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a complex consisting of an organic base in association with hydrogen chloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/04/13 22:36:00」(JST)

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Loperamide /loʊˈpɛrəmaɪd/, a piperidine derivative,^[1] is a drug used against diarrhoea resulting from gastroenteritis or inflammatory bowel disease. It was developed by Janssen in 1971.^[2] In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, Lopedium, Gastro-Stop and Pepto Diarrhea Control. It was developed at Janssen Pharmaceutica.^[3]

Medical uses

Loperamide is effective for the treatment of a number of types of diarrhea.^[4]

Mechanism of action

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; by itself it does not affect the central nervous system. It works similarly to morphine, by decreasing the activity of the myenteric plexus, which in turn decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall.^[5]^[6] 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.^[7]

Ability to cross the blood–brain barrier

It is a misconception that loperamide does not cross the blood–brain barrier. Loperamide does cross this barrier, although it is immediately pumped back out into non–central nervous system (CNS) circulation by P-glycoprotein. While this mechanism effectively shields the CNS from exposure (and thus risk of CNS tolerance/dependence) to loperamide, many drugs are known to inhibit P-glycoprotein and may thus render the CNS vulnerable to opiate agonism by loperamide.^[8]

Concurrent administration of P-glycoprotein inhibitors such as quinidine and its other isomer quinine (although much higher doses must be used), PPIs like omeprazole (Prilosec OTC) and even black pepper (piperine as the active ingredient) could potentially allow loperamide to cross the blood–brain barrier. It should however be noted that only quinidine with loperamide was found to produce respiratory depression, indicative of central opioid action.^[9]

Loperamide has been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal have been observed following abrupt discontinuation of long-term therapy with loperamide.^[10]^[11]

Contraindications

The use of loperamide (Imodium) in children under 2 years is not recommended. There have been rare reports of fatal paralytic ileus associated with abdominal distention. Most of these reports occurred in the setting of acute dysentery, overdose, and with very young children less than two years of age.^[12] In 1990, all pediatric formulations of the antidiarrheal loperamide (Imodium and others) were banned in Pakistan.^[13]

Treatment should be avoided in the presence of high fever or if the stool is bloody (dysentery).^[14] It is of no value in diarrhea caused by cholera, Shigella or Campylobacter.^[14] Treatment is not recommended for patients that could suffer detrimental effects from rebound constipation. If there is a suspicion of diarrhea associated with organisms that can penetrate the intestinal walls, such as E. coli O157:H7 or salmonella, loperamide is contraindicated.^[15]^[16]

Loperamide treatment is not used in symptomatic C. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon.

Loperamide is not recommended in the UK for use during pregnancy nor by nursing mothers.^[17] In the US, loperamide is classified by the FDA as pregnancy category B, and should be used only for 24 hours and after 12 weeks of gestation.^[18]

Loperamide should be administered with caution to patients suffering from hepatic impairment due to reduced first pass metabolism.^[19]

Adverse effects

Adverse drug reactions (ADRs) associated with loperamide include abdominal pain and bloating, nausea, vomiting and constipation. Rare side-effects associated with loperamide are paralytic ileus, dizziness and rashes.In high doses, loperamide in conjunction with Cimetadine, can cause ventricular fibrillation and death.^[20]

The most frequent symptoms of loperamide overdose are drowsiness, vomiting and abdominal pain or burning.^[21]

Hepatic

It is not recommended for use in hepatic failure since it can precipitate hepatic encephalopathy.^[20]

References

^ US National Cancer Institute, Drug Dictionary
^ US Patent Janssen US3714159
^ Stokbroekx, R. A.; Vanenberk, J.; Van Heertum, A. H. M. T.; Van Laar, G. M. L. W.; Van der Aa, M. J. M. C.; Van Bever, W. F. M.; Janssen, P. A. J. (1973). "Synthetic Antidiarrheal Agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides". Journal of Medicinal Chemistry 16 (7): 782–786. doi:10.1021/jm00265a009.
^ Hanauer, S. B. (Winter 2008). "The Role of Loperamide in Gastrointestinal Disorders". Reviews in Gastroenterological Disorders 8 (1): 15–20. PMID 18477966.
^ http://www.drugbank.ca/drugs/DB00836
^ http://www.drugs.com/mmx/loperamide-hydrochloride.html
^ Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.). ISBN 0-07-141092-9. ^{[page needed]}
^ Upton, R. N. (2007). "Cerebral Uptake of Drugs in Humans". Clinical and Experimental Pharmacology and Physiology 34 (8): 695–701. doi:10.1111/j.1440-1681.2007.04649.x. PMID 17600543. edit
^ Sadeque, A. J.; Wandel, C.; He, H.; Shah, S.; Wood, A. J. (September 2000). "Increased Drug Delivery to the Brain by P-glycoprotein Inhibition". Clinical Pharmacology and Therapeutics 68 (3): 231–237. doi:10.1067/mcp.2000.109156. PMID 11014404.
^ Yanagita, T.; Miyasato, K.; Sato, J. (1979). "Dependence Potential of Loperamide Studied in Rhesus Monkeys". NIDA Research Monograph 27: 106–113. PMID 121326.
^ Nakamura, H.; Ishii, K.; Yokoyama, Y. et al. (November 1982). "[Physical Dependence on Loperamide Hydrochloride in Mice and Rats]". Yakugaku Zasshi (in Japanese) 102 (11): 1074–1085. PMID 6892112.
^ "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH.
^ "E-DRUG: Chlormezanone". Essentialdrugs.org.
^ ^a ^b Butler, T. (October 2008). "Loperamide for the Treatment of Traveler's Diarrhea: Broad or Narrow Usefulness?". Clinical Infectious Diseases 47 (8): 1015–1016. doi:10.1086/591704. PMID 18781871.
^ http://www.drugs.com/pro/loperamide.html
^ http://www.peteducation.com/article.cfm?c=0+1303+1459&aid=1432
^ http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Diarrhoea&medicine=imodium
^ Diarrhea During Pregnancy from PregMed.org. September 19th 2013
^ "rxlist.com". 2005.
^ ^a ^b Bichner, F., ed. (2010). Australian Medicine Handbook. Adelaide: Australian Medicine Handbook Pty Ltd.
^ Litovitz, T.; Clancy, C.; Korberly, B.; Temple, A. R.; Mann, K. V. (1997). "Surveillance of loperamide ingestions: An analysis of 216 poison center reports". Journal of toxicology. Clinical toxicology 35 (1): 11–19. doi:10.3109/15563659709001159. PMID 9022646. edit

External links

Imodium Website
Imodium UK Website
Imodium Middle East Website

UpToDate Contents

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廣瀬哲朗,西村充孝,東大介,高橋則尋,山岡竜也,安田勝太郎,石川順英,嶋田俊秀,荻野哲朗,西平友彦
日本消化器外科学会雑誌 43(6), 640-646, 2010-06-01
症例は60歳の女性で,1年前より腸炎症状にて輸液治療をされており,低カリウム,脚力低下にても入院歴あり.本年になり糖尿病指摘.交通事故を契機の精査で膵臓に10cm大の腫瘍を指摘された.治療目的で近隣病院に入院中1日あたり5?8回におよぶ下痢による腎不全となり当院へ転送,循環不全,高度アシドーシス,低カリウムに対し輸液管理,塩酸ロペラミド・酢酸オクトレオチド投与,透析・持続的血液濾過透析で生命維持を …
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藥學雜誌 128(9), 1311-1316, 2008-09-01
… We chose PYY as an index of the intrinsic factor in diarrhea and examined the influence of changes induced in a diarrhea rat model by administration of 4 types of laxative and loperamide hydrochloride (loperamide) as an agent for the treatment of diarrhea. … Next, we examined the influence of loperamide administration on the intestinal mucosa and plasma PYY concentrations in these rats. …
NAID 110006873989

「ロペラミド」

Loperamide
Systematic (IUPAC) name
	4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]- N,N-dimethyl-2,2-diphenylbutanamide
Clinical data
Trade names	Imodium
AHFS/Drugs.com	monograph
MedlinePlus	a682280
Pregnancy cat.	B3 (AU) C (US)
Legal status	Pharmacy Only (S2) (AU) OTC (CA) GSL (UK) OTC (US)
Routes	oral, insufflation
Pharmacokinetic data
Bioavailability	0.3%
Protein binding	97%
Metabolism	Hepatic (extensive)
Half-life	7-14 hours
Excretion	Faeces (30-40%), urine (1%)
Identifiers
CAS number	53179-11-6 ; 34552-83-5 (with HCl)
ATC code	A07DA03; A07DA05 (oxide)
PubChem	CID 3955
DrugBank	DB00836
ChemSpider	3818
UNII	6X9OC3H4II
KEGG	D08144
ChEBI	CHEBI:6532
ChEMBL	CHEMBL841
Synonyms	R-18553
Chemical data
Formula	C29H33ClN2O2
Mol. mass	477.037 g/mol (513.506 with HCl)
	SMILES ClC1=CC=C(C2(CCN(CC2)CCC(C3=CC=CC=C3)(C(N(C)C)=O)C4=CC=CC=C4)O)C=C1;
	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 ; Key:RDOIQAHITMMDAJ-UHFFFAOYSA-N ;
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　　[★]

英: loperamide
化: 塩酸ロペラミド loperamide hydrochloride
商: Imodium。カグダリン、クラレット、タイペミン、ミロピン、ロスポリア、ロペカルド、ロペナ、ロペミック、ロペミン、ロペラン、ロンバニン
関: 止瀉薬; 止しゃ剤，整腸剤

効能又は効果

下痢症

禁忌

1. 出血性大腸炎の患者［腸管出血性大腸菌（Ｏ157等）や赤痢菌等の重篤な細菌性下痢患者では、症状の悪化，治療期間の延長をきたすおそれがある。］
2. 抗生物質の投与に伴う偽膜性大腸炎の患者［症状の悪化，治療期間の延長をきたすおそれがある。］
3. 低出生体重児，新生児および6カ月未満の乳児［外国で、過量投与により、呼吸抑制，全身性痙れん，昏睡等の重篤な副作用の報告がある。］
4. 本剤の成分に対し過敏症の既往歴のある患者

原則禁忌

1. 細菌性下痢患者［治療期間の延長をきたすおそれがある。］
2. 潰瘍性大腸炎の患者［中毒性巨大結腸を起こすおそれがある。］
3. 6カ月以上2歳未満の乳幼児（「小児等への投与」の項参照）

添付文書

http://www.info.pmda.go.jp/go/pack/2319001C2060_1_02/2319001C2060_1_02?view=body

タイペミンカプセル1mg

http://www.info.pmda.go.jp/go/pack/2319001M1264_1_02/2319001M1264_1_02?view=body

「hydrochloride」

　　[★] 塩酸塩、ハイドロクロライド　

[1] US National Cancer Institute, Drug Dictionary

[2] US Patent Janssen US3714159

[3] Stokbroekx, R. A.; Vanenberk, J.; Van Heertum, A. H. M. T.; Van Laar, G. M. L. W.; Van der Aa, M. J. M. C.; Van Bever, W. F. M.; Janssen, P. A. J. (1973). "Synthetic Antidiarrheal Agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides". Journal of Medicinal Chemistry 16 (7): 782–786. doi:10.1021/jm00265a009.

[4] Hanauer, S. B. (Winter 2008). "The Role of Loperamide in Gastrointestinal Disorders". Reviews in Gastroenterological Disorders 8 (1): 15–20. PMID 18477966.

[5] ttp://www.drugbank.ca/drugs/DB00836

[6] ttp://www.drugs.com/mmx/loperamide-hydrochloride.html

[7] Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.). ISBN 0-07-141092-9. ^{[page needed]}

[8] Upton, R. N. (2007). "Cerebral Uptake of Drugs in Humans". Clinical and Experimental Pharmacology and Physiology 34 (8): 695–701. doi:10.1111/j.1440-1681.2007.04649.x. PMID 17600543. edit

[9] Sadeque, A. J.; Wandel, C.; He, H.; Shah, S.; Wood, A. J. (September 2000). "Increased Drug Delivery to the Brain by P-glycoprotein Inhibition". Clinical Pharmacology and Therapeutics 68 (3): 231–237. doi:10.1067/mcp.2000.109156. PMID 11014404.

[10] Yanagita, T.; Miyasato, K.; Sato, J. (1979). "Dependence Potential of Loperamide Studied in Rhesus Monkeys". NIDA Research Monograph 27: 106–113. PMID 121326.

[11] Nakamura, H.; Ishii, K.; Yokoyama, Y. et al. (November 1982). "[Physical Dependence on Loperamide Hydrochloride in Mice and Rats]". Yakugaku Zasshi (in Japanese) 102 (11): 1074–1085. PMID 6892112.

[12] "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH.

[13] "E-DRUG: Chlormezanone". Essentialdrugs.org.

[Butler2008-14] Butler, T. (October 2008). "Loperamide for the Treatment of Traveler's Diarrhea: Broad or Narrow Usefulness?". Clinical Infectious Diseases 47 (8): 1015–1016. doi:10.1086/591704. PMID 18781871.

[15] ttp://www.drugs.com/pro/loperamide.html

[16] ttp://www.peteducation.com/article.cfm?c=0+1303+1459&aid=1432

[17] ttp://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Diarrhoea&medicine=imodium

[18] Diarrhea During Pregnancy from PregMed.org. September 19th 2013

[19] "rxlist.com". 2005.

[AustralianMedicine-20] Bichner, F., ed. (2010). Australian Medicine Handbook. Adelaide: Australian Medicine Handbook Pty Ltd.

[21] Litovitz, T.; Clancy, C.; Korberly, B.; Temple, A. R.; Mann, K. V. (1997). "Surveillance of loperamide ingestions: An analysis of 216 poison center reports". Journal of toxicology. Clinical toxicology 35 (1): 11–19. doi:10.3109/15563659709001159. PMID 9022646. edit

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案内

loperamide hydrochloride