DOPA) is the metabolic precursor of dopamine and remains the most effective symptomatic treatment for the motor features of Parkinson disease, particularly bradykinesia and rigidity.

Dopamine itself cannot effectively cross the blood–brain barrier. Levodopa, however, can cross into the CNS and is then converted into dopamine by DOPA decarboxylase.

Therefore:

Levodopa crosses blood–brain barrier → converted to dopamine in brain → replenishes striatal dopamine → improves Parkinsonian motor symptoms.

2. Levodopa with Carbidopa or Benserazide

Levodopa is almost always given with a peripheral DOPA-decarboxylase inhibitor, such as:

Carbidopa.

Benserazide.

These drugs inhibit the peripheral conversion of levodopa into dopamine but do not significantly cross the blood–brain barrier.

Consequently, more levodopa reaches the CNS and peripheral dopaminergic adverse effects are reduced.

3. Why Levodopa Is Not Given Alone

If levodopa were given alone, a substantial amount would be converted into dopamine in peripheral tissues before reaching the brain.

Peripheral dopamine can cause adverse effects such as:

Nausea and vomiting.

Postural hypotension.

Cardiovascular effects.

Adding carbidopa or benserazide therefore both increases CNS availability of levodopa and reduces peripheral adverse effects.

4. Effects of Levodopa

Levodopa is particularly effective at improving:

Bradykinesia.

Rigidity.

It also improves tremor in many patients.

Its effect on later problems such as postural instability, freezing, speech disturbance, and some non-motor manifestations may be less predictable.

5. Motor Fluctuations with Levodopa

After prolonged treatment, patients may develop motor fluctuations.

One important pattern is wearing-off, in which the effect of each levodopa dose becomes progressively shorter.

The patient improves after taking a dose but develops recurrent Parkinsonian symptoms before the next dose is due.

This is sometimes called end-of-dose deterioration.

6. On–Off Phenomenon

Patients receiving long-term levodopa may also experience an on–off phenomenon.

During an “on” period, mobility is relatively good and the medication is working effectively.

During an “off” period, Parkinsonian symptoms suddenly become much more prominent, with severe bradykinesia or inability to move.

These fluctuations can become unpredictable in advanced disease.

7. Levodopa-Induced Dyskinesia

Long-term levodopa therapy can produce dyskinesias, meaning involuntary abnormal movements.

These are often choreiform or writhing movements and commonly occur when levodopa concentrations are relatively high.

Thus:

Long-term levodopa → motor fluctuations + dyskinesias.

8. Neuropsychiatric Effects of Levodopa

Dopaminergic treatment may cause neuropsychiatric complications, particularly in older or cognitively vulnerable patients.

These can include:

Hallucinations.

Confusion.

Vivid dreams.

Psychotic symptoms.

Hallucinations are therefore an important adverse effect to remember.

9. Dopamine Agonists

Dopamine agonists directly stimulate dopamine receptors and therefore do not require conversion into dopamine.

The older table lists:

Bromocriptine.

Pergolide.

These are older ergot-derived dopamine agonists and are now much less commonly used for Parkinson disease because of their adverse-effect profiles.

10. Modern Dopamine Agonists

More commonly encountered modern dopamine agonists include:

Pramipexole.

Ropinirole.

Rotigotine.

Apomorphine is another dopamine agonist used in selected patients, particularly for troublesome “off” episodes or advanced disease.

11. Mechanism of Dopamine Agonists

Dopamine agonists directly stimulate dopamine receptors in the basal ganglia.

Many have substantial activity at the D₂-family of dopamine receptors.

They can improve:

Bradykinesia.

Rigidity.

Tremor.

They may be used alone in selected patients or together with levodopa.

12. Advantages of Dopamine Agonists

Dopamine agonists have longer pharmacological effects than levodopa and can sometimes reduce “off” time when added to levodopa.

However, they are generally less effective than levodopa for overall motor symptom control and often produce more troublesome neuropsychiatric and behavioural adverse effects.

13. Adverse Effects of Dopamine Agonists

Important adverse effects include:

Nausea.

Postural hypotension.

Hallucinations.

Confusion.

Somnolence and sudden sleep attacks.

Peripheral oedema.

14. Impulse-Control Disorders

An especially important adverse effect of dopamine agonists is the development of impulse-control disorders.

These may include:

Pathological gambling.

Compulsive shopping.

Binge eating.

Hypersexuality.

Patients and families should therefore be warned about potentially major behavioural changes.

15. Fibrotic Reactions with Older Dopamine Agonists

The table correctly lists fibrotic reactions, but these are particularly associated with the older ergot-derived dopamine agonists, such as bromocriptine and pergolide.

They may cause:

Pleuropulmonary fibrosis.

Retroperitoneal fibrosis.

Cardiac valvular fibrosis.

This is an important reason why pergolide is no longer routinely used in many countries and non-ergot dopamine agonists are generally preferred.

16. Selegiline

Selegiline is a selective monoamine oxidase-B (MAO-B) inhibitor.

MAO-B is involved in dopamine metabolism within the brain.

By inhibiting MAO-B:

Dopamine breakdown ↓ → dopamine availability in the brain ↑ → Parkinsonian symptoms improve.

17. Other MAO-B Inhibitors

Other drugs in this class include:

Rasagiline.

Safinamide.

These agents may be used alone in selected early disease or as adjuncts to levodopa to reduce motor fluctuations.

18. Does Selegiline Slow Disease Progression?

The original table states that selegiline “may slow progression of disease.”

This should be updated.

MAO-B inhibitors provide symptomatic benefit, but convincing evidence that selegiline meaningfully prevents or reverses the underlying neurodegenerative progression of Parkinson disease is lacking.

Therefore, it is better remembered as a symptomatic and adjunctive treatment, rather than a proven neuroprotective treatment.

19. Adverse Effects of Selegiline

Potential adverse effects include:

Postural hypotension.

Hallucinations.

Confusion.

Nausea.

Dyskinesia when combined with levodopa.

Because selegiline has metabolites with stimulant properties, it may also contribute to insomnia, particularly if taken late in the day.

20. Entacapone

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor.

It is used together with levodopa rather than as effective Parkinson therapy on its own.

COMT normally contributes to the peripheral metabolism of levodopa.

21. Mechanism of Entacapone

Entacapone inhibits peripheral COMT and therefore reduces the breakdown of levodopa.

This results in:

Reduced peripheral levodopa metabolism → prolonged levodopa availability → more sustained dopaminergic effect.

It is particularly useful for patients who experience end-of-dose wearing-off.

22. Entacapone and Wearing-Off

A patient may initially respond well to levodopa but find that symptoms return before the next dose.

Adding entacapone can extend the duration of each levodopa dose.

Therefore:

Levodopa wearing-off → consider a COMT inhibitor such as entacapone.

23. Adverse Effects of Entacapone

Important adverse effects include:

Diarrhoea.

Nausea.

Postural hypotension.

Increased levodopa-related dyskinesia.

Entacapone can also cause harmless orange-brown or reddish-brown discoloration of urine.

The old table describes this simply as “brown urine.”

24. Other COMT Inhibitors

Other COMT inhibitors include:

Opicapone.

Tolcapone.

Tolcapone acts both centrally and peripherally but is used much less because of the risk of serious hepatotoxicity and the need for appropriate liver monitoring.

25. Anticholinergic Drugs

Anticholinergic drugs used in Parkinsonism are predominantly central antimuscarinic agents.

Examples from the table include:

Benztropine.

Procyclidine.

Another traditional example is trihexyphenidyl (benzhexol).

26. Mechanism of Anticholinergic Drugs

Loss of dopamine in Parkinson disease creates a relative excess of cholinergic activity within the basal ganglia.

Antimuscarinic drugs reduce this cholinergic influence.

They are particularly useful for reducing:

Tremor.

Rigidity to some extent.

They have relatively little effect on bradykinesia.

27. Drug-Induced Parkinsonism

Anticholinergic drugs can be particularly useful for drug-induced Parkinsonism, such as Parkinsonian symptoms caused by dopamine-blocking antipsychotic drugs.

However, the underlying medication should also be reviewed whenever possible.

They are not usually preferred as routine first-line treatment for typical Parkinson disease, particularly in older patients.

28. Adverse Effects of Anticholinergic Drugs

Because these drugs block muscarinic acetylcholine receptors, they produce characteristic anticholinergic adverse effects:

Dry mouth.

Constipation.

Urinary retention.

Blurred vision.

Tachycardia.

29. Psychiatric and Cognitive Effects

Central anticholinergic effects can cause:

Confusion.

Memory impairment.

Hallucinations.

Agitation.

Because these effects are particularly problematic in older patients, anticholinergic drugs are generally avoided or used very cautiously in elderly people or patients with cognitive impairment.

30. Drugs Used in Parkinsonism – Note Form

Levodopa + carbidopa/benserazide: levodopa enters the brain and is converted to dopamine; the peripheral decarboxylase inhibitor prevents excessive peripheral conversion.

Main benefit of levodopa: strongest symptomatic improvement, particularly for bradykinesia and rigidity.

Major long-term levodopa problems: wearing-off, on–off fluctuations and dyskinesia.

Other levodopa adverse effects: nausea, postural hypotension, hallucinations and confusion.

Dopamine agonists: directly stimulate dopamine receptors.

Modern dopamine agonists: pramipexole, ropinirole and rotigotine; apomorphine is important in selected advanced disease.

Major dopamine-agonist adverse effects: hallucinations, hypotension, sleep attacks and impulse-control disorders.

Bromocriptine/pergolide: older ergot dopamine agonists associated with fibrotic complications; pergolide is largely obsolete in modern Parkinson treatment.

Selegiline: MAO-B inhibitor → decreases dopamine breakdown.

MAO-B inhibitors: provide symptomatic benefit but should not be regarded as proven treatments that stop Parkinson disease progression.

Entacapone: COMT inhibitor → reduces peripheral levodopa metabolism and prolongs levodopa action.

Best use of entacapone: end-of-dose wearing-off.

Entacapone adverse effects: diarrhoea, dyskinesia and harmless urine discoloration.

Anticholinergics: benztropine and procyclidine.

Anticholinergic benefit: mainly improve tremor; relatively little effect on bradykinesia.

Anticholinergic adverse effects: dry mouth, urinary retention, constipation, blurred vision, tachycardia, confusion and psychiatric disturbance.

Key Clinical Pattern

The easiest way to remember Parkinson drugs is according to where they increase dopaminergic activity:

Levodopa → supplies the precursor for dopamine.

Dopamine agonists → directly stimulate dopamine receptors.

MAO-B inhibitors → reduce dopamine breakdown in the brain.

COMT inhibitors → prolong the effect of levodopa.

Anticholinergics → reduce relative cholinergic activity, particularly helping tremor.

For examinations, remember the characteristic drug–adverse effect associations:

Levodopa → dyskinesia + on–off fluctuations + hallucinations.

Dopamine agonists → impulse-control disorders + hallucinations + sleep attacks.

Selegiline → postural hypotension + hallucinations ± insomnia.

Entacapone → diarrhoea + urine discoloration + increased dyskinesia.

Anticholinergics → dry mouth + constipation + urinary retention + confusion.