Amitriptyline

Serotonin Transporter (SERT) Interaction Dynamics

This compound inhibits the reuptake of serotonin by blocking the serotonin transporter (SERT) at presynaptic terminals. nih.gov Studies have reported varying affinity values for this compound at the human SERT. For instance, the hydrochloride salt of this compound has been shown to inhibit human SERT with a Kᵢ of 3.45 nM. arctomsci.comclinisciences.commedchemexpress.commedchemexpress.commedchemexpress.comselleckchem.com Another study reported a Kᵢ range of 3-4 nM for SERT inhibition by this compound. caldic.com This high affinity for SERT contributes significantly to its pharmacological profile.

Norepinephrine Transporter (NET) Interaction Dynamics

In addition to its effects on SERT, this compound also inhibits the reuptake of norepinephrine by blocking the norepinephrine transporter (NET). nih.gov The affinity of this compound for NET is generally lower than its affinity for SERT, though it is still considered potent. Reported Kᵢ values for human NET inhibition by this compound hydrochloride are around 13.3 nM. arctomsci.comclinisciences.commedchemexpress.commedchemexpress.comselleckchem.comselleck.co.jpclinisciences.com Other research indicates a Kᵢ range of 19-35 nM for NET inhibition. caldic.com The inhibition of NET is believed to play a role in the analgesic effects of this compound. wikipedia.org

Comparative Potency of this compound and Metabolites on Monoamine Transporters

This compound undergoes significant metabolism, primarily in the liver, producing several active and inactive metabolites. wikipedia.org The main active metabolite is nortriptyline, which is also a TCA. mims.comwikipedia.orgnih.gov Other metabolites include 10-hydroxythis compound and 10-hydroxynortriptyline. wikipedia.orguni.lunih.govnih.govnih.govnih.govuni.lucenmed.comdelta-f.com

The comparative potency of this compound and its key metabolites on monoamine transporters reveals differences in their inhibitory profiles. While this compound is a potent inhibitor of both SERT and NET, its metabolite nortriptyline is generally considered a more potent inhibitor of NET than SERT. mims.comwikipedia.orgcaldic.com

Limited specific comparative data on the potency (e.g., Kᵢ or IC₅₀ values) of 10-hydroxythis compound and 10-hydroxynortriptyline on SERT and NET were readily available in the search results. However, one source suggests that the 10-hydroxy metabolites are equipotent to this compound in inhibiting reuptake. caldic.com Another source indicates that (E)-10-hydroxynortriptyline is about 50% as potent as nortriptyline in inhibiting norepinephrine uptake in vitro. medchemexpress.com

A simplified comparison of reported Kᵢ values for this compound and nortriptyline on human SERT and NET is presented in the table below:

Histamine H1 Receptor Antagonism

This compound is a potent antagonist of the histamine H1 receptor. wikipedia.orgpatsnap.comnih.govresearchgate.net This antagonism is associated with sedative properties. patsnap.comnih.govresearchgate.net Reported Kᵢ values for this compound at the histamine H1 receptor are very low, indicating high affinity. Values include 0.5 nM selleckchem.comselleck.co.jpclinisciences.com and 1.1 nM. arctomsci.comclinisciences.comcaymanchem.com Studies in guinea pig ileum showed a Kᵢ of 0.4 nM against histamine-stimulated contractility in muscle. nih.gov

A table summarizing reported Kᵢ values for this compound at the Histamine H1 receptor:

Alpha-Adrenergic Receptor Antagonism (α1A)

This compound also exhibits antagonistic activity at alpha-adrenergic receptors, particularly the α1A subtype. wikipedia.orgpatsnap.comnih.govresearchgate.net This action can contribute to effects such as orthostatic hypotension. patsnap.comnih.gov Reported Kᵢ values for this compound at α1-adrenergic receptors vary. One source indicates a Kᵢ of 27 nM for α1-adrenergic receptors. caymanchem.com Another study in rat brain reported a Kᵢ of 182 ± 16 nM for α1-ARs. nih.gov Research comparing affinities for α1-adrenoceptor subtypes suggests this compound has considerably higher affinities for α1A and α1D than for α1B. researchgate.net Specifically, reported pKᵢ values (which correlate inversely with Kᵢ, higher pKᵢ means higher affinity) for human α1A-adrenoceptor are around 8.2. drugbank.comguidetopharmacology.org

A table summarizing reported affinity values for this compound at Alpha-1A adrenergic receptors:

Muscarinic Acetylcholine Receptor Antagonism (M1-M5)

This compound demonstrates significant anticholinergic properties by acting as a potent antagonist at muscarinic acetylcholine receptors (mAChRs). drugbank.com These receptors, classified into five subtypes (M1 to M5), are G protein-coupled receptors widely distributed throughout the central and peripheral nervous systems. mdpi.com Studies using cloned human muscarinic receptor subtypes expressed in Chinese hamster ovary (CHO-K1) cells have shown that this compound exhibits high affinity binding to these receptors. nih.gov

Research indicates that this compound does not show significant selectivity among the five cloned subtypes (M1-M5). nih.gov The affinity of this compound for these receptors is in the nanomolar range, with reported equilibrium dissociation constants (Kd) between 7 and 16 nM. nih.gov This potent, non-selective antagonism of muscarinic receptors contributes to some of the characteristic side effects associated with this compound, although these are outside the scope of this article. The interaction with muscarinic receptors in different brain regions and the heart has also been investigated, showing similar potency in inhibiting binding and antagonizing receptor-mediated responses like the inhibition of adenylate cyclase activity. drugbank.com

Serotonin Receptor Modulation (5-HT2A, 5-HT2C)

Beyond its role as a serotonin reuptake inhibitor, this compound also modulates the activity of certain serotonin receptor subtypes, particularly 5-HT2A and 5-HT2C receptors. This compound acts as a potent antagonist of the serotonin 5-HT2A and 5-HT2C receptors. wikipedia.org

Studies have investigated the affinity of this compound for these receptors. For the 5-HT2 receptor family (which includes 5-HT2A, 5-HT2B, and 5-HT2C), this compound has been reported to have a Ki of 235 nM. selleckchem.com More specific research indicates that this compound has high affinity for 5-HT2C receptors. researchgate.net Blockade of 5-HT2A/2C receptors has been suggested to improve the antidepressant action of selective serotonin reuptake inhibitors (SSRIs). csic.es

Research in rats has shown that acute administration of this compound can enhance dopamine release in the nucleus accumbens by blocking 5-HT2C receptors. researchgate.net This effect was observed at doses of 5 mg/kg and 10 mg/kg (intraperitoneal) and was comparable to the effect of mianserin, another antidepressant with high affinity for 5-HT2C receptors. researchgate.net Lower doses of this compound (5 mg/kg) were found to block the inhibitory action of a selective 5-HT2C receptor agonist on dopamine release. researchgate.net

Adenosine Reuptake Inhibition and Receptor Stimulation

This compound has been shown to interact with the adenosine system by inhibiting the cellular uptake of adenosine. clinmedjournals.orgmdpi.com This inhibition leads to increased extracellular concentrations of adenosine, which can then enhance the stimulation of adenosine receptors in both the peripheral and central nervous systems. mdpi.commdpi.com This mechanism is proposed to contribute to the analgesic effects of this compound. mdpi.commdpi.com

Peripheral adenosine A1 receptors have been implicated in systemically administered this compound-induced antinociception. mdpi.com While the exact mechanisms underlying adenosine A3 receptor activation by this compound are still being investigated, studies suggest an antinociceptive effect via this receptor in neuropathic pain models in rats. painphysicianjournal.com

Research on the role of adenosine receptors in this compound-induced cardiovascular effects has also been conducted. Studies in isolated rat aorta suggest that adenosine A2a receptor stimulation may be partly responsible for this compound-induced vasodilation and hypotension. nih.gov An adenosine A1 antagonist was found to increase this compound-induced vasodilation in this preparation. nih.gov

Investigation into Opioid and N-methyl-D-aspartate (NMDA) Receptor Interactions

Investigations have explored the potential interactions of this compound with opioid and NMDA receptors, suggesting additional mechanisms that may contribute to its therapeutic, particularly analgesic, effects. clinmedjournals.orgmdpi.com

Regarding opioid receptors, accumulated evidence suggests that this compound may interact with these receptors. clinmedjournals.org Some studies have found that this compound can bind to opioid receptors. mdpi.com Research examining the interaction of tricyclic antidepressants with opioid binding sites in bovine adrenal medulla found that this compound showed significant interaction with subtypes of the kappa binding site, exhibiting the highest interaction with the kappa 1 subtype compared to other tested TCAs. drugbank.com Studies using human brain tissue have also shown that this compound can inhibit opioid receptor binding, with a slight selectivity for the kappa receptor type. nih.gov The IC50 values for this inhibition were in the 10-6 M concentration range. nih.gov While some studies suggest potential agonist activity on kappa opioid receptors, the interaction with opioid receptors at therapeutic drug concentrations has been a subject of debate. mdpi.commdpi.com

This compound has also been found to interact with NMDA receptors. clinmedjournals.orgmdpi.com It is described as an antagonist of NMDA receptors, which are important in the generation of neuropathic pain. clinmedjournals.orgpainphysicianjournal.com Studies have shown that this compound can reduce glutamate-induced intracellular calcium accumulations by binding to the NMDA receptor, potentially suppressing cell excitation. mdpi.com Research in rats suggests that intrathecal administration of this compound can act as an NMDA receptor antagonist, reversing inflammation-induced hyperalgesia through a mechanism likely related to this antagonism rather than monoamine reuptake inhibition. nih.gov this compound has been shown to prevent NMDA-induced toxicity in cerebellar granule neurons, although it did not prevent NMDA-induced elevations of extracellular glutamate, suggesting an interaction at sites removed from the receptor. nih.gov The ED50 for this compound protection against NMDA-induced toxicity was reported as 6.9 µM. nih.gov

Voltage-Gated Sodium Channel Blockade and Associated Biophysical Effects

This compound is a non-selective blocker of multiple voltage-gated sodium channels (VGSCs). wikipedia.org These channels are crucial for the initiation and propagation of action potentials in neurons and other excitable cells. This compound can block both tetrodotoxin-sensitive (TTX-s) and tetrodotoxin-resistant (TTX-R) sodium currents. researchgate.net

Specific VGSC subtypes shown to be blocked by this compound include NaV1.3, NaV1.5, NaV1.6, NaV1.7, and NaV1.8. wikipedia.org The blocking effect of this compound on sodium channels is thought to contribute to its efficacy in pain conditions, potentially by inhibiting ectopic discharges in injured nerves. wikipedia.orgmdpi.com

Studies have investigated the biophysical effects of this compound on VGSCs. This compound exhibits state-dependent block of VGSCs, meaning its affinity for the channel varies depending on the channel's conformational state (resting, open, or inactivated). researchgate.net Research indicates that this compound has the highest affinity for the open channel state, with a 50% inhibitory concentration (IC50) of 0.26 µM. researchgate.net The affinity for the inactivated channel block is weaker (0.51 µM), while the resting channel block shows the weakest affinity (33 µM). researchgate.net This state-dependent block, particularly the high affinity for open and inactivated states, is a characteristic shared by some antiseizure drugs. researchgate.net

This compound's effects on the cardiac sodium channel NaV1.5 have also been studied. Acute treatment with this compound has been shown to decrease NaV1.5 current densities and prolong the recovery time constants from inactivation. frontiersin.orgresearchgate.net These effects on cardiac sodium channels can contribute to electrocardiogram abnormalities. researchgate.net

Human Ether-a-go-go Related Gene (hERG) Channel Inhibition

This compound is known to inhibit the human ether-a-go-go-related gene (hERG) channel, a voltage-gated potassium channel critical for cardiac repolarization. drugbank.comechinobase.org Inhibition of the hERG channel can lead to QT interval prolongation and increase the risk of cardiac arrhythmias. drugbank.comechinobase.orgresearchgate.net

Studies have demonstrated that this compound blocks the hERG channel in a dose-dependent and voltage-dependent manner. echinobase.org The block becomes more pronounced at more positive membrane potentials. echinobase.org The IC50 values for hERG block by this compound vary depending on the voltage and external potassium concentration. For example, IC50 values at different voltages were reported as 23.0 µM at -30 mV, 8.71 µM at -10 mV, 5.96 µM at +10 mV, and 4.66 µM at +30 mV. echinobase.org The block is also use-dependent, with faster block occurring at higher activation frequencies. echinobase.org

Research using different expression systems has yielded comparable IC50 values for hERG inhibition by this compound. Studies using Xenopus oocytes reported IC50 values ranging from 3.3 to 4.8 µM (depending on external K+ concentration), while studies using HEK293 cells reported an IC50 of 10 µM or 10.7 ± 2.25 µM. researchgate.netcaldic.com Inhibition of hERG currents by this compound at concentrations in the upper micromolar range of therapeutic plasma concentrations may contribute to the risk of cardiac arrhythmia. drugbank.com

Calcium and Potassium Channel Modulation

This compound has demonstrated the ability to modulate both calcium and potassium channels, contributing to its diverse effects. Studies have shown that this compound can inhibit voltage-dependent calcium channels. In synaptosomes isolated from rat brain cortex, this compound inhibited potassium-induced ⁴⁵Ca uptake with an IC₅₀ value in the range of 26–31 µM. nih.gov Another study using acutely dissociated basal forebrain neurons from juvenile rats investigated the effect of this compound on whole-cell high-voltage-activated (HVA) calcium currents. This compound inhibited these currents in a concentration-dependent manner, with increasing inhibition observed at higher concentrations (3 µM, 10 µM, 30 µM, 100 µM, and 300 µM). frontiersin.org At clinically relevant concentrations (0.5-3 µM), this compound has been shown to activate cardiac ryanodine channels (RyR2), leading to spontaneous sarcoplasmic reticulum Ca²⁺ release in intact cardiomyocytes. nih.gov This activation of RyR2 channels and increased SR Ca²⁺ leak may contribute to the proarrhythmic and cardiotoxic effects observed with this compound, particularly in overdose situations. nih.govphysiology.org

This compound also modulates potassium channels. Central antinociception induced by this compound has been reported to involve the opening of different subtypes of K⁺ channels, including voltage-gated, KATP, and Ca²⁺-gated channels. unifi.itresearchgate.net Research using the mouse hot plate test indicated that the administration of modulators of different subtypes of K⁺ channels affected the antinociceptive effect of this compound. The voltage-gated K⁺ channel blocker tetraethylammonium prevented this compound-induced antinociception. unifi.it Similarly, the KATP channel blocker gliquidone prevented the antinociceptive effect, while KATP channel openers like minoxidil and pinacidil potentiated it. unifi.itresearchgate.net The Ca²⁺-gated K⁺ channel blocker apamin also completely prevented this compound analgesia. unifi.itresearchgate.net These findings suggest that the opening of these potassium channel subtypes is involved in the central antinociceptive mechanism of this compound. unifi.itresearchgate.net this compound has also been shown to inhibit TREK1, a two-pore domain potassium (K2P) channel, which is involved in regulating neuronal excitability and pain perception. researchgate.net The inhibition of TREK1 current by this compound was significant and concentration-dependent. researchgate.net Furthermore, this compound has an affinity for the Kv7 family of potassium channels. mdpi.com In isolated rat sympathetic neurons, this compound blocked potassium currents, with the uncharged form of the drug being significantly more potent than the charged form. westminster.ac.uk

Table 1: this compound Inhibition of Voltage-Gated Calcium Channels

Table 2: this compound Inhibition of HVA Calcium Currents in Rat Basal Forebrain Neurons

Table 3: Modulation of Potassium Channels by this compound and Channel Modulators in Mouse Antinociception

Gastrointestinal Absorption Dynamics

This compound is readily absorbed from the gastrointestinal tract following oral administration, with reported absorption rates as high as 90–95%. wikipedia.orgmdpi.com Studies using simulated gastric and intestinal fluids have explored the adsorption behavior of this compound onto various materials, such as activated carbons, relevant in overdose scenarios. researchgate.net Research indicates that the presence of food can influence the efficacy of activated charcoal in adsorbing this compound, potentially by slowing gastric emptying. researchgate.net Low-dose this compound has also been shown in research to slow orocecal transit time and potentially affect gastric sensitivity. nih.gov

First-Pass Metabolism Implications for Systemic Bioavailability

Despite its high rate of gastrointestinal absorption, this compound undergoes significant first-pass metabolism in the liver. mdpi.comdrugbank.compharmgkb.org This extensive presystemic elimination substantially reduces the fraction of the administered dose that reaches systemic circulation, resulting in an average oral bioavailability ranging from approximately 30% to 60%. drugbank.comnih.govnih.gov Some studies report bioavailability values around 45-53%. wikipedia.orgmdpi.com Research in rats has suggested that a considerable portion of the first-pass effect may occur in the intestine, in addition to hepatic metabolism, contributing to the relatively low oral bioavailability. nih.gov

Protein and Tissue Binding Characteristics

This compound is characterized by high protein binding in plasma and tissues. drugbank.comnih.gov Approximately 95% of the drug in plasma is bound to proteins. drugbank.com This high degree of protein binding influences its distribution and limits the amount of free, pharmacologically active drug available to exert its effects. Research, including in silico studies, has investigated the binding of this compound to various plasma proteins, such as human serum albumin (HSA), human ceruloplasmin (HCP), and cellular retinol-binding protein (CRBP). innovareacademics.inresearchgate.net These studies suggest that this compound can bind to all three proteins, with different types of interactions (polar, hydrophobic, and hydrogen bonding) contributing to the binding affinity. innovareacademics.inresearchgate.net The apparent volume of distribution for this compound is large, estimated to be around 1221 L ± 280 L (or 16 ± 3 L/kg) after intravenous administration, indicating its extensive distribution throughout the body. drugbank.com

Cytochrome P450 (CYP) Isoenzyme Involvement (CYP2C19, CYP2D6, CYP3A4, CYP1A2, CYP2C9)

The hepatic cytochrome P450 enzymes, particularly CYP2C19 and CYP2D6, play a central role in this compound metabolism. pharmgkb.orgresearchgate.netkentpharma.co.uknih.gov CYP2C19 is identified as the most important enzyme for the N-demethylation of this compound, which is a quantitatively significant metabolic pathway. nih.govkarger.com CYP2D6 is primarily responsible for the hydroxylation of this compound, specifically at the 10-position. nih.govkarger.com Other CYP isozymes, including CYP3A4, CYP1A2, and CYP2C9, also participate in this compound metabolism, although their contribution may be less significant than CYP2C19 and CYP2D6, particularly at therapeutic doses. drugbank.comkentpharma.co.uknih.govkarger.com In vitro studies using cDNA-expressed human CYP enzymes have provided detailed insights into the roles and kinetics of these enzymes. nih.govkarger.com CYP2C19 and CYP2D6 exhibit high affinities for this compound (Km values in the range of 5-13 µmol/l), while CYP1A2, CYP3A4, and CYP2C9 show lower affinities (Km values ranging from 74 to 92 µmol/l). nih.govkarger.com CYP2C19 has demonstrated the highest reaction capacity per mole of enzyme (Vmax equal to 475 mol h-1 (mol CYP)-1) compared to the other participating enzymes (Vmax values in the range of 90-145 mol h-1 (mol CYP)-1). nih.govkarger.com Simulation studies based on typical hepatic CYP enzyme distribution suggest that at therapeutic doses, approximately 60% of this compound metabolism depends on CYP2C19. nih.govkarger.com However, at higher or toxic doses, CYP3A4 may become more dominant as CYP2C19 can become saturated. nih.govkarger.com The metabolism of this compound is subject to genetic polymorphisms, particularly in CYP2D6 and CYP2C19, which can lead to significant inter-individual variability in plasma concentrations. drugbank.compharmgkb.orgresearchgate.netkentpharma.co.uknih.gov Research indicates that individuals with reduced activity of CYP2C19 (poor metabolizers) have decreased this compound metabolism and higher plasma concentrations. researchgate.netnih.gov Similarly, reduced CYP2D6 activity can also lead to increased this compound plasma concentrations. researchgate.net

Formation of Active Metabolites (Nortriptyline) and Less Active Metabolites (10-hydroxy metabolites)

Hydroxylation of this compound, mainly mediated by CYP2D6, leads to the formation of 10-hydroxy metabolites, specifically (E)-10-hydroxythis compound and (Z)-10-hydroxythis compound. researchgate.netnih.govkarger.comscielo.br These 10-hydroxy metabolites are generally considered less active than this compound and nortriptyline. drugbank.compharmgkb.org Research indicates that CYP2D6 stereospecifically produces the (-)-(E)-hydroxyl form as the major product among the hydroxylated isomers. researchgate.netscielo.br Nortriptyline is also hydroxylated by CYP2D6 to form (E)-10-hydroxynortriptyline and (Z)-10-hydroxynortriptyline. researchgate.netscielo.br While less active than the parent compounds, (E)-10-hydroxynortriptyline still exhibits norepinephrine uptake inhibitory activity. caymanchem.com Some research suggests that (E)-10-hydroxynortriptyline may contribute to the therapeutic effects of this compound, particularly given its concentration in cerebrospinal fluid. wikipedia.org Other metabolites, such as demethylnortriptyline and this compound N-oxide, are present in plasma in negligible amounts, with the latter being mostly inactive. drugbank.com this compound and its metabolites are primarily excreted in the urine, largely as glucuronide or sulfate conjugates. drugbank.comnih.gov

Data Tables

Note: The data presented in these tables are derived from research findings and represent typical values or ranges observed in studies. Inter-individual variability exists due to genetic and other factors.

N-demethylation and Hydroxylation Processes

The metabolism of this compound involves key Phase I reactions, including N-demethylation and hydroxylation. N-demethylation of this compound leads to the formation of its active metabolite, nortriptyline. This metabolic step is primarily catalyzed by the cytochrome P450 enzyme CYP2C19 at therapeutic concentrations drugbank.comdrugbank.comkarger.compharmgkb.orgnih.gov. Other CYP enzymes, such as CYP1A2, CYP3A4, and CYP2C9, also contribute to the N-demethylation of this compound, although to a lesser extent drugbank.comdrugbank.comkarger.com.

Hydroxylation is another significant metabolic pathway for both this compound and nortriptyline. The hydroxylation of this compound predominantly occurs at the 10-position of the ethylene bridge in the central seven-membered ring, resulting in the formation of 10-hydroxythis compound tandfonline.comresearchgate.net. This reaction is mediated almost exclusively by the enzyme CYP2D6 drugbank.comkarger.com. Similarly, nortriptyline undergoes hydroxylation at the 10-position, catalyzed by CYP2D6, to form 10-hydroxynortriptyline tandfonline.compgkb.org. Research indicates that the formation of the (E)-isomer of 10-hydroxythis compound is exclusively mediated by CYP2D6 drugbank.comkarger.com. The hydroxylation process can occur with high stereo- and enantioselectivity, with the (-)-(E)-10-hydroxy compounds often being the major products researchgate.net.

In vitro studies using cDNA-expressed human CYP enzymes have provided quantitative data on the relative contributions of different enzymes to this compound metabolism. For N-demethylation, CYP2C19 exhibits the highest reaction capacity (Vmax) and a high affinity (low Km), suggesting its dominant role at therapeutic concentrations drugbank.comkarger.com. CYP2D6 also participates in N-demethylation, but its contribution is less significant compared to CYP2C19 tandfonline.com. For hydroxylation, CYP2D6 is the primary enzyme involved drugbank.comkarger.com.

N-oxidation Pathways

In addition to N-demethylation and hydroxylation, this compound can also undergo N-oxidation. This pathway results in the formation of this compound N-oxide researchgate.netmdpi.comacs.orgwisdomlib.org. Research suggests that this metabolic route is mediated by flavin-containing monooxygenase (FMO) enzymes acs.org. This compound N-oxide can be excreted unchanged or further metabolized, for instance, to a 10-hydroxy derivative researchgate.net. Interestingly, this compound N-oxide can also be reduced back to the parent drug, this compound, in vivo researchgate.netmdpi.comacs.org. While this compound N-oxide is present in plasma, its concentrations are generally considered negligible, and it is largely considered inactive drugbank.com.

Renal Excretion of Metabolites (Glucuronide and Sulfate Conjugates)

The major route of excretion for this compound metabolites is renal elimination following conjugation drugbank.comnih.govpharmascience.comhres.caaapharma.cabcrenal.ca. Phase II metabolism involves the conjugation of hydroxylated and demethylated metabolites with highly polar molecules, such as glucuronic acid and sulfate, increasing their water solubility and facilitating their excretion in urine drugbank.comnih.govbcrenal.camdpi.com. Virtually the entire dose of this compound is excreted as glucuronide or sulfate conjugates of its metabolites drugbank.comnih.gov. Studies have shown that 25-50% of a single oral dose can be excreted in urine as inactive metabolites within 24 hours drugbank.comnih.gov. Direct glucuronidation of the parent drug, this compound, appears to be a minor metabolic pathway in humans nih.gov.

Biliary Elimination and Fecal Excretion of Metabolites

While renal excretion is the primary route, a smaller proportion of this compound metabolites is eliminated via the biliary route, leading to their excretion in feces drugbank.comnih.govhres.caaapharma.camedsafe.govt.nz. Animal studies have provided evidence for the biliary excretion of this compound and its metabolites hres.camedsafe.govt.nz.

CYP2D6 Polymorphisms (Poor, Intermediate, Extensive, Ultrarapid Metabolizers)

Polymorphisms in the CYP2D6 gene lead to distinct metabolizer phenotypes: Poor Metabolizers (PMs), Intermediate Metabolizers (IMs), Extensive Metabolizers (EMs), and Ultrarapid Metabolizers (UMs) frontiersin.org. These variations in CYP2D6 activity have a strong effect on the plasma concentrations of both this compound and its metabolite, nortriptyline frontiersin.org.

Individuals who are CYP2D6 PMs or IMs have reduced enzyme activity, leading to decreased hydroxylation of this compound and nortriptyline nih.govpgkb.orgresearchgate.net. This can result in higher plasma concentrations of the parent drug and its active metabolite compared to EMs pgkb.orgfrontiersin.org. Studies have shown that PMs and IMs exhibit increased metabolic ratios of this compound to its hydroxylated metabolites pgkb.org.

Conversely, CYP2D6 UMs possess increased enzyme activity due to gene duplication or multiplication nih.gov. This can lead to more rapid metabolism and potentially lower plasma concentrations of this compound and nortriptyline pgkb.org. Research has indicated that UM status may be associated with treatment failure, likely due to sub-therapeutic drug levels pgkb.org.

Research findings highlight the importance of considering CYP2D6 genotype in predicting this compound and nortriptyline plasma concentrations and understanding inter-individual variability in drug disposition nih.govpgkb.orgresearchgate.netfrontiersin.org.

While CYP2D6 significantly impacts hydroxylation, CYP2C19 polymorphisms also play a crucial role, primarily affecting the N-demethylation of this compound to nortriptyline pharmgkb.orgnih.govresearchgate.net. Studies have shown that CYP2C19 PMs have significantly decreased N-demethylation of this compound, leading to higher exposure to the parent drug nih.govresearchgate.net.

CYP2C19 Polymorphisms and Nortriptyline Formation

This compound is primarily metabolized in the liver. A major metabolic pathway involves N-demethylation of this compound to its active metabolite, nortriptyline. This conversion is significantly catalyzed by the cytochrome P450 enzyme CYP2C19. nih.govg-standaard.nlpharmgkb.orgmims.comnih.gov

Genetic polymorphisms in the CYP2C19 gene lead to different metabolizer phenotypes, ranging from poor metabolizers (PMs) with significantly reduced enzyme activity to ultrarapid metabolizers (UMs) with increased activity. nih.gov Studies have demonstrated that the extent of N-demethylation of this compound is significantly decreased in individuals carrying two nonfunctional alleles of CYP2C19, characteristic of the PM phenotype. nih.govresearchgate.net This reduced metabolic capacity in PMs results in higher plasma concentrations of the parent drug, this compound, and lower plasma concentrations of the active metabolite, nortriptyline, compared to normal metabolizers (NMs). nih.govg-standaard.nl Conversely, individuals who are CYP2C19 rapid or ultrarapid metabolizers may be at risk for having low plasma concentrations of this compound and an imbalance between the parent drug and its metabolites. nih.gov While the CYP2C19 *17 allele, associated with increased function, may not alter the sum of this compound and nortriptyline plasma concentrations, it has been linked to higher nortriptyline plasma concentrations. nih.gov

Research findings highlight the influence of CYP2C19 genotype on the ratio of nortriptyline to this compound plasma concentrations. tandfonline.com Although CYP2C19 genotype may not have a significant effect on this compound pharmacokinetics itself, individuals with higher CYP2C19 activity tend to show higher nortriptyline AUC (Area Under the Curve) and Cmax (maximum concentration) values compared to those with lower activity. frontiersin.org

Impact of Genetic Variation on Therapeutic Response and Adverse Event Propensity

Genetic variations in CYP2C19, as well as other genes involved in this compound metabolism like CYP2D6, can influence both therapeutic response and the likelihood of experiencing adverse events. nih.govfrontiersin.org The effectiveness and tolerability of tricyclic antidepressants like this compound are affected by metabolism mediated by both CYP2D6 and, partially, by CYP2C19. nih.gov

Individuals who carry genetic variants that influence the activity of CYP2D6 or CYP2C19 may face an increased risk of treatment failure if drug plasma levels are too low or drug toxicity if levels are too high. nih.gov For instance, CYP2C19 poor metabolizers have a reduced rate of this compound metabolism, leading to higher plasma levels of this compound and potentially increasing the risk of side effects. nih.gov Conversely, CYP2C19 rapid or ultrarapid metabolizers might have low plasma concentrations, potentially leading to treatment failure. nih.gov

Studies have explored the correlation between drug concentrations, genotypes, and clinical outcomes. Some research indicates that nortriptyline concentrations, rather than this compound concentrations, may correlate with side effects. psu.edu Furthermore, specific combinations of CYP2D6 and CYP2C19 genotypes have been associated with differing risks of adverse events. For example, carriers of two functional CYP2D6 alleles may have a significantly lower risk of side effects compared to carriers of only one functional allele. psu.edu The lowest risk of adverse events has been observed in individuals with two functional CYP2D6 alleles combined with only one functional CYP2C19 allele. psu.edu

However, some studies have not found a significant effect of CYP2C19 phenotype on clinical improvement or remission rates in depression. g-standaard.nl Similarly, the impact of CYP2C19 phenotype on the intensity of certain adverse events, such as fatigue, has not always been statistically significant in research settings. g-standaard.nl

Research findings on the association between pharmacokinetic gene variation and therapeutic response have yielded mixed results. One study investigating depression cohorts found that while serum concentrations of this compound were associated with CYP2D6 genotype, pharmacokinetic gene variation did not affect treatment response. researchgate.net

Multidrug Resistance Protein 1 (MDR1) Genotype and Adverse Event Risk

Beyond metabolic enzymes, drug transporters also play a role in the pharmacokinetics of this compound. The multidrug resistance protein 1 (MDR1), encoded by the ABCB1 gene, is an efflux transporter that regulates the passage of various substances, including some antidepressants and their metabolites, across the blood-brain barrier. nih.gov this compound and its metabolites, including nortriptyline, are substrates for P-glycoprotein (P-gp), the protein encoded by ABCB1. nih.gov

Research has investigated the association between polymorphisms in the ABCB1 gene and the risk of adverse events with this compound. A study examining a single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) found a significant association between nortriptyline-induced postural hypotension and this polymorphism. nih.gov The results suggested that homozygosity for the 3435T alleles of ABCB1 is a risk factor for the occurrence of nortriptyline-induced postural hypotension. nih.gov

Receptor Affinity and Functional Assays

This compound interacts with a variety of neurotransmitter receptors. Receptor binding studies have characterized its affinity for several sites. It is known to act as a potent antagonist at serotonin 5-HT2A and 5-HT2C receptors, alpha1A-adrenergic receptors, histamine H1 receptors, and muscarinic acetylcholine receptors (M1-M5). wikipedia.org Studies using rat brain muscarinic receptors have shown that this compound displaces muscarinic ligand binding from a single high-affinity site in homogenates of various brain regions, demonstrating comparable affinity across regions with different M1 and M2 receptor subtype distributions. capes.gov.br Functional assays have corroborated this non-selective nature, showing this compound to be equipotent in antagonizing M1-mediated phosphoinositide hydrolysis and M2-mediated inhibition of cyclic AMP formation in dissociated cortical cells. capes.gov.br this compound also shows high affinity for the histamine H1 receptor. mdpi.com

Ion Channel Activity Profiling

This compound is recognized as a non-selective blocker of multiple ion channels. wikipedia.org This includes voltage-gated sodium channels (Nav1.3, Nav1.5, Nav1.6, Nav1.7, and Nav1.8) and voltage-gated potassium channels (Kv7.2/Kv7.3, Kv7.1, Kv7.1/KCNE1, and hERG). wikipedia.org Through patch-clamp techniques, this compound has been shown to trigger effects on sodium channels similar to local anesthetics, a mechanism potentially contributing to its analgesic properties. mdpi.com It has also been shown to inhibit human Kv1.1 and Kv7.2/7.3 channels. drugbank.com Studies investigating the inhibition of voltage-dependent calcium ion channels, specifically the human CaV2.2 channel endogenously expressed in SH-SY5Y neuroblastoma cells, have shown this compound to be a moderately effective inhibitor. Molecular docking studies suggest that this compound may bind within the channel cavity, interfering with the selectivity filter and potentially hindering channel opening.

Neurotransmitter Uptake Inhibition Assays

A primary mechanism of action for this compound is the inhibition of neuronal reuptake of serotonin (5-HT) and norepinephrine (NE). wikipedia.org This interference with the neuronal membrane pump mechanism prolongs and potentiates the action of these neurotransmitters in the synaptic cleft. mims.commedicines.org.uk In vitro and ex vivo studies have consistently shown that this compound is a potent inhibitor of the uptake of both NE and 5-HT by nerve endings in the peripheral and central nervous systems. uliege.be Compared to its metabolite nortriptyline, which is a stronger NE reuptake inhibitor, this compound inhibits the uptake of NE and 5-HT with approximately equal efficacy. wikipedia.orgdrugbank.commedicines.org.uk Studies have shown that the order of potency for inhibiting 5-HT uptake among several TCAs is clomipramine > imipramine > this compound > nortriptyline > desipramine, while the order for NE uptake inhibition is desipramine > nortriptyline > imipramine > this compound > clomipramine. uliege.be

Cellular Toxicity Investigations (e.g., Hepatocyte Models)

Investigations into this compound's cellular toxicity have frequently utilized hepatocyte models due to the association of the drug with rare but severe hepatotoxicity. researchgate.netnih.gov Studies using human HepG2 cells and primary human hepatocytes have shown that this compound can induce cell death in a dose-dependent manner. genesandcancer.com this compound demonstrated a greater ability to induce cell death in cultured HepG2 cells compared to primary human hepatocytes at certain concentrations (10, 25, and 50 µM). genesandcancer.com The mechanisms involved in this compound-induced hepatotoxicity are not fully understood, but intermediate metabolites produced by CYP450 enzymes are suspected to play a role. researchgate.netnih.gov Studies in isolated rat hepatocytes have shown that this compound can lead to cytotoxicity characterized by reduced cell viability, increased reactive oxygen species (ROS) formation and lipid peroxidation, mitochondrial membrane potential collapse, and a reduction in cellular glutathione content. researchgate.netnih.gov Inhibition of CYP3A enzymes has been shown to attenuate the cytotoxicity of this compound in hepatocytes, suggesting that metabolic activation participates in this toxicity. acs.org this compound has also been shown to induce mitophagy that precedes apoptosis in human HepG2 cells. genesandcancer.com

Influence on Brain Biomarker Expression in Astrocytes (e.g., PPARG, CREB1, CACNA1C)

Preclinical research has explored the effects of this compound on the expression of various brain biomarkers in astrocytes, which are crucial glial cells in the central nervous system. Studies using human astrocytes have investigated the impact of this compound on the expression of genes such as PPARG, CREB1, and CACNA1C. Exposure of astrocytes to this compound has been shown to increase the expression of CACNA1C and decrease the expression of PPARG. vcu.eduvcu.edu The effect on CREB1 expression appears to be concentration-dependent, with one study reporting decreased expression at 220 µM and increased expression at 50 µM. vcu.eduvcu.edu These findings suggest that this compound can significantly alter the expression of these genes in astrocytes, which may be relevant to the cognitive effects associated with the drug. vcu.eduvcu.edu Furthermore, studies in hippocampal astrocyte cultures have shown that this compound treatment significantly increased the expression of neurotrophic/growth factors like fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) mRNA. plos.org The effect on FGF-2 expression by this compound in astrocytes appears to be independent of adrenergic receptors. plos.org Research in depression model mice has identified Transcription factor 7 like 2 (TCF7L2) as a gene in hippocampal astrocytes whose expression is decreased in depression models and restored by this compound treatment, suggesting its potential role in astrocyte-mediated antidepressant effects. nih.gov

Models of Depressive-Like Behaviors

Animal models designed to mimic aspects of human depression are commonly used to evaluate the antidepressant-like potential of compounds. Key methodologies include behavioral despair tests such as the Forced Swimming Test (FST) and the Tail Suspension Test (TST). In these tests, reduced immobility time is often interpreted as an antidepressant-like effect. Preclinical studies have shown that administration of this compound can decrease immobility in both FST and TST in rodents nih.govnih.govjsmcentral.org.

Another model used is the Unpredictable Chronic Mild Stress (UCMS) paradigm, where animals are exposed to a series of mild, unpredictable stressors over several weeks, leading to behavioral changes indicative of depressive-like states, such as anhedonia (measured by reduced sucrose preference) and increased immobility in the TST. Chronic treatment with this compound has been shown to prevent or reverse the increased immobility time induced by UCMS in mice jsmcentral.org.

Neuropathic Pain Models (e.g., Chronic Constriction Injury, Diabetic Neuropathy Models)

Preclinical research on this compound in neuropathic pain has frequently employed models like the Chronic Constriction Injury (CCI) and chemically induced diabetic neuropathy models, such as those using streptozotocin (STZ). These models aim to replicate the mechanical and thermal hypersensitivity observed in human neuropathic pain conditions.

Studies using the CCI model in rodents have demonstrated that this compound can produce anti-allodynic effects, reducing sensitivity to non-painful stimuli clinmedjournals.org. While some studies in CCI models have shown that chronic this compound administration can reduce thermal hyperalgesia (increased sensitivity to heat), its effect on mechanical allodynia has yielded mixed results researchgate.netbrieflands.combmj.com.

In STZ-induced diabetic rat models, which mimic painful diabetic peripheral neuropathy, this compound has demonstrated therapeutic effects. Both peripheral and systemic administration of this compound have shown anti-allodynic effects in these models clinmedjournals.org. Similar to CCI models, this compound has been reported to attenuate thermal hyperalgesia in STZ-induced diabetic rats brieflands.com.

Preclinical studies have also explored different routes of administration, including topical application, suggesting its potential utility in treating painful diabetic neuropathy clinmedjournals.org.

Neurobiological Effects and Neuroplasticity Research

Preclinical investigations have explored the impact of this compound on neurobiological processes and neuroplasticity, which are implicated in mood disorders and pain. Antidepressants, including this compound, are understood to influence neuroplasticity by modulating the levels of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mdpi.compreprints.orgnih.gov.

Research indicates that chronic stress, often used in depression models, can decrease neuroprotective factors, negatively impacting neuronal plasticity mdpi.compreprints.org. Antidepressant treatments, including this compound, have been shown in preclinical studies to potentially reverse these effects, promoting neurogenesis (the birth of new neurons), dendritic branching, and synaptogenesis (the formation of new synapses) in brain regions like the hippocampus and prefrontal cortex mdpi.compreprints.org.

Studies investigating the neurobiological effects of this compound have also examined its influence on synaptic proteins. For instance, acute administration of this compound increased hippocampal levels of Growth-Associated Protein 43 (GAP43), a protein involved in synaptic plasticity jsmcentral.org. Chronic this compound treatment in a UCMS model prevented the stress-induced decrease in GAP43 immunostaining in the hippocampal CA3 region jsmcentral.org. Furthermore, studies have shown that this compound treatment can affect levels of phosphorylated heavy neurofilament subunit (NF-H) in the hippocampus, suggesting an influence on cytoskeletal remodeling associated with neuronal structure and plasticity researchgate.net.

This compound has also been shown to increase GDNF production by astroglial cells in a monoamine-independent manner, involving pertussis toxin-sensitive Gαi/o activation nih.gov.

Neuroprotective Properties in Degenerative Disease Models (e.g., Parkinson's Disease)

Preclinical research has explored the potential neuroprotective properties of this compound in models of neurodegenerative diseases, particularly Parkinson's disease (PD). Animal models of PD, such as those induced by 6-hydroxydopamine (6-OHDA) or rotenone, are used to study the degeneration of dopaminergic neurons in the substantia nigra and its impact on motor function.

Studies using the 6-OHDA rat model have investigated the capacity of this compound to protect the dopamine system. Chronic treatment with this compound (5 mg/kg) in lesioned animals resulted in a significant sparing of tyrosine hydroxylase-immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and preserved striatal fibers, which was accompanied by attenuated functional motor deficits researchgate.net. Some evidence suggests this compound may protect against 6-OHDA toxicity and increase BDNF levels scholaris.ca. However, one study using a more severe 6-OHDA model did not find a protective effect michaeljfox.org.

In the rotenone model of PD in rats, pretreatment with this compound prevented rotenone-induced neuronal degeneration, increased striatal dopamine levels, and led to motor recovery nih.gov. These neuroprotective effects were associated with the restoration of striatal monoamines and BDNF levels, as well as a reduction in oxidative damage, microglial activation, and the expression of proinflammatory cytokines nih.gov. These findings suggest that modulation of noradrenaline and serotonin, up-regulation of neurotrophins, and anti-inflammatory/antioxidant activities may contribute to this compound's neuroprotective effects in this model nih.gov.

Preclinical studies in a transgenic mouse model of Multiple System Atrophy (an alpha-synucleinopathy) also indicated that this compound treatment decreased the number of alpha-synuclein-positive cells in the basal ganglia and reduced astrogliosis, suggesting potential anti-inflammatory and alpha-synuclein-reducing properties nih.gov.

Reproductive Toxicity Studies

Preclinical studies have assessed the potential reproductive toxicity of this compound in various animal species. Investigations in mice, rats, and rabbits have examined the effects of oral administration at doses significantly higher than typical human therapeutic doses.

In reproductive studies, teratogenic effects (malformations) were not observed in mice, rats, or rabbits at oral doses of 2-40 mg/kg/day kentpharma.co.ukhpra.ieeuropa.eu. However, literature data suggested a risk for malformations and delays in ossification in mice, hamsters, rats, and rabbits at higher doses, specifically at 9 to 33 times the maximum recommended human dose kentpharma.co.ukhpra.ieeuropa.eu.

A possible association with an effect on fertility in rats, specifically a lower pregnancy rate, has also been observed in preclinical studies kentpharma.co.ukhpra.ieeuropa.eu. The reason for this effect on fertility is not fully understood kentpharma.co.ukhpra.ieeuropa.eu.

Genotoxicity Investigations

The genotoxic potential of this compound has been investigated through various in vitro and in vivo studies, yielding some contradictory results kentpharma.co.ukhpra.ieeuropa.eudrugbank.com.

Some in vivo studies in mice have indicated that this compound can induce chromosomal aberrations in a dose-dependent manner in bone marrow cells and spermatocytes researchgate.net. These studies also reported a decrease in both mitotic and meiotic activity and an increase in the incidence of sperm-cell head and tail abnormalities with increasing doses researchgate.net. These findings suggested that this compound could be a genotoxic agent for both somatic and germ cells in mice researchgate.net.

Conversely, other genotoxicity assays, such as those evaluating wing development in Drosophila melanogaster, suggested that this compound was not genotoxic, unlike some other tricyclic antidepressants psychiatrist.comekb.eg.

Despite some conflicting findings, the possibility of this compound inducing chromosome aberrations cannot be definitively excluded based on the available preclinical data kentpharma.co.ukhpra.ieeuropa.eudrugbank.com.

Table 1: Summary of Selected Preclinical Findings

Modulation of Central and Peripheral Nociceptive Processes

The anti-nociceptive mechanisms of this compound are considered multi-modal and involve actions at both central and peripheral levels. clinmedjournals.orgmdpi.com A well-known mechanism is the inhibition of presynaptic reuptake of serotonin (5-HT) and norepinephrine (NE), increasing their concentrations in the synaptic cleft. clinmedjournals.orgclinmedjournals.org These neurotransmitters are crucial components of the pain modulation system and can enhance the descending inhibitory system for pain, leading to a supraspinal analgesic effect. clinmedjournals.orgclinmedjournals.orgwearesrna.org Research suggests that norepinephrine may play a more significant role in this compound's analgesic properties compared to serotonin, as tricyclic antidepressants generally show better clinical efficacy for chronic pain than selective serotonin reuptake inhibitors (SSRIs). clinmedjournals.orgclinmedjournals.org

Beyond monoamine reuptake inhibition, studies indicate that this compound can interact with ion channels, particularly voltage-gated sodium channels (VGSCs). clinmedjournals.orgclinmedjournals.org VGSCs in small diameter nociceptive nerve fibers in the peripheral nervous system are involved in the generation and conduction of pain signals. clinmedjournals.org Dysregulation of VGSCs can contribute to neuropathic pain. clinmedjournals.org Research using whole-cell patch clamp techniques has shown that this compound can block VGSCs in a use-dependent manner, which may represent a peripheral mechanism contributing to its analgesic effect. clinmedjournals.org this compound may also affect potassium channels, with some studies suggesting their involvement in central antinociception, although the precise mechanisms require further evaluation. clinmedjournals.orgclinmedjournals.orgmdpi.com

Additional interactions include potential effects on adenosine uptake, leading to enhanced stimulation of adenosine receptors, and blocking of N-methyl-D-aspartate (NMDA) receptors. clinmedjournals.orgmdpi.com this compound has also been shown to enhance Ca2+-dependent receptor desensitization and act as an open channel blocker of NMDARs, which may contribute to its efficacy against neuropathic pain. nih.gov Furthermore, preclinical studies suggest a neuro-immunological influence, with TCAs potentially affecting glial cell function and preventing the activation of glial cells and increased cytokine expression in the spinal cord induced by chronic pain states. clinmedjournals.orgclinmedjournals.org

Major Depressive Disorder: Efficacy and Comparative Studies (e.g., second-line status)

This compound was historically a first-line treatment for major depressive disorder and has been used as a benchmark comparator in trials of newer antidepressants. researchgate.netscispace.com A systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs for acute treatment of major depressive disorder found that all antidepressants were more effective than placebo. nih.gov this compound demonstrated one of the higher odds ratios for efficacy compared to placebo (OR 2.13, 95% CrI 1.89-2.41). nih.gov

However, due to its side effects and potential toxicity in overdose, this compound is often considered a second or third-line treatment for depression in current clinical practice. vivli.org Comparative studies have evaluated this compound against newer antidepressants like SSRIs. An open-label, randomized, prospective study comparing this compound and escitalopram in patients with major depression found comparable decreases in mean Hamilton Depression Rating Scale (HDRS) scores for both groups over a four-week period. scispace.com The percentage reduction in mean HDRS score was 58.29% for this compound and 60.78% for escitalopram. scispace.com While this compound has shown strong efficacy in research, its tolerability profile often leads to it being prescribed after other options have been considered. researchgate.netscispace.comnih.gov

Table 1: Efficacy of this compound vs. Placebo in Major Depressive Disorder

*Data compiled from a meta-analysis of randomized controlled trials comparing this compound with placebo for major depressive disorder. researchgate.net

Neuropathic Pain Syndromes: Efficacy in Diabetic Neuropathy and Post-Herpetic Neuralgia

This compound is widely recommended as a first-line treatment for chronic neuropathic pain, including painful diabetic neuropathy (PDN) and post-herpetic neuralgia (PHN). aafp.orgprohealthclinic.co.uknih.gov Research has consistently demonstrated its efficacy in these conditions.

For painful diabetic neuropathy, studies have shown that this compound can lead to significant pain relief. One study involving patients with PDN found that 74% of those treated with this compound experienced moderate to complete pain relief, which was significantly greater than the placebo group, regardless of the presence of depression. mdpi.com

In the case of post-herpetic neuralgia, research has also supported this compound's effectiveness. One study evaluating this compound in patients with PHN identified good to excellent pain relief in a significant proportion of participants, an effect not associated with an antidepressant effect. mdpi.com A Cochrane review on this compound for neuropathic pain in adults, while noting that much of the evidence was considered third-tier due to methodological limitations of older studies, indicated that for two out of seven studies reporting useful efficacy data, this compound was significantly better than placebo. nih.gov

A Cochrane review focusing on antidepressants for neuropathic pain found that tricyclic antidepressants, particularly this compound, are effective for PDN and PHN. aafp.org This review calculated a Number Needed to Treat (NNT) of 2 (95% confidence interval [CI], 1.7 to 2.5) for this compound to achieve at least moderate pain relief when compared with placebo. aafp.org

While topical formulations of this compound have also been explored for neuropathic pain, including PDN and PHN, studies have yielded mixed results. A randomized, placebo-controlled study of topical this compound and ketamine in patients with PDN, PHN, or complex regional pain syndrome type II found no significant differences in pain score changes between the treatment groups and placebo. actaneurologica.com However, other reports suggest that topical tricyclic antidepressants like this compound have demonstrated efficacy in some neuropathic pain states. actaneurologica.com

Table 2: Efficacy of this compound in Neuropathic Pain Syndromes (Selected Findings)

Fibromyalgia: Symptom Modulation and Quality of Life Outcomes

Clinical research has investigated the efficacy of this compound in modulating symptoms and improving quality of life in adults with fibromyalgia. A systematic review of randomized controlled studies published up to July 2020 included 10 studies examining this compound. painpluscpn.caacpjournals.org The review found that this compound was effective for several fibromyalgia treatment outcomes, with benefits ranging from small to large depending on the symptom. painpluscpn.caacpjournals.org

Data from a systematic review comparing this compound to placebo and other treatments for fibromyalgia symptoms are summarized in the table below:

Headache Prophylaxis: Migraine and Chronic Tension Headache Research

This compound has been a mainstay in the prophylactic treatment of headaches, including migraine and chronic tension-type headache (TTH), for several decades. nih.govihs-headache.orgrsdjournal.org Its efficacy in preventing both migraine and chronic TTH has been well-documented in placebo-controlled trials. nih.gov

Studies have found that this compound treatment results in lower scores on headache indices compared to placebo in patients with both migraine and chronic TTH. nih.gov A meta-analysis of controlled studies for TTH showed an average 33% reduction in headache activity with this compound. nih.gov this compound has also shown efficacy in patients experiencing both migraine and TTH. nih.gov

Research indicates that tricyclic antidepressants, including this compound, are effective in preventing migraine and tension-type headaches. bmj.com Patients treated with tricyclics were more likely to experience at least a 50% improvement in their headaches than those taking placebo, with a 40% increased probability for tension-type headaches and an 80% increased probability for migraine headaches. bmj.com A 2019 literature review concluded that among antidepressants commonly prescribed for migraine prevention, this compound has the most supporting evidence for effectiveness. healthline.com

Irritable Bowel Syndrome (IBS): Gut-Brain Axis Modulation and Symptom Improvement

This compound is utilized in the management of Irritable Bowel Syndrome (IBS), a disorder involving the gut-brain axis. healthline.commdpi.comjnmjournal.org Its potential benefits in IBS are thought to be related to regulating the nervous system and influencing serotonin reuptake. healthline.com

A systematic review and meta-analysis found that this compound, compared to placebo, improved treatment response rates and reduced the severity of IBS symptoms. jnmjournal.org It also showed improvement in diarrhea symptoms. jnmjournal.org The findings support the use of this compound for IBS management, particularly in patients with the diarrhea-predominant subtype. jnmjournal.org

The ATLANTIS trial indicated that low-dose this compound effectively alleviated symptoms in patients with IBS in a primary care setting, demonstrating a significant decrease in IBS symptom severity scores over a 6-month period compared to baseline. mdpi.com this compound's efficacy in this trial persisted regardless of the duration of the disease or symptom severity. mdpi.com

Research findings on the efficacy of this compound in IBS are summarized below:

Interstitial Cystitis/Bladder Pain Syndrome: Long-term Efficacy Research

This compound has been investigated for the long-term treatment of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), a chronic condition characterized by pelvic pain, urgency, and frequency. auajournals.orgresearchgate.netnih.gov

A randomized, controlled trial also showed significant improvement in IC symptoms after 4 months of this compound treatment. auajournals.org this compound in the management of IC/BPS has demonstrated efficacy rates ranging from 50% to 66% in controlled and noncontrolled trials. nih.gov Higher efficacy rates, up to 77%, were observed at sustained higher doses (at least 50 mg daily). nih.gov

Data from the long-term open-label study on this compound for IC are presented below:

Other Exploratory Clinical Applications (e.g., Post-COVID Headaches, Vestibular Migraine, Traumatic Brain Injury)

Exploratory clinical research is investigating the potential utility of this compound in other conditions, including post-COVID headaches, vestibular migraine, and headaches following traumatic brain injury (TBI).

Headache is a frequently reported symptom in post-COVID patients, often presenting with features of both tension-type headache and migraine. nih.gov An observational multicentric study provided real-world evidence of the potential benefit of this compound in patients with post-COVID-19 headache. nih.gov The study observed a reduction in the number of headache days during this compound use. nih.gov Prior history of tension-type headache and the absence of concomitant nausea were identified as potential predictors of response to this compound in this population. nih.gov

For vestibular migraine, tricyclic antidepressants, including this compound, are frequently used for treatment, although they can potentially affect cognitive function and cause fatigue, which might exacerbate cognitive dysfunction. frontiersin.org

In the context of headaches after traumatic brain injury (TBI), research is limited. A single-center phase II trial assessed the efficacy of this compound for preventing persistent headache after mild TBI. researchgate.netnih.gov However, this study faced challenges with recruitment and compliance, and was unable to definitively determine whether there is a benefit for this compound use as a headache preventive in this population. researchgate.netnih.gov No differences were found in headache frequency or severity between groups receiving immediate versus delayed initiation of this compound. researchgate.netnih.gov

Metabolic Interactions via Cytochrome P450 Enzymes (Inducers/Inhibitors)

This compound is extensively metabolized in the liver, primarily by cytochrome P450 (CYP) enzymes. rsdjournal.org The CYP450 enzyme system plays a crucial role in drug metabolism, and interactions involving these enzymes can significantly affect drug plasma levels and clinical outcomes. aafp.orgnih.gov Two of the most significant enzymes in drug metabolism are CYP3A4 and CYP2D6, both of which are involved in this compound metabolism. aafp.orgnih.gov

Concomitant use of this compound with drugs that inhibit or induce CYP450 enzymes can lead to altered this compound concentrations. aafp.orghres.cawikidoc.orgnih.gov Inhibitors of CYP450 enzymes can decrease the metabolism of this compound, potentially leading to increased plasma concentrations. aafp.orghres.cawikidoc.orgnih.gov This is particularly relevant for inhibitors of CYP2D6, as this compound is a substrate for this enzyme. nih.govwikidoc.org Examples of drugs that inhibit CYP2D6 include certain other antidepressants (such as selective serotonin reuptake inhibitors like fluoxetine, sertraline, and paroxetine), quinidine, and cimetidine. nih.govwikidoc.orgnih.gov The extent of inhibition can vary among different inhibitors. wikidoc.orgnih.gov

Conversely, inducers of CYP450 enzymes can increase the metabolism of this compound, potentially leading to decreased plasma concentrations. aafp.orghres.ca Dosage adjustments of this compound may be required when co-administered with either inhibitors or inducers of CYP450 enzymes. aafp.orghres.cawikidoc.orgnih.gov Monitoring this compound plasma levels is desirable when co-administering with known inhibitors of CYP2D6. wikidoc.orgnih.gov

Genetic variations (polymorphisms) in CYP enzymes, particularly CYP2D6 and CYP2C19, can also influence the metabolism of this compound and a patient's response to the drug. aafp.orgnih.gov Individuals classified as poor metabolizers for these enzymes may have higher plasma concentrations of this compound when given standard doses. hres.cawikidoc.orgnih.gov

Pharmacodynamic Interactions (e.g., Serotonergic Agents, CNS Depressants, Sympathomimetics)

This compound, a tricyclic antidepressant (TCA), interacts with various drug classes through pharmacodynamic mechanisms, primarily due to its effects on neurotransmitter reuptake and receptor binding.

Serotonergic Agents: Concomitant use of this compound with other serotonergic agents can increase the risk of serotonin syndrome, a potentially life-threatening condition. This compound inhibits the reuptake of serotonin, increasing its concentration in the synaptic cleft drugbank.compatsnap.com. When combined with other medications that also enhance serotonergic activity, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), triptans, and certain opioids like tramadol, the risk of excessive serotonin levels rises droracle.aigoodrx.comscielo.org.co. This interaction is particularly noted with MAOIs, where concomitant use is contraindicated due to the risk of severe convulsions, hyperpyretic crises, and fatalities medsafe.govt.nzmedicinesinformation.co.nzhres.ca.

Research findings indicate that the interaction between this compound and tramadol, both possessing serotonergic action, can inhibit the metabolism of tramadol, potentially contributing to serotonin syndrome scielo.org.coredalyc.org.

CNS Depressants: this compound can enhance the sedative effects of central nervous system (CNS) depressants, including alcohol, barbiturates, benzodiazepines, and other sedatives goodrx.commedsafe.govt.nzmedicinesinformation.co.nznih.gov. This interaction leads to increased sedation and potential impairment of cognitive and psychomotor skills singlecare.comdrugs.com. Studies suggest that coadministration of CNS depressants with this compound can result in additive or synergistic effects, particularly in elderly or debilitated patients drugs.com.

Sympathomimetics: Tricyclic antidepressants like this compound can significantly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine, epinephrine, and phenylephrine medsafe.govt.nzdrugs.comhres.cadrugs.com. The mechanism involves the inhibition of norepinephrine reuptake in adrenergic neurons by TCAs, leading to increased stimulation of adrenergic receptors drugs.comdrugs.com. This can result in hypertension, tachycardia, palpitations, and cardiac dysrhythmias medsafe.govt.nzdrugs.com. Caution is advised when administering this compound with sympathomimetic drugs, including those found in local anesthetics and nasal decongestants hres.camedicines.org.ukhres.ca.

The interaction with sympathomimetics can be complex, as TCAs may either increase or decrease their effects depending on whether the sympathomimetic is direct or indirect-acting drugs.commedscape.com.

Cardiovascular Interactions (e.g., QT-prolonging agents, Sodium Channel Blockers)

This compound has notable effects on the cardiovascular system and can interact with other agents affecting cardiac function.

QT-prolonging Agents: this compound is known to prolong the QTc interval, which can increase the risk of ventricular arrhythmias, including torsade de pointes singlecare.comnih.govdergipark.org.trnih.gov. This effect is primarily attributed to this compound's ability to inhibit ion channels essential for cardiac repolarization, such as hERG channels drugbank.comnih.govnih.gov. Concomitant use with other medications that prolong the QT interval can result in additive effects, further increasing the risk of arrhythmias singlecare.comdrugs.com. Examples of such agents include antiarrhythmics (e.g., amiodarone, quinidine, sotalol, procainamide, disopyramide, ibutilide), antipsychotics, and some antibiotics singlecare.comhres.camedscape.com.

Research indicates a significant correlation between QTc interval and serum concentration of this compound, although this correlation can depend on the method of frequency correction used thieme-connect.com.

Sodium Channel Blockers: this compound itself exhibits sodium channel blocking properties patsnap.comnih.gov. This action can reduce neuronal excitability and contribute to its therapeutic effects, particularly in neuropathic pain patsnap.com. However, this property also plays a role in its cardiac effects, contributing to QRS widening and the risk of arrhythmias, especially in overdose dergipark.org.trnih.gov. While this compound is a sodium channel blocker, specific research detailing interactions with other therapeutic sodium channel blockers within the provided search results is limited. However, the additive effects on cardiac conduction from multiple agents with similar mechanisms would be a theoretical concern.

Effects on Seizure Threshold with Co-administered Medications

This compound can lower the seizure threshold drugbank.comhres.canih.govhres.ca. This effect necessitates caution in patients with a history of seizure disorders hres.canih.gov. The mechanism by which this compound lowers the seizure threshold is not fully elucidated, but it is suggested to be related to its effects on neurotransmitter levels and alterations in EEG patterns drugbank.comhres.ca.

Anticholinergic Syndrome: Underlying Receptor Mechanisms

This compound possesses potent anticholinergic properties due to its antagonistic action at muscarinic acetylcholine receptors patsnap.comhres.canih.govnih.gov. This receptor blockade underlies the constellation of symptoms characteristic of anticholinergic syndrome.

The peripheral manifestations of anticholinergic effects result from the inhibition of acetylcholine's action at muscarinic receptors in various tissues. These include dry mouth (decreased salivary secretion), blurred vision (cycloplegia and mydriasis), constipation (decreased gastrointestinal motility), and urinary retention (decreased bladder detrusor muscle contraction) patsnap.comhres.canih.govnih.gov. Tachycardia can also occur due to blockade of muscarinic receptors in the heart hres.canih.govnih.gov.

Central anticholinergic effects arise from muscarinic receptor blockade in the brain and can lead to cognitive impairment, confusion, delirium, and sedation hres.canih.govnih.gov. Research suggests that chronic treatment with this compound can even lead to supersensitivity of central muscarinic cholinergic mechanisms upon withdrawal capes.gov.br.

Cardiovascular Complications: QTc Prolongation, Arrhythmogenesis, Orthostatic Hypotension

This compound's cardiovascular complications stem from its effects on ion channels and adrenergic receptors.

QTc Prolongation and Arrhythmogenesis: this compound can prolong the QTc interval by blocking ion channels involved in cardiac repolarization, particularly hERG potassium channels drugbank.comnih.govnih.gov. This delay in repolarization increases the risk of early afterdepolarizations, which can trigger polymorphic ventricular tachycardia, such as torsade de pointes nih.gov. This compound also has quinidine-like effects on the heart, indicating effects on sodium channels which contribute to widened QRS complexes and conduction abnormalities drugbank.comhres.cadergipark.org.tr. These effects are thought to be dose-dependent, with higher concentrations increasing the risk of serious arrhythmias medicinesinformation.co.nzdergipark.org.tr.

Orthostatic Hypotension: Orthostatic hypotension, a sudden drop in blood pressure upon standing, is a common cardiovascular adverse effect of this compound nih.govdroracle.aifrontiersin.org. This is primarily mediated by its antagonistic activity at alpha-1 adrenergic receptors patsnap.comnih.govdroracle.aifrontiersin.org. Blockade of these receptors in blood vessels impairs the normal vasoconstriction response necessary to maintain blood pressure when changing position droracle.aifrontiersin.org. This leads to peripheral vasodilation and pooling of blood in the lower extremities, resulting in decreased venous return and a drop in blood pressure droracle.ai. This effect is particularly relevant in elderly patients nih.govdroracle.ai.

Central Nervous System Effects: Sedation, Cognitive Changes, Seizures

This compound's influence on various neurotransmitter systems contributes to its CNS adverse effects.

Sedation: Sedation is a frequent adverse effect of this compound, largely attributed to its potent antagonistic action at histamine H1 receptors patsnap.comnih.govnih.gov. This blockade of histamine receptors in the brain promotes drowsiness and sedation patsnap.comvin.com.

Cognitive Changes: Cognitive impairments and confusion can occur due to this compound's anticholinergic effects in the central nervous system, as discussed in Section 5.4.1 hres.canih.govnih.gov.

Seizures: As mentioned in Section 5.3.4, this compound lowers the seizure threshold drugbank.comhres.canih.govhres.ca. The exact mechanism is not fully understood but is thought to involve alterations in neurotransmitter balance and neuronal excitability drugbank.comhres.cascielo.org.mx. This effect can manifest as seizures, particularly in individuals predisposed to them or when combined with other proconvulsant agents medsafe.govt.nzhres.canih.gov.

Hepatic Injury Mechanisms: Role of Metabolites and Oxidative Stress

This compound-induced hepatotoxicity is a rare but potentially severe adverse effect. The exact mechanisms underlying this liver injury are not yet completely understood, but research suggests a significant role for its metabolism and the resulting oxidative stress. This compound undergoes extensive hepatic metabolism, primarily via cytochrome P450 (CYP) enzymes, particularly CYP2C19 and CYP2D6, though other enzymes like CYP1A2 and CYP2C9 are also involved drugbank.comwikipedia.orginchem.org. This metabolism can lead to the formation of reactive metabolites, including arene oxide intermediates, which are hypothesized to contribute to cellular damage researchgate.netresearchgate.net.

Studies in isolated rat hepatocytes have shown that this compound can induce cytotoxicity characterized by reduced cell viability, increased reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential collapse, and a reduction in cellular glutathione content researchgate.netscispace.com. These findings confirm the involvement of oxidative stress in this compound-induced hepatotoxicity researchgate.netscispace.com. The accumulation of aren oxide metabolites is assumed to be a responsible mechanism for the cellular damage researchgate.net. Mitochondrial dysfunction, often induced by reactive metabolites, contributes to increased ROS formation and oxidative damage in liver cells mdpi.com.

Research using human HepG2 cells demonstrated that this compound induces mitochondrial dysfunction and oxidative stress, specifically inhibiting mitochondrial complex III activity, leading to decreased mitochondrial membrane potential and increased ROS production nih.govgenesandcancer.com. This toxicity involves early mitophagy activation, a process where damaged mitochondria are selectively degraded, which precedes apoptosis (programmed cell death) nih.govgenesandcancer.com. While mitophagy initially appears to be an adaptive survival mechanism, persistent mitochondrial damage can lead to extensive and lethal mitophagy, eventually causing cell death nih.govgenesandcancer.com.

Table 1: Proposed Mechanisms in this compound-Induced Hepatic Injury

Metabolic and Endocrine Effects (e.g., Glucose Levels)

This compound has been associated with various metabolic and endocrine effects, including potential impacts on glucose levels. While some reports suggest that this compound can cause increased glucose levels, the effects on glucose metabolism appear to be inconsistent drugbank.comnih.gov.

Some studies suggest a potential benefit of this compound on blood sugar regulation, with findings indicating lower fasting glucose levels and improved insulin sensitivity in individuals with type 2 diabetes in some instances src.gov.sc. However, other research indicates that the effects on glucose metabolism are inconclusive nih.gov. Animal studies in rabbits have shown that this compound can produce significant hyperglycemia, potentially due to the blockade of the uptake of monoaminergic transmitters . It also appeared to cause glucose intolerance in the early hours, possibly by interfering with gastrin function .

Long-term use of tricyclic antidepressants, including this compound, has been associated with weight gain nih.gov. This weight gain can potentially lead to insulin resistance and poor diabetes control nih.gov.

Regarding endocrine effects beyond glucose, studies have investigated the impact of this compound on hormone levels. A study in healthy participants found that a single dose of this compound led to a significant reduction in morning serum ghrelin and cortisol levels, with no observed effects on leptin and prolactin levels d-nb.infonih.gov. Chronic treatment in rats with this compound has been shown to attenuate the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, resulting in decreased basal and stress-induced plasma ACTH and corticosterone levels oup.com.

Table 2: Observed Metabolic and Endocrine Effects of this compound

Bone Health and Hematological System Effects

Research suggests a potential link between tricyclic antidepressants, including this compound, and effects on bone health and the hematological system.

Regarding bone health, some studies indicate that tricyclic antidepressants may increase the risk of bone fractures goodrx.com. While the exact reason is not fully understood, some experts hypothesize that common side effects like dizziness and drowsiness could lead to an increased risk of falls, subsequently causing fractures goodrx.com. Observational studies suggest a complex relationship between depression, antidepressants, and fracture risk nih.gov. Current use of tricyclics has been linked to an increased fracture risk compared to non-users, even after accounting for potential confounding factors nih.gov. However, one study specifically looking at bone mineral density in older men and women found that while SSRIs were associated with lower bone mineral density and a higher rate of yearly bone loss, tricyclic antidepressants were not associated with increased bone loss in these populations sciencedaily.com. Animal studies investigating the effects of systemic this compound administration on alveolar bone remodeling in dogs showed a decrease in bone formation rate, although this reduction was not statistically significant biomedpharmajournal.org.

In terms of hematological effects, rare cases of bone marrow depression, including agranulocytosis, leukopenia, eosinophilia, purpura, and thrombocytopenia, have been reported with tricyclic antidepressants drugs.comrxlist.comhres.ca. Studies have investigated the association between this compound and blood disorders, with findings suggesting a low risk of such issues nih.gov. One study following a large cohort of patients prescribed this compound found no cases of aplastic anaemia, agranulocytosis, or leucopenia severe enough to endanger life, with only a small number of cases where a causal association was likely nih.gov. The incidence of leucopenia, if caused by this compound, is estimated to be in the range of 1 in 10,000 to 1 in 100,000 patients nih.gov. Animal studies in rats treated with this compound showed an insignificant decrease in platelets, white blood cells, and red blood cells researchgate.net.

Table 3: Effects on Bone Health and Hematological System

Psychiatric Manifestations (e.g., Mania Induction)

This compound, like other antidepressants, has the potential to induce psychiatric manifestations, particularly the induction of mania or hypomania in susceptible individuals. This phenomenon, often referred to as "affective switching," is a known concern, especially in patients with underlying bipolar disorder nih.govhims.comclevelandclinic.orgpsychcentral.com.

Studies have shown that antidepressants can increase the chances of a manic or hypomanic episode in individuals being treated for depression, including those with previously undiagnosed bipolar disorder psychcentral.com. While not everyone taking antidepressants will experience mania, the risk is particularly relevant in the context of bipolar disorder psychcentral.com.

Retrospective studies analyzing mood conversions in bipolar inpatients treated with antidepressants have indicated that the risk of switching to mania or hypomania is higher with tricyclic antidepressants compared to non-TCA drugs nih.gov. Within the tricyclic class, this compound has been specifically associated with a higher percentage of mood conversions nih.govpsychiatrist.com. One study reported that the risk of switching was highest with this compound (42% of treated episodes) among the tricyclics studied nih.gov. It has been hypothesized that the anticholinergic activity of TCAs, including this compound, may contribute to this higher frequency of mood conversions nih.govpsychiatrist.com.

Current treatment guidelines for bipolar depression often reflect the consensus that antidepressant treatment can induce mania and generally discourage antidepressant monotherapy in bipolar I disorder to minimize this risk, recommending concurrent use with a mood stabilizer webmd.compsychiatryonline.org. Risk factors for this compound-induced mania include a history of bipolar disorder, a family history of mania, and pharmacologically induced hypomania nih.gov.

Table 4: Mania Induction Risk with this compound

Cognitive Effects and Potential Neurodegenerative Associations

The long-term cognitive effects of this compound and its potential association with neurodegenerative conditions, such as dementia, have been a subject of research. This compound possesses anticholinergic properties, which are known to potentially impact cognitive function, particularly in older adults efda.gov.etmdpi.com.

Studies have investigated the link between antidepressant use, including tricyclic antidepressants like this compound, and the risk of dementia. Some research suggests that antidepressants classified as "potentially inappropriate" for use in the elderly, such as this compound, may be associated with a long-term increase in dementia risk explorationpub.com. Large studies have indicated that certain anticholinergic drugs, including antidepressants like this compound, have been linked to a higher likelihood of developing dementia, even when used years beforehand mdpi.commedicalnewstoday.comalzheimers.org.uk. The risk of dementia has been shown to be directly proportional to the dosage of anticholinergics used mdpi.com.

Meta-analytic reviews have concluded that antidepressant use, particularly TCAs, may be associated with an increased risk of subsequent cognitive impairment or dementia explorationpub.com. The risk of dementia appeared slightly greater with TCAs compared to SSRIs explorationpub.com. Anticholinergic drugs may not only hinder cognitive function by reducing acetylcholine neurotransmission but could also potentially accelerate neurodegeneration by inhibiting an acetylcholine-dependent anti-inflammatory system mdpi.com.

However, other long-term observational studies have produced conflicting results regarding the association between antidepressant use and dementia risk or accelerated cognitive decline explorationpub.comnih.gov. Some studies have not found a consistent association between antidepressant use and long-term dementia risk, accelerated cognitive decline, or brain atrophy in cognitively healthy populations nih.gov.

Table 5: Long-term Cognitive Effects and Neurodegenerative Associations

Cardiac Toxicity: Sodium Channel Blockade, Myocardial Depression, Arrhythmias

Cardiovascular toxicity is a major concern in this compound overdose and a leading cause of fatality. The principal mechanism involves the blockade of fast cardiac sodium (Na+) channels. ekb.egmedbullets.comresearchgate.netlitfl.com This blockade is similar to that of Type IA antiarrhythmics and leads to a slowing of depolarization in cardiac action potentials, delaying propagation through myocardial and conducting tissues. medbullets.comanatoljcardiol.com This effect is often described as a quinidine-like effect. inchem.org

The consequence of sodium channel blockade is evident on the electrocardiogram (ECG), presenting as prolongation of the PR, QRS, and QT intervals. medbullets.comresearchgate.net A QRS duration greater than 100 ms is associated with an increased incidence of serious toxicity, including arrhythmias. nih.govrch.org.au A QRS duration exceeding 160 ms is particularly linked to ventricular arrhythmias. rch.org.au Furthermore, a rightward axis deviation of the terminal 40 ms vector of the QRS complex in the frontal plane and a terminal R wave in aVR with an R/S ratio greater than or equal to 0.7 are also sensitive indicators of potential seizures and dysrhythmias. medbullets.comnih.gov

Beyond sodium channel effects, this compound also influences potassium channels, although its capacity to block fast sodium channels is considered the primary mechanism for QRS prolongation. anatoljcardiol.com Hypotension, another critical cardiovascular effect, results from a combination of reduced myocardial contractility and decreased systemic vascular resistance. medbullets.comd-nb.info The latter is attributed to alpha-1 adrenergic receptor blockade. medbullets.cominchem.orgnih.govucsf.edu Sinus tachycardia is a common arrhythmia observed, often due to anticholinergic activity and the inhibition of norepinephrine uptake, while more severe supraventricular and ventricular arrhythmias, including ventricular tachycardia and fibrillation, can occur. medbullets.cominchem.orgd-nb.info Myocardial depression, a direct toxic effect on heart muscle function, further contributes to hemodynamic instability. litfl.cominchem.orgd-nb.infoucsf.edu

Central Nervous System Toxicity: Seizures, Altered Consciousness

Central nervous system (CNS) toxicity is another prominent feature of acute this compound poisoning. Altered mental status, ranging from drowsiness and confusion to delirium, coma, and seizures, is a primary manifestation. inchem.orgnih.govucsf.edu Lethargy and alterations in consciousness are common consequences. nih.gov These effects are thought to be due in part to the drug's antihistamine and anticholinergic properties. nih.gov

Seizures occur in a significant percentage of patients with this compound overdose. inchem.org The mechanism underlying seizures is believed to involve the antagonism of GABA-A receptors in the brain. litfl.comnih.govnih.govwikitox.org Acidosis can exacerbate CNS toxicity by increasing the formation of the ionized form of TCAs, which potentiates sodium channel blockade in the CNS. nih.govwikitox.org The level of consciousness at presentation is considered a sensitive clinical indicator of potential complications, including seizures and arrhythmias. medbullets.comnih.govucsf.eduwikitox.org

Hepatotoxicity: Role of Metabolites, Oxidative Stress, Mitochondrial Dysfunction

While less immediately apparent than cardiac or CNS effects in acute overdose, research indicates that this compound can induce hepatotoxicity, involving the role of metabolites, oxidative stress, and mitochondrial dysfunction. Although clinically apparent liver toxicity is rare, liver test abnormalities can occur. wikipedia.org

Studies have shown that this compound can induce oxidative stress in liver cells, characterized by increased reactive oxygen species (ROS) production and lipid peroxidation. nih.govresearchgate.netmdpi.comscience.gov This oxidative damage can contribute to mitochondrial dysfunction. nih.govresearchgate.netmdpi.comscience.govfrontiersin.org this compound has been shown to induce mitochondrial dysfunction in various cell types, including human HepG2 hepatocellular carcinoma cells and primary human fibroblasts. nih.govresearchgate.netscience.govfrontiersin.org This dysfunction can manifest as reduced mitochondrial content, altered protein expression, increased mitochondrial membrane permeability transition, and decreased mitochondrial membrane potential. nih.govscience.govfrontiersin.org

The metabolism of this compound in the liver can produce reactive metabolites. wikipedia.orgmdpi.com These metabolites can contribute to hepatotoxicity by forming adducts with proteins and inducing oxidative damage. mdpi.comfrontiersin.org Specifically, this compound has been shown to inhibit mitochondrial complex III activity, which is associated with decreased mitochondrial membrane potential and increased ROS production. nih.gov This mitochondrial dysfunction can trigger mitophagy, a process of selective degradation of damaged mitochondria. nih.govresearchgate.net While initially a protective mechanism, persistent mitochondrial damage can lead to extensive mitophagy, autophagy stress, and ultimately cell death by apoptosis. nih.govresearchgate.net

Furthermore, some research suggests that this compound, by inhibiting acidic sphingomyelinase, might sensitize the liver to toxicity from other substances, such as acetaminophen, by causing lysosomal cholesterol accumulation. frontiersin.org

High-Performance Liquid Chromatography (HPLC)

HPLC is a widely used technique for the determination of this compound due to its versatility, sensitivity, and ability to handle complex samples. Reversed-phase HPLC, typically employing C18 columns, is a common approach for this compound analysis.

HPLC methods have been developed and validated for the quantification of this compound in both pharmaceutical formulations and biological matrices such as plasma and urine. For instance, a reversed-phase HPLC method for the simultaneous estimation of this compound hydrochloride and chlordiazepoxide in tablets utilized a mobile phase of methanol:acetonitrile:0.065 M ammonium acetate buffer (50:20:30, v/v/v) with the pH adjusted to 5.5, and UV detection at 240 nm. This method showed linearity in the range of 0.25-4 μg/ml for this compound hydrochloride. nih.gov Another RP-HPLC method for this compound hydrochloride in tablets and urine used a C18 column with a mobile phase of acetonitrile and water (50% v/v) adjusted to pH 5 with phosphoric acid, and UV detection at 254 nm. ajrconline.orgresearchgate.net This method demonstrated linearity in the range of 0.5-3 µg/mL. ajrconline.orgresearchgate.net

HPLC methods coupled with UV detection are frequently used for their simplicity and cost-effectiveness. scribd.com However, for increased sensitivity and specificity, especially in biological samples, HPLC is often coupled with mass spectrometry. nih.gov

Table 1 summarizes representative HPLC methods for this compound analysis.

Table 1: Representative HPLC Methods for this compound Analysis