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Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

Breast Feeding; Lactation; Milk, Human; Antidiarrheals; Gastrointestinal Agents

Pharmaceuticals

Medicines for other common symptoms in palliative care

Positive

5.26360044

2.7

Thermo LTQ

Electrospray ionization

formic acid (5.3nM)

222.7 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

218.84 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

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 chloroform; slightly soluble in dilute acids; very slightly soluble in isopropyl alcohol. Solubility (g/100 mL): water (pH 7.1) 0.14; citrate-phosphate (pH 6.1) 0.008; methanol 28.6; ethanol 5.37; 2-propanol 1.11; dichloromethane 35.1; acetone 0.20; ethyl acetate 0.035; diethyl ether <0.001; hexane <0.001; toluene 0.001; N,N-dimethylformamide 10.2; tetrahydrofuran 0.32; 4-methyl-2-pentanone 0.02; propylene glycol 5.64; polyethylene glycol 400 1.40; dimethylsulfoxide 20.5; 2-butanone 0.18. pKa 8.66. Practically insoluble at physiological pH (0.002%). Stable, can be stored for several years under normal conditions; not hygroscopic; not affected by light /Loperamide hydrochloride/

Danger

H301 (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.

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/

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/

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/

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 scrubber; Contaminated packaging: Dispose of as unused product. /Loperamide hydrochloride/

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.

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/

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, 1.2-5.0; p < 0.001) and the total area under the plasma loperamide concentration-time curve (AUC(0-infinity)) 3.8-fold (1.4-6.6; p < 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 (0.9-3.2; P < 0.05) and its AUC(0-infinity) 2.2-fold (1.0-3.7; P < 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 (1.5-8.7; P < 0.001) and its AUC(0-infinity) 12.6-fold (4.3-21.8; P < 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.

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.

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).

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 rate; number of implantations per dam; litter size, percentage of live, dead and resorbed fetuses; distribution of live, dead and resorbed fetuses in the left and right uterine horns; and 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.

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/[USEPA; ICSS Dashboard Application; Available from, as of July 7, 2016: http://actor.epa.gov/dashboard/]

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 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 exercise; p = 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 loperamide; p < 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 loperamide; p = 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.

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).

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

loperamide

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

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).

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/

A07DA03

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

A07DA03

Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days. While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity. At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na⁺-gated cardiac channels and ether-a-go-go–related gene potassium channels, the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death.

Enteric neurons synthesize and release endogenous opioid peptides and other neurotransmitters, such as acetylcholine and substance P. Endogenous opioids bind to opioid receptors expressed on these neurons to regulate gastrointestinal signalling, motility, and balance of fluids and electrolytes. Loperamide acts on the mu (μ)-opioid receptor expressed on the circular and longitudinal intestinal muscle. Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity. By inhibiting the excitability of enteric neurons, loperamide suppresses neurotransmitter release, pre-synaptic and post-synaptic inhibition of transmission of excitatory and inhibitory motor pathways, and secretomotor pathways. Loperamide inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin. Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools.

... The present study investigates the mechanism of the central analgesic effect of loperamide. Adult male Sprague-Dawley rats were subjected to surgery for catheter placement. Following baseline testing, different groups of rats were administered fixed intrathecal doses (1 ug, 3 ug, 10 ug and 30 ug) of loperamide and morphine. Analgesia was compared employing Hargreaves paw withdrawal apparatus at 15 min, 30 min, 60 min, 90 min and 120 min. Additionally, CTOP, a specific mu-opioid receptor antagonist was co-administered with loperamide to examine the mu-opioid receptor mediated loperamide analgesia. Furthermore, nefiracetam, a calcium channel opener, was co-administered with loperamide or morphine to evaluate the involvement of Ca(2+) channels in loperamide showed an analgesic effect which was comparable to morphine. However, loperamide produced longer analgesia and the analgesic effect was significantly better at 42 hr and 49 hr compared to morphine. CTOP completely reversed loperamide analgesia. Though nefiracetam significantly reversed loperamide analgesia, it did not have any effect on morphine induced analgesia. Our findings suggest that loperamide administered intrathecally produces analgesia which is mediated through mu-opioid receptor and subsequent blockade of downstream calcium channels.

The effects of the antidiarrheal agent loperamide on high-voltage-activated (HVA) calcium channel activity and excitatory amino acid-evoked responses in two preparations of cultured hippocampal pyramidal neurons were examined. In rat hippocampal neurons loaded with the calcium-sensitive dye fura-2, rises in intracellular free calcium concentration ([Ca2+]i) evoked by transient exposure to 50 mM K(+)-containing medium [high extracellular potassium concentration ([K+]o)] were mediated by Ca2+ flux largely through nifedipine-sensitive Ca2+ channels, with smaller contributions from omega-conotoxin GVIA (omega-CgTx)-sensitive Ca2+ channels and channels insensitive to both nifedipine and omega-CgTx. Loperamide reversibly blocked rises in [Ca2+]i evoked by high [K+]o in a concentration-dependent manner, with an IC50 of 0.9 +/- 0.2 microM. At the highest concentration tested (50 microM), loperamide eliminated rises in [Ca2+]i evoked by high [K+]o, a result otherwise achieved only in Ca(2+)-free medium or by the combined application of nifedipine, omega-CgTx, and funnel web spider venom to Ca(2+)-containing medium. The action of loperamide was neither naloxone sensitive nor mimicked by morphine and was seen at concentrations substantially less than those required to block influx of Ca2+ through the N-methyl-D-aspartate (NMDA) receptor-operated ionophore. Similar results were obtained in cultured mouse hippocampal pyramidal neurons under whole-cell voltage clamp. Voltage-activated Ca2+ channel currents carried by barium ions (IBa) could be discriminated pharmacologically into nifedipine-sensitive (L-type) and nifedipine-resistant, omega-CgTx-sensitive (N-type) components. Loperamide (0.1-50 uM) produced a concentration-dependent reduction of the peak IBa with an IC50 value of 2.5 +/- 0.4 uM and, at the highest concentration tested, could fully block IBa in the absence of any other pharmacological agent. The loperamide-induced block was rapid in onset and offset, was fully reversible, and did not appear to be related to the known calmodulin antagonist actions of loperamide. The current-voltage characteristics of the whole-cell IBa were unaffected by loperamide and the block was not voltage dependent. Loperamide also attenuated NMDA-evoked currents recorded at a membrane potential of -60 mV, with an IC50 of 73 +/- 7 uM. The block of NMDA-evoked currents was not competitive in nature, was not reversed by elevation of the extracellular glycine or spermine concentration, and was not affected by changes in the membrane holding potential. Steady state currents evoked by kainate and DL-alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid were, in contrast, relatively unaffected by 100 microM loperamide.

The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anesthetized rats. Both effects were inhibited by the opiate antagonists naloxone and MRZ 2266 BS. Bilateral vagotomy also inhibited both effects whereas atropine only reduced the bradycardia, but the combination of atropine and tertatolol suppressed the bradycardia. A high dose of loperamide induced bradycardia in pithed rats. This effect was prevented by MRZ 2266 BS but not by naloxone. It is concluded that loperamide can elicit a vagally mediated reflex involving vagal and sympathetic mechanisms and could stimulate cardiac opiate receptors, probably kappa, both effects leading to bradycardia.

Motility in the gut is the result of cholinergic and noncholinergic biphasic stimulation of the intestinal musculature. The cholinergic mediator, acetylcholine (ACh), is responsible for the first phase of peristalsis, while prostaglandins (PG) are thought to mediate the second phase. Loperamide has been shown to inhibit release of both ACh and PG from isolated guinea pig ileum, as well as directly block the action of PG on smooth muscle preparations from rats. The net result is a reduction in the number of peristaltic waves, the fluid expelled by each wave, and overall gut motility. Loperamide produces a sustained inhibition of the peristaltic activity of the guinea pig ileum in vitro at doses as low as 0.005 mg/L. The inhibitory effects are dose-related, the activity of both the longitudinal and circular muscles being affected. At dose levels inhibiting peristaltic activity, loperamide antagonizes the spasmogenic effects of electrical- and nicotine-induced stimulation of this preparation. As well, the angiotensin-5- hydroxytryptamine-, bradykinin-barium chloride- and histamine-induced contractions of the guinea pig ileum preparation are inhibited by doses of 0.14 mg/L or more. On the other hand, loperamide is inactive against 5-hydroxytryptamine on the rat fundus, epinephrine on the rabbit spleen, acetylcholine on the rabbit duodenum and isoproterenol on the hen rectal caecum preparations at dose levels of up to 10 mg/L. A moderate negative inotropic effect is produced on the cat papillary muscle at 3 and 10 mg/L, and a moderate negative chronotropic effect is produced on the guinea pig atrium at 0.16 mg/L. This antagonism is thought to be unspecific.

The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 hours.

The apparent elimination half-life of loperamide in healthy adults is 10.8 hours (range 9.1-14.4 hours).

Loperamide is extensively metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, to form N-demethyl loperamide. CYP2B6 and CYP2D6 play a minor role in loperamide N-demethylation. Metabolites of loperamide are pharmacologically inactive.

Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

In contrast with the Parkinson's-like effects associated with the mitochondrial neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroleptic agent haloperidol, there exist no reports on adverse central nervous system (CNS) effects with the structurally related N-substituted-4-arylpiperidin-4-ol derivative and antidiarrheal agent loperamide. Although this difference can be attributed to loperamide's P-glycoprotein substrate properties that prevent it from accessing the brain, an alternative possibility is that loperamide metabolism in humans is different from that of MPTP and haloperidol and does not involve bioactivation to a neurotoxic pyridinium species. In the current study, loperamide bioactivation was examined with particular focus on identification of pyridinium metabolites. A NADPH-dependent disappearance of loperamide was observed in both rat and human liver microsomes (human t(1/2) = 13 min; rat t(1/2) = 22 min). Loperamide metabolism was similar in human and rat and involved N-dealkylation to N-desmethylloperamide (M3) as the principal metabolic fate. Other routes of loperamide biotransformation included N- and C-hydroxylation to the loperamide-N-oxide (M4) and carbinolamide (M2) metabolites, respectively. Furthermore, the formation of an additional metabolite (M5) was also discernible in human and rat liver microsomes. The structure of M5 was assigned to the pyridinium species (LPP(+)) based on comparison of the liquid chromatography/tandem mass spectrometry characteristics to the pyridinium obtained from loperamide via a chemical reaction. Loperamide metabolism in human microsomes was sensitive to ketoconazole and bupropion treatment, suggesting P4503A4 and -2B6 involvement. Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes, whereas P4502B6 was only responsible for N-dealkylation and N-oxidation routes. The wide safety margin of loperamide (compared with MPTP and haloperidol) despite metabolism to a potentially neurotoxic pyridinium species likely stems from a combination of factors that include a therapeutic regimen normally restricted to a few days and the fact that loperamide and perhaps LPP(+) are P-glycoprotein substrates and are denied entry into the CNS. The differences in safety profile of haloperidol and loperamide despite a common bioactivation event supports the notion that not all compounds undergoing bioactivation in vitro will necessarily elicit a toxicological response in vivo.

Loperamide has known human metabolites that include N-Desmethyloperamide.

6X9OC3H4II

LOPERAMIDE

Established Pharmacologic Class [EPC] - Opioid Agonist

Mechanisms of Action [MoA] - Opioid Agonists

Loperamide is an Opioid Agonist. The mechanism of action of loperamide is as an Opioid Agonist.

Loperamide is well absorbed from the gastrointestinal tract; however, it undergoes extensive first-pass metabolism to form metabolites that are excreted in the bile. Therefore, little loperamide actually reaches the systemic circulation. The drug bioavailability is less than 1%. Following oral administration of a 2 mg capsule of loperamide, plasma concentrations of unchanged drug were below 2 ng/mL. Plasma loperamide concentrations are highest approximately five hours after administration of an oral capsule of loperamide and 2.5 hours after the liquid formulation of the drug.

Loperamide and its metabolites in the systemic circulation undergo biliary excretion. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. Only 1% of an absorbed dose excreted unchanged in the urine.

Loperamide has a large volume of distribution. Although highly lipophilic, loperamide does not cross the blood-brain barrier and generally acts peripherally.

Tritium-labelled loperamide was administered orally to eight groups of five fasted male Wistar rats (250 +/- 10 g) at a dosage of 1.25 mg/kg. Urine and feces were collected for up to 4 days. The rats were killed at different times from 1 to 96 hours after drug administration in order to examine blood, organs and tissues. In one rat, the bile was cannulated for 48 hours. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites, and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. Only 5% of the drug and its metabolites was recovered from the urine, the bulk being excreted with the feces. Drug plasma levels were low at all times. Maximum plasma levels of unchanged loperamide did not exceed 0.22% of the administered dose corresponding to about 75 mg/mL of plasma. The gastrointestinal tract contained about 85% of loperamide 1 hour after dosing. Brain levels were extremely low, never exceeding 22 ng/g brain tissue, or 0.005% of the administered dose. The existence of an enterohepatic shunt was shown, but the uptake of the drug into the general circulation was low. Differentiation between total radioactivity and nonvolatile radioactivity demonstrated that most of the residual organ radioactivity was due to tritiated water.

Three male volunteers received orally 2.0 mg of 3H-loperamide (specific activity 64 mCi/mM) in gelatine capsules. Control samples of blood, urine and feces were obtained before administration. Blood was collected on heparin 1, 2, 4, 8, 24, 72 and 168 hours thereafter. Urine was collected for seven days and feces for eight days. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. The fate of orally administered 3H-loperamide in man appeared to be similar to that in rats. The peak plasma level of loperamide occurred 4 hours after treatment and was less than 2 ng/mL or about 0.3% of the administered dose. About 1% of the administered dose was excreted unaltered with the urine and 6% as nonvolatile metabolites. About 40% of the administered dose was excreted with the feces, mainly within the first four days; 30% of this amount was due to unchanged drug.

Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.

Antidiarrheals

MEDICATION

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >250

4-Bromo-2,2-diphenylbutyric acid is converted in a series of reactions to dimethyl(tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide, which is reacted with p-chlorophenyl-4-piperidinol to produce loperamide.

Preparation: Janssen et al., France patent 2100711; eidem, United States of American patent 3714159 (1972, 1973 to Janssen).

Table: Loperamide Hydrochloride Preparations [Table#8355]

Table: Loperamide Hydrochloride Combinations Preparations [Table#8356]