Which condition is a contraindication for administration of carbidopa-levodopa

Indications

ValueUnitsPrep. and Route of Admin.ReferenceCommentsParkinson's disease; hyperprolactinemia

Contraindications

For carbidopa and benserazide the contraindications are: narrow-angle glaucoma, or psychosis. In combination with a monoamine oxidase A inhibitor; for the receptor stimulants: hypersensitivity to ergot alkaloids; and for entacapone: hepatic impairment, pheochromocytoma, pregnancy, and lactation.

Adverse Effects

The adverse effects for all the drugs in this group are associated with excessive stimulation of dopaminergic receptors, namely, dyskinesias, nausea, vomiting, psychotic reactions, and occasionally severe hypotension.

Agent-Agent Interactions

Agent NameMode of InteractionAntipsychotic drugsInhibition through blockade of postsynaptic receptors for dopamine.Monoamine oxidase A inhibitorsL-dopa has sympathomimetic activity and antagonism of the degradative enzyme, monoamine oxidase A, may lead to increased sympathetic activity.

5.14.3.4.14.1 Levodopa/carbidopa intestinal gel (LCIG; duodopa)

Duodopa or LCIG is an aqueous intestinal gel which contains 20 mg/mL of levodopa and 5 mg/mL of carbidopa, and this gel is administered via a portable pump.385 A 100 mL cassette contains 2000 mg of levodopa, which is enough for a full day of treatment. The cassette is used to attach to a portable infusion pump, and the gel is pumped through a transabdominal tube connected to a percutaneous endoscopic gastrostomy (PEG) tube with the tip positioned in the proximal jejunum or duodenum. The gel can be infused during waking hours or around-the-clock. It was shown to be effective in reducing motor fluctuations and dyskinesia in advanced PD.385–387 In a randomized, crossover trial, nasoduodenal infusion of LCIG was compared with carbidopa/levodopa controlled release tablets 50/200 mg/and immediate release 12.5/50 mg.388 The pharmacokinetics of LCIG revealed that the intraindividual variation for plasma levodopa concentration was 34% with oral medication compared with 14% with LCIG infusion (p < 0.01). Also, motor assessments have shown increased near-normal state observations (80% vs. 61%, p < 0.01) with LCIG compared with oral medication. Bradykinesia and dyskinesia have also shown reduction with LCIG.

A study named DIREQT (Duodopa infusion: randomized efficacy and quality of life trial) was conducted to compare the nasoduodenal infusion of LCIG to individually optimized combinations of pharmacotherapy in a randomized crossover trial using two 3-week treatment periods for 25 patients.389 This study revealed that the median percentage of ratings in the functional on state increased significantly with LCIG compared to standard pharmacotherapy (100% vs. 81%, p < 0.01). Dyskinesia appeared to be uncommon and not different for the two treatment periods. Quality-of-life scores achieved significantly higher scores with LCIG. Multiple longer-duration open-label studies have also demonstrated benefit with LCIG delivered via PEG. In the HORIZON study, a 12-week, randomized, double-blind, double-dummy, double-titration phase III trial, LCIG showed a promising option for control of advanced Parkinson’s disease with motor complications.390 In this multicenter study, the primary end point was the change in motor off time from baseline to final visit. Patients receiving LCIG showed superior outcomes in the off times, and 14% of the patients showed significant adverse events mainly associated with the percutaneous gastrojejunostomy tube and related issues. In the United States, this drug was approved by US FDA in 2015. The main drawbacks of LCIG use is the invasiveness of the procedure, the inconvenience of carrying the pump, and the problems associated with managing device malfunctions, including tube dislocations and obstructions.

Antagonist / Inhibitor

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: Caffeic acidKd:2μMPigKidneyBarboni et al (1982)In vitro

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: CathecolKd:30μMPigKidneyBarboni et al (1982)In vitro

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: L-Dopa methyl esterKd:0.05μMPigKidneyMoore et al (1997)In vitro

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: (-)-epigallocatechin-3-O-gallateKi:29μMPigKidneyBertoldi et al (2001)In vitro

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: (-)-epigallocatechinKi:17μMPigKidneyBertoldi et al (2001)In vitro

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: L-alpha-methyl-alpha-hydrazino-3,4 dihydrxyphenylpropionic acid (carbidopa)Kd:<< 1μMPigKidneyBorri Voltattorni et al (1977a)In vitro

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: N-(DL-seryl) N[prime]-(2,3,4-trihydroxybenzyl)-hydrazine (benserazide)Kd:340μMPigKidneyBorri Voltattorni et al (1977b)In vitro

ValueUnitsOrganismOrgan TissueCell Line/TypeReferenceCommentsAgent: N-(5[prime]-phosphopyridoxyl)-D-5-hydroxytryptophanIC50:0.1μMPigKidneyDominici et al (1984)In vitro

Human Pharmacokinetics

L-Dopa, an intermediate in the synthesis of dopamine, is rapidly and extensively absorbed after oral administration. Approximately 90% of an administered dose of L-dopa is converted by L-aromatic amino acid decarboxylase in the periphery into dopamine, which does not cross the blood-brain barrier (BBB). A further 8-9% of the administered L-dopa is converted to dopamine by the same enzyme at the BB B. The peripheral conversion of L-dopa may is inhibited by carbidopa or benserazide, increasing the amount of the parent compound that reaches the brain. Peak concentrations of L-dopa are attained within 0.5-2 hours after an oral dose.

Therapeutics

Istradefylline (KW 6002) entered Phase II trials in the US in 10/99 and completed Phase IIa trials showing good tolerability. Given as monotherapy (40 or 80 mg, p.o.), istradefylline had no effect on the severity of PD signs Chase et al (2003). Similar doses had no effect on PD or dyskinesis scores in patients receiving an optimal infused dose of L-dopa (+ carbidopa), but potentiated the antiparkinsonian actions of low dose L-Dopa (+ carbidopa) that by itself had no antiparkinsonian actions. Tremor was improved with low dose L-dopa + KW 6002 and choreiform dyskinesias were 50% less severe with the combination than with high dose L-Dopa (+ carbidopa) alone (P < 0.05). KW 6002 also prolonged the duration of the antiparkinsonian action of optimal-dose L-dopa with efficacy half-life values increasing by up to 75%. No consistent changes in heart rate or blood pressure were observed with KW 6002 administration Chase et al (2003).Clinical development of KW 6002 was delayed in Phase II in 2002-2003 due to focal mineralization changes in small blood vessels and perivascular space of brain observed in a long term rat study Scrip (2004), but was reinitiated in 2004. The compound was also in phase II trials for depression, but these studies appear to have been discontinued.

Standard Therapies

The basic aim in treating Parkinson's Disease is to enhance the dopaminergic activity in relevant area of the brain and/or to inhibit the interneuronal cholinergic pathways to restore balance in the corpus striatum.

Agent NameDiscussionL-dopaA precursor to dopamine, l-dopa, unlike dopamine, crosses the blood-brain barrier after systemic administration. In the brain, it is converted to dopamine, which stimulates dopamine receptors in the basal ganglia, re-establishing the balance between dopaminergic and cholinergic activity. Only 1% of the l-dopa reaches the central nervous system because it is extensively metabolized in the gastrointestinal tract and peripheral tissues Nutt and Fellman (1984). To increase the therapeutic effect of l-dopa, carbidopa, a peripheral dopa decarboxylase inhibitor, is administered with it. While l-dopa is effective in treating the bradykinesia and rigidity associated with Parkinson's Disease, it not as effective in treating tremor. Concurrent use with anticonvulsants may reduce the effectiveness of l-dopa, whereas concurrent administration with MAO inhibitors may precipitate a hypertensive crisis.CarbidopaCarbidopa is a peripheral dopa decarboxylase inhibitor. By inhibiting dopa decarboxylase outside of the brain, carbidopa, which does not cross the blood-brain barrier, enables a larger percentage of administered l-dopa to penetrate into the central nervous system where it is converted to dopamine. In the absence of carbidopa, a large percentage of an administered dose of l-dopa is converted to dopamine in the periphery, which is of no benefit to the patient. Therefore, when combined with l-dopa (Sinemet), carbidopa reduces the amount of l-dopa needed as well as minimizing the side effects associated with l-dopa monotherapy.BromocriptineA dopamine receptor agonist, bromocriptine stimulates these receptors in the basal ganglia, an area affected in Parkinson's Disease. Bromocriptine is associated with a lower incidence of dyskinesias than l-dopa. Bromocriptine is used to supplement carbidopa plus l-dopa therapy, and is used to treat those who become tolerant to l-dopa.PergolidePergolide is a dopamine receptor agonist used as an adjunctive treatment for Parkinson's Disease. It prolongs the effects of l-dopa.PramipexolePramipexole is a dopamine receptor agonist used to treat Parkinson's Disease in its early stages and as an adjunct with other antiparkinson agents.RopiniroleRopinirole is a dopamine receptor agonist used to treat Parkinson's Disease in its early stages and as an adjunct with other antiparkinson agents.BenztropineBenztropine is a cholinergic muscarinic receptor antagonist that acts in the corpus striatum. It is employed most often in the early stages of mild Parkinson's Disease or as an adjunctive agent. While benztropine is effective against treating tremor and rigidity, it is of little value in easing bradykinesia. It is effective in reversing the extrapyramidal effects of neuroleptics.TrihexyphenidylLike benztropine, trihexyphenidyl is a cholinergic muscarinic receptor antagonist that acts in the corpus striatum. It is used as an adjunctive agent and for the treatment of drug-induced Parkinson's Disease. Antimuscarinics are contraindicated in those with narrow angle glaucoma, prostatic hypertrophy, and obstructive gastrointestinal disease.DiphenhydramineDiphenhydramine is an H-1 histamine receptor antagonist with cholinergic muscarinic receptor antagonist properties. It is most commonly used to treat dystonias induced by antipsychotics.AmantadineAn antiviral agent, amantadine also appears to enhance the release and inhibit the reuptake of dopamine. It is used to treat Parkinson's Disease in its early stages and as an adjunct with other antiparkinson agents.SelegilineSelegiline is a selective inhibitor of MAO- B. As such, it decreases dopamine metabolism, increasing the concentration of the neurotransmitter in brain. Selegiline is used as an adjunct to l-dopa/carbidopa therapy. It has been suggested that selegiline may retard the progression of Parkinson's Disease by decreasing the formation of neurotoxic metabolites in brain.Ablative SurgerySurgery is reserved for those Parkinson patients who do not respond to pharmacotherapy. For thalamotomy, which reduces tremor, the lesion targets the ventral intermediate nucleus of the thalamus. For pallidotomy, the lesion targets the globus pallidus interna and is of value for reducing bradykinesia and tremor. Subthalamotomy has been shown to be beneficial for tremor, rigidity, and bradykinesia.Deep Brain Stimulation SurgeryThere are three types of deep brain stimulation surgery: thalamic, pallidal, and subthalamic. While thalamic and pallidal utilize ablative or deep brain stimulation, ablations of the subthalamic nucleus are dangerous in individuals as they may cause hemiballismus. Instead, deep brain stimulation of the subthalamic nucleus is used. It is beneficial in treating bradykinesia and tremor.Stem Cell TransplantationStem cell transplantation involves the insertion of stem cells into affected brain regions with the aim of their differentiating into dopaminergic neurons to replace missing pathways in Parkinson's Disease.

19.2.2.2 Anti-Parkinsonism drugs

l-Dopa, l-3-(3,4-dihydroxyphenyl)alanine provides another example, taken from our own work published quite recently [76]. l-Dopa is commonly used for the treatment of Parkinson’s disease. It acts as the precursor of dopamine, which is deficient in patients suffering from the disease. However, d-dopa is toxic and its presence in the drug has to be monitored since large amounts of the drug are usually taken during the treatment. l-Dopa is converted into dopamine by the enzyme decarboxylase and the concentration of dopamine is increased. The increased levels of dopamine outside the blood–brain barrier causes adverse reactions such as nausea, vomiting and cardiac arrhythmias. In order to reduce these side effects, l-dopa is generally combined with a peripheral decarboxylate inhibitor, l-carbidopa. Several combinations of l-dopa and l-carbidopa are commercially available as different formulations. In such formulations small amounts of d-carbidopa are generally present owing to the procedures involved in the manufacture but this and d-dopa cause serious side effects such as dyskinesia and psychosis. Therefore, the assurance of quality of l-dopa formulations has gained importance in the treatment of Parkinson’s disease.

A LC method, utilizing the principles of CLEC, with the mobile-phase addition of the chiral constitutent has proved to be very useful for the above purpose. The chromatographic system consists of a Lichrospher C18 column which has been equilibrated with a mobile phase composed of l-phenylalanine (6 mM) and copper sulfate (3 mM) in water. Eluted species are detected by UV at 280 nm. Fig. 19.7 shows the HPLC chromatogram of a typical formulation. It can be seen that very small amounts of d-dopa and d-carbidopa which are known to be inactive, are present in the formulations. The results are given in Table 19.9. These results show that the method is suitable for the determination of the enantiomeric excess of levodopa and carbidopa simultaneously, using a reversed-phase C18 column with aqueous copper-l-phenylalanine as the mobile phase. d-phenylglycine, d-hydroxyphenylglycine and d-mandelic acid, which are known as useful intermediates in the synthesis of β-lactam antibiotics have also been analysed by the same methodology and their purities have been determined [77]. It may be seen from Table 19.10 that all the d-enantiomers are eluted prior to the l-forms. Lin et al. have monitored the process development of a potential anti-epiliptic agent S-(+)-isobutyl GABA, using chiral columns with hexane–propan-2-ol–formic acid as mobile phase [78]. Experimental conditions for the enantiomeric separation of all the impurities encountered during the synthesis of S-(+)-isobutyl GABA have been established.

Table 19.9. Levels of d-DOPA and d-Carbidopa Determined in Anti-Parkinsonism Drug Formulations by HPLC

SampleImpurityConcentration (%)R.S.D.a (%)Formulation 1d-Dopa0.891.6d-Carbidopa——Formulation 2d-Dopa0.542.0d-Carbidopa0.082.6Formulation 3d-Dopa0.272.4d-Carbidopa0.152.2

Table 19.10. Ligand-Exchange Liquid Chromatographic Separation and Enantiomeric Excess in Some Important Raw Materials Used in the Synthesis of β-Lactam Antibiotics and Other Drugs

CompoundRelative retention time (min)Capacity factor (k′)Separation factor (α)d-Phenylglycine3.681.301.45l-Phenylglycine4.601.88d-Hydroxyphenylglycine33.631.261.48l-Hydroxyphenylglycine4.521.82d-Mandelic acid19.6811.301.13l-Mandelic acid22.0812.80d-Dopa4.281.671.63l-Dopa5.962.73d-Carbidopa7.553.722.38l-Carbidopa15.758.84d-Lactic acid7.451.782.48l-Lactic acid8.674.42