Levodopa and Decarboxylase Inhibitors
Examples
- Co-careldopa (Carbidopa and Levadopa)
- Co-beneldopa (Benserazide and Levodopa)
Indications
Parkinson's Disease
Contraindications
Caution
- Severe Cardiovascular or Pulmonary Disease
- Endocrine Disorders (e.g. Cushing’s syndrome, diabetes, hyperthyroidism)
- Glaucoma
- Hepatic or Renal Impairment
- Pregnancy
- Psychiatric illness
Mechanism
Replaces dopamine levels in the basal ganglia.
Dopamine cannot be given directly as it does not cross the blood-brain barrier, meaning it can have no direct effect on the central nervous system. However it can be given as Levadopa which is a natural precursor of dopamine.
The enzyme which converts levadopa to dopamine is found not only in the brain, but also peripherally. If levodopa is broken down to dopamine out with the CNS, it can cause important cardiovascular side-effects such as hypotension and arrhythmias, as well as profound nausea and vomiting.
Levodopa is therefore given with a decarboxylase inhibitor in one combined tablet. The decarboxylase inhibitor prevents the levodopa being broken down peripherally, increasing the amount available to the basal ganglia and preventing the serious side effects of peripheral utilisation.
Levodopa crosses the blood brain barrier (but the decarboxylase inhibitor does not) and either joins with the dopamine receptors themselves or increases the release of dopamine from neurones.
Administration
Oral. Available in modified release preparations.
Time of administration can be very important for levodopa and decarboxylase inhibitors and it is one of the rare occasions where patients may need to have their medicines prescribed and administered outside of normal drug round times. Parkinson’s UK has done a number of campaigns to raise awareness about this called ‘Get it on Time’.
Adverse Reactions
It is important to start patients on a low dose of levodopa and titrate upwards until an effective dose is reached. Even when established on the drug it is strongly recommended to use as low a dose as possible.
Important side effects of levodopa include:
- Dyskinesia
- 'On and off' fluctuations, levodopa has a half life of two hours, therefore Parkinson's patients can quickly turn 'off' - become bradykinetic again
- Psychiatric symptoms - hallucinations, delusions, nightmares
- Sudden Onset of Sleep
- Hypotension and syncope
- Dementia
- Hypertension
Very rare, but important side effects to recognise include:
- GI Bleeding
- Thrombocytopenia and Leucopenia
- Urinary Retention
- Neuroleptic malignant syndrome on withdrawal
Interactions
- MAOIs (Monoamine Oxidase Inhibitors) which are used to treat depression are contraindicated in patients on levodopa, as they can cause a hypertensive crisis.
- Antihypertensive drugs - may interact with levodopa to cause severe hypotension.
- Anti-psychotics- can decrease the effects of levodopa
- Isoniazid and Phenytoin - may reduce efficacy of levodopa
- Metoclopramide - Interferes with levodopa effects, as it is a dopamine receptor antagonist.
Education
Patients should be warned about abruptly stopping the medication, as it can cause Neuroleptic Malignant Syndrome - a syndrome associated with increased levels of creatine phosphokinase, which is characterised by delirium and muscle cramps, fever, and instability of the autonomic nervous system.
In addition, all patients should be warned of the potential side effect of sudden onset of sleep. This has important implications for driving or operating heavy machinery, and patients should be warned not to do either should they feel extremely fatigued.
Patients should be informed that the medication may colour their urine a dark reddish colour and that it is harmless.
Finally, much like patients with dementia, those with Parkinson's should be advised that using levodopa can provide effective control of symptoms, but is not a cure for the disease, and does not halt the disease process. As mentioned in "Adverse Reactions" it is important to inform patients of the potential consequence of long term treatment with levodopa - namely the dyskinesias which can be experienced.
Pharmacokinetics
Around 95% of L-Dopa is metabolised in the stomach, and only 1% of each dose actually crosses the Blood Brain Barrier and reaches the brain. This emphasises the importance of Carbidopa to prevent the other 99% being converted to dopamine in the periphery!
