carbidopa/levodopa (Sinemet, Parcopa, Atamet, Crexont)

Introduction

Sinemet for sin + emesis (without emesis)

Indications

• symptomatic treatment of Parkinson's disease
• post-encephalitic parkinsonism
• parkinsonism following carbon monoxide intoxication or manganese intoxication in adults

Contraindications

pregnancy-category C

safety in lactation -

Dosage

• start 1 tab PO TID (25/100)
• increase 1/2 tab/dose as needed every several days
• higher doses generally divided QID
  • even more frequent dosing may be needed
• doses of 600-1000 mg of L-dopa suggests addition of another agent such as selegiline may be indicated
• give on an empty stomach

Tabs: 10/100, 25/100, 25/250 mg carbidopa/levodopa.

Extended-release:

• Sinemet CR:
  • Start 1 mg PO BID, then increase as needed.
  • Dosing interval should not be < 6 hours
• Crexont
  • combines immediate-release granules of carbidopa & levodopa with extended-release pellets of levodopa

Tabs: 50/200 mg carbidopa/levodopa.

65 or 105 mg of carbidopa with 75, 100, 125, or 150 mg of levodopa

• IPXO66 (experimental) extends "on" time by about 1 hour

Parcopa: dissolves on the tongue

Tabs: 10/100, 25/100, 25/250 mg carbidopa/levodopa.

Pharmacokinetics

• good oral bioavailability
  • dietary protein (neutral amino acids) may interfere with absorption
  • H pylori may interfere with absorption, eradication may improve absorption, effectiveness
• peak serum levels 1-2 hours after oral administration
• 1/2 life 1.5-2 hours, longer with the extended release product
• carbidopa does not cross the blood brain barrier, thus does not interfere with CNS conversion of L-dopa to dopamine
• elimination: liver

Adverse effects

• common (> 10%)
  • choreiform & involuntary movements*, orthostatic hypotension*, blepharospasm, anorexia, nausea/vomiting, difficult urination, arrhythmias, anxiety, confusion, constipation, nightmares
• less common (1-10%)
  • eyelid spasms, anorexia, diarrhea, dry mouth, headache, muscle twitching, discoloration of urine/sweat
• uncommon (< 1%)
  • duodenal ulcer, hypertension, hemolytic anemia, GI bleeding, blurred vision
• other
  • cardiac arrhythmias are rare with inclusion of carbidopa which blocks decarboxylation of L-dopa
  • orthostatic hypotension: usually transient
  • GI complaints: nausea/vomiting
    • most common complaint
    • prescribe higher dose of carbidopa
    • carbidopa/L-dopa 25/100 is least offensive because of less perpipheral conversion of L-dopa to dopamine
  • psychosis
    • hallucinations
    • confusion
    • nightmares
    • clozapine may be useful for L-dopa induced psychosis
  • dark color of body fluids
  • see dopamine receptor agonist for general adverse effects
  • see levodopa for on-off effect
• management of motor fluctuations, & dyskinesias (wearing off effect)
  • usually choreiform movements
  • effect is dose dependent
  • generally occurs after prolonged therapy
  • minimized by giving smaller doses more frequently
  • amantadine (Gocovri) for treatment of Sinemet-induced dyskinesias
• abrupt withdrawal can result in neuroleptic malignant syndrome

* minimized by giving smaller doses of levpdopa more frequently

* prescribe higher dose of carbidopa (carbidopa/levodopa 25/100)

Drug interactions

• pyridoxine:
  • rapid reversal of L-dopa's effects when not used in combination with carbidopa
  • cofactor in catabolism of L-dopa
• hydantoins decrease effect of L-dopa
• hypertensive reactions with concurrent administration of MAO inhibitors
• increased dietary protein (> 1 g/kg body weight) decreases L-dopa absorption due to intestinal transport saturation mechanisms
• dopamine antagonists block effects of L-dopa
• selegiline inhibits dopamine catabolism, thus effects may be additive with sinemet
• meperidine used in combination may cause lethal seizures
• benzodiazepines
• reserpine
• methyldopa
• antihypertensive agents
• antacids

Mechanism of action

• combination dopamine precursor & dopa-decarboxylase inhibitor used in the treatment of Parkinson's disease
• unlike dopamine, L-dopa (levodopa) crosses the blood brain barrier
• within the central nervous system, L-dopa is decarboxylated to form dopamine
• Carbidopa inhibits decarboxylation of L-dopa so that adequate amounts may gain access to the CNS & diminishes vomiting caused by action of dopamine on area postrema
• does levodopa/carbopa influence progression of disease?

More general terms

• combination therapy for Parkinson's disease
• antimigraine combination

Additional terms

• clozapine (Clozaril)

Components

• carbidopa (Lodosyn)
• levodopa; L-3-hydroxytyrosine; L-3,4-dihydroxyphenylalanine; L-dopa (Dopar, Larodopa, Inbrija)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=441193
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=104778