Hubbry Logo
LoperamideLoperamideMain
Open search
Loperamide
Community hub
Loperamide
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Contribute something
Loperamide
Loperamide
Loperamide
View on Wikipedia
from Wikipedia

Loperamide
Clinical data
Pronunciation/loʊˈpɛrəmaɪd/
Trade namesImodium, others[1]
Other namesR-18553, Loperamide hydrochloride (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa682280
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability0.3%
Protein binding97%
MetabolismLiver (extensive)
Elimination half-life9–14 hours[5]
ExcretionFeces (30–40%), urine (1%)
Identifiers
  • 4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.053.088 Edit this at Wikidata
Chemical and physical data
FormulaC29H33ClN2O2
Molar mass477.05 g·mol−1
3D model (JSmol)
  • ClC1=CC=C(C2(CCN(CC2)CCC(C3=CC=CC=C3)(C(N(C)C)=O)C4=CC=CC=C4)O)C=C1
  • InChI=1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3
  • Key:RDOIQAHITMMDAJ-UHFFFAOYSA-N

Loperamide, sold under the brand name Imodium, among others,[1] is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea.[6][5] It is often used for this purpose in irritable bowel syndrome, inflammatory bowel disease, short bowel syndrome,[5] Crohn's disease, and ulcerative colitis.[6] Loperamide is taken by mouth.[5]

Common side effects include abdominal pain, constipation, sleepiness, vomiting, and dry mouth.[5] It may increase the risk of toxic megacolon.[5] Loperamide's safety in pregnancy is unclear, but no evidence of harm has been found.[7] It appears to be safe in breastfeeding.[8] It is an opioid with no significant absorption from the gut and does not cross the blood–brain barrier when used at normal doses.[9] It works by slowing the contractions of the intestines.[5]

Loperamide was first made in 1969 and used medically in 1976.[10] It is on the World Health Organization's List of Essential Medicines.[11] Loperamide is available as a generic medication.[5][12] In 2023, it was the 276th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[13][14]

Medical uses

[edit]

Loperamide is effective for the treatment of a number of types of diarrhea.[15]

Loperamide is often compared to diphenoxylate. Studies suggest that loperamide is more effective and has lower neural side effects.[16][17][18]

Side effects

[edit]

Adverse drug reactions most commonly associated with loperamide are constipation (which occurs in 1.7–5.3% of users), dizziness (up to 1.4%), nausea (0.7–3.2%), and abdominal cramps (0.5–3.0%).[3] Rare, but more serious, side effects include toxic megacolon, paralytic ileus, angioedema, anaphylaxis/allergic reactions, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, urinary retention, and heat stroke.[19] The most frequent symptoms of loperamide overdose are drowsiness, vomiting, and abdominal pain, or burning.[20] High doses may result in heart problems such as abnormal heart rhythms.[21]

Contraindications

[edit]

Treatment should be avoided in the presence of high fever or if the stool is bloody. Treatment is not recommended for people who could have negative effects from rebound constipation. If suspicion exists of diarrhea associated with organisms that can penetrate the intestinal walls, such as E. coli O157:H7 or Salmonella, loperamide is contraindicated as a primary treatment.[3] Loperamide treatment is not used in symptomatic C. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon.

Loperamide should be administered with caution to people with liver failure due to reduced first-pass metabolism.[22] Additionally, caution should be used when treating people with advanced HIV/AIDS, as cases of both viral and bacterial toxic megacolon have been reported. If abdominal distension is noted, therapy with loperamide should be discontinued.[23]

Children

[edit]

A review of loperamide in children under twelve years of age found that serious adverse events occurred only in children under three years of age.[24] The study reported that the use of loperamide should be contraindicated in children who are under three years of age, systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea.[24]

In 1990, all formulations of loperamide for children were banned in Pakistan.[25]

Formulations for children aged less than twelve years of age are only available via prescription in the UK.[26]

Pregnancy and breast feeding

[edit]

Loperamide is not recommended in the United Kingdom for use during pregnancy or by nursing mothers.[27] Studies in rat models have shown no teratogenicity, but sufficient studies in humans have not been conducted.[28] One controlled, prospective study of 89 women exposed to loperamide during their first trimester of pregnancy showed no increased risk of malformations. This, however, was only one study with a small sample size.[29] Loperamide can be present in breast milk and is not recommended for breastfeeding mothers.[23]

Drug interactions

[edit]

Loperamide is a substrate of P-glycoprotein; therefore, the concentration of loperamide increases when given with a P-glycoprotein inhibitor.[3] Common P-glycoprotein inhibitors include quinidine, ritonavir, and ketoconazole.[30] Loperamide can decrease the absorption of some other drugs. As an example, saquinavir concentrations can decrease by half when given with loperamide.[3]

Loperamide is an antidiarrheal agent, which decreases intestinal movement. As such, when combined with other antimotility drugs, the risk of constipation is increased. These drugs include other opioids, antihistamines, antipsychotics, and anticholinergics.[31]

Mechanism of action

[edit]
Ball-and-stick model of loperamide molecule

Loperamide is an opioid-receptor agonist and acts on the μ-opioid receptors in the myenteric plexus of the large intestine. It works like morphine, decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall.[32][33] This increases the time material stays in the intestine, allowing more water to be absorbed from the fecal matter. It also decreases colonic mass movements and suppresses the gastrocolic reflex.[34]

Loperamide's circulation in the bloodstream is limited in two ways. Efflux by P-glycoprotein in the intestinal wall reduces the passage of loperamide, and the fraction of drug crossing is then further reduced through first-pass metabolism by the liver.[35][36] Loperamide metabolizes into an MPTP-like compound, but is unlikely to exert neurotoxicity.[37]

Blood–brain barrier

[edit]

Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood-brain barrier,[38] so it can generally only agonize mu-opioid receptors in the peripheral nervous system, and currently has a score of one on the anticholinergic cognitive burden scale.[39] Concurrent administration of P-glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood-brain barrier and produce central morphine-like effects. At high doses (>70mg), loperamide can saturate P-glycoprotein (thus overcoming the efflux) and produce euphoric effects.[40] Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action.[41]

High doses of loperamide have been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal were observed following abrupt discontinuation of long-term treatment of animals with loperamide.[42][43]

Chemistry

[edit]

Synthesis

[edit]

Loperamide is synthesized starting from the lactone 3,3-diphenyldihydrofuran-2(3H)-one and ethyl 4-oxopiperidine-1-carboxylate, on a lab scale.[44] On a large scale a similar synthesis is followed, except that the lactone and piperidinone are produced from cheaper materials rather than purchased.[45][46]

Synthetic route to Loperamide.

Physical properties

[edit]

Loperamide is typically manufactured as the hydrochloride salt. Its main polymorph has a melting point of 224 °C and a second polymorph exists with a melting point of 218 °C. A tetrahydrate form has been identified which melts at 190 °C.[47]

History

[edit]

Loperamide hydrochloride was first synthesized in 1969[10] by Paul Janssen from Janssen Pharmaceuticals in Beerse, Belgium, following previous discoveries of diphenoxylate hydrochloride (1956) and fentanyl citrate (1960).[48]

The first clinical reports on loperamide were published in 1973[44] with the inventor being one of the authors. The trial name for it was "R-18553".[49] Loperamide oxide has a different research code: R-58425.[50]

The trial against placebo was conducted from December 1972 to February 1974, its results being published in 1977.[51]

In 1973, Janssen started to promote loperamide under the brand name Imodium. In December 1976, Imodium got US FDA approval.[52]

During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.[53]

In March 1988, McNeil Pharmaceutical began selling loperamide as an over-the-counter drug under the brand name Imodium A-D.[54]

In the 1980s, loperamide also existed in the form of drops (Imodium Drops) and syrup. Initially, it was intended for children's usage, but Johnson & Johnson voluntarily withdrew it from the market in 1990 after 18 cases of paralytic ileus (resulting in six deaths) were registered in Pakistan and reported by the World Health Organization (WHO).[55] In the following years (1990-1991), products containing loperamide have been restricted for children's use in several countries (ranging from two to five years of age).[56]

In the 1980s, before the US patent expired on 30 January 1990,[53] McNeil started to develop Imodium Advanced containing loperamide and simethicone for treating both diarrhea and gas. In March 1997, the company patented this combination.[57] The drug was approved in June 1997, by the FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.[58] A caplet formulation was approved in November 2000.[59]

In November 1993, loperamide was launched as an orally disintegrating tablet based on Zydis technology.[60][61]

In 2013, loperamide was added to the WHO Model List of Essential Medicines.[11][62]

Society and culture

[edit]
[edit]

United States

[edit]

Loperamide was formerly a controlled substance in the United States. First, it was a Schedule II controlled substance. However, this was lowered to Schedule V. Loperamide was finally removed from control by the Drug Enforcement Administration in 1982, courtesy of then-Administrator Francis M. Mullen Jr.[63]

UK

[edit]

Loperamide can be sold freely to the public by chemists (pharmacies) as the treatment of diarrhea and acute diarrhea associated with medically diagnosed irritable bowel syndrome to adults aged 18 years of age and older.[64]

Economics

[edit]

Loperamide is available as a generic medication.[5][12] In 2016, Imodium was one of the biggest-selling branded over-the-counter medications sold in Great Britain, with sales of £32.7 million.[65]

Brand names

[edit]

Loperamide was originally sold as Imodium, and many generic brands are sold.[1]

Off-label/unapproved use

[edit]

Loperamide has typically been deemed to have a relatively low risk of misuse.[66] In 2012, no reports of loperamide abuse were made.[67] In 2015, however, case reports of extremely high-dose loperamide use were published.[68][69] The primary intent of users has been to manage symptoms of opioid withdrawal such as diarrhea, although a small portion derive psychoactive effects at these higher doses.[70] At these higher doses central nervous system penetration occurs and long-term use may lead to tolerance, dependence, and withdrawal on abrupt cessation.[70] Dubbing it "the poor man's methadone", clinicians warned that increased restrictions on the availability of prescription opioids enacted in response to the opioid epidemic were prompting recreational users to turn to loperamide as an over-the-counter treatment for withdrawal symptoms.[71] The FDA responded to these warnings by calling on drug manufacturers to voluntarily limit the package size of loperamide for public-safety reasons.[72][73] However, there is no quantity restriction on number of packages that can be purchased, and most pharmacies do not feel capable of restricting its sale, so it is unclear that this intervention will have any impact without further regulation to place loperamide behind the counter.[74] Since 2015, several reports of sometimes-fatal cardiotoxicity due to high-dose loperamide abuse have been published.[75][76]

Research

[edit]

In 2020, some research found that loperamide is effective at killing glioblastoma cells.[77]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Loperamide

View on Grokipedia
from Grokipedia

Loperamide is a synthetic phenylpiperidine derivative that functions as a , primarily employed as an medication to reduce gastrointestinal and in the treatment of acute nonspecific and chronic associated with . By binding to opioid receptors in the intestinal , it inhibits , prolongs gut transit time, and enhances absorption of water and electrolytes, thereby decreasing stool frequency and volume. First synthesized in 1969 by researchers at Janssen Pharmaceutica and approved for medical use in 1976, loperamide is marketed under the brand name Imodium and available over-the-counter in many countries for self-treatment of , reflecting its established efficacy and favorable safety profile at recommended doses of up to 16 mg per day for adults. Its peripheral action stems from poor penetration of the blood-brain barrier under therapeutic conditions, minimizing central effects while targeting gut-specific receptors. However, supratherapeutic doses, often exceeding 100 mg daily, have been increasingly abused since the as a surrogate for opioids to achieve or mitigate withdrawal symptoms, circumventing its central exclusion via inhibition or massive intake. This misuse has precipitated severe cardiotoxicity, including prolongation, ventricular dysrhythmias such as , and fatal , prompting FDA warnings in 2016 about the risks of high-dose ingestion and subsequent regulatory efforts to limit package sizes. Empirical data from case reports and surveillance indicate that such toxicity arises from loperamide's blockade of cardiac ion channels, including hERG potassium and sodium channels, at elevated plasma concentrations.

Clinical Applications

Approved Indications

Loperamide is approved by the U.S. (FDA) for the symptomatic relief of acute nonspecific in adults and children aged 2 years and older, where it reduces stool frequency and consistency without addressing underlying causes. For diarrhea from food poisoning, which often involves bacterial pathogens, loperamide can provide symptomatic relief in select cases lacking signs of invasive infection (such as bloody stools or fever), but is not always recommended as slowing intestinal motility may prolong toxin exposure and potentially worsen the illness; hydration with oral rehydration solutions should be prioritized, as dehydration represents the primary risk. Clinical guidelines recommend an initial oral dose of 4 mg, followed by 2 mg after each unformed stool, not exceeding 16 mg per day in adults or 3 mg per day in children aged 6-8 years (with weight-based adjustments for younger children), and discontinuation if no improvement occurs within 48 hours. This indication extends to traveler's , with evidence from controlled trials showing efficacy in shortening episode duration when used adjunctively with rehydration. For chronic diarrhea linked to (IBD), including and , loperamide is indicated for ongoing symptom control at maintenance doses of 4-8 mg daily, up to a maximum of 16 mg per day under physician oversight to avoid complications like during acute flares. Studies in IBD patients demonstrate sustained reduction in stool frequency, with one trial reporting effective relief in 21 of 27 participants, dropping average daily stools from eight to fewer than three. Loperamide is also approved to decrease output volume, mitigating risks of and disturbances in patients with high-output stomas. Randomized controlled trials confirm a output reduction of 16.5% (range -5% to 46%) with standard dosing, alongside slowed intestinal transit, improving patient hydration status and without altering stool sodium concentration significantly. Dosing for this use typically starts at 2-4 mg daily, titrated based on response and monitored for tolerability.

Off-Label Uses

Loperamide is employed off-label for managing -induced , particularly associated with agents like , where aggressive dosing—such as 2 mg every 2 hours—has reduced severe episode incidence to approximately 9% in clinical studies. Initial administration typically involves 4 mg followed by 2 mg after each loose stool, with daily limits up to 16 mg in specialized protocols, though persistence beyond 48 hours necessitates switching to alternatives like to mitigate risks of or incomplete resolution. While effective as first-line symptomatic relief in many cases, evidence from guidelines underscores the need for close monitoring due to variable across chemotherapy regimens and potential for high-dose cardiac complications. Higher-than-standard doses of loperamide are used off-label to control output in high-output or , aiming to reduce fluid losses through enhanced gut motility inhibition; dosing may escalate to 4-16 mg daily or more under specialist supervision, with monitoring for and imbalances essential given the paucity of large randomized trials. Similarly, in chronic diarrheas linked to beyond routine indications, small studies report marked symptom improvement in 68% of cases involving or , though long-term data remain limited and benefits must be balanced against risks of dependency or in active inflammation. Loperamide is also utilized off-label for symptomatic relief of diarrhea in diarrhea-predominant irritable bowel syndrome (IBS-D), with as-needed dosing typically ranging from 2-16 mg daily in divided doses under medical guidance. However, it is not suitable for continuous daily long-term administration, particularly in mixed IBS (IBS-M), due to the risk of exacerbating constipation during non-diarrheal phases; guidelines recommend episodic use to manage acute symptoms while minimizing adverse effects. As an adjunct for mild symptoms, loperamide is sometimes self-administered due to its peripheral mu-opioid agonism alleviating cramps and , but clinical endorsement is absent owing to sparse controlled evidence, high abuse potential, and documented at supratherapeutic doses exceeding 70 mg daily. Case series indicate misuse prevalence aligns with trends, yet prospective studies highlight inefficacy for central symptoms like anxiety and elevated risks of QT prolongation, rendering it unsuitable as formal therapy. Rare palliative use in secretory diarrheas from neuroendocrine tumors, such as , provides transient relief but lacks disease-modifying effects and is overshadowed by somatostatin analogs like , with primary literature emphasizing evidence gaps over routine application.

Pharmacology

Mechanism of Action

Loperamide functions as a selective at mu-opioid receptors located in the of the intestinal wall, where it inhibits the release of and other excitatory neurotransmitters from enteric neurons, thereby suppressing peristaltic contractions and reducing propulsive motility in the gut. This action prolongs intestinal transit time, allowing greater reabsorption of water and electrolytes from luminal contents, which empirically decreases stool volume and frequency in diarrheal states. Manometry studies in humans and animal models confirm this by demonstrating dose-dependent prolongation of small bowel and colonic transit without significant impact on gastric emptying or proximal motility. Additionally, loperamide enhances tone through similar mu-opioid mediated inhibition of inhibitory neural pathways, contributing to fecal continence by resisting premature evacuation. Beyond motility effects, loperamide exerts antisecretory actions by modulating ion transport in intestinal enterocytes, particularly inhibiting cyclic AMP- and calcium-dependent secretion across the mucosal , which reduces fluid accumulation in the gut lumen. This has been observed using Ussing chambers with rabbit ileal mucosa and rat colonic preparations, where loperamide attenuated efflux stimulated by secretagogues like or enterotoxins, and corroborated in studies showing decreased fecal water loss independent of changes. At therapeutic doses (typically 2-16 mg daily), loperamide exhibits minimal systemic activity, lacking analgesia or , due to its recognition as a substrate for (P-gp), an efflux transporter abundantly expressed in the and blood-brain barrier that actively pumps the drug out of enterocytes and back into the gut lumen or excludes it from entry. This peripheral restriction ensures actions remain localized to the , as evidenced by undetectable or low plasma levels post-oral administration and absence of central pupillary effects in pharmacodynamic assessments.

Pharmacokinetics

Loperamide demonstrates poor oral of approximately 0.3%, primarily attributable to extensive first-pass in the liver following absorption from the . Peak plasma concentrations occur 4 to 5 hours post-administration, with levels remaining low even at therapeutic doses; for instance, after a single 2 mg dose, unchanged drug concentrations do not exceed 2 ng/mL. This limited systemic exposure confines its primary effects to peripheral mu-opioid receptors in the gut, as evidenced by plasma assays in clinical pharmacokinetic studies. The drug is highly bound to plasma proteins (97%), which further restricts free fractions available for distribution beyond the gastrointestinal tract. occurs predominantly in the liver via oxidative N-demethylation, mediated by enzymes and CYP2C8, yielding the active metabolite N-desmethyl loperamide. Elimination follows an apparent of 9.1 to 14.4 hours, with the majority (>90%) excreted unchanged in feces via biliary secretion and minimal renal clearance (<1% as parent compound). In chronic therapeutic use, steady-state plasma concentrations remain sub-therapeutic for central nervous system effects, typically ranging from 0.2 to 1.2 ng/mL, as confirmed by assays in dosing trials adhering to recommended limits (up to 16 mg daily). Phase I studies indicate that food intake may delay time-to-peak absorption without significantly altering overall bioavailability.

Blood-Brain Barrier Dynamics

Loperamide, a substrate for the efflux transporter (P-gp, encoded by ABCB1/MDR1), exhibits restricted penetration across the blood-brain barrier (BBB) due to active extrusion from the central nervous system (CNS). At therapeutic doses, typically up to 16 mg per day for adults, P-gp maintains negligible brain concentrations, as evidenced by positron emission tomography (PET) imaging with radiolabeled ¹¹C-loperamide or its N-desmethyl metabolite, which shows low and stable uptake (standardized uptake value ~15%) in human and wild-type rodent brains. In P-gp-deficient mouse models, brain uptake increases dramatically (up to 16-fold), confirming the transporter's causal role in limiting CNS exposure under normal conditions. Supraphysiologic doses, often exceeding 50–100 mg in misuse scenarios, can overwhelm P-gp transport capacity, enabling dose-dependent accumulation in the brain and manifestation of opioid-like central effects such as euphoria or respiratory depression. This saturation mechanism is supported by pharmacokinetic principles and case observations where high plasma levels correlate with CNS penetration, distinct from therapeutic pharmacokinetics where barrier integrity remains intact. Inhibition of P-gp pharmacologically further elevates brain loperamide levels, inducing opioid agonist activity, underscoring the transporter's saturability rather than an absolute barrier. Genetic variants in MDR1, such as the C3435T polymorphism, have been investigated for potential influence on loperamide disposition, but clinical studies in humans demonstrate no significant association with altered plasma concentrations or CNS effects. Population-level data thus indicate limited vulnerability from common polymorphisms at standard doses, reinforcing that BBB dynamics pose no inherent risk in approved use while highlighting dose escalation as the primary disruptor. This distinction counters unsubstantiated concerns of routine CNS liability, grounded instead in transporter kinetics.

Adverse Effects and Safety Profile

Effects at Therapeutic Doses

At therapeutic doses, loperamide primarily causes mild gastrointestinal and central nervous system effects, with constipation reported in 1.7% to 5.3% of patients across clinical trials for acute and chronic diarrhea, alongside abdominal cramps (1.4%), nausea (1.8%), dizziness (1.4%), dry mouth, flatulence, and drowsiness. These effects are typically self-limiting and resolve upon dose reduction or discontinuation, contributing to the drug's established safety profile for short-term antidiarrheal use in adults. Rare serious adverse events at recommended doses include toxic megacolon, particularly in patients with inflammatory bowel disease or conditions impairing intestinal motility, such as ulcerative colitis; loperamide is contraindicated in acute dysentery, pseudomembranous colitis, bacterial enterocolitis caused by invasive organisms, or abdominal pain without diarrhea due to risks of worsening these states by inhibiting peristalsis. In pediatric patients, loperamide is contraindicated for those under 2 years of age owing to the potential for central nervous system depression and serious cardiac events, with cautious use recommended in children aged 2 to 12 years at the lowest effective dose to minimize dehydration risks or variability in response. For breastfeeding, loperamide is excreted into human milk, though at low concentrations; use requires weighing benefits against possible infant effects like constipation or diarrhea, with monitoring advised. Loperamide carries a pregnancy category C designation, with animal reproduction studies showing no evidence of teratogenicity or fetal harm, but limited controlled data in humans; administration is advised only when potential benefits justify possible risks, particularly avoiding unnecessary use in the first trimester. Overall, post-marketing surveillance and controlled trial data affirm a low incidence of severe adverse events at therapeutic doses (typically 4-16 mg/day for adults), supporting its risk-benefit favorability for indicated antidiarrheal therapy.

Overdose and Toxicity Risks

Overdoses of loperamide, typically involving ingestion of 40 to 100 times the recommended therapeutic dose (exceeding 160 mg daily), can precipitate severe gastrointestinal stasis, manifesting as paralytic ileus, megacolon, or toxic megacolon due to exaggerated mu-opioid receptor agonism in the enteric nervous system. Central nervous system effects, including sedation, miosis, and respiratory depression, occur infrequently in isolated loperamide overdose because of poor blood-brain barrier penetration under normal conditions, but may emerge with cofactors such as P-glycoprotein inhibitors (e.g., quinidine) or CYP3A4 inhibitors that elevate plasma concentrations and enable central opioid activity. Cardiac toxicity predominates in severe cases, with doses exceeding 200 mg linked to dose-dependent blockade of the hERG potassium channel, resulting in QT interval prolongation, torsades de pointes, ventricular arrhythmias, syncope, and sudden death; the FDA's Adverse Event Reporting System (FAERS) has documented multiple fatalities in this context, often involving intentional high-dose abuse. Management centers on gastrointestinal decontamination with activated charcoal if ingestion occurred within 1 to 4 hours, alongside supportive measures such as fluid resuscitation, electrolyte correction, and continuous ECG monitoring; for arrhythmias, intravenous magnesium sulfate is indicated to stabilize cardiac membranes, while no specific antidote exists, and naloxone proves ineffective against predominantly peripheral opioid effects. Population-level toxicity risk remains low, with U.S. poison center reports of loperamide-related exposures numbering in the low hundreds annually (e.g., 41 abuse/misuse calls in 2014, rising modestly thereafter) against billions of over-the-counter doses sold yearly, indicating that adverse outcomes stem primarily from deliberate supratherapeutic dosing rather than routine use or inherent pharmacological peril.

Drug Interactions

Pharmacodynamic Interactions

Loperamide, acting as a mu-opioid receptor agonist primarily in the gastrointestinal tract, can interact pharmacodynamically with other agents that modulate intestinal motility. Concomitant use with additional opioid agonists, such as or , leads to additive suppression of peristalsis and prolongation of gut transit time, elevating the risk of severe constipation, paralytic ileus, or toxic megacolon. This potentiation arises from shared agonism at enteric mu-opioid receptors, which inhibit acetylcholine release and reduce propulsive activity. Additive effects also occur with anticholinergic medications, including antispasmodics like dicyclomine or , due to combined inhibition of muscarinic receptors in the gut smooth muscle. Loperamide possesses weak intrinsic antimuscarinic activity, and coadministration exacerbates hypomotility, further increasing susceptibility to constipation and ileus. In terms of cardiac pharmacodynamics, loperamide at supratherapeutic concentrations inhibits hERG potassium channels and sodium channels, potentially prolonging the QT interval. Concurrent use with other QT-prolonging drugs, such as fluoroquinolone antibiotics (e.g., moxifloxacin) or macrolides (e.g., erythromycin), may synergistically heighten the risk of QTc prolongation and torsades de pointes via compounded ion channel blockade, even if loperamide remains at therapeutic levels. Caution is warranted, as case reports document amplified arrhythmogenic potential in such combinations. Prokinetic agents like metoclopramide, which promote gastrointestinal motility through dopamine D2 antagonism and enhanced acetylcholine release, can antagonize loperamide's antimotility effects, potentially diminishing its antidiarrheal efficacy. This opposition, while not always resulting in clinically documented interactions, stems from mechanistic counteraction on enteric neural pathways.

Pharmacokinetic Interactions

Loperamide undergoes extensive first-pass metabolism primarily via oxidative N-demethylation by and CYP2C8 enzymes in the liver, with limited oral bioavailability of approximately 0.3% due to this process and efflux in the gut. Concomitant administration of strong inhibitors, such as ketoconazole or ritonavir, significantly elevates loperamide plasma concentrations by inhibiting its metabolism; for instance, coadministration with ketoconazole increased area under the curve (AUC) by approximately 5-fold and maximum concentration (C_max) by 3- to 4-fold in pharmacokinetic studies. Similarly, CYP2C8 inhibitors like gemfibrozil can raise plasma levels up to 4-fold, amplifying risks of toxicity including QT prolongation at supratherapeutic exposures. P-gp inhibitors, such as quinidine, primarily enhance central nervous system penetration of loperamide rather than substantially altering systemic plasma levels, as demonstrated in studies where quinidine coadministration increased brain uptake without proportional changes in peripheral concentrations, leading to opioid-like effects including miosis and respiratory depression. This interaction exploits loperamide's substrate affinity for P-gp at the blood-brain barrier, potentially enabling euphoria or abuse when combined, though plasma elevations remain modest (2- to 3-fold at most). CYP3A4 inducers like rifampin decrease loperamide exposure by accelerating its metabolism, potentially reducing antidiarrheal efficacy in patients on chronic polypharmacy; while direct interaction studies are limited, general pharmacokinetic principles for CYP3A4 substrates predict substantial reductions in AUC (up to 90% in analogous cases), necessitating dose adjustments or monitoring of therapeutic response. These pharmacokinetic alterations underscore the need for caution in polypharmacy, particularly with antiretrovirals or antifungals that overlap inhibitory effects.

Abuse, Misuse, and Controversies

Motivations for Abuse

Loperamide misuse primarily stems from its exploitation as an inexpensive opioid surrogate to produce euphoria or mitigate withdrawal symptoms amid tightened restrictions on prescription opioids and heroin. Case series and user reports document abusers consuming 50–300 mg daily—exceeding therapeutic limits by over tenfold—to bypass P-glycoprotein efflux and achieve central opioid agonism. This pattern emerged as individuals with opioid use disorder sought unregulated alternatives during the post-2010 escalation of regulatory crackdowns on controlled analgesics. Over-the-counter status, exemplified by formulations like Imodium A-D, lowers barriers to procurement for self-treatment, enabling rapid escalation in dependent users facing scarcity. Yet, abuse remains rare, with U.S. poison center data logging fewer than 200 intentional misuse exposures annually through 2016 despite millions of opioid-dependent individuals, equating to under 1% involvement per national surveys of substance users. Such sparsity highlights misuse as driven by individual volition rather than inherent product flaws or broad accessibility failures. Poison control trends reveal a 91% surge in loperamide exposures from 2010 to 2015, temporally aligned with opioid prescription curbs, but without substantiation for a gateway role in broader escalation—therapeutic consumers overwhelmingly adhere to labeled dosing without progression. Empirical tracking via the National Poison Data System underscores that reported incidents, while rising modestly, constitute a marginal fraction of overall opioid-related calls, affirming limited propagation beyond self-selected cohorts.

Physiological Effects of High-Dose Use

At sufficiently high doses, typically exceeding 70 mg daily, loperamide saturates (P-gp) efflux pumps at the blood-brain barrier, enabling significant central nervous system penetration and mu-opioid receptor agonism. This results in opioid-mimetic effects including sedation, euphoria, analgesia, and respiratory depression, akin to low-potency mu-agonists such as codeine, though with delayed onset due to loperamide's pharmacokinetics. Receptor saturation models, supported by pharmacokinetic studies, predict these outcomes as plasma concentrations rise to levels where P-gp transport capacity is overwhelmed, allowing cerebrospinal fluid accumulation and direct brainstem mu-receptor activation. Autopsy data from overdose cases corroborate central opioid effects, with histopathological evidence of hypoxic neuronal injury consistent with respiratory depression, though often confounded by concurrent cardiotoxicity. Chronic high-dose administration induces tolerance to central mu-agonism, necessitating dose escalation—often to hundreds of milligrams daily—to sustain effects, mirroring classical opioid pharmacodynamics where receptor downregulation and desensitization occur. Withdrawal upon cessation manifests as standard opioid abstinence syndrome, featuring anxiety, myalgias, piloerection, and dysphoria, but uniquely complicated by gastrointestinal dysmotility; abrupt discontinuation exacerbates intestinal hypermotility and secretory diarrhea due to unopposed rebound from loperamide's peripheral antisecretory actions. These symptoms can be mitigated by mu-agonists like buprenorphine, underscoring shared mechanistic pathways with other opioids. Therapeutic doses (≤16 mg/day) exhibit negligible addictive liability, as P-gp restriction precludes meaningful CNS exposure and reward signaling. High-dose dependency remains uncommon outside contexts of pre-existing substance use disorders, where individuals exploit loperamide's availability to self-medicate opioid withdrawal, rather than initiating de novo abuse. This pattern aligns with loperamide's low intrinsic reward potency compared to centrally acting opioids, limited by its partial agonism profile and pharmacokinetic barriers at non-excessive exposures.

Cardiovascular Complications

High doses of loperamide potently inhibit the human ether-à-go-go-related gene (hERG) potassium channel, delaying cardiac repolarization and prolonging the QTc interval on electrocardiograms, with values exceeding 500 ms documented in clinical cases of abuse. This mechanism underlies ventricular arrhythmias, including , polymorphic ventricular tachycardia, and sudden cardiac arrest, as evidenced by case series linking supratherapeutic ingestion (typically 50–300 mg daily) to these outcomes. Empirical ECG data from affected patients confirm causality through reversal of abnormalities following drug cessation and supportive care, though persistent QTc prolongation has been observed for weeks post-exposure in chronic abusers. Surveillance reports highlight these risks in misuse contexts, with the Centers for Disease Control and Prevention documenting cardiac dysrhythmias and four deaths among 195 U.S. poison center cases involving loperamide abuse from January to June 2016 alone. Medical examiner reviews of fatalities frequently identify loperamide as contributory or primary, often alongside polydrug use (e.g., opioids or sedatives), which amplifies exposure via pharmacokinetic interactions like or inhibition. In one analysis of 21 North Carolina deaths, the drug was deemed additive or causal in 19 instances, underscoring the role of elevated serum levels in arrhythmogenesis. At recommended therapeutic doses (≤16 mg/day), cardiovascular events remain rare, with randomized trials showing no QTc prolongation of clinical concern even at single supratherapeutic doses up to 48 mg. The U.S. Food and Drug Administration's 2016 warning emphasized high-dose risks based on post-marketing reports of QT prolongation and arrhythmias, but these were exceptional relative to widespread safe use.

Public Health and Regulatory Responses

In response to reports of loperamide abuse leading to cardiac toxicity, the U.S. Food and Drug Administration (FDA) issued a safety communication on June 7, 2016, warning of serious heart rhythm problems, including QT prolongation and torsades de pointes, associated with doses exceeding recommended therapeutic levels of up to 16 mg per day. On January 30, 2018, the FDA announced voluntary packaging limits for over-the-counter loperamide products, capping cartons at 48 mg total (equivalent to a three-day supply at maximum approved doses) and requiring unit-dose blister packaging to deter bulk ingestion for non-medical purposes; these measures were approved for implementation by September 2019. Data from the National Poison Data System indicate these interventions correlated with a decline in loperamide-related exposures involving abuse or intentional misuse, which peaked at a rate of 0.02 per 1,000 total exposures in 2015 before decreasing to 0.01 by 2022, reflecting roughly a 50% reduction in abuse-associated cases post-restrictions, though overall exposures remained stable. This outcome suggests efficacy in curbing reported overdoses through reduced accessibility of large quantities, as poison center calls for serious outcomes (e.g., cardiac events) also trended downward after 2016. However, critics argue such limits may inadvertently elevate black-market sourcing or substitution with more hazardous alternatives, potentially offsetting public health gains without comprehensive evidence of net harm reduction. Internationally, loperamide remains available over-the-counter without U.S.-style quantity caps in numerous countries, including much of and , where abuse incidence appears lower relative to opioid epidemic contexts, prompting questions about the necessity of stringent U.S. measures amid varying baseline risks. Regulatory divergences highlight potential over-reliance on paternalistic restrictions in the U.S., which may impede legitimate access for scenarios like extended travel or acute diarrhea outbreaks, where self-limiting therapeutic use predominates and severe self-harm remains rare outside vulnerable subpopulations. Emphasis on education regarding dose limits and cardiac risks, rather than packaging constraints, could better promote personal responsibility while preserving utility for the majority of users. Market data from 2023 onward show steady global sales growth, projected to rise from approximately USD 3.5 billion in 2025 to USD 5.2 billion by 2032 at a compound annual growth rate of around 5-6%, indicating no disruption to therapeutic demand or emergence of an abuse-driven epidemic despite warnings. This stability underscores that regulatory responses have mitigated acute misuse signals without broader supply chain impacts, though ongoing surveillance is warranted to assess unintended access barriers.

Chemistry

Chemical Structure and Properties

Loperamide hydrochloride is the hydrochloride salt form of 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide, with the molecular formula C29H34Cl2N2O2 and a molecular weight of 513.5 g/mol. The compound is achiral, possessing no stereocenters, which eliminates the need for stereochemical control in synthesis or to ensure therapeutic consistency. Loperamide exhibits high , characterized by an (logP) of 5.13, contributing to its limited of approximately 0.14 g/100 mL at 1.7 and slight in neutral . The salt form enhances in dilute acids compared to the , facilitating dissolution in gastrointestinal conditions. Freely soluble in organic solvents such as and , it supports various extraction and analytical procedures. The of loperamide is 223–225 °C, indicating stability suitable for solid oral like capsules, tablets, and liquids. It remains stable under physiological conditions (approximately 1.2–7.4 in the ), with a pKa of 8.66 ensuring and cationic form predominance at these values, which minimizes degradation and supports consistent in formulations.
PropertyValueSource
Molecular Weight513.5 g/molPubChem
logP5.13PubChem
Melting Point223–225 °CChemicalBook
Water Solubility (pH 1.7)0.14 g/100 mLScienceDirect
United States Pharmacopeia (USP) specifications require loperamide hydrochloride to contain not less than 98.0% and not more than 102.0% of the labeled amount on the dried basis, ensuring high purity for pharmaceutical consistency.

Synthesis Methods

The original Janssen process for loperamide synthesis centers on the condensation of 3,3-diphenyltetrahydro-2-furylidene(dimethyl)ammonium bromide with 4-(4-chlorophenyl)-4-piperidinol in the presence of sodium carbonate and catalytic potassium iodide, conducted under reflux in solvents such as 4-methyl-2-pentanone for 15-39 hours. The piperidinol intermediate is obtained via Grignard addition of p-chlorophenylmagnesium bromide to methyl 3-methyl-4-oxo-1-piperidinecarboxylate, followed by hydrolysis with potassium hydroxide in 2-propanol. This route delivers overall yields exceeding 80% on laboratory scale, supporting efficient pharmaceutical production. Subsequent variants prioritize process optimization for industrial scalability, retaining the key nucleophilic while substituting safer solvents to minimize hazards. One approach employs glycerol formal (3-5 mL per gram of ) at 55-65°C with 1.1 equivalents of the piperidinol and base, achieving completion in under 3 hours and a 67% yield, thereby avoiding toxic alternatives like . These modifications reduce reaction times and environmental risks without altering core intermediates. Recent emphases in synthesis lie in rigorous impurity profiling and purification protocols to ensure compliance with standards, as no s introduce novel core methodologies.

History

Development and Early Research

Loperamide hydrochloride was first synthesized in 1969 by at Janssen Pharmaceutica in , as part of efforts to develop potent antidiarrheal agents with reduced central effects compared to existing compounds like diphenoxylate. Preclinical animal studies conducted in the early 1970s, including evaluations in rats, dogs, and rabbits, confirmed loperamide's high antidiarrheal potency by slowing intestinal motility and affecting water and electrolyte movement, while demonstrating no significant addiction liability or central nervous system depression akin to codeine. These investigations, such as subacute and chronic toxicity assessments published in 1974, further validated its selectivity for peripheral mu-opioid receptors in the gut, with minimal analgesia in standard pain models indicating restricted blood-brain barrier penetration. By the mid-1970s, phase III clinical trials had substantiated loperamide's efficacy for acute nonspecific and its margin suitable for over-the-counter use, culminating in U.S. approval on December 28, 1976, for marketing as Imodium capsules at a 2 mg dose. This timeline reflected empirical progression from synthesis to validated therapeutic application, prioritizing agents that mitigated without the abuse risks of centrally acting opioids.

Regulatory Approval and Post-Market Surveillance

Loperamide was approved for medical use in the in 1976 and by the U.S. (FDA) that same year for the symptomatic control of acute nonspecific and chronic associated with . The (WHO) has included loperamide on its Model List of , recognizing its role in managing , particularly in resource-limited settings for conditions like traveler's . This status underscores its established efficacy at recommended doses for reducing intestinal motility without systemic effects due to poor blood-brain barrier penetration and efflux. Post-marketing surveillance, particularly through the FDA Adverse Event Reporting System (FAERS) and U.S. poison center data, identified rising signals of misuse starting around 2010, with reports of high-dose ingestion for opioid withdrawal self-management or euphoria, often exceeding 100 mg daily. These trends prompted the FDA to issue a Drug Safety Communication on June 7, 2016, warning of serious cardiac risks including QT prolongation, torsades de pointes, and ventricular arrhythmias associated with supratherapeutic doses beyond the approved OTC maximum of 8 mg per day or prescription limit of 16 mg per day. In response, product labels were updated to emphasize these dose limits, contraindicate use in patients with cardiac conditions or concurrent QT-prolonging drugs, and advise against misuse for opioid substitution. Similar alerts emerged from the European Medicines Agency and UK Medicines and Healthcare products Regulatory Agency, noting comparable cardiac events from abuse. To mitigate abuse potential, the FDA mandated packaging restrictions in September 2019, limiting over-the-counter cartons to no more than 48 mg total (e.g., 24 capsules of 2 mg each) and requiring packs or individual dosing units to discourage bulk consumption. Surveillance data into the 2020s, including poison center reports through 2021 showing stabilized but persistent misuse cases, have not led to market withdrawal, as therapeutic benefits at labeled doses outweigh risks for approved indications, with no evidence of widespread inefficacy or unacceptable safety profiles in standard use. Loperamide continues to be recommended in protocols for acute management, including in WHO-supported kits, affirming its ongoing regulatory endorsement amid vigilant monitoring.

Society and Culture

In the , loperamide is classified as an over-the-counter (OTC) medication without federal scheduling under the , reflecting its historically low abuse potential following decontrol in 1982 after initial Schedule V placement. However, in response to rising reports of misuse for opioid-like effects via high dosing, the FDA issued warnings in 2018 about serious cardiac risks and facilitated voluntary manufacturer agreements in 2019 to restrict packaging: single cartons limited to 48 mg maximum (e.g., 12 capsules of 4 mg each), with packaging for individual doses to deter bulk purchases for . These measures maintain OTC access for therapeutic use while curbing mega-dosing, with no shift to prescription-only status as of 2025. In the , loperamide is designated a (P) medicine, available OTC but requiring supervision and sale from behind the counter, not general retail shelves, for adults treating acute ; prescription is mandated for children under 12 or chronic conditions. Across the , availability varies by member state but generally permits OTC purchase in pharmacies without a prescription for short-term adult use, often with dosage limits (e.g., 16 mg daily maximum) and pharmacist advice to prevent misuse, though not uniformly scheduled as controlled. Globally, loperamide remains unscheduled and freely available OTC or in pharmacies in most countries, including many low-regulation markets in , , and , with rare outright bans—such as Pakistan's 1990 prohibition on pediatric formulations due to concerns unrelated to . Documented misuse cases cluster primarily in high-income nations like the amid broader epidemics, rather than correlating with lax availability elsewhere, indicating limited spikes in diversion or in unrestricted settings based on available data. The global loperamide market, predominantly composed of generic formulations, was valued at approximately USD 1.25 billion in 2024. Projections indicate growth at a (CAGR) of 5% through 2033, reaching USD 1.85 billion, fueled by rising incidences of gastrointestinal disorders such as associated with traveler's issues, infections, and chronic conditions, alongside market expansion in emerging economies with improving healthcare access. Alternative analyses estimate a slightly higher baseline for loperamide at USD 3.52 billion in 2025, with a 5.75% CAGR to USD 5.21 billion by 2032, reflecting sustained demand for over-the-counter treatments. Loperamide's low production and wholesale costs, typically $0.01 to $0.05 per 2 mg dose for generics, facilitate broad accessibility in both developed and developing regions, underpinning its market resilience. In the United States, retail prices for generic 2 mg tablets average around $0.06 per unit in bulk purchases, further emphasizing cost-effectiveness despite occasional branded premiums. U.S. sales volumes have remained stable post-2018 FDA-imposed restrictions limiting carton quantities to 48 mg maximum and mandating , suggesting inelastic demand driven by essential therapeutic use rather than abuse-related fluctuations. Primary production occurs in and , with accounting for the majority of global exports of finished loperamide products (over 5,700 shipments recorded) and dominating active pharmaceutical (API) supply chains due to cost advantages and scale. No significant supply shortages have been reported, though regulatory shifts toward unit-dose packs have marginally elevated expenses without disrupting overall availability.

Brand Names and Formulations

Loperamide is primarily marketed under the brand name Imodium by Janssen Pharmaceutica, a of marketed through , with numerous generic equivalents available globally, including store brands such as Diamode and Equate Anti-Diarrheal. Available formulations include immediate-release 2 mg capsules, film-coated tablets, and softgel capsules for standard adult administration; chewable tablets, frequently combined with simethicone to address associated gas and ; orodispersible tablets designed to dissolve rapidly on the tongue for improved compliance in patients with difficulties; and oral solutions at 1 mg per 7.5 mL or 2 mg per 15 mL concentrations, facilitating precise dosing for pediatric or low-volume needs. No extended-release formulations exist, as loperamide's therapeutic effect stems from localized agonism in the intestinal mucosa with negligible systemic absorption ( <1%), rendering sustained-release unnecessary for its rapid, gut-confined action. FDA-approved generic versions of these formulations are bioequivalent to Imodium capsules or caplets, meeting pharmacokinetic criteria for area under the curve and maximum concentration within 80-125% of the reference product, ensuring equivalent clinical performance irrespective of variations that do not alter the active moiety's gut-limited profile.

References

  1. https://go.drugbank.com/drugs/DB00836
  2. https://www.ncbi.nlm.nih.gov/books/NBK557885/
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Loperamide
  4. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-heart-problems-high-doses-antidiarrheal
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC6931594/
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC8792126/
  7. https://www.mayoclinic.org/diseases-conditions/food-poisoning/diagnosis-treatment/drc-20356236
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC7119329/
  9. https://www.drugs.com/dosage/loperamide.html
  10. https://reference.medscape.com/drug/imodium-k-pek-ii-loperamide-342041
  11. https://www.gastrojournal.org/article/S0016-5085%2876%2980303-4/fulltext
  12. https://www.sciencedirect.com/science/article/pii/S0016508576803034
  13. https://www.drugs.com/loperamide.html
  14. https://pubmed.ncbi.nlm.nih.gov/28627732/
  15. https://onlinelibrary.wiley.com/doi/abs/10.1111/bcpt.12830
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC4420828/
  17. https://jhoponline.com/issue-archive/2012-issues/december-2012-vol-3-no-4/15408:chemotherapy-unduced-diarrhea-options
  18. https://www.sciencedirect.com/science/article/pii/S0885392499001499
  19. https://www.sps.nhs.uk/articles/using-loperamide-in-high-output-stoma-or-short-bowel-syndrome/
  20. https://pubmed.ncbi.nlm.nih.gov/7101949/
  21. https://www.mdcalc.com/guidelines/10450/aga/pharmacological-management-irritable-bowel-syndrome-diarrhea-ibs-d
  22. https://iffgd.org/gi-disorders/long-term-use-of-loperamide/
  23. https://pubmed.ncbi.nlm.nih.gov/30585509/
  24. https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1449
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC3492991/
  26. https://www.sciencedirect.com/science/article/abs/pii/001650858690079X
  27. https://link.springer.com/article/10.1007/BF02047873
  28. https://www.karger.com/Article/Pdf/90308
  29. https://jpet.aspetjournals.org/article/S0022-3565%2824%2938892-5/abstract
  30. https://www.sciencedirect.com/science/article/abs/pii/0014299988907169
  31. https://onlinelibrary.wiley.com/doi/full/10.1211/jpp.62.04.0001
  32. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017694s050lbl.pdf
  33. https://pubmed.ncbi.nlm.nih.gov/438356/
  34. https://www.pharmacytimes.com/view/loperamide-danger-of-elevated-plasma-concentrations
  35. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021855s000_ClinPharmR.pdf
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC2856602/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC2792991/
  38. https://jnm.snmjournals.org/content/49/4/649
  39. https://journalce.powerpak.com/ce/pharmacist-review-of-loperamide-abuse
  40. https://www.mdpi.com/1422-0067/23/22/14125
  41. https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1016/S0009-9236%2803%2900234-0
  42. https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1016/S0009-9236%252803%252900234-0
  43. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017694s052lbl.pdf
  44. https://www.medsafe.govt.nz/profs/datasheet/d/diamidereliefcap.pdf
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC6663275/
  46. https://pubmed.ncbi.nlm.nih.gov/28073687/
  47. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050587
  48. https://academic.oup.com/ehjcr/article/3/4/1/5575238
  49. https://www.upstate.edu/poison/pdf/loperamide.pdf
  50. https://www.emdocs.net/loperamide-toxicity/
  51. https://pubmed.ncbi.nlm.nih.gov/27995643/
  52. https://www.sciencedirect.com/science/article/abs/pii/S0736467917302305
  53. https://www.ncbi.nlm.nih.gov/books/NBK594999/
  54. https://www.pdr.net/drug-summary/Loperamide-Hydrochloride-loperamide-hydrochloride-2664
  55. https://www.drugs.com/interactions-check.php?drug_list=288-8719,1482-0&professional=1
  56. https://www.drugs.com/interactions-check.php?drug_list=1482-0,1617-0&professional=1
  57. https://my.clevelandclinic.org/health/drugs/20481-loperamide-solution
  58. https://www.goodrx.com/metoclopramide/interactions
  59. https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/j.1875-9114.1989.tb04130.x
  60. https://www.hep-druginteractions.org/interactions/42854
  61. https://pubmed.ncbi.nlm.nih.gov/11014404/
  62. https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.910684/full
  63. https://www.pharmacytimes.com/view/drug-interactions-with-cyp3a4-an-update
  64. https://pubmed.ncbi.nlm.nih.gov/11719726/
  65. https://www.cdc.gov/mmwr/volumes/65/wr/mm6545a7.htm
  66. https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1885
  67. https://pubmed.ncbi.nlm.nih.gov/27823872/
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC5468105/
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC3633632/
  70. https://injepijournal.biomedcentral.com/articles/10.1186/s40621-023-00473-2
  71. https://pubmed.ncbi.nlm.nih.gov/20604828/
  72. https://onlinelibrary.wiley.com/doi/10.1111/dar.13860
  73. https://pubmed.ncbi.nlm.nih.gov/29759761/
  74. https://www.cureus.com/articles/37853-loperamide-induced-torsades-de-pointes
  75. https://www.heartrhythmcasereports.com/article/S2214-0271%2818%2930261-6/fulltext
  76. https://pubmed.ncbi.nlm.nih.gov/27474361/
  77. https://www.sciencedirect.com/science/article/pii/S0379073824002111
  78. https://www.sciencedirect.com/science/article/pii/S2949962324000020
  79. https://www.fda.gov/drugs/drug-safety-and-availability/fda-limits-packaging-anti-diarrhea-medicine-loperamide-imodium-encourage-safe-use
  80. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-approves-new-packaging-brand-name-over-counter-loperamide-help-curb-abuse-and-misuse
  81. https://www.coherentmarketinsights.com/industry-reports/loperamide-hydrochloride-market
  82. https://pubchem.ncbi.nlm.nih.gov/compound/Loperamide-Hydrochloride
  83. https://gsrs.ncats.nih.gov/ginas/app/beta/substances/77TI35393C
  84. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8758181.htm
  85. https://www.sigmaaldrich.com/US/en/product/sigma/l4762
  86. https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/loperamide-hcl-rb-notice-20200529.pdf
  87. https://patents.google.com/patent/US3714159A/en
  88. https://patents.google.com/patent/EP2132175B1/en
  89. https://www.researchgate.net/publication/8221460_LC-MS_determination_and_bioavailability_study_of_loperamide_hydrochloride_after_oral_administration_of_loperamide_capsule_in_human_volunteers
  90. https://pubmed.ncbi.nlm.nih.gov/4479778/
  91. https://www.gov.uk/drug-safety-update/loperamide-imodium-reports-of-serious-cardiac-adverse-reactions-with-high-doses-of-loperamide-associated-with-abuse-or-misuse
  92. https://pmc.ncbi.nlm.nih.gov/articles/PMC10668506/
  93. https://combatmedicine101.com/loperamide/
  94. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/loperamide-marketed-imodium-d-information
  95. https://www.nhs.uk/medicines/loperamide/who-can-and-cannot-take-loperamide/
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC10379004/
  97. https://www.researchgate.net/publication/309706292_Epidemiologic_Trends_in_Loperamide_Abuse_and_Misuse
  98. https://www.verifiedmarketreports.com/product/loperamide-market/
  99. https://www.pharmacychecker.com/loperamide/
  100. https://www.volza.com/p/loperamide/export/export-from-india/
  101. https://www.nbinno.com/article/active-pharmaceutical-ingredients-apis/global-supply-of-loperamide-hcl-benefits-of-china-manufacturers-ow
  102. https://www.drugs.com/ingredient/loperamide.html
  103. https://www.drugs.com/condition/diarrhea.html
  104. https://my.clevelandclinic.org/health/drugs/18425-loperamide-simethicone-chewable-tablets
  105. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_019860.pdf
  106. https://www.accessdata.fda.gov/drugsatfda_docs/anda/2000/75-232_Loperamide_bioeqr.pdf
Add your contribution
Related Hubs
Contribute something
User Avatar
No comments yet.