Metoclopramide

Dopamine D2 Receptor Antagonism: Central and Peripheral Mechanisms

This compound functions as a dopamine D2 receptor antagonist. nih.govpatsnap.comguidetopharmacology.org This antagonism occurs in both central and peripheral locations. Centrally, this compound blocks D2 receptors in the chemoreceptor trigger zone (CTZ), an area in the brainstem that lies outside the blood-brain barrier and is sensitive to emetogenic substances. wileymicrositebuilder.comdrugbank.commdpi.compatsnap.com By inhibiting D2 receptors in the CTZ, this compound suppresses the vomiting reflex triggered by various stimuli. wikipedia.orgmdpi.compatsnap.com

Peripherally, this compound antagonizes presynaptic and postsynaptic D2 receptors in the gastrointestinal tract. drugbank.commdpi.comnih.gov Dopamine typically exerts an inhibitory effect on gastrointestinal motility by activating D2 receptors. drugbank.compatsnap.comnih.gov By blocking these peripheral D2 receptors, this compound counteracts the inhibitory effects of dopamine, thereby promoting smoother and more coordinated contractions of the stomach and intestines. patsnap.com This peripheral D2 antagonism contributes to this compound's prokinetic activity, leading to increased gastric emptying and improved transit through the gut. drugbank.comnih.gov

5-Hydroxytryptamine 4 (5-HT4) Receptor Agonism

This compound acts as an agonist at 5-HT4 receptors, primarily located peripherally in the gastrointestinal tract. nih.govdrugbank.commdpi.compatsnap.comnih.gov Activation of these receptors stimulates the release of acetylcholine from enteric cholinergic neurons. mdpi.compatsnap.comnih.gov Increased acetylcholine levels enhance gastrointestinal smooth muscle contraction and motility, contributing significantly to this compound's prokinetic effects, including increased lower esophageal sphincter tone, enhanced gastric antral contractions, and accelerated gastric emptying. wileymicrositebuilder.comdrugbank.comnih.gov

5-Hydroxytryptamine 3 (5-HT3) Receptor Antagonism: Concentration-Dependent Contributions

This compound is also an antagonist at 5-HT3 receptors. nih.govwikipedia.orgdrugbank.com This action contributes to its antiemetic properties, particularly at higher concentrations. wileymicrositebuilder.comwikipedia.org 5-HT3 receptors are found in the CTZ and on vagal afferent nerves in the gastrointestinal tract. mdpi.comamegroups.orgamegroups.cn Serotonin released from enterochromaffin cells in the gut can activate these receptors, triggering nausea and vomiting. mdpi.comamegroups.cn By blocking 5-HT3 receptors, this compound inhibits these signals, preventing the activation of the vomiting reflex. mdpi.comamegroups.cn While this compound is considered a weak antagonist at 5-HT3 receptors compared to more selective agents like ondansetron or granisetron, this activity becomes more significant at higher doses, augmenting its antiemetic effects. wikipedia.orgamegroups.orgnih.gov

Facilitation of Acetylcholine Release and Cholinergic Activity Enhancement

A key mechanism underlying this compound's prokinetic effects is its ability to enhance cholinergic activity in the gastrointestinal tract. This compound facilitates the release of acetylcholine from enteric cholinergic neurons. mdpi.compatsnap.commsdvetmanual.com This action is considered a primary contributor to the increased gastrointestinal motility observed with this compound administration. Experiments have shown that this compound facilitates ongoing cholinergic activity evoked by stimuli such as electrical field stimulation in isolated gastrointestinal tissues, including human stomach. jscimedcentral.com This facilitation leads to increased lower esophageal sphincter (LES) and gastric tone, accelerating gastric emptying and transit through the gut. mdpi.comdrugbank.com The enhancement of acetylcholine release appears to be mediated, at least in part, by this compound's agonist activity at serotonin 5-HT4 receptors located on enteric neurons. mdpi.compatsnap.commsdvetmanual.comjscimedcentral.com Activation of these receptors stimulates muscle contractions by increasing acetylcholine release. patsnap.com This prokinetic property results in increased duodenal peristalsis and improved gastric emptying. mdpi.com

Muscarinic Receptor Sensitization and Indirect Effects

Beyond directly facilitating acetylcholine release, this compound may also exert its cholinergic effects by sensitizing muscarinic receptors in the smooth muscles of the gastrointestinal tract. dergipark.org.trnih.govacpjournals.org This sensitization means that the smooth muscle becomes more responsive to the acetylcholine that is present, whether released spontaneously or in response to stimuli. Some research suggests that this compound's effect on motility is not dependent on intact vagal innervation but can be blocked by anticholinergic drugs, supporting a peripheral site of action involving cholinergic pathways. drugs.com The cholinergic effect of this compound can be achieved either by releasing acetylcholine from nerve extremities or by sensitizing muscarinic receptors in the smooth muscles. dergipark.org.tr This dual action, enhancing acetylcholine release and potentially sensitizing its receptors, contributes to the increased tone and amplitude of gastric contractions, relaxation of the pyloric sphincter and duodenal bulb, and increased peristalsis of the duodenum and jejunum, ultimately accelerating gastric emptying and intestinal transit. drugs.com

Mechanisms of Dopamine D2 Receptor Blockade in Striatal Areas

The extrapyramidal side effects of this compound are primarily linked to its blockade of dopamine D2 receptors in the striatum, a key component of the basal ganglia. sandoz.commdpi.comjscimedcentral.comdrugbank.comnih.govjuniperpublishers.com The striatum plays a vital role in regulating motor output. mdpi.com Dopamine exerts an inhibitory influence on motor activity within the nigrostriatal pathway. By blocking D2 receptors, this compound disrupts this inhibitory control, leading to an imbalance in neurotransmission. juniperpublishers.com Studies in rats have shown that chronic treatment with this compound can lead to an increase in the density of D2 receptors in the striatum, a phenomenon known as upregulation. nih.govnih.gov This suggests a compensatory response to prolonged receptor blockade. nih.govnih.gov The affinity of this compound for D2 receptors in the striatum is influenced by the presence of sodium ions. pnas.org

Dopamine-Cholinergic Imbalance Hypothesis in Extrapyramidal Symptom Induction

The induction of extrapyramidal symptoms by dopamine receptor-blocking drugs like this compound is often explained by the dopamine-cholinergic imbalance hypothesis. drugbank.comjuniperpublishers.comnih.gov In the striatum, there is a balance between the inhibitory effects of dopamine on D2 receptors and the excitatory effects of acetylcholine on muscarinic receptors. juniperpublishers.com Dopamine typically inhibits the release of acetylcholine. sandoz.com When dopamine D2 receptors are blocked by this compound, the inhibitory dopaminergic input is reduced, leading to a relative overactivity of cholinergic neurotransmission. juniperpublishers.comnih.gov This shift in the dopamine-cholinergic balance is thought to contribute to the motor abnormalities observed as extrapyramidal symptoms. juniperpublishers.comnih.gov this compound's ability to augment acetylcholine release and sensitize muscarinic receptors in the gastrointestinal tract also highlights its influence on cholinergic systems, although the central mechanism in EPS is primarily related to the disruption of dopaminergic inhibition leading to relative cholinergic excess. mdpi.comnih.gov

Phenomenology of this compound-Induced Extrapyramidal Symptoms: Acute Dystonia, Akathisia, Parkinsonism, Tardive Dyskinesia

This compound can induce a range of extrapyramidal symptoms, varying in presentation and time of onset. drugbank.comjuniperpublishers.comvalpo.eduoup.com The four main types are acute dystonia, akathisia, parkinsonism, and tardive dyskinesia. nih.govjuniperpublishers.com

Acute Dystonia: Characterized by involuntary muscle contractions leading to abnormal postures and repetitive movements. nih.govnih.govoup.comresearchgate.net These can include spasms of the face, neck (torticollis), back (opisthotonus), and oculogyric crises (involuntary upward deviation of the eyes). nih.govvalpo.eduoup.comresearchgate.net Acute dystonic reactions can occur relatively early after exposure, sometimes even after a single dose, and are more common in children and young adults. juniperpublishers.comnih.govvalpo.eduresearchgate.netjournal-imab-bg.org

Akathisia: Presents as a subjective feeling of inner restlessness and a compelling need to move, often manifesting as motor restlessness, particularly in the lower extremities. mdpi.comnih.govvalpo.eduresearchgate.net The exact mechanism is not fully understood, but it is associated with dopaminergic inhibition. mdpi.comresearchgate.net Akathisia can also occur after a single dose of this compound. valpo.eduresearchgate.netjournal-imab-bg.org

Parkinsonism: Mimics the symptoms of Parkinson's disease, including bradykinesia (slowness of movement), rigidity, resting tremor, and postural instability. nih.govvalpo.eduresearchgate.netjournal-imab-bg.orgrwevansmd.com this compound-induced parkinsonism results from D2 receptor blockade in the nigrostriatal pathway, similar to the pathology in idiopathic Parkinson's disease. mdpi.comjournal-imab-bg.org This is generally observed after longer-term use. valpo.eduresearchgate.netjournal-imab-bg.org

Tardive Dyskinesia: A more serious and potentially irreversible syndrome characterized by involuntary, repetitive, and purposeless movements, often affecting the face (lip smacking, grimacing, tongue protrusion) and extremities. mdpi.comjscimedcentral.comnih.govvalpo.eduoup.comresearchgate.netjournal-imab-bg.org Tardive dyskinesia is typically associated with chronic exposure to dopamine receptor blockers. mdpi.comvalpo.eduresearchgate.netjournal-imab-bg.org The incidence of this compound-induced tardive dyskinesia is reported to be relatively low but is a significant concern due to its potential irreversibility. valpo.edujournal-imab-bg.org

A summary of the phenomenology and typical onset time is presented in the table below:

Risk Factor Analysis for Extrapyramidal Symptom Development

Several factors can increase the risk of developing this compound-induced extrapyramidal symptoms. These include:

Age: Both pediatric patients (specifically for dystonia) and the elderly (over 60) are at increased risk. mdpi.comvalpo.edujournal-imab-bg.org The risk in children is reported to be significantly higher than in adults. valpo.edujournal-imab-bg.org

Duration of Treatment: Prolonged treatment duration, generally exceeding 12 weeks, is a significant risk factor for tardive dyskinesia and parkinsonism. mdpi.comvalpo.edujournal-imab-bg.org

Dosage: Higher doses of this compound are associated with an increased risk of neurological adverse events. valpo.eduresearchgate.netjournal-imab-bg.org

Gender: Female gender has been identified as a risk factor for tardive dyskinesia and parkinsonism. valpo.eduoup.comjournal-imab-bg.orgnih.gov

Concomitant Medications: Concurrent use of other neuroleptic medications or drugs that block dopamine receptors increases the risk. mdpi.com

Underlying Medical Conditions: Conditions such as diabetes mellitus, renal insufficiency, pre-existing abnormal movements, organic cerebral lesions, and psychic disorders can predispose individuals to developing these side effects. mdpi.comvalpo.eduoup.comjournal-imab-bg.org

Genetic Predisposition: Genetic factors related to the metabolism of this compound, such as decreased CYP2D6 metabolism, can also play a role. mdpi.com

A summary of identified risk factors is presented in the table below:

Renal Impairment

Renal function plays a significant role in this compound elimination. A substantial portion of this compound is excreted unchanged in the urine, and its clearance is reduced in patients with renal impairment. drugbank.comnih.govpfizer.commedicines.org.ukmedsafe.govt.nz Studies have shown that the clearance of this compound may be reduced by up to 50-70% in patients with renal impairment, particularly in those with severe impairment (creatinine clearance below 40 mL/min). drugbank.commedicines.org.ukmedsafe.govt.nznih.gov

This reduced clearance leads to increased plasma concentrations and a prolonged elimination half-life in patients with impaired renal function. nih.govpfizer.commedicines.org.uknih.gov For instance, the mean terminal half-life was reported to be 13.9 hours after intravenous administration and 14.8 hours after oral administration in patients with chronic renal failure, compared to a typical range of 5 to 6 hours in individuals with healthy renal function. drugbank.comnih.gov The reduction in clearance in renal failure is not solely accounted for by the change in renal clearance, suggesting potential impairment of metabolism or alteration in enterohepatic circulation. nih.gov

The kinetics of this compound in the presence of renal impairment have been reported to remain linear. pfizer.com

Hepatic Impairment

While this compound undergoes hepatic metabolism, primarily through CYP2D6 and conjugation pathways, its metabolism is considered minimal except for simple conjugation. drugbank.compfizer.commedsafe.govt.nz However, clinically significant hepatic impairment, such as severe liver cirrhosis, can affect this compound clearance. medicines.org.ukmedsafe.govt.nznih.gov

In patients with severe alcoholic cirrhosis, a 50% lower clearance of this compound has been observed compared to healthy volunteers. nih.gov This reduced clearance results in increased plasma drug concentrations and a longer half-life in these patients. medicines.org.uknih.gov Despite this, the volume of distribution and absolute bioavailability have been reported as similar in patients with severe cirrhosis and healthy volunteers. nih.gov The accumulation of this compound in patients with marked hepatic impairment is likely a consequence of impaired clearance. nih.gov

Pediatric Populations: Pharmacokinetic and Pharmacodynamic Considerations

The pharmacokinetics and pharmacodynamics of this compound in pediatric populations, including infants, children, and adolescents, exhibit variability and are not fully established. nih.govpfizer.comaditum.orgpfizermedicalinformation.com While some studies suggest that weight-normalized pharmacokinetic parameters in children might be comparable to adults, others indicate differences, particularly in infants. nih.gov

In infants, the elimination half-life of this compound has been reported to be longer than in older children and adults, potentially due to immature hepatic and renal systems at birth. pfizer.comaditum.org For example, in one study, the half-life in the youngest infant (3.5 weeks) was significantly longer after the first dose (23.1 hours) compared to other infants, decreasing to 10.3 hours at steady-state. pfizer.comnih.gov This suggests that this compound disposition can change during therapy in infants. aditum.org In contrast, the elimination half-life in children has been reported around 4.4 hours. aditum.org

The volume of distribution in infants and children is reported to be larger than the water volume. aditum.org While the pharmacodynamics in pediatric patients are highly variable and a clear concentration-effect relationship has not been established, some studies in infants with gastroesophageal reflux have explored the relationship between this compound exposure and pharmacodynamic effects, such as reduction in reflux time. nih.govpfizer.comnih.gov However, significant correlations between exposure and pharmacodynamic parameters have not always been found. nih.gov

Geriatric Populations: Susceptibility to Adverse Reactions

Geriatric patients may exhibit altered this compound pharmacokinetics and pharmacodynamics compared to younger adults. pfizer.comnih.gov While some studies suggest that clearance is similar in healthy young and healthy elderly individuals, it may be reduced in frail elderly subjects. nih.gov This reduction in clearance in frail elderly subjects has been observed even when expressed per unit liver volume, suggesting a potential general impairment of conjugation pathways. nih.gov

The increased susceptibility to adverse reactions observed in the elderly may be related to a combination of factors, including potential alterations in pharmacokinetics and possible age-related changes in receptor sensitivity or target sites. pfizer.comnih.gov Although pharmacokinetic differences did not always correlate with reported sedation in a study comparing young, healthy elderly, and frail elderly subjects, frail elderly individuals did report more sedation after intravenous administration. nih.gov

Geriatric patients are more likely to have decreased renal function, which, as discussed earlier, can lead to reduced this compound clearance and increased systemic exposure. pfizer.comfda.gov

Here is a table summarizing some key pharmacokinetic parameters discussed:

Other Genetic Deficiencies (e.g., NADH-cytochrome b5 reductase, G6PD)

Genetic deficiencies beyond those involving primary drug metabolizing enzymes like CYP2D6 can influence an individual's response to this compound, particularly concerning the risk of methemoglobinemia. Two such deficiencies are those affecting NADH-cytochrome b5 reductase and glucose-6-phosphate dehydrogenase (G6PD).

Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia when treated with this compound. pharmgkb.orgnih.govfda.govpharmgkb.orgnih.govpgkb.orgfda.govuptodateonline.ireuropa.eu This increased susceptibility is also observed in neonates, who naturally have reduced levels of NADH-cytochrome b5 reductase. nih.govpharmgkb.orguptodateonline.ir Methemoglobinemia is a condition where the iron in hemoglobin is oxidized, reducing its ability to bind oxygen. nih.gov

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is another genetic condition with implications for this compound use, specifically regarding the management of methemoglobinemia. pharmgkb.orgfda.govpharmgkb.orgnih.govpgkb.orgfda.govmedscape.commims.comdrugbank.compfizer.comresearchgate.net While this compound itself can induce methemoglobinemia, the standard treatment for this condition, methylene blue, is contraindicated in individuals with G6PD deficiency. pharmgkb.orgfda.govpharmgkb.orgpgkb.orgfda.govmedscape.commims.comdrugbank.compfizer.com Methylene blue requires NADPH, which is produced by G6PD, to convert methemoglobin back to hemoglobin. haematologica.org In G6PD-deficient individuals, the lack of sufficient NADPH means methylene blue is ineffective and can instead cause hemolytic anemia, which may be fatal. pharmgkb.orgfda.govpharmgkb.orgpgkb.orgfda.govnih.govmedscape.commims.comdrugbank.compfizer.com

Research highlights the importance of considering these deficiencies in clinical practice. A case study described an adult patient with impaired renal function who developed severe methemoglobinemia after this compound administration. haematologica.org This patient was subsequently found to have both NADH cytochrome b5 reductase deficiency and G6PD deficiency. haematologica.orgturkjemergmed.com The methylene blue treatment administered was ineffective and led to a hemolytic episode. haematologica.org This case underscores the combined risk posed by co-existing deficiencies and the critical need to assess G6PD status before using methylene blue for this compound-induced methemoglobinemia. haematologica.org

While specific population pharmacokinetic data directly quantifying the impact of isolated NADH-cytochrome b5 reductase or G6PD deficiency on this compound exposure (e.g., AUC, Cmax) is limited in the provided search results, the clinical observations strongly indicate a pharmacodynamic interaction leading to increased susceptibility to methemoglobinemia. The available information primarily focuses on the increased risk of methemoglobinemia and the contraindication of methylene blue in G6PD deficiency when methemoglobinemia occurs.

The product monographs and drug labels for this compound explicitly mention the increased risk of methemoglobinemia and/or sulfhemoglobinemia in patients with NADH-cytochrome b5 reductase deficiency. pharmgkb.orgnih.govfda.govpharmgkb.orgpgkb.orgfda.gov They also caution against the use of methylene blue in G6PD-deficient patients experiencing this compound-induced methemoglobinemia due to the risk of hemolytic anemia. pharmgkb.orgfda.govpharmgkb.orgpgkb.orgfda.govmedscape.commims.compfizer.com

Although detailed pharmacokinetic studies specifically in individuals with these rare deficiencies are scarce in the provided literature, the clear pharmacodynamic consequences (increased methemoglobinemia risk) necessitate clinical consideration.

Summary of Genetic Deficiency Impact

CYP2D6 Inhibition by this compound and Implications for Co-administered Substrates

This compound is metabolized, at least in part, by the cytochrome P450 2D6 (CYP2D6) isoenzyme medscape.comnih.govresearchgate.net. Furthermore, research indicates that this compound can act as a competitive inhibitor of CYP2D6 medscape.comnih.gov. This dual relationship means that this compound's own metabolism can be affected by other drugs, and this compound can, in turn, affect the metabolism of drugs that are substrates of CYP2D6.

In vitro studies have demonstrated that this compound is a potent inhibitor of CYP2D6 at therapeutically relevant concentrations nih.gov. This inhibition can lead to decreased clearance and increased plasma concentrations of drugs primarily metabolized by this enzyme nih.gov. While in vitro data suggest this inhibitory potential, some sources indicate that this compound is unlikely to interact with CYP2D6 substrates in vivo at clinically relevant concentrations fda.gov. However, other sources highlight the potential for increased plasma concentrations of this compound when co-administered with potent CYP2D6 inhibitors, which could exacerbate adverse effects, particularly extrapyramidal symptoms medcentral.com.

Examples of drugs that are substrates of CYP2D6 include certain antidepressants (e.g., fluoxetine, paroxetine, bupropion), antipsychotics (e.g., haloperidol, thioridazine, risperidone), opioids, and some cardiac medications medscape.compharmacytimes.com. Co-administration of this compound with these agents could theoretically lead to increased exposure to the co-administered drug, potentially increasing the risk of dose-related adverse effects.

Conversely, drugs that inhibit CYP2D6 can affect this compound's metabolism. Potent CYP2D6 inhibitors, such as fluoxetine, paroxetine, bupropion, quinidine, amiodarone, and others, can increase the plasma concentration and half-life of this compound medcentral.compharmacytimes.com. A study involving healthy subjects showed that pretreatment with fluoxetine significantly increased the maximum plasma concentration and area under the concentration-time curve (AUC) of this compound medcentral.compharmacytimes.com. This increased exposure to this compound may elevate the risk of its own adverse effects, including extrapyramidal symptoms medcentral.compharmacytimes.com.

Genetic variations in CYP2D6 activity can also influence this compound pharmacokinetics and the potential for interactions. Individuals classified as poor CYP2D6 metabolizers may have reduced this compound clearance, leading to higher plasma concentrations and a potentially increased risk of adverse reactions medcentral.com.

Influence on Gastrointestinal Absorption of Co-administered Medications

This compound is a prokinetic agent that accelerates gastric emptying and increases the transit rate through the small intestine pfizer.commedsafe.govt.nzpatsnap.com. This effect on gastrointestinal motility can significantly influence the absorption of other orally administered medications.

For drugs that are primarily absorbed in the stomach, this compound's acceleration of gastric emptying can lead to decreased absorption pfizer.commedsafe.govt.nzrxlist.com. Digoxin is an example of a drug whose absorption may be diminished when co-administered with this compound pfizer.comrxlist.com. Monitoring for reduced therapeutic effect of such drugs may be necessary fda.gov.

Conversely, for drugs that are primarily absorbed in the small intestine, the increased rate of gastric emptying and enhanced intestinal peristalsis induced by this compound can lead to increased absorption pfizer.commedsafe.govt.nzrxlist.com. Examples of drugs whose absorption may be accelerated or increased by this compound include acetaminophen, tetracycline, levodopa, ethanol, and cyclosporine pfizer.commedsafe.govt.nzrxlist.com. Increased absorption of cyclosporine, for instance, can lead to elevated serum levels, potentially increasing the risk of its associated toxicities medsafe.govt.nznih.govhealthline.com. Monitoring of cyclosporine concentrations may be necessary when co-administered with this compound medsafe.govt.nz.

The clinical significance of these interactions depends on the specific co-administered drug, its absorption characteristics, therapeutic index, and the clinical status of the patient nih.gov.

Additive Central Nervous System Effects (e.g., with Antipsychotics)

This compound exhibits effects on the central nervous system (CNS), primarily through its antagonism of dopamine D2 receptors in the chemoreceptor trigger zone nih.govwikipedia.org. Co-administration with other medications that depress the CNS can result in additive sedative effects pfizer.comrxlist.comfda.gov. These include alcohol, sedatives, hypnotics, narcotics, and tranquilizers pfizer.comrxlist.comfda.gov. The combination can lead to increased drowsiness, dizziness, and impaired cognitive and motor function patsnap.comgoodrx.comdrugs.com.

Furthermore, due to its dopamine receptor antagonist activity, this compound can potentiate the extrapyramidal symptoms (EPS) associated with antipsychotic medications pharmacytimes.comnih.govfda.gov. Both this compound and antipsychotics can cause involuntary muscle movements and other motor disturbances pharmacytimes.comfda.govgoodrx.com. Concurrent use, particularly with antipsychotics known to have a high risk of causing movement disorders (e.g., haloperidol, risperidone, fluphenazine, thioridazine), should generally be avoided due to the increased risk of developing or exacerbating EPS, including potentially irreversible tardive dyskinesia, and neuroleptic malignant syndrome (NMS) pharmacytimes.comnih.govfda.govgoodrx.commedscape.com.

Interactions with Cholinergic and Anticholinergic Agents

This compound is thought to sensitize tissues to the action of acetylcholine, contributing to its prokinetic effects pfizer.comrxlist.com. Its effects on gastrointestinal motility can be antagonized by anticholinergic drugs medcentral.compfizer.commedsafe.govt.nzrxlist.comdrugs.com. Anticholinergic agents, which inhibit the action of acetylcholine, can counteract the prokinetic effects of this compound, potentially reducing its efficacy in conditions like gastroparesis pfizer.commedsafe.govt.nzrxlist.comnih.govdrugs.com.

Conversely, this compound's cholinergic effects could theoretically interact with cholinergic agents, although detailed research findings on specific interactions are less widely documented in the provided sources compared to anticholinergic interactions. However, given its mechanism, it is plausible that co-administration with cholinergic agonists could lead to additive effects on gastrointestinal motility.

Interactions with Monoamine Oxidase Inhibitors

This compound has been reported to release catecholamines, particularly in patients with essential hypertension pfizer.commedsafe.govt.nzrxlist.com. This effect raises a theoretical concern regarding co-administration with Monoamine Oxidase Inhibitors (MAOIs) pfizer.commedsafe.govt.nzrxlist.comhealthline.comfda.gov. MAOIs inhibit the enzymes responsible for metabolizing neurotransmitters like norepinephrine, dopamine, and serotonin, leading to increased levels of these amines drugs.com.

Theoretically, the combination of this compound's catecholamine-releasing effect and the impaired metabolism of catecholamines by MAOIs could lead to a synergistic sympathomimetic effect, potentially resulting in hypertensive crisis healthline.comfda.govgoodrx.comdrugs.com. While clinical data specifically detailing this interaction with this compound is limited in the provided sources, the potential for increased blood pressure and other adverse effects warrants caution healthline.comfda.govgoodrx.com. Therefore, the co-administration of this compound with MAOIs is generally advised against healthline.comfda.govgoodrx.comdrugs.com.

Neuroendocrine Interactions (e.g., Insulin, Catecholamines)

This compound's influence on neuroendocrine function involves its interaction with dopaminergic pathways that regulate hormone release. This is particularly evident in its effects on insulin secretion and catecholamine levels.

Research findings indicate that this compound can affect insulin secretion, although the effects reported in studies are not always consistent. One study in healthy men observed that acute intravenous administration of this compound significantly decreased basal serum insulin levels and caused a parallel elevation in blood glucose over 120 minutes. nih.gov This effect was not observed with a placebo and is consistent with findings for other antidopaminergic agents, aligning with the understanding that dopamine infusion can stimulate insulin and glucagon release in humans. nih.gov

Another study investigating the effects of this compound during intraduodenal glucose infusion in healthy volunteers found that this compound was associated with lower plasma insulin concentrations compared to saline. physiology.orgresearchgate.net However, the area under the insulin curve over the entire study period did not differ significantly between the this compound and saline groups. physiology.org This study also noted that this compound increased plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), incretin hormones that typically enhance insulin secretion. physiology.orgresearchgate.net The paradoxical decrease in insulin release despite increased incretins suggests complex underlying mechanisms. physiology.orgresearchgate.net

Data regarding this compound's effect on insulin levels from a study on intraduodenal glucose infusion are presented below:

Note: The peak values are inferred from the AUC data provided in the source and represent the area under the curve for the first 60 minutes, not a single time point concentration.

This compound is also known to interact with catecholamine release, particularly in specific physiological or pathological states. It has been shown to increase the release of catecholamines from isolated human pheochromocytomas but not from isolated rat adrenal glands. nih.gov This selective effect in pheochromocytomas, tumors of the adrenal medulla or sympathetic ganglia that secrete excessive amounts of catecholamines, may be related to the high endogenous levels of catecholamines in these tumors or potentially through action on serotonin type 4 (5-HT4) receptors which are expressed in pheochromocytomas and can stimulate catecholamine and granin-derived peptide secretion. researchgate.nettandfonline.com

The ability of this compound to enhance catecholamine release in patients with pheochromocytoma is of significant clinical importance, as it can precipitate hypertensive crises. tandfonline.comresearchgate.netmhmedical.compgkb.org This effect is thought to be mediated, at least in part, by its dopamine D2 receptor antagonism, which can indirectly lead to catecholamine release, or by its partial agonist activity at 5-HT4 receptors. researchgate.nettandfonline.comresearchgate.net Studies in hypertensive patients have also indicated that intravenously administered this compound can enhance catecholamine release. mhmedical.compgkb.orgijcasereportsandimages.com

Research on the effects of this compound on norepinephrine and epinephrine levels, particularly in the context of pheochromocytoma, highlights this interaction. While specific quantitative data on the magnitude of catecholamine release in humans induced by this compound in controlled studies are varied and often context-dependent (e.g., presence of pheochromocytoma), the qualitative finding of enhanced release is consistently reported in susceptible individuals or tissues. nih.govresearchgate.nettandfonline.commhmedical.compgkb.orgijcasereportsandimages.com

High-Performance Liquid Chromatography (HPLC)

HPLC is a widely used technique for the analysis of this compound due to its versatility, sensitivity, and ability to handle various sample types. Numerous HPLC methods have been developed and validated for the determination of this compound in bulk drug, pharmaceutical formulations, and biological samples. researchgate.netijpsonline.comijrps.comtandfonline.comglobalresearchonline.netlcms.cz

Research findings highlight the effectiveness of HPLC for this compound analysis. For instance, a green HPLC method was developed for this compound quantification in pharmaceutical products, utilizing an Extend C18 column and a mobile phase of ethanol and formic acid solution (pH 2.0; 30:70 v/v) with detection at 273 nm. This method achieved analysis within 5 minutes and was successfully applied to pharmaceutical products without matrix interference. researchgate.net Another validated HPLC method for this compound hydrochloride in tablets employed a C18 rapid resolution column and a mobile phase of acetonitrile and buffer 4.6 (50:50 v/v) with detection at 248 nm. ijpsonline.com This method showed linearity in the concentration range of 2-10 µg/ml, with a limit of quantification (LLOQ) of 0.80 μg/ml and a limit of detection (LLOD) of 0.26 μg/ml. ijpsonline.com

HPLC methods are also crucial for stability-indicating assays, allowing for the separation and quantification of this compound in the presence of its degradation products. A stability-indicating RP-HPLC method for this compound in the presence of its acid degradation products used a Luna C18 column and an isocratic mobile phase of 0.1% formic acid in water-acetonitrile (20:80, v/v) with detection at 273 nm. ijrps.com This method demonstrated linearity over the range of 50.0 µg/ml to 250.0 µg/ml. ijrps.com

Here is a summary of some HPLC methods for this compound analysis:

Liquid Chromatography-Mass Spectrometry (LC-MS)

LC-MS techniques, particularly LC-MS/MS, offer high sensitivity and specificity for the determination of this compound, especially in complex biological matrices like plasma. researchgate.netnih.gov This hyphenated technique combines the separation power of liquid chromatography with the identification and quantification capabilities of mass spectrometry.

LC-MS methods have been developed for the determination of this compound in human plasma for pharmacokinetic and bioequivalence studies. One such method used liquid-liquid extraction with dichloromethane and separation on an Atlantis HILIC silica column with a mobile phase of acetonitrile-ammonium formate. nih.gov Detection was performed using electrospray ionization tandem mass spectrometry (ESI-MS/MS) in selected reaction monitoring mode. nih.gov This method showed linearity over the concentration range of 2.00 - 150 ng/mL with a small plasma sample volume. nih.gov

LC-MS is also invaluable for the characterization of this compound degradation products. LC-MS/MS has been used to identify photolysis products of this compound in aqueous solutions. researchgate.netucl.ac.be Studies have shown that photoirradiation of this compound can lead to the formation of numerous degradation products, and LC-MS/MS allows for the tentative identification of their structures based on their mass spectra and fragmentation patterns. researchgate.netucl.ac.be The main degradation mechanism observed under photoirradiation was the scission of chlorine, potentially followed by polymerization, leading to dimeric and trimeric products. researchgate.netucl.ac.be

An LC-MS method for this compound in human plasma involved extraction with ethyl acetate and chromatographic separation on a Thermo Hypersil-Hypurity C18 column. researchgate.net A single-quadrupole mass spectrometer with an electrospray interface was used in selected-ion monitoring mode to detect the [M+H]+ ions at m/z 300 for this compound. researchgate.netuni.lu This method was validated over a concentration range of 0.78-50.00 ng mL⁻¹. researchgate.net

UV-Spectrophotometry and Derivative Spectrophotometry

UV-Spectrophotometry is a simple and economical method for the quantitative determination of this compound, particularly in pharmaceutical formulations. This compound exhibits characteristic UV absorption, and methods based on direct absorbance measurements have been developed. researchgate.netijpcbs.comindexcopernicus.comatlantis-press.comresearchgate.net For example, a green spectrophotometric method determined this compound by direct absorbance measurement at 273 nm in ultrapure water. researchgate.net Another method found the maximum wavelength (λmax) for this compound to be 272 nm and obeyed Beer's law in the concentration range from 0.4 to 2.0 μg/ml. ijpcbs.com

Derivative spectrophotometry is a useful technique for the analysis of this compound in the presence of interfering substances or when dealing with overlapping spectra, such as in mixtures with other drugs or degradation products. oup.comresearchgate.netmedcraveonline.comajol.info This technique involves calculating the derivative of the absorbance spectrum with respect to wavelength, which can enhance resolution and eliminate interference.

Research has demonstrated the application of derivative spectrophotometry for the simultaneous determination of this compound with other drugs. A first-derivative spectrophotometric method was developed for the simultaneous quantification of this compound and aspirin, measuring the first derivative amplitudes at specific wavelengths. oup.comresearchgate.net This method was linear over the range of 0.25–20.0 µg/mL for this compound. oup.comresearchgate.net Derivative ratio spectrophotometric methods have also been developed for determining this compound in the presence of its acidic degradate, utilizing the first derivative of the ratio spectra at specific wavelengths. medcraveonline.com

Here is a summary of some Spectrophotometric methods for this compound analysis:

Fluorimetry

Fluorimetry is a highly sensitive spectroscopic technique that can be applied to compounds exhibiting native fluorescence or those that can be derivatized to become fluorescent. This compound has fluorescence properties, allowing for its determination using spectrofluorimetric methods. africaresearchconnects.comnih.govekb.egnih.govresearchgate.net

Spectrofluorimetric methods, including derivative and synchronous fluorescence spectroscopy, have been developed for the determination of this compound, often for simultaneous analysis with other drugs. A novel spectrofluorimetric method utilizing second derivative synchronous fluorescence spectroscopy was developed for the simultaneous determination of this compound and aspirin in pharmaceutical formulations and human plasma. africaresearchconnects.com This method measured second derivative peak amplitudes at 285 nm for this compound and showed a rectilinear response over a concentration range of 0.01 to 0.2 μg mL⁻¹ with a detection limit of 0.001 μg mL⁻¹. africaresearchconnects.com

Another second derivative synchronous fluorometric method was developed for the simultaneous determination of this compound and pyridoxine in syrup and human plasma, based on the native fluorescence of the drugs at a specific wavelength difference. nih.gov This method achieved limits of detection of 0.003 μg/mL for this compound. nih.gov Fluorescence quenching reactions have also been utilized for the spectrofluorimetric determination of this compound. ekb.egresearchgate.net

Here is a summary of some Fluorimetric methods for this compound analysis:

NMR Spectrometry

Nuclear Magnetic Resonance (NMR) spectrometry provides detailed structural information about this compound and can be used for its identification and quantitative analysis. While less commonly used for routine quantitative analysis compared to chromatographic or UV-spectrophotometric methods, NMR is a powerful tool for structural elucidation and purity assessment, particularly in research settings. bmrb.ionih.govuobaghdad.edu.iq

NMR spectroscopy, including ¹H NMR, has been applied in the study of this compound. nih.govuobaghdad.edu.iq Research indicates the use of 1D ¹H NMR and 2D NMR experiments such as [¹H,¹³C]-HMBC and [¹H,¹H]-COSY for analyzing this compound samples. bmrb.io These techniques provide valuable information about the connectivity and spatial arrangement of atoms within the this compound molecule. NMR spectrometry can also be used to study the interactions of this compound with other molecules or to characterize its degradation products.

Studies have utilized NMR spectrometry for the analysis of this compound in various contexts, including its determination in pharmaceutical formulations. nih.gov The detailed spectral information obtained from NMR can help confirm the identity and purity of this compound samples.

Pharmacodynamic Studies in Healthy Volunteers

Pharmacodynamic studies in healthy volunteers aim to understand the physiological effects of this compound in the absence of a specific disease state. These studies often involve assessing the drug's impact on gastrointestinal motility, gastric emptying rate, and other relevant physiological parameters. pfizer.com For example, studies have shown that this compound accelerates gastric emptying and intestinal transit in humans. pfizer.com It increases the tone and amplitude of gastric contractions and relaxes the pyloric sphincter. pfizer.com The onset of pharmacological action varies depending on the route of administration. pfizer.commims.com

Controlled Clinical Trials in Specific Conditions (e.g., Emesis, Gastroparesis, Stroke)

Controlled clinical trials are essential for evaluating the efficacy of this compound in treating specific medical conditions. These trials compare the effects of this compound to a placebo or another active control, often using randomized and double-blind designs.

In the context of emesis, particularly chemotherapy-induced nausea and vomiting, controlled trials have demonstrated the antiemetic potential of this compound. nih.govmdpi.com Early trials using traditional doses showed limited efficacy, but later studies with higher doses proved superior to placebo and other antiemetics in preventing cisplatin-induced emesis. nih.gov this compound's antiemetic action is primarily attributed to its D₂ receptor antagonism in the chemoreceptor trigger zone. wikipedia.orgresearchgate.net

For gastroparesis, this compound has been evaluated in controlled trials for its ability to improve gastric emptying and alleviate symptoms like nausea, vomiting, and fullness. nih.govnih.gov Studies have shown that this compound can improve symptom scores and accelerate gastric emptying in patients with diabetic gastroparesis. nih.govnih.gov

In stroke patients, this compound has been investigated for its potential to reduce the risk of aspiration pneumonia, a common complication in patients with dysphagia fed via nasogastric tubes. ahajournals.org A randomized placebo-controlled trial in stroke patients fed via nasogastric tubes showed significantly fewer episodes of pneumonia in the this compound group compared to the placebo group. ahajournals.org This effect is likely due to this compound's prokinetic action, which reduces gastric stasis and regurgitation. ahajournals.org

Bioequivalence Studies

Bioequivalence studies are conducted to determine if two different formulations of the same drug deliver the active ingredient to the bloodstream at the same rate and extent. These studies are crucial for approving generic drug products. dissolutiontech.com

Bioequivalence studies for this compound typically involve administering single doses of a test formulation and a reference formulation to healthy volunteers in a crossover design. researchgate.netnih.govresearchgate.net Plasma concentrations of this compound are measured over time using sensitive analytical methods like High-Performance Liquid Chromatography (HPLC). researchgate.netnih.govresearchgate.net Pharmacokinetic parameters such as peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), and time to peak concentration (tmax) are calculated and statistically compared. researchgate.netresearchgate.net Bioequivalence is generally concluded if the 90% confidence intervals for the ratios of the test and reference product's Cmax and AUC fall within a predefined range, typically 80% to 125%. researchgate.net Studies have demonstrated bioequivalence between different oral tablet formulations of this compound. nih.govresearchgate.net

In some cases, for drugs classified under the Biopharmaceutics Classification System (BCS) as highly soluble and having low permeability (BCS Class 3), in vitro dissolution studies can serve as a surrogate for in vivo bioequivalence studies, provided certain criteria regarding excipient composition are met. dissolutiontech.com this compound is considered a BCS Class 3 drug. dissolutiontech.com