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Loperamid
C07080 · Tebloc · utanamide · LOPERAMIDE · Loperamide Monomer · Loperamide USP/EP/BP · 4-(4-chlorophenyl)-n,n-dimethyl-alpha · 4-(4-chlorophenyl)-n,n-dimethyl-alpha,alpha-diphenyl-4-hydroxy-1-piperidineb
Identifikatoren & physikalische Daten
| CAS No. | 53179-11-6 |
|---|---|
| Summenformel | C29H33ClN2O2 |
| Durchschnittliche Molmasse | 477 g/mol |
| Monoisotopische Masse | 476,22305598 g/mol |
| SMILES | CN(C)C(=O)C(CCN1CCC(O)(c2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1 |
| InChIKey | RDOIQAHITMMDAJ-UHFFFAOYSA-N |
| PubChem CID | 3955 |
| ChEMBL | CHEMBL841 |
| ChEBI | CHEBI:6532 |
| EC No. | 258-416-5 |
| DTXSID | DTXSID6045165 |
| Lokaler Name | Loperamid |
Chemische & physikalische Eigenschaften
| XLogP | 5 |
|---|---|
| Polarare Oberfläche (TPSA) | 43,8 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 3 |
| Frei drehbare Bindungen | 7 |
| Schwere Atome | 34 |
| Formalladung | 0 |
| Komplexität | 623 |
| Stoffklassen | Pharmaceutical |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| Human Drugs | Breast FeedingLactationMilk, HumanAntidiarrhealsGastrointestinal AgentsPharmaceuticalsMedicines for other common symptoms in palliative care |
| Schmelzpunkt | 220-228 |
| Physical Description | Solid |
| Ionization Efficiency | Positive5.263600442.7Thermo LTQElectrospray ionizationformic acid (5.3nM) |
| Collision Cross Section | 222.7 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]218.84 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards] |
| Other Experimental Properties | Crystals from isopropanol. MP: 222-223 °C. UV Max (0.1N HCl.2-propanol, 10.90 v/v): 253, 259, 265, 273 nm (epsilon 532, 648, 581, 233). Freely soluble in chloroformslightly soluble in dilute acidsvery slightly soluble in isopropyl alcohol. Solubility (g/100 mL): water (pH 7.1) 0.14citrate-phosphate (pH 6.1) 0.008methanol 28.6ethanol 5.372-propanol 1.11dichloromethane 35.1acetone 0.20ethyl acetate 0.035diethyl ether <0.001hexane <0.001toluene 0.001N,N-dimethylformamide 10.2tetrahydrofuran 0.324-methyl-2-pentanone 0.02propylene glycol 5.64polyethylene glycol 400 1.40dimethylsulfoxide 20.52-butanone 0.18. pKa 8.66. Practically insoluble at physiological pH (0.002%). Stable, can be stored for several years under normal conditionsnot hygroscopicnot affected by light /Loperamide hydrochloride/ |
| Siedepunkt | 647.2±55.0 °C(Predicted) |
| Dichte | 1.187±0.06 g/cm3(Predicted) |
| pKa (Säurekonstante) | pKa 8.66(H2O) (Uncertain) |
| BCS Class | 4 |
| InChI | 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 |
| InChIKey | RDOIQAHITMMDAJ-UHFFFAOYSA-N |
| SMILES | C(C(=O)N(C)C)(CCN1CCC(O)(C2=CC=C(Cl)C=C2)CC1)(C1=CC=CC=C1)C1C=CC=CC=1 |
| LogP (Verteilungskoeffizient) | 2.641 at 25℃ and pH6.95 |
| CAS Datenbank | 53179-11-6(CAS DataBase Reference) |
| NIST chemische Informationen | Loperamide(53179-11-6) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]P264, P270, P301+P316, P321, P330, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 7 reports by companies from 1 notifications to the ECHA C&L Inventory. |
|---|---|
| Regulatorische Informationen | REACH registered substance: Loperamide (EC: 258-416-5) |
| Weitere Sicherheitsinformationen | IMAP assessments - 1-Piperidinebutanamide, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-.alpha.,.alpha.-diphenyl-: Environment tier I assessment |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including loperamide hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Loperamide hydrochloride/The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed over-the-counter drug products, including loperamide hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Loperamide hydrochloride/ |
| Toxic Combustion Products | Special hazards arising from the substance or mixture: Carbon oxides, Nitrogen oxides (NOx), Hydrogen chloride gas /Loperamide hydrochloride/ |
| Hazard Classes and Categories | Acute Tox. 3 (100%) |
| Hazardous Reactivities and Incompatibilities | Incompatible materials: Strong oxidizing agents /Loperamide hydrochloride/ |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Loperamide hydrochloride/Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Loperamide hydrochloride/ |
| Lagerbedingungen | Keep container tightly closed in a dry and well-ventilated place. Light sensitive. /Loperamide hydrochloride/ |
| Reinigungsverfahren | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Loperamide hydrochloride/ |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubberContaminated packaging: Dispose of as unused product. /Loperamide hydrochloride/ |
| Preventive Measures | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. ... /Loperamide hydrochloride/Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Loperamide hydrochloride/Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. /Loperamide hydrochloride/Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Loperamide hydrochloride/SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker. |
| Personal Protective Equipment (PPE) | Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Loperamide hydrochloride/Skin protection: Handle with gloves. /Loperamide hydrochloride/Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Loperamide hydrochloride/Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Loperamide hydrochloride/ |
| Wechselwirkungen | Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both Pglycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages is unknown.Concomitant treatment /of loperamide/ with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.Loperamide is biotransformed in vitro by the cytochromes P450 (CYP) 2C8 and 3A4 and is a substrate of the P-glycoprotein efflux transporter. Our aim was to investigate the effects of itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, and gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics of loperamide. In a randomized crossover study with 4 phases, 12 healthy volunteers took 100 mg itraconazole (first dose 200 mg), 600 mg gemfibrozil, both itraconazole and gemfibrozil, or placebo, twice daily for 5 days. On day 3, they ingested a single 4-mg dose of loperamide. Loperamide and N-desmethylloperamide concentrations in plasma were measured for up to 72 hr and in urine for up to 48 hr. Possible central nervous system effects of loperamide were assessed by the Digit Symbol Substitution Test and by subjective drowsiness. Itraconazole raised the peak plasma loperamide concentration (Cmax) 2.9-fold (range, 1.2-5.0p < 0.001) and the total area under the plasma loperamide concentration-time curve (AUC(0-infinity)) 3.8-fold (1.4-6.6p < 0.001) and prolonged the elimination half-life (t(1/2)) of loperamide from 11.9 to 18.7 hr (p < 0.001). Gemfibrozil raised the Cmax of loperamide 1.6-fold (0.9-3.2P < 0.05) and its AUC(0-infinity) 2.2-fold (1.0-3.7P < 0.05) and prolonged its t(1/2) to 16.7 hr (P < 0.01). The combination of itraconazole and gemfibrozil raised the Cmax of loperamide 4.2-fold (1.5-8.7P < 0.001) and its AUC(0-infinity) 12.6-fold (4.3-21.8P < 0.001) and prolonged the t(1/2) of loperamide to 36.9 hr (p < 0.001). The amount of loperamide excreted into urine within 48 hr was increased 3.0-fold, 1.4-fold and 5.3-fold by itraconazole, gemfibrozil and their combination, respectively (p < 0.05). Itraconazole, gemfibrozil and their combination reduced the plasma AUC(0-72) ratio of N-desmethylloperamide to loperamide by 65%, 46% and 88%, respectively (p < 0.001). No significant differences were seen in the Digit Symbol Substitution Test or subjective drowsiness between the phases. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Although not seen in the psychomotor tests used, an increased risk of adverse effects should be considered during concomitant use of loperamide with itraconazole, gemfibrozil and especially their combination. |
| Hepatotoxicity | As with most opiates in current use, therapy with loperamide has not been linked to serum enzyme elevations. There have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to either agent. The reason for its lack of hepatotoxicity may relate to the low doses used and lack of significant systemic absorption. What loperamide is absorbed is metabolized in the liver. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5.2X10+5(SRC), determined from a structure estimation method(2), indicates that loperamide is expected to be immobile in soil(SRC). The pKa of loperamide is 9.41(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Loperamide is predicted to be not readily biodegradable(5).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5.2X10+5(SRC), determined from a structure estimation method(2), indicates that loperamide is expected to adsorb to suspended solids and sediment(SRC). A pKa of 9.41(3) indicates loperamide will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces is not expected to be an important fate process. According to a classification scheme(4), an estimated BCF of 1200, provided the compound is not metabolized by the organism(SRC), from an estimated log Kow of 5.15(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). Loperamide is predicted to be not readily biodegradable(5).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), loperamide, which has an estimated vapor pressure of 7.9X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase loperamide may be removed from the air by wet and dry deposition(SRC). Loperamide does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC). |
| Unerwünschte Wirkungen | Common Adverse Drug Reactions |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Loperamide is a solid. Loperamide is used in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. HUMAN EXPOSURE AND TOXICITY: Loperamide is an over-the-counter antidiarrheal with mu-opioid agonist activity. Central nervous system opioid effects are not observed after therapeutic oral dosing because of poor bioavailability and minimal central nervous system penetration. However, central nervous system opioid effects do occur after supratherapeutic oral doses. Oral loperamide abuse as an opioid substitute has been seen among patients attempting to self-treat their opioid addiction. Ventricular dysrhythmias and prolongation of the QRS duration and QTc interval have been reported after oral loperamide abuse. In postmarketing experiences, paralytic ileus associated with abdominal distention has been reported rarely. Most of these cases occurred in patients with acute dysentery, following overdosage of the drug, or in children younger than 2 years of age. ANIMAL STUDIES: Loperamide administration significantly suppressed foraging behavior in rats and reduced their body weight. The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anesthetized rats. In a study in rats using loperamide dosages up to 133 times the maximum human dosage (on a mg/kg basis) for 18 months, there was no evidence of carcinogenicity. Beagle dogs were given loperamide in gelatin capsules at 5.0, 1.25 and 0.31 mg/kg six days a week for 12 months. Some depression was seen during the first week of drug administration at 1.25 and 5 mg/kg. Behavior and appearance were normal during the rest of the experiment, except that hemorrhagic stools were seen from time to time at 5 mg/kg and soft stools at 0.31 and 1.25 mg/kg, especially during the first 6 weeks of drug administration. Pregnant primiparous female rats were given loperamide in their diet at 40, 10 and 2.5 mg/100 g of food from day 6 through day 15 of pregnancy. On day 22, fetuses were delivered by caesarean section. At 40 mg/100 g food, only 1 female out of 20 became pregnant. There was no significant difference between the control group and the 2.5 and 10 mg/100 g food-dosed groups in pregnancy ratenumber of implantations per damlitter size, percentage of live, dead and resorbed fetusesdistribution of live, dead and resorbed fetuses in the left and right uterine hornsand body weight of live young. No macroscopic, visceral, or skeletal malformations were seen. Results of in vivo and in vitro studies carried out indicated that loperamide is not genotoxic.When loperamide is taken in large doses or with other drugs that may alter its pharmacokinetic effects, such as p-glycoprotein inhibitors, loperamide produces opioid-like symptoms. These include a sensation of euphoria, miosis, central nervous system depression, and respiratory depression. Treatment of loperamide overdose and toxicity is primarily supportive. Naloxone, including an intranasal naloxone bolus, intravenous naloxone bolus, or naloxone infusion, may be used in patients with respiratory depression. As naloxone has a shorter half-life than loperamide, patients should be observed for at least 24 hours after the last naloxone administration to ensure they do not deteriorate clinically. |
| Ongoing Test Status | EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPAICSS Dashboard ApplicationAvailable from, as of July 7, 2016: http://actor.epa.gov/dashboard/] |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of loperamide can be estimated to be 5.2X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that loperamide is expected to be immobile in soil. The pKa of loperamide is 9.41(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). |
| Human Toxicity Excerpts | /HUMAN EXPOSURE STUDIES/ This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10-30 cm abroad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered./HUMAN EXPOSURE STUDIES/ Loperamide (LOP) is an anti-diarrheal agent which is thought to act largely by slowing transit with an uncertain effect on the fluid content of the small and large bowel in humans. Adding simethicone (SIM) to LOP improves its efficacy, but the mechanism of interaction is unclear. Novel MRI techniques to assess small bowel water content (SBWC) have shown that mannitol solutions markedly increase SBWC and can be used as a model of diarrhea. We aimed to use quantitative MRI techniques to compare the actions in the gut of LOP and LOP + SIM in a model of secretory diarrhoea using mannitol. A total of 18 healthy volunteers ingested capsules containing placebo (PLA) or 12 mg LOP or 12 mg LOP + 125 mg SIM. After 100 min they were given a drink containing 5% mannitol in 350 mL of water. They underwent baseline fasting and postprandial serial MRI scans at 45 min intervals for 4.5 h after ingesting the drink. A range of MRI sequences was acquired to image the gut. LOP and LOP + SIM significantly accelerated gastric emptying (p < 0.03) and reduced SBWC during the late phase (135-270 min after mannitol ingestion), p < 0.009, while delaying arrival of fluid in the ascending colon (AC). The relaxation time T2 of the contents of the AC was reduced by both drugs (p < 0.0001). LOP and LOP + SIM accelerate gastric emptying, but reduce small bowel water content which may contribute to the delay in oral-caecal transit and overall anti-diarrheal effect./HUMAN EXPOSURE STUDIES/ Previous work in our laboratory has found that mild physical activity accelerates mouth-to-large intestinal transit of lactulose in a mixed liquid meal. Because loperamide is commonly used as an antidiarrheal agent, we wondered if it would blunt the orocecal transit acceleration provoked by mild exercise. We investigated this equation in 12 healthy persons by comparing orocolonic liquid transit at rest and in mild exercise. Each subject ingested 8 mg loperamide 1 hr prior to study under both resting and exercise conditions. With loperamide treatment, exercise (walking at 5.6 km/hr) failed to hasten increased H2 excretion (mean transit time 72 +/- 12 min at rest, 90 +/- 15 min in exercisep = NS). This result contrasts sharply with previously reported controls: loperamide completely abolished exercise-induced orocecal transit acceleration (-23 +/- 5 min in controls+18 +/- 13 min with loperamidep < 0.05). Compared with these same controls, resting transit was not significantly slowed by the drug, while transit in exercise was retarded (64 +/- 5 min in controls, 90 +/- 15 min with loperamidep = 0.06). Loperamide left unchanged the heart rate and oxygen uptake rises associated with exercise. In summary, by showing that loperamide blocks an exercise effect on the upper gut, these results suggest that the drug might prove effective in treating some gut symptoms induced by physical activity./SIGNS AND SYMPTOMS/ In cases of overdose (including relative overdose due to hepatic dysfunction), central nervous system depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia, respiratory depression), urinary retention and ileus may occur. Children may be more sensitive to CNS effects than adults.For more Human Toxicity Excerpts (Complete) data for Loperamide (29 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Loperamide's production and administration as a medication(1) and drug of abuse(2) may result in its release to the environment through various waste streams(SRC). It's potential use as a marine anti-fouling agent(3) will result in its direct release to the environment(SRC). |
| Environmental Biodegradation | AEROBIC: Loperamide is predicted to be not readily biodegradable(1). |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)loperamideDILI NegativeOralDOI:10.1016/j.drudis.2019.09.022 |
| Environmental Bioconcentration | An estimated BCF of 1200 was calculated in fish for loperamide(SRC), using an estimated log Kow of 5.15(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC). |
| Gefahrstoffdaten | 53179-11-6(Hazardous Substances Data) |
Anwendungen & Verwendung
Verwenden
Loperamide is presently used more often as an antidiarrheal drug than as an analgesic, and it is also included in the list of over-the-counter drugs because of its insignificant action on the CNS. It reduces intestinal smooth muscle tone and motility as a result of binding to intestinal opiate receptors. It is used for symptomatic treatment of severe and chronic diarrhea of various origins. The most popular synonym for loperamide is imodium.