galanthamine

Botanical Origins of this compound Alkaloids

This compound is predominantly found in plants belonging to the Amaryllidaceae family. Notable sources include various species of Galanthus (snowdrops), Narcissus (daffodils), and Leucojum aestivum (snowflake) wikipedia.orgnih.govrroij.comnih.gov. The alkaloid is extracted from the bulbs and flowers of these plants, although the concentration can be relatively low, typically less than 2% by dry weight wikipedia.orgchim.itwikipedia.org. Other genera within the Amaryllidaceae family, such as Lycoris and Hippeastrum, also contain this compound wikipedia.orgnih.govrroij.commdpi.com. The genus Lycoris, particularly Lycoris radiata, is used for commercial production of this compound in some regions rroij.comnih.gov. Wild Argentinian Amaryllidaceae species, including Zephyranthes filifolia, have also been identified as sources of this compound mdpi.com.

Table 1: Botanical Sources of this compound

Enzymatic Pathways in this compound Biosynthesis

The biosynthesis of this compound in Amaryllidaceae plants is a fascinating example of natural product synthesis, starting from common amino acid precursors, phenylalanine and tyrosine chim.itmdpi.comfrontiersin.orgfrontiersin.orggoogle.com. The pathway involves a series of enzymatic steps. Tyrosine is decarboxylated by tyrosine decarboxylase to produce tyramine chim.itgoogle.com. Phenylalanine contributes to the catechol portion of norbelladine google.com. Tyramine then condenses with a phenylalanine-derived aldehyde to form a Schiff base, which is subsequently reduced to norbelladine chim.itgoogle.com.

A crucial step in the biosynthesis is the oxidative phenol coupling of 4'-O-methylnorbelladine, a precursor obtained after methylation of norbelladine chim.itfrontiersin.orgrsc.org. This oxidative coupling reaction proceeds in a para-ortho fashion and is likely catalyzed by cytochrome P-450 dependent enzymes, such as NtCYP96T6 chim.itfrontiersin.orgfrontiersin.org. This coupling forms a highly reactive dienone intermediate, which undergoes intramolecular 1,4-addition of a phenolic hydroxyl group onto the enone moiety, leading to the formation of the benzofuran ring system chim.it. Subsequent reduction of a carbonyl group and final N-methylation complete the biosynthesis of this compound chim.it.

Key intermediates and enzymatic steps in the proposed biosynthetic pathway include:

Tyrosine decarboxylase (TyDC) converting tyrosine to tyramine frontiersin.orggoogle.com.

Condensation of tyramine with a phenylalanine-derived unit to form norbelladine chim.itgoogle.com.

Methylation of norbelladine to 4'-O-methylnorbelladine, potentially catalyzed by norbelladine 4'-O-methyltransferase (N4OMT) chim.itgoogle.com.

Oxidative para-ortho phenol coupling of 4'-O-methylnorbelladine catalyzed by cytochrome P450 enzymes (e.g., NtCYP96T6) to form the this compound skeleton (specifically, N-demethylnarwedine) chim.itfrontiersin.orgfrontiersin.orgrsc.org.

Reduction of the keto group and N-methylation catalyzed by enzymes such as NtAKR1 and NtNMT1, respectively, to yield this compound frontiersin.orgfrontiersin.orgrsc.org.

Figure 1 illustrates a schematic representation of the proposed biosynthetic pathway for this compound. frontiersin.orgfrontiersin.org

Table 2: Key Enzymatic Steps in this compound Biosynthesis

Retrosynthetic Approaches to this compound Core Structure

Various retrosynthetic strategies have been developed to access the this compound core structure. Many approaches converge on the formation of the key tetracyclic system, often involving the construction of the characteristic benzofuran and azepane rings.

A common retrosynthetic theme involves the oxidative phenol coupling as a key step to form the central C-C bond and the quaternary center, often from a norbelladine-type precursor chim.itwikipedia.orgrsc.orgrsc.org. This biomimetic approach, inspired by the natural biosynthesis, was first explored by Barton and co-workers chim.itrsc.org. The oxidative coupling of a diaryl ether precursor leads to a spirodienone intermediate (narwedine), which is then transformed into this compound wikipedia.orgrsc.org.

Other strategies have explored alternative ways to construct the tetracyclic core. Some approaches involve the formation of the azepane ring at a later stage bc.edu. Transition metal-catalyzed reactions, such as intramolecular Heck reactions, have been employed to build the quaternary center and the cyclic system rsc.orgsoton.ac.uk. Ring-closing metathesis (RCM) has also been utilized in the construction of the C ring rsc.org.

Electrochemical methods have emerged as a sustainable alternative for the key oxidative coupling step in some retrosynthetic plans rsc.orgrsc.orgcardiff.ac.uk. These methods aim to achieve the crucial aryl-phenol coupling electrochemically rsc.orgcardiff.ac.uk.

Table 3: Key Retrosynthetic Strategies

Stereoselective Synthesis of this compound Enantiomers

This compound is a chiral molecule, and its biological activity is associated with the (-)-enantiomer rsc.orgrsc.org. Achieving stereoselectivity in total synthesis is therefore crucial. Various methods have been employed to control the stereochemistry, particularly at the quaternary carbon center and the hydroxyl-bearing carbon.

One approach to obtaining enantiomerically pure this compound has been the resolution of racemic intermediates, such as narwedine wikipedia.orgrsc.orgrsc.orgx-mol.com. Racemic narwedine can be resolved through crystallization-induced dynamic chiral resolution using a chiral mediator wikipedia.orgrsc.org. This method has been utilized in industrial production wikipedia.orgrsc.org.

Asymmetric synthesis strategies have also been developed to directly construct the chiral centers with high enantioselectivity. These methods include:

Chiral pool synthesis, starting from enantiomerically pure precursors like L-tyrosine wikipedia.org.

Asymmetric induction using chiral reagents or catalysts in key steps, such as asymmetric ketone reduction wikipedia.orgrsc.org.

Asymmetric catalysis with chiral transition metal complexes or organocatalysts rsc.org.

Diastereoselective reactions where existing stereocenters in an intermediate influence the formation of new ones wikipedia.orgx-mol.com. For example, complementary reducing agents like Luche reduction and L-selectride reduction can lead to different diastereomers from a cyclic enone system x-mol.com.

Table 4: Methods for Achieving Stereoselectivity in this compound Synthesis

Kinetics of Acetylcholinesterase Binding by this compound

This compound is described as a competitive and reversible inhibitor of AChE. drugbank.com Early analyses using conventional steady-state models suggested a competitive inhibition pattern. researchgate.net However, more recent studies employing pre-steady-state analysis of reaction progress curves have indicated that this compound exhibits time-dependent inhibition, suggesting a more complex interaction than simple competitive binding. windows.net This time-dependent nature implies a long drug-target residence time, which was previously overlooked by conventional kinetic analyses and led to an underestimation of this compound's potency against AChE. windows.net Studies on human AChE have reported varying Ki values, with some indicating a competitive nature and others suggesting a mixed-type inhibition depending on the source of the enzyme (e.g., recombinant human AChE vs. Torpedo californica AChE). windows.net

Structural Basis of this compound-Acetylcholinesterase Interaction

The structural interaction between this compound and AChE has been elucidated through X-ray crystallography, notably with Torpedo californica acetylcholinesterase (TcAChE). nih.govrcsb.org this compound binds within the active site gorge of AChE. nih.govrcsb.org This gorge is approximately 20 Å deep and contains the catalytic machinery and binding subsites. researchgate.net this compound interacts with both the choline-binding site, involving residues like Trp-84, and the acyl-binding pocket, which includes residues such as Phe-288 and Phe-290. nih.gov

Interestingly, the tertiary amine group of this compound does not directly interact closely with Trp-84. nih.govrcsb.org Instead, the double bond of its cyclohexene ring is involved in stacking interactions with the indole ring of Trp-84. nih.gov The tertiary amine appears to form a non-conventional hydrogen bond with Asp-72, located near the top of the gorge. nih.gov A strong hydrogen bond is also formed between the hydroxyl group of this compound and Glu-199. nih.gov The rigid structure of this compound contributes to a low entropy cost upon binding, which, coupled with these moderate to weak interactions, contributes to its relatively tight binding to AChE. nih.gov Molecular docking studies have supported the observed binding orientation within the active site. rcsb.orgresearchgate.net

Subtype Specificity of nAChR Modulation by this compound

This compound has demonstrated allosteric potentiation on several neuronal nAChR subtypes. Studies using heterologous expression systems and patch-clamp recordings have shown this compound to be a potent APL for human α3β4, α4β2, and α6β4 nAChRs. wikipedia.orgresearchgate.net It also potentiates the activity of chicken/mouse chimeric α7/5-HT3 receptors. wikipedia.orgresearchgate.net The α4β2 and α7 subtypes are particularly abundant in the central nervous system and are implicated in cognitive function. mdpi.comnih.gov

While this compound potentiates agonist responses in a concentration-dependent manner, this effect is typically observed within a specific concentration window (e.g., 0.1-1 µM), with higher concentrations potentially leading to inhibition. researchgate.net This bell-shaped dose-response is characteristic of some positive allosteric modulators. researchgate.netmdpi.com Some studies, however, have reported no potentiation or even inhibitory effects of this compound on certain nAChR subtypes or under specific experimental conditions. scielo.br It is important to note that this compound selectively modulates nAChRs and does not significantly alter the activity of muscarinic acetylcholine receptors (mAChRs) at therapeutically relevant concentrations. researchgate.netfrontiersin.org

Impact on Receptor Function and Signaling Cascades

This compound's allosteric potentiation of nAChRs leads to several functional consequences. By binding to an allosteric site, this compound increases the probability of channel opening in response to acetylcholine and slows down receptor desensitization. This results in enhanced ion flux through the receptor channel.

The activation and potentiation of nAChRs by this compound can trigger downstream signaling cascades. For instance, nAChR activation, particularly of the α7 subtype, can lead to calcium influx into neurons and other cells. researchgate.netnih.gov This increase in intracellular calcium can then activate various signaling pathways. Research has shown that this compound-mediated potentiation of nAChRs can lead to the phosphorylation of Akt, a key effector of the phosphatidylinositol 3-kinase (PI3K) pathway. researchgate.net This α7 nAChR-PI3K-Akt pathway has been implicated in the neuroprotective effects of this compound. researchgate.net Furthermore, this compound-enhanced nAChR activity can modulate the release of neurotransmitters, including acetylcholine, glutamate, and serotonin, influencing synaptic plasticity and neuronal communication. drugbank.compnas.orgresearchgate.net In microglia, this compound-sensitized α7 nAChRs can induce calcium influx, leading to intracellular signaling cascades that stimulate processes like amyloid-β phagocytosis through actin reorganization. nih.gov

Anti-inflammatory Effects in Neural Systems

Neuroinflammation is a significant factor in the pathogenesis of various neurological disorders. Research indicates that galantamine exhibits anti-inflammatory properties within neural systems. Studies have shown that galantamine can prevent the activation of microglia and astrocytes, key cellular mediators of neuroinflammation, in the hippocampus nih.govfrontiersin.orgresearchgate.net. This effect is associated with the inhibition of inflammatory signaling molecules, such as NF-κB p65, and a reduction in the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 nih.govfrontiersin.orgresearchgate.net. The cholinergic anti-inflammatory pathway, mediated by the binding of acetylcholine to α7 nicotinic receptors, is believed to play a role in this process, as it suppresses NF-κB activation and inhibits pro-inflammatory cytokine production jddtonline.infonih.gov. Galantamine, by increasing acetylcholine levels through AChE inhibition and allosterically modulating nAChRs, can activate this pathway jddtonline.infonih.gov. In vitro studies using microglia and hippocampal neuronal cell lines have further demonstrated galantamine's ability to reduce inflammatory responses nih.gov.

Antioxidant Properties and Oxidative Stress Mitigation

Oxidative stress, resulting from an imbalance between reactive oxygen/nitrogen species (ROS/RNS) and the body's antioxidant defenses, contributes to neuronal damage in neurodegenerative diseases arphahub.com. Galantamine has been shown to possess antioxidant properties and mitigate oxidative stress in neural systems eurekaselect.comnih.goveuropeanreview.org. It can act as a scavenger of reactive oxygen species, thereby lowering oxidative neuronal damage eurekaselect.comarphahub.com. Studies using in vitro models of hydrogen peroxide-induced oxidative stress in neuronal cells have shown that galantamine can reduce the release of ROS and prevent the loss of mitochondrial activity nih.gov. Furthermore, galantamine has been observed to prevent oxidative stress induced by amyloid-beta peptide in cortical neurons nih.gov. This includes preventing the increase in reactive oxygen species and lipoperoxidation caused by amyloid-beta and preventing alterations in the glutathione (GSH) antioxidant system nih.gov. The antioxidant effects of galantamine may be linked to its ability to prevent the activation of P2X7 receptors, protect mitochondrial membrane potential, and prevent membrane fluidity disturbances eurekaselect.com. Additionally, the increase in acetylcholine levels due to AChE inhibition and allosteric potentiation of α7 nAChRs by galantamine can lead to a decrease in the overproduction of reactive oxygen species eurekaselect.com.

Modulation of Apoptotic Pathways

Apoptosis, or programmed cell death, is another critical process involved in neurodegeneration. Galantamine has demonstrated the ability to modulate apoptotic pathways, offering neuroprotective effects researchgate.neteuropeanreview.org. Research indicates that galantamine can prevent apoptosis induced by various cytotoxic agents, including amyloid-beta peptide and thapsigargin eurekaselect.comresearchgate.net. This protective effect may involve the activation of nicotinic acetylcholine receptors and the upregulation of anti-apoptotic proteins such as Bcl-2 eurekaselect.comresearchgate.net. Studies have shown that galantamine treatment can increase the expression of Bcl-2 in neuronal cells researchgate.net. The allosteric potentiation of α7 nAChRs by galantamine is thought to contribute to this by inducing the phosphorylation of serine-threonine protein kinase, stimulating phosphoinositide 3-kinase, and elevating Bcl-2 expression eurekaselect.com. Furthermore, galantamine has been found to inhibit amyloid-beta-induced apoptosis by activating the JNK signaling pathway, enhancing α7 nAChR expression, and inhibiting the Akt pathway, which promotes autophagosome biogenesis and autophagy nih.gov.

Effects on Cholinergic Neurotransmission Beyond Acetylcholinesterase

While galantamine is known for inhibiting AChE, thereby increasing acetylcholine concentration in the synaptic cleft, it also has significant effects on cholinergic neurotransmission through its interaction with nicotinic acetylcholine receptors (nAChRs) nih.govdrugbank.compatsnap.com. Galantamine acts as a positive allosteric modulator of certain nAChR subtypes, including α4β2 and α7 receptors drugbank.comnih.govwikipedia.org. By binding to an allosteric site distinct from the acetylcholine binding site, galantamine enhances the sensitivity of these receptors to acetylcholine, leading to increased cholinergic signaling drugbank.compatsnap.comnih.gov. This allosteric modulation facilitates the release of acetylcholine from presynaptic neurons, further contributing to increased cholinergic tone nih.gov. This dual mechanism of action – AChE inhibition and nAChR modulation – is considered clinically significant nih.govnih.gov.

Interactions with Other Neurotransmitter Systems

Galantamine's allosteric modulation of nicotinic receptors can influence the release of neurotransmitters other than acetylcholine nih.govresearchgate.net. Nicotinic acetylcholine receptors are located on presynaptic neurons and regulate the release of various neurotransmitters, including dopamine, glutamate, norepinephrine, and serotonin nih.gov. By modulating these receptors, galantamine can indirectly affect the activity of these neurotransmitter systems nih.govresearchgate.net. Studies suggest that galantamine can enhance dopaminergic neurotransmission, possibly via the activation of nicotinic α7-receptors researchgate.net. The modulated release of other neurotransmitters by galantamine may contribute to its broader effects on cognitive function and potentially other neurological processes drugbank.comresearchgate.net.

Compound Names and PubChem CIDs

Note: PubChem CIDs for some complex biological entities like proteins (TNF-α, IL-1β, IL-6, NF-κB, Bcl-2, Caspase-3, Caspase-9, Acetylcholinesterase) or general categories (Amyloid-beta peptide, Hydrogen Peroxide, GSH, ROS, NO, Dopamine, Glutamate, Serotonin, Norepinephrine, GABA) are not single, discrete chemical structures and therefore may not have a standard PubChem CID in the same way as small molecules like Galantamine or Acetylcholine. Where available, a relevant identifier like a CAS number for Acetylcholinesterase is provided.## The Molecular and Cellular Landscape of this compound's Actions

This compound, an alkaloid derived from Amaryllidaceae plants, is a compound with a well-established role in modulating cholinergic neurotransmission. Beyond its primary function as an acetylcholinesterase inhibitor, this compound exerts a range of molecular and cellular effects within the neural system, encompassing anti-inflammatory, antioxidant, and anti-apoptotic properties, as well as modulating nicotinic acetylcholine receptors and interacting with other neurotransmitter systems.

Anti-inflammatory Effects in Neural Systems

Neuroinflammation is increasingly recognized as a critical contributor to the progression of neurodegenerative diseases. This compound has demonstrated significant anti-inflammatory capabilities within the central nervous system. Studies have shown that this compound treatment can attenuate neuroinflammation by inhibiting the activation of glial cells, specifically microglia and astrocytes, in brain regions like the hippocampus nih.govfrontiersin.orgresearchgate.net. This inhibitory effect is associated with the suppression of key inflammatory signaling pathways. For instance, this compound has been shown to inhibit the activation and translocation of NF-κB p65, a crucial transcription factor involved in the expression of pro-inflammatory genes nih.govfrontiersin.orgresearchgate.net. Consequently, the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, is reduced following this compound administration nih.govfrontiersin.orgresearchgate.net.

A significant mechanism underlying this compound's anti-inflammatory effects is its interaction with the cholinergic anti-inflammatory pathway. This pathway is mediated by the binding of acetylcholine to α7 nicotinic acetylcholine receptors (α7 nAChRs), which leads to the suppression of NF-κB activation and the subsequent inhibition of cytokine release jddtonline.infonih.gov. As this compound inhibits acetylcholinesterase, it increases the availability of acetylcholine in the synaptic cleft. Furthermore, its allosteric modulation of nAChRs, including the α7 subtype, enhances the effects of acetylcholine on these receptors, thereby activating the cholinergic anti-inflammatory pathway jddtonline.infonih.gov. In vitro experiments using microglial and neuronal cell lines have provided further evidence of this compound's ability to mitigate inflammatory responses nih.gov.

Antioxidant Properties and Oxidative Stress Mitigation

Oxidative stress, characterized by an imbalance between the production of reactive oxygen/nitrogen species (ROS/RNS) and the capacity of antioxidant defense systems, is a major factor in neuronal damage observed in various neurological conditions arphahub.com. This compound exhibits antioxidant properties that contribute to its neuroprotective effects eurekaselect.comnih.goveuropeanreview.org. It functions as a scavenger of reactive oxygen species, thereby reducing oxidative damage to neurons eurekaselect.comarphahub.com.

Research utilizing in vitro models of oxidative stress, such as those induced by hydrogen peroxide, has shown that this compound can effectively decrease the generation of reactive oxygen species and preserve mitochondrial function in neuronal cells nih.gov. Furthermore, this compound has been shown to protect cortical neurons from oxidative stress induced by amyloid-beta peptide, a key pathological hallmark of Alzheimer's disease nih.gov. This protection involves preventing the increase in reactive oxygen species and lipid peroxidation, as well as mitigating alterations in the glutathione antioxidant system nih.gov. The mechanisms underlying this compound's antioxidant activity may include the prevention of P2X7 receptor activation, the protection of mitochondrial membrane potential, and the prevention of disturbances in membrane fluidity eurekaselect.com. Additionally, by increasing acetylcholine levels and potentiating α7 nAChRs, this compound can indirectly reduce the overproduction of reactive oxygen species eurekaselect.com.

Modulation of Apoptotic Pathways

Apoptosis, or programmed cell death, plays a crucial role in the neuronal loss observed in neurodegenerative disorders. This compound has demonstrated the capacity to modulate apoptotic pathways, thereby promoting neuronal survival researchgate.neteuropeanreview.org. Studies have indicated that this compound can protect neurons against apoptosis induced by various cytotoxic insults, including amyloid-beta peptide eurekaselect.comresearchgate.net.

This anti-apoptotic effect is closely linked to the modulation of nicotinic acetylcholine receptors and the subsequent activation of pro-survival signaling pathways. This compound has been shown to increase the expression of the anti-apoptotic protein Bcl-2 in neuronal cells researchgate.net. The allosteric potentiation of α7 nAChRs by this compound is thought to contribute to this effect by triggering intracellular signaling cascades, such as the phosphorylation of serine-threonine protein kinase and the stimulation of phosphoinositide 3-kinase, which ultimately lead to elevated Bcl-2 expression eurekaselect.com. Furthermore, this compound has been reported to inhibit amyloid-beta-induced apoptosis by activating the JNK signaling pathway, which enhances α7 nAChR expression, and by inhibiting the Akt pathway, which promotes autophagy – a cellular process involved in clearing damaged components and protein aggregates nih.gov.

Effects on Cholinergic Neurotransmission Beyond Acetylcholinesterase

While this compound is widely recognized for its competitive and reversible inhibition of acetylcholinesterase, which increases acetylcholine concentrations in the synaptic cleft, its influence on cholinergic neurotransmission extends beyond this mechanism nih.govdrugbank.compatsnap.com. This compound also acts as a positive allosteric modulator of certain subtypes of neuronal nicotinic acetylcholine receptors (nAChRs), notably the α4β2 and α7 subtypes drugbank.comnih.govwikipedia.org. By binding to an allosteric site on these receptors, distinct from the orthosteric site where acetylcholine binds, this compound enhances the receptor's sensitivity to acetylcholine drugbank.compatsnap.comnih.gov. This allosteric modulation facilitates the release of acetylcholine from presynaptic terminals, further augmenting cholinergic signaling nih.gov. This dual mechanism of action, combining AChE inhibition with nAChR modulation, is considered a key aspect of this compound's pharmacological profile and contributes to its clinical significance nih.govnih.gov.

Interactions with Other Neurotransmitter Systems

The allosteric modulation of nicotinic receptors by this compound has implications for the activity of neurotransmitter systems beyond the cholinergic system nih.govresearchgate.net. Nicotinic acetylcholine receptors are strategically located on presynaptic neurons where they regulate the release of various neurotransmitters, including dopamine, glutamate, norepinephrine, and serotonin nih.gov. By modulating the function of these presynaptic nAChRs, this compound can indirectly influence the release and activity of these diverse neurotransmitters nih.govresearchgate.net. For example, studies suggest that this compound can enhance dopaminergic neurotransmission, potentially through the activation of α7 nAChRs researchgate.net. These interactions with other neurotransmitter systems may contribute to the broader cognitive and potentially behavioral effects observed with this compound drugbank.comresearchgate.net.

Bioavailability Research and Factors Affecting Absorption

The absolute oral bioavailability of this compound is high, reported to be approximately 90% or ranging from 90% to 100%. nih.govwikipedia.orgfda.govnih.govdrugbank.comnih.govnih.govoup.com Pharmacokinetic studies indicate that galantamine exhibits a dose-linear profile over a range of 8 to 32 mg/day. nih.govfda.govnih.govdrugbank.comeurekaselect.com

Food can influence the rate, but generally not the extent, of galantamine absorption. fda.govhpra.iechula.ac.th While the area under the concentration-time curve (AUC) is typically unaffected by food, the peak plasma concentration (Cmax) may be reduced by approximately 25%, and the time to reach peak concentration (Tmax) can be delayed by about 1.5 hours when galantamine is administered with food. fda.govnih.govwikidoc.org For extended-release formulations, the rate of absorption may increase when administered with high-fat food, although Tmax may not be significantly different. chula.ac.th

Tissue Distribution and Blood-Brain Barrier Permeability Studies

This compound has a relatively large volume of distribution, with reported mean values around 175 L or 193 L. fda.govfda.govnih.govdrugbank.comnih.govnih.goveurekaselect.comwikidoc.org Plasma protein binding of galantamine is low, approximately 18% at therapeutic concentrations or ranging from 28.3% to 33.8%. nih.govfda.govnih.govdrugbank.comnih.govnih.goveurekaselect.comwikidoc.org In whole blood, galantamine is significantly distributed to red blood cells, accounting for about 52.7% of the distribution. fda.govnih.govdrugbank.comwikidoc.org The blood to plasma concentration ratio of galantamine is approximately 1.2. fda.govdrugbank.comwikidoc.org

This compound is known to cross the blood-brain barrier (BBB). nih.govnih.govdrugbank.com Studies, including those in rats, have shown distribution to various tissues, with notable levels observed in the liver, kidney, salivary glands, and adrenal glands. nih.govthieme-connect.com Distribution to the brain is also evident, although some research suggests that only a relatively small portion of the administered drug reaches the brain, as indicated by a brain-to-plasma ratio of approximately 1.3. google.comgoogle.com The distribution of unchanged galantamine to most tissues, particularly the brain, appears more pronounced than that of its metabolites. nih.gov Studies in rats have shown that tissue concentrations of unchanged drug and non-volatile radioactivity decline at a rate similar to plasma, indicating no significant tissue retention. nih.govthieme-connect.com Research also suggests that galantamine may decrease TBI-triggered blood-brain barrier permeability. nih.govnih.gov

Cytochrome P450 Enzyme Involvement in this compound Metabolism

Hepatic cytochrome P450 (CYP) enzymes play a major role in the biotransformation of galantamine. nih.govfda.govnih.govhpra.ie In vitro studies indicate that CYP2D6 and CYP3A4 are the primary isoenzymes involved. nih.govwikipedia.orgphcogcommn.orgfda.govnih.govdrugbank.comnih.govnih.govoup.comhpra.ietg.org.auspringermedicine.com

CYP2D6 is primarily involved in the O-demethylation of galantamine, leading to the formation of O-desmethyl-galantamine. fda.govnih.govdrugbank.comhpra.iewikidoc.org CYP3A4 mediates the formation of galantamine-N-oxide. nih.govfda.govdrugbank.comhpra.iewikidoc.org O-demethylation mediated by CYP2D6 is more prominent in individuals classified as extensive metabolizers of CYP2D6 compared to poor metabolizers. fda.govnih.govwikidoc.org Despite this, unchanged galantamine and its glucuronide metabolite account for the majority of plasma radioactivity in both poor and extensive CYP2D6 metabolizers. fda.govnih.govhpra.iewikidoc.orgresearchgate.net

Inhibitors of CYP2D6 or CYP3A4 can affect galantamine metabolism. Potent inhibitors of these enzymes may increase the AUC of galantamine. fda.gov For instance, co-administration with paroxetine (a strong CYP2D6 inhibitor) or ketoconazole (a strong CYP3A4 inhibitor) has been shown to increase galantamine exposure. nih.govresearchgate.net Specifically, paroxetine increased galantamine bioavailability by 40%, while ketoconazole and erythromycin (another CYP3A4 inhibitor) increased it by 30% and 12%, respectively. wikipedia.orgjddtonline.info Conversely, drugs that induce CYP3A4 or CYP2D6, such as carbamazepine or rifampin, can accelerate galantamine metabolism. nih.govnih.gov

In vitro studies suggest that galantamine has low inhibitory potential towards major cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6, and CYP2E1. fda.govnih.gov

Identification and Activity of this compound Metabolites

Several metabolic pathways contribute to galantamine biotransformation, including O-demethylation, N-demethylation, N-oxidation, epimerization, and glucuronidation. nih.govwikipedia.orgfda.govnih.govdrugbank.comhpra.iewikidoc.orgresearchgate.net

Identified metabolites include O-desmethyl-galantamine, galantamine-N-oxide, norgalantamine (N-desmethyl-galantamine), O-desmethyl-norgalantamine, epigalantamine, and galantaminone. nih.govfda.govdrugbank.comwikidoc.org Glucuronidation results in the formation of galantamine glucuronide. nih.govwikipedia.orgfda.govnih.govdrugbank.comhpra.iewikidoc.orgresearchgate.net

While O-desmethyl-galantamine is considered a pharmacologically active metabolite, it has not been detected in unconjugated form in the plasma of either poor or extensive CYP2D6 metabolizers in some studies. researchgate.net Other metabolites, such as norgalantamine, O-desmethyl-norgalantamine, epigalantamine, and galantaminone, are reported not to retain clinically significant pharmacological activities. nih.govdrugbank.com Galantamine glucuronide is also a significant metabolite found in plasma and urine. fda.govnih.govhpra.iewikidoc.orgresearchgate.net

Cognitive Enhancement in Mild-to-Moderate Alzheimer's Disease

Numerous randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of this compound in improving cognitive function in patients with mild to moderate AD. cochrane.orge-century.usnih.govjacobimed.orgodprn.ca Measures such as the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog) have consistently shown statistically significant improvements or a slower rate of cognitive decline in this compound-treated patients compared to those receiving placebo. e-century.usnih.govjacobimed.orgnih.govnih.gov

For example, a meta-analysis of randomized controlled trials indicated that cognitive effects were significantly increased in the this compound group when compared with the placebo group, with a mean difference on the ADAS-cog subscale of -3.15 (95% CI: -3.70 to -2.60, P<0.00001) for a dosage of 24 mg daily. e-century.us Another study reported a mean treatment effect of 3.1 points (95% confidence interval 1.7 to 4.5) for a lower dose and 4.1 points (2.7 to 5.6) for a higher dose on the ADAS-cog/11 at six months, both statistically significant compared to placebo (P<0.001). nih.gov

Interactive Table 1: Change from Baseline in ADAS-cog Scores in this compound Trials

Note: Negative values typically indicate improvement or less decline on the ADAS-cog scale.

Studies utilizing computerized neuropsychological tests have also shown positive effects of this compound on specific cognitive measures, such as attention and episodic memory, resulting in statistically significant reductions in reaction times after 12 weeks of treatment in patients with mild to moderate AD. scielo.br

Impact on Behavioral and Psychological Symptoms of Dementia

Behavioral and psychological symptoms of dementia (BPSD) are common in AD and contribute significantly to caregiver distress and can influence the decision for institutionalization. doi.orgresearchgate.netnih.govnih.govkarger.com Research has explored the impact of this compound on these symptoms.

Pooled data from multiple studies involving patients with mild to moderate AD have indicated that this compound treatment is associated with a reduction in the emergence of behavioral disturbances and improvement in existing behavioral problems. doi.orgresearchgate.netnih.govpsychiatryonline.org Specific symptoms that showed improvement with this compound in clinical trials include aberrant motor behavior, agitation, anxiety, apathy, and disinhibition. doi.orgpsychiatryonline.org One analysis of pooled data from three trials showed a statistically significant benefit of this compound over placebo on total Neuropsychiatric Inventory (NPI) scores. doi.orgresearchgate.netnih.gov

Interactive Table 2: Effect of this compound on Neuropsychiatric Inventory (NPI) Scores

The reduction in behavioral symptoms observed with this compound therapy has also been associated with a concomitant reduction in reported caregiver distress. researchgate.netnih.govpsychiatryonline.org

Long-term Efficacy and Potential for Disease Progression Modulation

Studies have investigated the long-term effects of this compound treatment in AD. While dementia is a progressive neurodegenerative disease and this compound is not known to alter the underlying disease process, long-term treatment has been associated with attenuated cognitive decline compared to predicted decline in untreated patients. drugbank.commedscape.comnih.govjnj.com

A 2-year randomized, placebo-controlled study in patients with mild to moderate AD reported that long-term treatment with this compound significantly reduced the decline in cognition and activities of daily living. dovepress.com Cognitive impairment, based on the mean change in Mini-Mental State Examination (MMSE) scores from baseline to month 24, significantly worsened in the placebo group (-2.14) compared with the this compound group (-1.41) (P<0.001). dovepress.com Functional impairment, assessed by the Disability Assessment in Dementia (DAD) score, also worsened significantly less in the this compound group (-8.16) versus the placebo group (-10.81) at month 24 (P=0.002). dovepress.com

Interactive Table 3: Long-term Outcomes in a 2-Year this compound Study in AD

Note: For MMSE, a smaller negative change indicates less cognitive decline. For DAD, a smaller negative change indicates less functional decline.

Furthermore, one long-term study suggested a significantly lower mortality rate in patients treated with this compound compared to placebo over two years. jnj.comdovepress.com The mortality rate was 3.2% in the this compound group and 5.5% in the placebo group (P=0.011). jnj.com While this compound is considered a symptomatic treatment, these long-term findings suggest potential benefits beyond just cognitive effects. drugbank.comjnj.com

Vascular Dementia Research

Vascular dementia (VaD) is the second most common type of dementia. nih.govcochrane.orgbmj.com Given the cholinergic deficit observed in VaD, similar to AD, cholinesterase inhibitors like this compound have been investigated for their potential therapeutic effects. nih.govcochrane.orgneurology.org

Clinical trials have evaluated the efficacy of this compound in patients with probable VaD or AD with concomitant cerebrovascular disease. nih.govnih.govcochrane.orgresearchgate.netjwatch.org Some studies have indicated that this compound may be effective in improving cognition, including executive function, in patients with vascular dementia. nih.govresearchgate.net

In a randomized trial involving patients with probable VaD, this compound treatment resulted in a greater improvement in ADAS-cog/11 scores after 26 weeks compared with placebo (-1.8 vs -0.3; p < 0.001). nih.govresearchgate.net A difference favoring this compound was also detected on the EXIT-25, a measure of executive functioning (p = 0.041). nih.govresearchgate.net However, this study did not find a significant difference between this compound and placebo on measures of activities of daily living. nih.govresearchgate.net

A review of two trials in vascular cognitive impairment or VaD found evidence of benefit for this compound over placebo in measures of cognition and global clinical state. cochrane.org Another randomized trial in patients with probable vascular dementia or AD combined with cerebrovascular disease showed that this compound had greater efficacy than placebo on ADAS-cog and Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus). nih.gov Activities of daily living and behavioral symptoms were also significantly improved compared with placebo in this study. nih.gov

Interactive Table 4: Efficacy of this compound in Vascular Dementia/AD with CVD

Lewy Body Dementia Research

Dementia with Lewy bodies (DLB) is another common form of dementia characterized by a significant cholinergic deficit. tandfonline.comnih.govnih.gov Cholinesterase inhibitors are often considered for the management of cognitive and neuropsychiatric symptoms in DLB. tandfonline.comnih.gov

Research on this compound specifically in DLB is less extensive compared to AD. A small, open-label study evaluated the efficacy of this compound in 50 patients with DLB over 24 weeks. tandfonline.comnih.govresearchgate.net This study reported beneficial effects on neuropsychiatric symptoms, particularly visual hallucinations and nighttime behaviors, as measured by the Neuropsychiatric Inventory (NPI-12). nih.govresearchgate.net The NPI-12 total score improved by 8.24 points from baseline (p = 0.01). nih.govresearchgate.net Improvements were also observed in the Clinician's Global Impression of Change scores. nih.govresearchgate.net However, this study did not find a significant change in cognitive function as assessed by a computerized cognitive assessment system. nih.govresearchgate.net

While donepezil and rivastigmine have more robust evidence and are recommended as first-line treatments for DLB in some guidelines, open-label trial data for this compound provides preliminary evidence of potential benefits on cognitive fluctuation, sleep disturbances, and psychiatric symptoms in DLB. tandfonline.comnih.gov Further large-scale, controlled studies are needed to definitively establish the role of this compound in the treatment of DLB. tandfonline.comnih.gov

Potential in Other Neurodegenerative Disorders (e.g., Parkinson's Disease Dementia)

This compound, an acetylcholinesterase inhibitor (AChEI) and a positive allosteric modulator of nicotinic acetylcholine receptors (nAChRs), has been investigated for its potential therapeutic effects in neurodegenerative disorders beyond Alzheimer's disease, particularly in Parkinson's disease dementia (PDD) nih.govmdpi.com. PDD is a progressive neurodegenerative condition characterized by cognitive impairment in individuals with Parkinson's disease nih.govresearchgate.net. The rationale for exploring this compound in PDD stems from the significant cholinergic deficit observed in this population, similar to Alzheimer's disease nih.govnih.gov.

Studies have explored this compound's impact on cognitive and neuropsychiatric symptoms in PDD patients. An open-label trial involving participants with PDD demonstrated statistically significant improvements in several cognitive assessments, including the Mini-Mental State Examination (MMSE), the Cognitive Alzheimer's Disease Assessment Scale (ADAS-cog), the clock drawing test, and the Frontal Assessment Battery (FAB) nih.gov. Additionally, this trial indicated benefits in neuropsychiatric symptoms such as hallucinations, anxiety, sleep disturbance, and apathy, as measured by the Neuropsychiatric Inventory (NPI) nih.gov. Another open-label trial in PDD patients also suggested that this compound may be useful, with observed improvements in clock drawing and trends towards improvement in MMSE and verbal fluency capes.gov.brresearchgate.net.

While randomized controlled trials (RCTs) specifically for this compound alone in PD have not consistently shown success, the combination of this compound and memantine has demonstrated synergistic effects on cognitive enhancement in animal models and is considered to have therapeutic potential that warrants further assessment in RCTs nih.gov. This potential combination therapy is thought to target multiple pathways involved in PD pathophysiology, including the kynurenine pathway nih.gov.

The dual mechanism of action of this compound – AChE inhibition and positive allosteric modulation of nAChRs, particularly the α7 and α4β2 subtypes – is considered advantageous nih.govmdpi.com. Stimulation of nicotinic receptors may help counteract the downregulation that can occur with cholinesterase inhibition and facilitate the release of neurotransmitters like dopamine, which is relevant in PD capes.gov.brresearchgate.net.

The International Parkinson and Movement Disorder Society Evidence-Based Medicine Review considers this compound potentially useful for treating PDD nih.gov.

Exploratory Studies in Neurological and Psychiatric Conditions

Beyond its primary indication in Alzheimer's disease and its potential in PDD, this compound has been the subject of exploratory research in a range of other neurological and psychiatric conditions. These studies investigate its potential based on its cholinergic effects and its modulation of nicotinic receptors, which are involved in various neural circuits.

Research suggests potential benefits in cognitive dysfunction associated with bipolar disorder nih.govjst.go.jp. Proof-of-concept studies and case reports have explored this compound's effects on cognitive impairment in this population jst.go.jp.

Exploratory studies have also examined this compound in conditions like chronic post-stroke aphasia, where it has shown beneficial effects nih.gov. Its potential in managing dementia associated with Down syndrome has also been noted nih.gov. Furthermore, this compound has been explored as a potential treatment for cognitive impairment associated with electroconvulsive therapy, both alone and in combination with memantine nih.gov.

The drug's influence on nicotinic receptors and its impact on various neurotransmitter systems like monoamines, glutamate, and GABA are thought to contribute to its potential effects in these diverse neurological and psychiatric conditions jst.go.jp.

Anti-Inflammatory and Immunomodulatory Potentials Beyond Neurodegeneration

Emerging research highlights this compound's anti-inflammatory and immunomodulatory properties, effects that extend beyond its established role in neurodegenerative conditions. These actions are significantly linked to the cholinergic anti-inflammatory pathway (CAP), a physiological mechanism by which the nervous system regulates immune responses plos.orgfrontiersin.orgnih.govnih.gov.

This compound is understood to activate the CAP, primarily through its interaction with α7 nicotinic acetylcholine receptors (α7nAChR) plos.orgfrontiersin.orgnih.govnih.govjddtonline.info. Activation of α7nAChRs on immune cells, such as macrophages, can suppress the release of pro-inflammatory cytokines nih.govnih.gov. Studies have shown that this compound can reduce levels of key inflammatory mediators like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) plos.orgnih.govmedrxiv.orgprobiologists.comnih.gov.

Preclinical studies in various inflammatory models have demonstrated this compound's anti-inflammatory effects. These include murine models of endotoxemia, inflammatory bowel disease (IBD), hemorrhagic shock, lupus, sepsis, and colitis frontiersin.orgmedrxiv.orgprobiologists.comnih.gov. In a mouse model of familial Mediterranean fever (FMF), an autoinflammatory disease, long-term this compound treatment attenuated markers of inflammation and chronic disease complications, potentially by inhibiting macrophage overactivation nih.gov. Research in a tularemia-infected mouse model showed that this compound influenced the immune response by down-regulating IL-6 and up-regulating interferon-gamma (IFN-gamma), leading to mitigation of nephropathy and reduced mortality nih.gov.

Clinical research is also exploring these anti-inflammatory effects. A randomized, double-blind, placebo-controlled trial in patients with metabolic syndrome (MetS) demonstrated that this compound treatment significantly alleviated systemic inflammation and insulin resistance medrxiv.orgnorthwell.edu. The study reported a reduction in pro-inflammatory molecules like TNF and leptin and an increase in the anti-inflammatory molecule adiponectin medrxiv.org. This effect was associated with beneficial alterations in autonomic regulation, as indicated by changes in heart rate variability medrxiv.org.

Furthermore, studies suggest this compound's potential in conditions like acute pancreatitis, where it has shown to attenuate pancreatic histologic injury and modulate inflammatory cytokines in experimental models, although the mechanism may not solely involve previously established CAP components researchgate.net. In collagen-induced arthritis models, this compound has shown a positive impact on joint collagen degradation, suggesting an immunomodulatory activity in this context probiologists.comprobiologists.com.

The anti-inflammatory and immunomodulatory potentials of this compound, mediated significantly through the CAP, indicate a broader therapeutic scope beyond its primary neurological applications.

Gastrointestinal System Manifestations

Gastrointestinal adverse events are among the most common reactions reported with this compound. These are largely attributed to the increased cholinergic activity in the digestive tract.

Nausea and vomiting are particularly frequent, especially during the dose escalation phase, and often resolve within about a week. medicinenet.comdrugs.comhres.ca While clinical trials have not shown an increased incidence of peptic ulcer disease or gastrointestinal bleeding compared to placebo, patients with a history of these conditions or those taking NSAIDs should be monitored due to the potential for increased gastric acid secretion with increased cholinergic activity. nih.govcbg-meb.nlhealthline.commayoclinic.orghres.cagov.bc.ca

Central Nervous System Effects

This compound's effects on the central nervous system are also related to its cholinergic activity.

Headache and dizziness are frequently reported. nih.gov While seizures are uncommon, they have been reported, and individuals with a history of seizures may be more susceptible. healthline.commayoclinic.orghres.camedlineplus.gov Hallucinations have also been observed. drugbank.comrxlist.com

Cardiovascular System Effects

This compound can exert vagotonic effects on the cardiac conduction system, potentially leading to cardiovascular adverse events. nih.gov

Bradycardia (slow heart rate) and syncope (fainting) are commonly reported cardiovascular effects, with an increased risk in individuals with pre-existing cardiac issues. healthline.commayoclinic.orgnih.gov While less common than gastrointestinal effects, these cardiovascular events are important considerations, particularly in susceptible patients. nih.gov Heart block and pauses in heart rate have also been observed, especially with faster dose escalation. hres.cahres.ca

Genetic Polymorphisms and Metabolic Status

This compound is primarily metabolized in the liver by cytochrome P450 enzymes, specifically CYP2D6 and CYP3A4. nih.govwikipedia.orgdrugbank.comunboundmedicine.comdrugsporphyria.net Genetic variations (polymorphisms) in the genes encoding these enzymes can affect how efficiently this compound is metabolized, leading to variations in drug concentrations and potentially influencing the risk of adverse effects.

Approximately 75% of this compound is metabolized by CYP2D6 and CYP3A4. nih.govdrugbank.com Individuals who are poor metabolizers due to CYP2D6 genetic polymorphisms may have significantly higher this compound concentrations, increasing the risk of adverse effects. medlink.comunboundmedicine.com Studies have indicated that carrying certain detrimental allelic variants of CYP2D6, CYP3A5, and UGT1A1 may be associated with higher this compound plasma concentrations. nih.gov

Comorbidities and Concomitant Medications

The presence of certain comorbidities and the use of concomitant medications can also increase the risk or severity of this compound-associated adverse events.

Patients with a history of stomach problems, ulcers, or bleeding are at increased risk of gastrointestinal complications, including stomach ulcers and bleeding, as this compound can increase stomach acid. healthline.commayoclinic.org Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) further elevates this risk. cbg-meb.nlhealthline.commayoclinic.orghres.ca

Individuals with heart problems, particularly those with a history of slow or irregular heart rate, are at a higher risk of experiencing bradycardia and syncope. healthline.commayoclinic.org this compound should be used with caution in patients with supraventricular cardiac conduction defects or those taking medications that slow heart rate, such as digoxin and beta-blockers. cbg-meb.nlunboundmedicine.com

Patients with a history of asthma or other lung diseases may experience a worsening of their condition with this compound use. healthline.commayoclinic.org

Renal and hepatic impairment can affect the clearance of this compound, potentially leading to increased drug levels and a higher risk of adverse effects. mayoclinic.orgunboundmedicine.comgmmmg.nhs.uk Severe hepatic or renal impairment is a contraindication for this compound use. mayoclinic.orgunboundmedicine.com

Concomitant use of medications that inhibit CYP2D6 or CYP3A4 can decrease this compound metabolism and increase its concentration, potentially leading to increased cholinergic adverse effects, predominantly nausea and vomiting. wikipedia.orggov.bc.cagmmmg.nhs.uk Examples of such inhibitors include paroxetine (CYP2D6) and ketoconazole and erythromycin (CYP3A4). wikipedia.org Conversely, inducers of CYP2D6 and CYP3A4 may decrease this compound levels. gov.bc.ca

This compound can also interact with other medications affecting the cholinergic system, potentially increasing cholinergic effects when combined with other cholinergic agonists or decreasing the effectiveness of anticholinergic medications. medlink.comdrugbank.comunboundmedicine.commedscape.commedindia.net Caution is also advised when this compound is used with certain anesthetic agents, as it may prolong the effects of succinylcholine-type neuromuscular blocking agents and potentially antagonize the effects of non-depolarizing neuromuscular blocking drugs. nih.govunboundmedicine.comgmmmg.nhs.uk

Interactions with CYP450 Enzyme Inhibitors and Inducers

This compound is primarily metabolized in the liver, with hepatic cytochrome P450 (CYP) enzymes, specifically CYP2D6 and CYP3A4, playing significant roles in its metabolic pathways. CYP2D6 is involved in the O-demethylation of this compound to form O-desmethyl-galanthamine, while CYP3A4 mediates the formation of this compound-N-oxide. drugbank.comnih.govfda.gov Approximately 75% of the drug is metabolized by these two enzymes. drugbank.com

Inhibitors of CYP2D6 and CYP3A4 can decrease the metabolism of this compound, leading to increased plasma concentrations and potentially enhanced cholinergic effects. nih.govfda.govwikipedia.orgjddtonline.infotaylorandfrancis.comresearchgate.net Studies have shown that potent inhibitors of these enzymes can increase the bioavailability of this compound. For instance, paroxetine, a strong CYP2D6 inhibitor, has been shown to increase this compound bioavailability by 40%. wikipedia.orgjddtonline.infocbg-meb.nlgmmmg.nhs.uk Similarly, the CYP3A4 inhibitors ketoconazole and erythromycin have been reported to increase this compound bioavailability by 30% and 12%, respectively. fda.govwikipedia.orgjddtonline.infocbg-meb.nl

Conversely, drugs that induce CYP3A4 or CYP2D6 enzymes, such as carbamazepine, phenytoin, phenobarbital, rifampin, or dexamethasone, can accelerate the metabolism of this compound, potentially leading to decreased plasma concentrations and reduced efficacy. nih.govnih.gov

The following table summarizes the observed effects of some CYP enzyme inhibitors on this compound bioavailability:

Note: This table presents data from specific studies and the magnitude of interaction may vary depending on individual patient factors and study design.

Genetic variations in CYP2D6 activity can also influence this compound pharmacokinetics. Individuals classified as poor metabolizers of CYP2D6 may exhibit higher plasma concentrations of this compound compared to extensive metabolizers. nih.govfda.govhres.ca

Protein Binding Displacement Interactions

This compound exhibits relatively low plasma protein binding, reported to be around 18% at therapeutically relevant concentrations or between 28.3% and 33.8%. drugbank.comwikipedia.orgjddtonline.infonih.gov Due to this low protein binding, displacement interactions with other highly protein-bound drugs are generally not considered clinically significant. nice.org.uk While displacement from protein binding can theoretically increase the free fraction of a drug, this typically only leads to a detectable increase in effect for extensively bound drugs (>90%) that are not widely distributed in the body. nice.org.uk

Interactions with Cholinergic Agents

As a cholinesterase inhibitor, this compound increases the availability of acetylcholine in the synaptic cleft. wikipedia.orgnih.govmedlink.com Therefore, co-administration with other cholinergic agents or cholinesterase inhibitors can result in synergistic effects, potentially increasing the risk of cholinergic overstimulation. nih.govnih.govhres.cadrugs.com This includes other acetylcholinesterase inhibitors (such as donepezil, rivastigmine, neostigmine, pyridostigmine, ambenonium) and cholinergic agonists (such as bethanechol or systemically administered pilocarpine). nih.govcbg-meb.nlnih.govhres.cadrugs.com

A notable interaction exists with succinylcholine and similar neuromuscular blocking agents. This compound is likely to exaggerate the muscle relaxation effects of succinylcholine-type agents during anesthesia due to its inhibition of cholinesterase, which is responsible for the breakdown of succinylcholine. nih.govjddtonline.inforesearchgate.netcbg-meb.nlgmmmg.nhs.ukdrugs.com

Interactions with Anticholinergic Agents

Anticholinergic medications have effects opposite to those of cholinergic agents by blocking the action of acetylcholine. drugs.com Therefore, co-administration of this compound with anticholinergic drugs can lead to a pharmacodynamic antagonism, where the effects of both medications may be reduced. nih.govcbg-meb.nlhres.cadrugs.commedscape.com this compound has the potential to interfere with the activity of anticholinergic medications. hres.cadrugs.com If anticholinergic medication is abruptly stopped, there is a potential risk that this compound's effect could be exacerbated. cbg-meb.nl This interaction is particularly relevant as some medications, including certain antipsychotics (e.g., clozapine, olanzapine), possess anticholinergic properties that could counteract this compound's beneficial effects. droracle.ai

Interactions with Cardiovascular Medications

This compound can have vagotonic effects on the sinoatrial and atrioventricular nodes, potentially leading to bradycardia or heart block. nih.govdrugs.comdrugs.com Consequently, a pharmacodynamic interaction is possible when this compound is administered concurrently with other medications that significantly reduce heart rate. jddtonline.inforesearchgate.netcbg-meb.nlmedlink.com This includes agents such as digoxin, beta-blockers (e.g., acebutolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, pindolol, propranolol, timolol), and certain calcium-channel blocking agents (e.g., diltiazem, verapamil), and amiodarone. nih.govcbg-meb.nlnice.org.ukmedlink.com While a study showed that multiple doses of this compound did not affect the pharmacokinetics of digoxin or warfarin, pharmacodynamic interactions, such as heart block, have been reported with digoxin co-administration. nih.govjddtonline.infocbg-meb.nl Caution should also be exercised with medicinal products that have the potential to cause torsades de pointes. cbg-meb.nl