Levodopa

Indications for Use

Levodopa is generally used as the first line treatment for the motor symptoms of Parkison’s disease. It is usually administered in combination with a peripheral dopa-decarboxylase inhibitor, such as carbidopa or benserazide. 

Examples of combinations include:

• Levodopa + carbidopa – co-careldopa, e.g. Sinemet
• Levodopa + benserazide – co-beneldopa, e.g. Madopar

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Fig 2
Parkinsons disease symptoms.

Mechanism of Action

Levodopa 

Dopamine itself cannot cross the blood-brain barrier in therapeutically useful amounts. Therefore, levodopa, the metabolic precursor of dopamine, is used to increase dopamine concentrations within the brain. Levodopa crosses into the brain using a large neutral amino acid transport system and is quickly converted to dopamine by dopa decarboxylase (DDC).

The resulting increase in dopamine concentrations within the striatum helps restore dopaminergic signalling and improves motor symptoms. 

Levodopa is usually administered in combination with a peripheral DDC inhibitor, such as carbidopa or benserazide, which reduces the peripheral conversion of levodopa to dopamine. Thus preventing peripheral effects of levodopa (such as nausea, vomiting and cardiac arrhythmias), whilst maintaining the therapeutic benefit in the brain and reducing the dose requirement of levodopa by 10 fold. 

Carbidopa produces near-complete inhibition of peripheral dopa-decarboxylase at approximately 70–100 mg daily. Patients receiving less than this amount may be more likely to experience nausea and vomiting. 

The addition of a dopa-decarboxylase inhibitor therefore:

• increases the proportion of levodopa reaching the brain
• allows lower doses of levodopa to be used
• reduces peripheral dopaminergic adverse effects, particularly nausea and vomiting.
• helps to treat ‘end of dose’ motor fluctuations. 

The effectiveness of levodopa diminishes with duration of treatment and patient may develop motor fluctuations and dyskinesias. This may be due to progression of the disease and receptor downregulation. 

Created in BioRender. Boucher, M. (2026) https://BioRender.com/lo7nlpg

Fig 3
Drugs Against Parkinson’s Disease – Mechanism of Action

Pharmacokinetics

Levodopa has a short half life, therefore is given frequently; it is vital that patients get their doses on time to avoid significant deterioration in motor symptoms. Patients will often take their levodopa at specific times of the day. 

Contraindications

Important contraindications to levodopa/carbidopa preparations include: 

• Narrow-angle glaucoma –  levodopa may raise intraocular pressure
• Severe psychoses
• Severe cardiac arrhythmias and cardiac failure
• Malignant melanoma – can be activated by levodopa
• Pregnancy (Madopar)

Adverse Effects and Cautions

Nausea and Vomiting

Nausea and vomiting are side effects of nearly all drugs that increase dopamine release in the brain, as dopaminergic neurons play a vital role in nausea and vomiting, with D2 receptors present in the chemoreceptor trigger zone which are associated with vomiting. 

Antiemetics which work as dopamine antagonists in the chemoreceptor trigger zone, such as domperidone, may be an effective treatment option in this case. Domperidone does not act on dopamine receptors in the basal ganglia, therefore is not expected to worsen Parkinson’s symptoms or antagonise the effects of dopamine agonists for Parkinson’s.

On the other hand, metoclopramide should be avoided in Parkinson’s disease. Metoclopramide is an antiemetic which antagonises dopamine receptors in the basal ganglia therefore is contraindicated in Parkinson’s disease due to risk of worsening of symptoms. 

Motor Fluctuations

Due to the short acting nature of levodopa and fluctuating plasma levels, patients experience motor fluctuations such as dyskinesias, wearing off and on-off periods. 

• Dyskinesias (involuntary movements such as twitches, jerks or twisting movements) develop in the majority of patients with prolonged treatment. They are usually worse at the peak of levodopa plasma levels.
• The “wearing off” effect occurs when levodopa plasma levels are at their lowest and the effect of levodopa starts to wear off
• Rapid worsening of bradykinesia (“off” phase) can occur followed by an improvement (“on” phase). This can lead to patients being unable to rise from a chair or continue walking. This is described as an “on-off” period. 

Cardiac Effects

Dopaminergic drugs can cause hypotension therefore should be used with caution in cardiovascular disease. 

Neuropsychiatric Effects

Dopaminergic drugs can also cause psychological effects such as:

• Schizophrenia-like syndrome
• Confusion
• Disorientation
• Insomnia
• Sudden onset of sleep or nightmares

For this reason, levodopa should be used with caution in cognitive or psychiatric disease and in the elderly.

Impulse-control disorders

Impulse control disorders can occur with dopaminergic drugs such as levodopa. Examples of this behaviour can include gambling, overeating, compulsive buying and sexual excess. 

Withdrawal

Abrupt withdrawal of dopaminergic agents can cause neuroleptic malignant-like syndrome which may include symptoms such as muscular rigidity, hyperpyrexia and psychological changes. Gradual tapering should occur if therapy is to be stopped, and it is vital patients get their medications on time. 

Interactions

Absorption

• Iron may reduce the absorption of carbidopa and/or levodopa when given concomitantly, administration can be separated if found to have a negative impact on motor control
• Anticholinergics may reduce absorption of levodopa 
• Levodopa competes with amino acids for absorption, therefore absorption may be reduced with high protein diets.

Postural Hypotension

• Drugs that can cause postural hypotension such as antihypertensives should be used with caution alongside levodopa due to a risk of additive effect 

Pharmacokinetic Interaction

• Pyridoxine (vitamin B6) can reduce the effectiveness of levodopa by increasing its peripheral conversion to dopamine, however this is prevented when levodopa is combined with a DDC.

Pharmacodynamic Interaction

• Dopamine antagonists such as antipsychotics may worsen Parkinson’s symptoms via antagonism of dopaminergic drugs, therefore concomitant administration should only be undertaken with caution. 

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.
2. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier.
3. Sinemet 12.5 mg/50 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 1654  Accessed 24/8/26
4. Madopar 100 mg/25 mg Dispersible Tablets – Summary of Product Characteristics (SmPC) – (emc) | 6924 Accessed 24/8/26
5. Scenario: Confirmed Parkinson’s disease | Management | Parkinson’s disease | CKS | NICE  Accessed 21/09/26