with Parkinson's disease are known to have a deficiency of dopamine in the
brain.1 In particular, the dopaminergic neurons within the substantia
nigra begin to degenerate where they decrease the amount of dopamine
transmitted to the corpus striatum. This decrease in dopamine production
and release in the striatum leads to an overall net inhibition of the thalamus
and communication to the cerebral cortex for proper modulation of motor
movements. When approximately 80% of these dopaminergic neurons within
the substantia nigra are depleted, symptoms of Parkinson's disease will begin
symptoms of Parkinson's disease most commonly include bradykinesia (slow
voluntary motor movement), rigidity (increased resistance to passive movements)
and resting tremor.3 In order to correct or minimize these complications,
patients will need to increase dopamine production and/or release in the
brain. Unfortunately, peripheral dopamine administration is not effective
because dopamine cannot cross the blood brain barrier.4 However, the
precursor to dopamine, levodopa (L-Dopa; 3,4-dihydroxyphenyl-L-alanine), can
cross the blood brain barrier and be converted to dopamine for use in
controlling these symptoms.5 Levodopa is one of the first line
medications for many patients suffering from Parkinson's disease, yet it is
most commonly prescribed in a formulation that combines it with carbidopa which
by itself has no therapeutic benefit. The combination product of levodopa
and carbidopa is marketed as Sinemet and/or Sinemet CR.4
If carbidopa offers no therapeutic effect itself, why then is it being
given along with levodopa (L-Dopa)?
After oral administration, levodopa undergoes significant metabolism by the
enzyme, amino acid decarboxylase (or dopa decarboxylase) in the
gastrointestinal tract and blood vessels to form dopamine (see figure 1).4,6
Levodopa can also be metabolized by catechol-O-methyltransferase (COMT) to form
inactive metabolites.7,8 The preferential conversion of levodopa to
dopamine in the periphery will decrease the amount of levodopa that passes into
the brain (dopamine cannot penetrate the blood brain barrier) where its
therapeutic benefit is needed and contributes significantly to drug related
side effects, in particular gastrointestinal (GI) side effects.4 In fact,
up to 80% of patients will experience clinically relevant nausea and vomiting
which may lead to anorexia.4 In order to decrease the occurrence of this
side effect and improve motor symptoms, the peripheral conversion of levodopa
to dopamine must be inhibited. This is where carbidopa's main therapeutic
benefit lies. Carbidopa is an inhibitor of amino acid decarboxylase (dopa
decarboxylase), which is the enzyme present in both the peripheral and central
tissue.9,10 Carbidopa only inhibits the peripheral conversion of
levodopa.9,10 It does not inhibit the decarboxylase enzyme in the brain
because it does not cross the blood brain barrier.4 This is important
since inhibition of both central and peripheral amino acid decarboxylase would
prevent levodopa from being converted to dopamine.
the coadministration of carbidopa with levodopa not only improves dopamine
production in the brain, but also significantly reduces the incidence of nausea
and vomiting when compared to levodopa being administered alone. In fact,
the incidence GI side effects decrease to less than 10%.4,10 This
improves adherence and tolerability as well as quality of life.
- Shastry BS. Parkinson's disease: etiology, pathogenesis and future gene therapy. Neurosci Res 2001;41:5-12.
- Parkinson's Disease Foundation. Understanding Parkinson's. Accessed on May 19, 2009 at: http://www.pdf.org/en/understanding_pd
R, Factor SA, Lyons KE et al. Practice parameter: treatment of
Parkinson disease with motor fluctuations and dyskinesia (an
evidence-based review): report of the Quality Standards Subcommittee of
the American Academy of Neurology. Neurology 2006;66:983-95.
- Aminoff MJ. Pharmacologic management of Parkinsonism & other movement disorders. In: Basic & Clinical Pharmacology. Katzung BG ed. 9th edition. Lange Medical Books/McGraw-Hill. New York, NY. 2004;447-449.
LA, Katzman R. Synthetic amino acids and the nature of L-DOPA
transport at the blood-brain barrier. J Neurochem 1975;25:837-42.
JG, Woodward WR, Anderson JL. The effect of carbidopa on the
pharmacokinetics of intravenously administered levodopa: the mechanism
of action in the treatment of parkinsonism. Ann Neurol
- Backstrom R, Honkanen
E, Pippuri A et al. Synthesis of some novel potent and selective
catechol-O-methyltransferase inhibitors. J Med Chem 1989;32:841-6.
- Katzung BG. Introduction to autonomic pharmacology. In: Basic & Clinical Pharmacology. Katzung BG ed. 9th edition. Lange Medical Books/McGraw-Hill. New York, NY. 2004;75-83.
- Bartholini G, Pletscher A. Decarboxylase inhibitors. Pharmacol Ther [B]. 1975;1:407-21.
- Levodopa/carbidopa (Sinemet CR) product package insert. Merck & Co., Inc. West Point, PA. June 1999.