Patients 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 to manifest.2 

The 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.

Therefore, 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.

References:

1. Shastry BS.  Parkinson's disease: etiology, pathogenesis and future gene therapy.  Neurosci Res  2001;41:5-12.  
2. Parkinson's Disease Foundation.  Understanding Parkinson's.  Accessed on May 19, 2009 at: http://www.pdf.org/en/understanding_pd
3. Pahwa 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.  
4. Aminoff MJ.  Pharmacologic management of Parkinsonism & other movement disorders.  In: Basic & Clinical Pharmacology.  Katzung BG ed.  9^th edition.  Lange Medical Books/McGraw-Hill.  New York, NY.  2004;447-449.
5. Wade LA, Katzman R.  Synthetic amino acids and the nature of L-DOPA transport at the blood-brain barrier.  J Neurochem  1975;25:837-42.  
6. Nutt 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  1985;18:537.43. 
7. 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.  
8. Katzung BG.  Introduction to autonomic pharmacology.  In: Basic & Clinical Pharmacology.  Katzung BG ed.  9^th edition.  Lange Medical Books/McGraw-Hill.  New York, NY.  2004;75-83.
9. Bartholini G, Pletscher A.  Decarboxylase inhibitors.  Pharmacol Ther [B].  1975;1:407-21.  
10. Levodopa/carbidopa (Sinemet CR) product package insert.  Merck & Co., Inc. West Point, PA.  June 1999.

• Pharmacology:  Why Can't Peripherally Administered Dopamine Be Used to Treat Parkinson's Disease?
  

Carbidopa, Levodopa, L-dopa, Parkinson's Disease, PD