Saturday, 19 July 2014

Ranitidine








Ranitidine Structural Formulae.png


Ranitidine

Ranitidine-A-3D-balls.png
Systematic (IUPAC) name
N-(2-[(5-[(dimethylamino)methyl]furan-2-yl)methylthio]ethyl)-N'-methyl-2-nitroethene-1,1-diamine
Clinical data
Trade namesZantac
AHFS/Drugs.commonograph
MedlinePlusa601106
Licence dataUS FDA:link
Pregnancy cat.B1 (AU) B (US)
Legal statusPharmacy Only (S2) (AU)OTC/RX (US) P/POM (UK)
RoutesOral, IV
Pharmacokinetic data
Bioavailability39 to 88%
Protein binding15%
MetabolismHepatic
Half-life2–3 hours
Excretion30–70% Renal
Identifiers
CAS number66357-35-5 Yes
ATC codeA02BA02
A02BA07 (ranitidine bismuth citrate)
PubChemCID 657345
IUPHAR ligand1234
DrugBankDB00863
ChemSpider571454 Yes
UNII884KT10YB7 Yes
KEGGD00422 Yes


Chemical data
FormulaC13H22N4O3S 
Mol. mass314.4 g/mol










Ranitidine


  Synthetic procedure/method of synthesis

The reaction of 5-dimethylaminomethyl-2-furanylmethanol (I) with 2-mercaptoethylamine (II) by means of aqueous HCl gives 2-[[(5-dimethylamino-methyl-2-furanyl)methylthio]ethaneamine (III), which is then condensed with N-methyl-1-methylthio-2-nitrotheneamine (IV) by heating at 120 C. Compound (IV) is obtained by reaction of 1,1-bis(methylthio)-2-nitroethene (V) with methylamine in refluxing ethanol


Ranitidine reference for above synthesis
  1. Serradell, M.N.; Blancafort, P.; Casta馿r, J.; Hillier, K.; Ranitidine. Drugs Fut 1979, 4, 9, 663
  2.  Price, B.J. et al. (Allen and Hanburys, Ltd.); US 4128658.
  3. Price, B.J.; Bradshaw, J.; Clitherow, J.W. (Allen & Hansburys Ltd.); Aminoalkyl furan derivatives.. DE 2734070; FR 2360587; US 4128658 ,DE 2734070; FR 2360587; US 4128658.


Ranitidine (/rəˈnɪtɨdiːn/; trade name Zantac) is a histamine H2-receptor antagonist that inhibits stomach acid production. It iscommonly used in treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions such as hives. Ranitidine is also known to give false positives for methamphetamine on drug tests.[1]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Medical use
  • Recurrent postoperative ulcer
  • Upper GI bleeding
  • Prevention of acid-aspiration pneumonitis during surgery: Ranitidine can be administered preoperatively to reduce the risk of aspiration pneumonia. The drug not only increases gastric pH, but also reduces the total output of gastric juice. In a 2009 meta-analysis comparing the net benefit of proton pump inhibitors and ranitidine to reduce the risk of aspiration before anesthesia, ranitidine was found to be more effective than proton pump inhibitors in reducing the volume of gastric secretions.[4] Ranitidine may have an antiemetic effect when administered preoperatively.
  • Prevention of stress-induced ulcers in critically ill patients.[5]

Preparations

Certain preparations of ranitidine are available over the counter (OTC) in various countries. In the United States, 75-mg and 150-mg tablets are available OTC. Zantac OTC is manufactured by Boehringer Ingelheim. In Australia, packs containing seven or 14 doses of the 150-mg tablet are available in supermarkets, small packs of 150-mg and 300-mg tablets are schedule 2 pharmacy medicines. Larger doses and pack sizes still require a prescription.

Dosing

For ulcer treatment, a night-time dose is especially important - as the increase in gastric/duodenal pH promotes healing overnight when the stomach and duodenum are empty. Conversely, for treating reflux, smaller and more frequent doses are more effective.
Ranitidine used to be administered long term for reflux treatment, sometimes indefinitely. However, PPIs have taken over this role. In addition, a fairly rapid tachyphylaxis can develop within 6 weeks of initiation of treatment, further limiting its potential for long-term use.[6]
People with Zollinger-Ellison syndrome have been given very high doses without any harm.[7]

Contraindications

Ranitidine is contraindicated for patients known to have hypersensitivity to the drug.

Adverse effects

The following adverse effects have been reported as events in clinical trials

Central nervous system

There have been rare reports of malaise, dizziness, somnolence, insomnia, and vertigo. In severely ill, elderly patients, there have been rare cases of reversible mental confusion, agitation, depression, and hallucinations.[8] Ranitidine causes fewer CNS adverse reactions and drug interactions compared to cimetidine.

Cardiovascular

There have been rare reports of arrhythmias such as tachycardia, bradycardia, atrioventricular block, and premature ventricular beats.[8]

Gastrointestinal

All drugs in its class have the potential to cause vitamin B12 deficiency secondary to a reduction in food-bound vitamin B12 absorption.[9] Elderly patients taking H2 receptor antagonists are more likely to require B12 supplementation than those not taking such drugs.[10] H2 blockers may also reduce the absorption of drugs (azole antifungals, calcium carbonate) that require an acidic stomach.[11] In addition, multiple studies suggest the use of H2 receptor antagonists such as raniditine may increase the risk of infectious diarrhoea, including traveller's diarrhoea and salmonellosis.[12][13][14][15][16] Finally by suppressing acid-mediated breakdown of proteins, ranitidine may lead to an elevated risk of developing food or drug allergies, due to undigested proteins then passing into the gastrointestinal tract, where sensitisation occurs. Patients who take these agents develop higher levels of IgE against food, whether they had prior antibodies or not.[17] Even months after discontinuation, an elevated level of IgE in 6% of patients was still found in this study.

Hepatic

There have been rare, reported cases of cholestatic hepatitis, hepatic failure, hepatitis, jaundice. These symptoms require immediate discontinuation of the drug.[8]

Respiratory

Ranitidine and other histamine H2 receptor antagonists may increase the risk of pneumonia in hospitalized patients.[18] They may also increase the risk of community-acquired pneumonia in adults and children.[19]

Hematologic

Thrombocytopenia is a rare but known side effect. Drug-induced thrombocytopenia usually takes weeks or months to appear, but may appear within 12 hours of drug intake in a sensitized individual. Typically, the platelet count falls to 80% of normal, and thrombocytopenia may be associated with neutropenia and anemia.[20]

Interaugmentary[

Rash, including rare cases of erythema multiforme. Rare cases of hair loss and vasculitis.[8]

Warnings and precautions

Disease related concerns

With gastric malignancies, relief of symptoms due to the use of ranitidine does not exclude the presence of a gastric malignancy. In addition with renal or hepatic impairment, ranitidine must be used with caution. Finally, ranitidine should be avoided in patients with porphyria as it may precipitate an attack.[21]

Pregnancy[edit]

Pregnancy Category B.

Lactation[edit]

Ranitidine enters breast milk, with peak concentrations seen at 5.5 hours after the dose in breast milk. Caution should be exercised when prescribed to nursing women.[22]

Children[edit]

In children, the use of gastric acid inhibitors has been associated with an increased risk for development of acute gastroenteritis and community-acquired pneumonia.[23] A cohort analysis including over 11,000 neonates reported an association of H2 blocker use and an increased incidence of necrotizing enterocolitis in very low birth weight (VLBW) neonates.[24] In addition, there was an approximately sixfold increase in mortality, necrotizing enterocolitis, and infection ( such as sepsis, pneumonia, urinary tract infection) was reported in patients receiving ranitidine in a cohort analysis of 274 VLBW neonates.[25]

Pharmacology

Mechanism of action

Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H2-receptors found in gastric cells. This results in decreased gastric acid secretion and gastric volume, and reduced hydrogen ion concentration.

Pharmacokinetics

Absorption: Oral: 50%
Protein binding: 15%
Metabolism: N-oxide is the principal metabolite.
Half-life elimination: With normal renal function, ranitidine taken orally has a half-life of 2.5–3 hours. If taken intravenously, the half-life is generally 2-2.5 hours in a patient with normal creatinine clearance.
Excretion: The primary route of excretion is the urine. In addition, approximately 30% of the orally administered dose is collected in the urine as non-absorbed drug in 24 hours.

Elderly

In the elderly population, the plasma half-life of ranitidine is prolonged to 3–4 hours secondary to decreased kidney function causing decreased clearance.[26]

Children[

In general, studies looking pediatric patients (aged 1 month to 16 years) have showed no significant differences in pharmacokinetic parameter values in comparison to healthy adults, when correction is made for body weight.[26]

History


Zantac (ranitidine) 300 mg tablets
Ranitidine was first prepared as AH19065 by John Bradshaw in the summer of[ in the Ware research laboratories of Allen & Hanburys Ltd, part of the Glaxo organization.[27][28] Its development was a response to the first in class histamine H2-receptor antagonist,cimetidine, developed by Sir James Black at Smith, Kline and French, and launched in the United Kingdom as Tagamet in November 1976. Both companies would eventually become merged as GlaxoSmithKline following a sequence of mergers and acquisitions starting with the integration of Allen & Hanbury's Ltd and Glaxo to form Glaxo Group Research in 1979, and ultimately with the merger of Glaxo Wellcome and SmithKline Beecham in 2000. Ranitidine was the result of a rational drug-design process using what was by then a fairly refined model of the histamine H2-receptor and quantitative structure-activity relationships.
Glaxo refined the model further by replacing the imidazole ring of cimetidine with a furan ring with a nitrogen-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer adverse drug reactions), longer-lasting action, and 10 times the activity of cimetidine. Ranitidine has 10% of the affinity that cimetidine has to CYP450, so it causes fewer side effects, but other H2 blockers famotidine and nizatidine have no CYP450 significant interactions.[29]
Ranitidine was introduced in 1981 and was the world's biggest-selling prescription drug by 1988. It has since largely been superseded by the even more effective proton-pump inhibitors, with omeprazole becoming the biggest-selling drug for many years. When omeprazole and ranitidine were compared in a study of 144 people with severe inflammation and erosions or ulcers of the esophagus, 85% of those treated with omeprazole healed within eight weeks, compared to 50% of those given ranitidine. In addition, the omeprazole group reported earlier relief of heartburn symptoms.[30]

Synthesis

  1. Dimethylamine.HCl + paraformaldehyde + furfural alcohol → 5-(dimethylaminomethyl)furfuryl alcohol.
  2. 5-(dimethylaminomethyl)furfuryl alcohol + cysteamine.HCl → 2-(((5-((dimethylamino)methyl)furan-2-yl)methyl)thio)ethanamine
  3. Product above step + N-methyl-1-methylthio-2-nitro-ethenamine → Ranitidine.

or



Ranitidine synthesis.[31]

See also[

  • Famotidine, aka Pepcid AC, Pepcidine: another popular H2-receptor antagonist

References

  1. Jump up^ Poklis, A; Hall KV, Still J, Binder SR (March 1991). "Ranitidine interference with the monoclonal EMIT d.a.u. amphetamine/methamphetamine immunoassay". Journal of analytical toxicology 15 (2): 101–103. doi:10.1093/jat/15.2.101. PMID 2051743.
  2. Jump up^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
  3. Jump up^ "Reflux Remedies: ranitidine". PharmaSight OTC Health. PharmaSight.org. Retrieved 16 November 2011.
  4. Jump up^ Clark, K., Lam, L. T., Gibson, S. and Currow, D. (2009), The effect of ranitidine versus proton pump inhibitors on gastric secretions: a meta-analysis of randomised control trials. Anaesthesia, 64: 652–657.
  5. Jump up^ Dellinger, R. Phillip, et al. "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012." Intensive care medicine 39.2 (2013): 165-228.
  6. Jump up^ Lightdale, J. R., Gremse, D. A., Heitlinger, L. A., Cabana, M., Gilger, M. A., Gugig, R., & Hill, I. D. (2013). Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics, 131(5), e1684-e1695
  7. Jump up^ "Ranitidine Drug Information". Lexicomp. Retrieved 20 April 2014.
  8. ^ Jump up to:a b c d "ZANTAC Drug Insert". GlaxoSmithKline. Retrieved 19 April 2014.
  9. Jump up^ Force, R. W., and M. C. Nahata. "Effect of histamine H2-receptor antagonists on vitamin B12 absorption." The Annals of pharmacotherapy 26.10 (1992): 1283-1286.
  10. Jump up^ Mitchell SL, Rockwood K. (2001). "The association between antiulcer medication and initiation of cobalamin replacement in older persons". J Clin Epidemiol 54 (5): 531–534.doi:10.1016/S0895-4356(00)00340-1.
  11. Jump up^ "Reflux Remedies: ranitidine". PharmaSight OTC Health. PharmaSight.org. Retrieved 16 November 2011.
  12. Jump up^ Cobelens FGJ, Leentvarr-Kuijpers A, Kleijnen J, Coutinho RA. (1998). "Incidence and risk factors of diarrhoea in Dutch travellers: Consequences for priorities in pre-travel health advice". Trop Med Intern Health 3: 896–903.
  13. Jump up^ Neal KR, Briji SO, Slack RCB, et al. (1994). "Recent treatment with H2-antagonists and antibiotics and gastric surgery as risk factors for Salmonella infection". Br Med J 308(6922): 176. doi:10.1136/bmj.308.6922.176. PMID 7906170.
  14. Jump up^ Neal KR, Scott HM, Slack RC, Logan RF. (1996). "Omeprazole as a risk factor forCampylobacter gastroenteritis: Case-control study". BMJ 312 (7028): 414–415.doi:10.1136/bmj.312.7028.414. PMID 8601113.
  15. Jump up^ Wickramasinghe LSP, Basu SK. (1984). "Salmonellosis during treatment with ranitidine". Br Med J 289 (6454): 1272. doi:10.1136/bmj.289.6454.1272.
  16. Jump up^ Ruddell WS, Axon AT, Findlay JM, et al. (1980). "Effect of cimetidine on gastric bacterial flora". Lancet i: 672–674.
  17. Jump up^ Untersmayr E, Bakos N, Scholl I, et al. (2005). "Anti-ulcer drugs promote IgE formation toward dietary antigens in adult patients". FASEB J 19 (6): 656–658. doi:10.1096/fj.04-3170fje. PMID 15671152.
  18. Jump up^ Mallow S, Rebuck JA, Osler T, et al. (2004). "Do proton pump inhibitors increase the incidence of nosocomial pneumonia and related infectious complications when compared with histamine-2 receptor antagonists in critically ill trauma patients?". Curr Surg 61 (5): 452–458. doi:10.1016/j.cursur.2004.03.014. PMID 15475094.
  19. Jump up^ Canani, RB; Cirillo, P; Roggero, P; Romano, C; Malamisura, B; Terrin, G; Passariello, A; Manguso, F; Morelli, L; Guarino, A; Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition, (SIGENP) (May 2006). "Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children.". Pediatrics 117 (5): e817–20.doi:10.1542/peds.2005-1655. PMID 16651285.
  20. Jump up^ Amit V Bangia, Narendra Kamath, and Vidushi Mohan (2011). "Ranitidine-induced thrombocytopenia: A rare drug reaction". Indian J Pharmacol 43 (1): 76–7.doi:10.4103/0253-7613.75676. PMC 3062128. PMID 21455428.
  21. Jump up^ "Ranitidine Drug Information". Lexicomp. Retrieved 19 April 2014.
  22. Jump up^ "Ranitidine". Lexicomp. Retrieved 19 April 2014.
  23. Jump up^ Canani RB, Cirillo P, Roggero P, et al, "Therapy With Gastric Acidity Inhibitors Increases the Risk of Acute Gastroenteritis and Community-Acquired Pneumonia in Children," Pediatrics, 2006, 117(5):e817-20
  24. Jump up^ Guillet R, Stoll BJ, Cotten CM, et al, "Association of H2-Blocker Therapy and Higher Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants," Pediatrics, 2006, 117(2):137-42.[PubMed 16390920]
  25. Jump up^ Terrin G, Passariello A, De Curtis M, et al, "Ranitidine Is Associated With Infections, Necrotizing Enterocolitis, and Fatal Outcome in Newborns," Pediatrics, 2012, 129(1):40-5.[PubMed 22157140]
  26. ^ Jump up to:a b "Zantac Package Insert". FDA.
  27. Jump up^ Lednicer, Daniel (Editor). "Chronicles of Drug Discovery". ACS Professional Reference Books, Volume 3, pages 45-81 1993. ISBN 0-8412-2733-0.
  28. Jump up^ US patent US4128658, "Aminoalkyl furan derivatives", 1978
  29. Jump up^ Laurence Brunton, John Lazo, Keith Parker (August 2005). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11 ed.). McGraw-Hill. p. 972.doi:10.1036/0071422803. ISBN 0-07-142280-3.
  30. Jump up^ Pelot, Daniel, (M.D.). "Digestive System : New Drug for Heartburn". The New Book of Knowledge : Medicine & Health, Grolier : Danbury, Connecticut. 1990. p.262. ISBN 0-7172-8244-9. Library of Congress 82-645223
  31. Jump up^ "Synthesis of Ranitidine". http://drugsynthesis.blogspot.co.uk/. 2014. Retrieved 2014-07-18.

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