Methyldopa Levodopa

Cimbura and Kofoed (50),mentioned earlier, used GLC to separate amphetamine and methamphetamine after acetylation with acetic anhydride in methanol. Derivatives were extracted using diethyl ether and chromatographed op columns of either 3% OV-17, OV-1, or SE-30. Column temperature was 160°C. They also reported the chromatographic determination of acetylated morphine on 3% SE-30, OV-1, or OV-17 at temperatures of 220°C. Cruickshank et al.(21) separated 21 amino acids as their trifluoroacetylated methyl esters. The column was 5% neopentyl glycol succinate on Gas Chrom P. Column temperatures were both isothermal and programmed 65°C for 20 min at 1.5°C/min then 2°C/min until 42.5 min then 4°C/min until 60 min then isothermal until about 75 min (see Figure 12.2). Chang et al. (19), used BSA/pyridine to form the TMS derivatives of levodopa, methyldopa, tyrosine. 

If a drag is sufficiently similar to a substance naturally transported by a carrier-mediated system, the drag may also be transported by the same system. For example, the drags levodopa, methyldopa and... 

LEVODOPA, METHYLDOPA IRON-CONTAINING COMPOUNDS 1 plasma concentrations of methyldopa (peak levels 1 by 55%) and levodopa, with risk of therapeutic failure Iron preparations impair the absorption of methyldopa and levodopa Be aware and separate oral intake by at least 2 hours... 

Adrenaline, betanaphthol, dobutamine, dopamine, ethamivan, ethylnoradren-aline, hexylresorcinol, hydroquinone, hyd-roxyquinoline, isoetharine, isoprenaline, levodopa, methyldopa, methyldopate, noradrenaline, paraphenylenediamine, phenothiazine, protokylol, rimiterol... 

Noninterfering dopamine, levodopa, methyldopa, methyldopate, norepinephrine... 

Simultaneous carbidopa, dopamine, epinephrine, isoproterenol, levodopa, methyldopa, norepinephrine, phenylephrine... 

Noninterfering dopamine, levodopa, methyldopa, methyldopate, norepinephrine Interfering acetylcodeine, amphetamine, chlorphentermine, fencamfamin, fenfluramine, methylenedioxyamphetamine, monoacetylmorphine, norpseudoephedrine, phentermine, phenylpropanolamine, thebacon, thebaine... 

Drug metabolism as a mechanism of drug activation Prodrugs (eg. levodopa. methyldopa, parathion) are inactive as administered and must be metabolized in the body to become active. Many drugs are active as administered and have active metabolites as well, eg, many benzodiazepines. 

The estimation of catechol and its derivatives such as dopamine hydrochloride, levodopa, methyldopa, and adrenaline hydrochloride in both pure form and in pharmaceutical formulation is based on the interaction of diazotized sulfanilamide with catechol derivatives in the presence of molybdate ions in acidic medium. Absorbance of the resulting red-colored product is measured at 490 nm for pyrocatechol and at 500 nm for other catechol derivatives. The color reaction is stable for 24-30 h. 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

A glance at Fig. 15.4 will show that levodopa is metabolised primarily by dopa decarboxylase to DA and by COMT to 3-methoxy tyrosine, but usually referred to as OMD (o-methyldopa). 

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

Opioids, benzodiazepines, barbiturates, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H2-receptor antagonists, anticholinergics (e.g., diphenhydramine, trihexylphenidyl), P-adrenergic blockers, clonidine, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), and interleukin-2... 

Dolezalova, M. and Tkaczykova, M., Direct high-performance liquid chromatographic determination of the enantiomeric purity of levodopa and methyldopa comparison with pharmacopoeial polarimetric methods, J. Pharm. Biomed. Anal., 19, 555, 1999. 

Methyldopa is an a-methoxylated derivative of levodopa that exhibits hypotensive action by reducing overall peripheral vascular resistance and reducing heart work. Antihypertensive action of methyldopa consists of the biotransformation of methyldopa into methylnoradrenaline (methylnorepinephrine), which acts as a pseudo neurotransmitter. The current, universally accepted point of view is that the action of methyldopa is carried out through the CNS, where methylnorepinephrine, a powerful stimulant of a-adrenergic receptors of the medulla, inhibits the vasomotor center. 

Entacapone is a reversible inhibitor of peripheral catechol-O-methyltransferase (COMT). It is given at the dose of 200 mg with each dose of levodopa. It prolongs the action of levodopa and reduces synthesis of 3-O-methyldopa which is presumed to antagonize dopa passage through the blood-brain barrier. 

Active transport of a particular substance occurs in one direction only. The number of molecules transported per unit of time will reach a maximum (T ,) once the binding capacity of the carrier becomes saturated. Drugs such as levodopa (for parkinsonism) and a-methyldopa (for hypertension) are actively transported. 

Pharmacologic strategies for dopaminergic therapy of Parkinson s disease. Drugs and their effects are highlighted (see text). MAO, monoamine oxidase COMT, catechol-O-methyltransferase DOPAC, dihydroxyphenylacetic acid L-DOPA, levodopa 3-OMD, 3-0-methyldopa. 

Methyldopa [Aldomet) [Antihypertensive/Centrally Acting Antiadrenergic] Uses HTN Action Centrally acting antihypertensive Dose Adults. 250-500 mg PO bid-dd (max 2-3 g/d) or 250 mg-1 g IV q6-8h Peds. 10 mg/kg/24 h PO in 2-3 + doses (max 40 mg/kg/24 h - q6-l2h) or 5-10 mg/kg/dose IV q6-8h to total dose of 20—40 mg/kg/24 h i in renal insuff/elderly Caution [B (PO), C (IV), +] Contra Liver Dz MAOIs Disp Tabs, inj SE Discolors urine inidal transient sedadon/drowsiness frequent, edema, hemolydc anemia, hepadc disorders Interactions T Effects W/ anesthetics, diuredcs, levodopa, Li, methotrimeprazine, thioxanthenes, vasodilators, verapamil T effects OF haloperidol, Li, tolbutamide 1 effects W7amphetamines, Fe, phenothiazine, TCAs 1 effects OF ephedrine EMS Use diuredcs, verapamil, and sympathomimedcs w/ caudon may T risk hypotension, arrhythmias and pressors effects OD May cause profound hypotension, drowsiness, and impaired myocardial conduction activated charcoal may be effective... 

The catecholamine-synthesizing enzymes are not only able to synthesize dopamine and norepinephrine from a physiologically occurring substrate such as levodopa, but also from exogenous substrates such as a-methyldopa, which is converted to a-methyldopamine and in turn to a-methylnorepinephrine. a-methyldopamine and a-methylnorepinephrine are called false transmitters and, in general (except for a-methylnorepinephrine), are weaker agonists, a-methyldopa is used in the management of hypertension. 

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