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Identification
Name Loperamide
Accession Number DB00836 (APRD00275)
Type small molecule
Groups approved
Description

One of the long-acting synthetic antidiarrheals; it is not significantly absorbed from the gut, and has no effect on the adrenergic system or central nervous system, but may antagonize histamine and interfere with acetylcholine release locally. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Apo-Loperamide
Diarr-Eze
Imodium
Imodium A-D
Imodium A-D Caplets
Ioperamide
Kaopectate II
Loperacap
Loperamida [INN-Spanish]
Loperamide HCL
Loperamidum [INN-Latin]
Maalox Anti-Diarrheal
Nu-Loperamide
Pepto Diarrhea Control
PMS-Loperamide
Rho-Loperamide
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Brand mixtures Not Available
Categories
  • Antidiarrheals
CAS number 53179-11-6
Weight Average: 477.038
Monoisotopic: 476.223056017
Chemical Formula C29H33ClN2O2
InChI Key InChIKey=RDOIQAHITMMDAJ-UHFFFAOYSA-N
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
Plain Text
IUPAC Name
4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide
SMILES
CN(C)C(=O)C(CCN1CCC(O)(CC1)C1=CC=C(Cl)C=C1)(C1=CC=CC=C1)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenylpiperidines
  • Diphenylmethanes
Substructures
  • Carbonyl Compounds
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Amino Ketones
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Phenylpiperidines
  • Aryl Halides
  • Halobenzenes
  • Alcohols and Polyols
  • Diphenylmethanes
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Piperidines
Pharmacology
Indication For the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease or gastroenteritis. Also used for reducing the volume of discharge from ileostomies.
Pharmacodynamics Loperamide is a synthetic anti-diarrheal indicated for the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. Loperamide is also indicated for reducing the volume of discharge from ileostomies. In man, Loperamide prolongs the transit time of the intestinal contents. It reduces the daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes. Tolerance to the antidiarrheal effect has not been observed. Loperamide is an opioid receptor agonist and acts on the mu opioid receptors in the myenteric plexus large intestines; it does not affect the central nervous system like other opioids. It works specifically by decreasing the activity of the myenteric plexus which decreases the motility of the circular and longitudinal smooth muscles of the intestinal wall. This increases the amount of time substances stay in the intestine, allowing for more water to be absorbed out of the fecal matter. Loperamide also decreases colonic mass movements and suppresses the gastrocolic reflex.
Mechanism of action In vitro and animal studies show that Loperamide acts by slowing intestinal motility and by affecting water and electrolyte movement through the bowel. Loperamide inhibits peristaltic activity by a direct effect on the circular and longitudinal muscles of the intestinal wall. It is a non-selective calcium channel blocker and binds to opioid mu-receptors. Evidence also suggests that at higher concentrations it binds to calmodulin.
Absorption Not significantly absorbed from the gut
Volume of distribution Not Available
Protein binding 97%
Metabolism Hepatic
Route of elimination Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces.
Half life 9.1 to 14.4 hours (average 10.8 hours)
Clearance Not Available
Toxicity Oral, mouse: LD50 = 105 mg/kg. Symptoms of overdose include constipation, drowsiness, lethargy, and nausea.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Mcneil consumer healthcare
  • Mcneil pediatrics
  • Janssen pharmaceutica products lp
Packagers
Dosage forms
Form Route Strength
Solution Oral
Tablet Oral
Prices
Unit description Cost Unit
Loperamide hcl powder 26.01 USD g
Loperamide HCl 2 mg capsule 0.64 USD capsule
Imodium a-d 2 mg caplet 0.49 USD caplet
Imodium advanced caplet 0.46 USD caplet
Imodium ms relief caplet 0.46 USD caplet
Kaopectate 262 mg caplet 0.37 USD caplet
Loperamide 2 mg caplet 0.37 USD caplet
Qc anti-diarrheal adv caplet 0.3 USD caplet
Diamode 2 mg tablet 0.28 USD tablet
Kaopectate 240 mg softgel 0.25 USD softgel capsule
Anti-diarrheal 2 mg caplet 0.18 USD caplet
CVS Pharmacy anti-diarrheal 2 mg caplet 0.14 USD caplet
Kaopectate children's suspension 0.02 USD ml
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DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
Canada 2134611 2002-12-24 2014-10-28
Properties
State solid
Experimental Properties
Property Value Source
melting point 228 °C Not Available
water solubility Slight Not Available
logP 5.5 Not Available
Predicted Properties
Property Value Source
water solubility 8.60e-04 g/l ALOGPS
logP 4.44 ALOGPS
logP 4.77 ChemAxon
logS -5.7 ALOGPS
pKa (strongest acidic) 13.96 ChemAxon
pKa (strongest basic) 9.41 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 43.78 ChemAxon
rotatable bond count 7 ChemAxon
refractivity 139.32 ChemAxon
polarizability 52.67 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07080 Link_out
PubChem Compound 3955 Link_out
PubChem Substance 46504591 Link_out
ChemSpider 3818 Link_out
BindingDB 50017698 Link_out
ChEBI 6532 Link_out
ChEMBL 6532 Link_out
Therapeutic Targets Database DAP000425 Link_out
PharmGKB PA450262 Link_out
Drug Product Database 2240415 Link_out
RxList http://www.rxlist.com/cgi/generic3/loperamide.htm Link_out
Drugs.com http://www.drugs.com/cdi/loperamide.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/imo1206.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Loperamide Link_out
ATC Codes
  • A07DA03
  • A07DA05
AHFS Codes
  • 56:08.00
PDB Entries Not Available
FDA label show (55.5 KB)
MSDS show (73.8 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals. Increase liquid intake.
Targets

1. Mu-type opioid receptor

Pharmacological action: yes
Actions: agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for beta-endorphin

Organism class: human
UniProt ID: P35372 Link_out
Gene: OPRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, Yaksh T: Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502. Pubmed
  2. Tan-No K, Niijima F, Nakagawasai O, Sato T, Satoh S, Tadano T: Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice. Eur J Pharm Sci. 2003 Nov;20(3):357-63. Pubmed
  3. Roge J, Baumer P, Berard H, Schwartz JC, Lecomte JM: The enkephalinase inhibitor, acetorphan, in acute diarrhoea. A double-blind, controlled clinical trial versus loperamide. Scand J Gastroenterol. 1993 Apr;28(4):352-4. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  5. Giagnoni G, Casiraghi L, Senini R, Revel L, Parolaro D, Sala M, Gori E: Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8. Pubmed
  6. di Bosco AM, Grieco P, Diurno MV, Campiglia P, Novellino E, Mazzoni O: Binding site of loperamide: automated docking of loperamide in human mu- and delta-opioid receptors. Chem Biol Drug Des. 2008 Apr;71(4):328-35. Epub 2008 Feb 12. Pubmed

2. Delta-type opioid receptor

Pharmacological action: yes
Actions: agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Highly stereoselective. receptor for enkephalins

Organism class: human
UniProt ID: P41143 Link_out
Gene: OPRD1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Giagnoni G, Casiraghi L, Senini R, Revel L, Parolaro D, Sala M, Gori E: Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8. Pubmed
  3. di Bosco AM, Grieco P, Diurno MV, Campiglia P, Novellino E, Mazzoni O: Binding site of loperamide: automated docking of loperamide in human mu- and delta-opioid receptors. Chem Biol Drug Des. 2008 Apr;71(4):328-35. Epub 2008 Feb 12. Pubmed

3. Kappa-type opioid receptor

Pharmacological action: yes
Actions: agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for dynorphins. May play a role in arousal and regulation of autonomic and neuroendocrine functions

Organism class: human
UniProt ID: P41145 Link_out
Gene: OPRK1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, Yaksh T: Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502. Pubmed

4. Voltage-dependent P/Q-type calcium channel subunit alpha-1A

Pharmacological action: unknown
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the "high-voltage activated" (HVA) group and are blocked by the funnel toxin (Ftx) and by the omega-agatoxin- IVA (omega-Aga-IVA). They are however insensitive to dihydropyridines (DHP), and omega-conotoxin-GVIA (omega-CTx-GVIA)

Organism class: human
UniProt ID: O00555 Link_out
Gene: CACNA1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Church J, Fletcher EJ, Abdel-Hamid K, MacDonald JF: Loperamide blocks high-voltage-activated calcium channels and N-methyl-D-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons. Mol Pharmacol. 1994 Apr;45(4):747-57. Pubmed

5. Corticotropin-lipotropin

Pharmacological action: unknown
Actions: modulator

Beta-endorphin and Met-enkephalin are endogenous opiates

Organism class: human
UniProt ID: P01189 Link_out
Gene: POMC Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nomura A, Iwasaki Y, Aoki Y, Yamamori E, Mutsuga N, Yoshida M, Asai M, Oiso Y, Saito H: Effects of loperamide and other opioid-related substances on the transcriptional regulation of the rat pro-opiomelanocortin gene in AtT20 cells. Neuroendocrinology. 2001 Aug;74(2):87-94. Pubmed
  2. Auernhammer CJ, Stalla GK, Lange M, Pfeiffer A, Muller OA: Effects of loperamide on the human hypothalamo-pituitary-adrenal axis in vivo and in vitro. J Clin Endocrinol Metab. 1992 Aug;75(2):552-7. Pubmed
  3. Ambrosi B, Bochicchio D, Ferrario R, Colombo P, Faglia G: Effects of the opiate agonist loperamide on pituitary-adrenal function in patients with suspected hypercortisolism. J Endocrinol Invest. 1989 Jan;12(1):31-5. Pubmed
  4. Ambrosi B, Bochicchio D, Colombo P, Ferrario R, Faglia G: Loperamide modifies but does not block the corticotropin-releasing hormone-induced ACTH response in patients with Addison’s disease. Horm Metab Res Suppl. 1987;16:74-5. Pubmed
  5. Bochicchio D, Ambrosi B, Faglia G: Loperamide, an opiate analog, differently modifies the adrenocorticotropin responses to corticotropin-releasing hormone and lysine vasopressin in patients with Addison’s disease. Neuroendocrinology. 1988 Dec;48(6):611-4. Pubmed

6. Calmodulin

Pharmacological action: unknown
Actions: inhibitor

Calmodulin mediates the control of a large number of enzymes and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases

Organism class: human
UniProt ID: P62158 Link_out
Gene: CALM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Daly JW, Harper J: Loperamide: novel effects on capacitative calcium influx. Cell Mol Life Sci. 2000 Jan 20;57(1):149-57. Pubmed
  2. Suzuki T, Sakai H, Ikari A, Takeguchi N: Inhibition of thromboxane A(2)-induced Cl(-) secretion by antidiarrhea drug loperamide in isolated rat colon. J Pharmacol Exp Ther. 2000 Oct;295(1):233-8. Pubmed
  3. Mellstrand T: Loperamide—an opiate receptor agonist with gastrointestinal motility effects. Scand J Gastroenterol Suppl. 1987;130:65-6. Pubmed
  4. Stoll R, Ruppin H, Domschke W: Calmodulin-mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum. Gastroenterology. 1988 Jul;95(1):69-76. Pubmed
  5. Diener M, Knobloch SF, Rummel W: Action of loperamide on neuronally mediated and Ca2+- or cAMP-mediated secretion in rat colon. Eur J Pharmacol. 1988 Aug 2;152(3):217-25. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. Pubmed
  2. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed

2. Cytochrome P450 2C8

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed

3. Cytochrome P450 2B6

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed

4. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: substrate, inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wandel C, Kim R, Wood M, Wood A: Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology. 2002 Apr;96(4):913-20. Pubmed
  2. Adachi Y, Suzuki H, Sugiyama Y: Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8. Pubmed
  3. Schinkel AH, Wagenaar E, Mol CA, van Deemter L: P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996 Jun 1;97(11):2517-24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19