Actions of Madopar Quick 62.5 in details
ATC Code: N04BA.
Pharmacology: Pharmacodynamics: Mechanism of Action: Dopamine, which acts as a neurotransmitter in the brain, is not present in sufficient quantities in the basal ganglia of Parkinsonian patients. Levodopa (Madopar Quick 62.5) (INN) or L-DOPA (3,4-dihydroxy L-phenylalanine) is an intermediate in dopamine biosynthesis. Levodopa (Madopar Quick 62.5) (dopamine precursor) is used as a prodrug to increase dopamine levels since it is able to cross the blood-brain barrier whereas dopamine itself cannot. Once Levodopa (Madopar Quick 62.5) has entered the central nervous system (CNS), it is metabolized to dopamine by aromatic L-amino acid decarboxylase.
After administration, Levodopa (Madopar Quick 62.5) is rapidly decarboxylated to dopamine in extracerebral as well as cerebral tissues. As a result, most of the Levodopa (Madopar Quick 62.5) administered is not available to the basal ganglia and the dopamine produced peripherally frequently causes unwanted effects. It is therefore, particularly desirable to inhibit extracerebral decarboxylation of Levodopa (Madopar Quick 62.5). This can be achieved by simultaneous administration of Levodopa (Madopar Quick 62.5) and Benserazide (Madopar Quick 62.5), a peripheral decarboxylase inhibitor.
Madopar Quick 62.5 is a combination of these 2 substances in a ratio of 4:1. This ratio having proved optimal in clinical trials and therapeutic use and is just as effective as large doses of Levodopa (Madopar Quick 62.5) given alone.
Pharmacokinetics: Absorption: Standard Forms: Levodopa (Madopar Quick 62.5) is mainly absorbed from the upper regions of the small intestine and absorption there is independent of the site. Maximum plasma concentrations of Levodopa (Madopar Quick 62.5) are reached approximately 1 hr after ingestion of standard Madopar Quick 62.5.
Capsules and tablets of standard Madopar Quick 62.5 are bioequivalent.
The maximum plasma concentration of Levodopa (Madopar Quick 62.5) and the extent of Levodopa (Madopar Quick 62.5) absorption [area under the concentration-time curve (AUC)] increase proportionally with dose (Levodopa (Madopar Quick 62.5) 50-200 mg).
Food intake reduces the rate and extent of Levodopa (Madopar Quick 62.5) absorption. The peak Levodopa (Madopar Quick 62.5) plasma concentration is 30% lower and occurs later when standard Madopar Quick 62.5 is administered after a standard meal. The extent of Levodopa (Madopar Quick 62.5) absorption is reduced by 15%.
Dispersible Form: The pharmacokinetic profiles of Levodopa (Madopar Quick 62.5) following administration of Madopar Quick 62.5 dispersible in healthy volunteers and Parkinsonian patients are very similar to those following administration of standard Madopar Quick 62.5, but time to peak concentrations tends to be shorter after Madopar Quick 62.5 dispersible. There is less interindividual variability in absorption parameters for Madopar Quick 62.5 dispersible taken as a suspension.
Controlled-Release Form: The pharmacokinetic properties of Madopar Quick 62.5 HBS differ from those of standard Madopar Quick 62.5 (capsules, tablets) and dispersible form. The active ingredients are released slowly in the stomach. Maximum plasma concentrations of Levodopa (Madopar Quick 62.5), which are 20-30% of those achieved with the standard dosage forms, are reached about 3 hrs after administration. The AUC shows a longer 'half-value duration' (time span during which plasma concentrations are equal to or exceed half the maximum concentration) than with standard Madopar Quick 62.5, which indicates pronounced controlled-release properties. The bioavailability of Madopar Quick 62.5 HBS is 50-70% of that of standard Madopar Quick 62.5 and is not affected by food. Maximum plasma concentrations of Levodopa (Madopar Quick 62.5) are not affected by food, but occur later (5 hrs) after postprandial administration of Madopar Quick 62.5 HBS.
Distribution: Levodopa (Madopar Quick 62.5) crosses the blood-brain barrier by a saturable transport system. It is not bound to plasma proteins and its volume of distribution is 57 L. The AUC of Levodopa (Madopar Quick 62.5) in cerebrospinal fluid is 12% of that in plasma.
In contrast to Levodopa (Madopar Quick 62.5), Benserazide (Madopar Quick 62.5) does not penetrate the blood-brain barrier at therapeutic doses. It is concentrated mainly in the kidneys, lungs, small intestine and liver.
Metabolism: Levodopa (Madopar Quick 62.5) is metabolized by 2 major pathways (decarboxylation and O-methylation) and 2 minor ones (transamination and oxidation).
Aromatic amino acid decarboxylase converts Levodopa (Madopar Quick 62.5) to dopamine. The major end-products of this pathway are homovanillic acid and dihydroxyphenylacetic acid. Catechol-O-methyltransferase methylates Levodopa (Madopar Quick 62.5) to 3-O-methyldopa. This major plasma metabolite has an elimination half-life (t½) of 15 hrs, and it accumulates in patients who receive therapeutic doses of Madopar Quick 62.5.
Decreased peripheral decarboxylation of Levodopa (Madopar Quick 62.5) when it is administered with Benserazide (Madopar Quick 62.5) is reflected in higher plasma levels of Levodopa (Madopar Quick 62.5) and 3-O-methyldopa and lower plasma levels of catecholamines (dopamine, noradrenaline) and phenolcarboxylic acids (homovanillic acid, dihydroxyphenylacetic acid).
Benserazide (Madopar Quick 62.5) is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver. This metabolite is a potent inhibitor of the aromatic amino acid decarboxylase.
Elimination: In the presence of peripherally inhibited Levodopa (Madopar Quick 62.5) decarboxylase the elimination t½ of Levodopa (Madopar Quick 62.5) is approximately 1.5 hrs. The elimination t½ is slightly longer (approximately 25%) in elderly patients (65-78 years) with Parkinson's disease. The clearance of Levodopa (Madopar Quick 62.5) from plasma is about 430 mL/min.
Benserazide (Madopar Quick 62.5) is almost entirely eliminated by metabolism. The metabolites are mainly excreted in the urine (64%) and to a smaller extent in feces (24%).
Special Populations: No pharmacokinetic data are available in uremic and hepatic patients.
Effect of Age on the Pharmacokinetics of Levodopa (Madopar Quick 62.5): In older Parkinsonian patients (65-78 years) both the elimination t½ and the AUC of Levodopa (Madopar Quick 62.5) is about 25% higher than in younger patients (34-64 years). The statistically significant age effect is clinically negligible and is of minor importance for the dosing schedule of any indication.
Toxicology: Preclinical Safety Data: Carcinogenicity: Carcinogenicity studies were not conducted with Madopar Quick 62.5.
Mutagenicity: Madopar Quick 62.5 and its constituents (Levodopa (Madopar Quick 62.5) and Benserazide (Madopar Quick 62.5)) were not observed to be mutagenic in the Ames test. No further data are available.
Impairment of Fertility: No animal studies on fertility were performed with Madopar Quick 62.5.
Teratogenicity: Teratogenicity studies showed no teratogenic effects or effects on skeletal development in mice [400 mg/kg; rats (600 mg/kg; 250 mg/kg) and rabbits (120 mg/kg; 150 mg/kg)].
At maternally toxic dose levels, intrauterine deaths increased (rabbits) and/or fetal weight decreased (rats).
Other: General toxicological studies in rats have shown the possibility of disturbed skeletal development.
No further animal data of relevance are available.
Madopar Quick 62.5 pharmacology
Sulfonylureas such as Madopar Quick 62.5 likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin.
References
- DailyMed. "CARBIDOPA; ENTACAPONE; LEVODOPA: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Levodopa: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "L-Dopa: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
