Tuesday, 6 May 2014

Racecadotril, a truly unique drug and another reason why I'm envious of the British

Figure 1: Racecadotril
Interestingly there's a drug called racecadotril (many different brand names see the end of this blog for a list of them) that's used in a number of countries worldwide (although Australia, Canada and the U.S. are not amongst them) for the treatment of diarrhoea that's got a truly unique mechanism of action.1 Diarrhoea is the fifth leading cause of death worldwide, at 1.7 million per year and diarrhoeal diseases (i.e. diseases that cause diarrhoea as a dominant feature) affect an estimated 1.7 billion people, or about one-quarter of the world's current population. Death usually occurs as a result of malnutrition, electrolyte abnormalities (such as low blood potassium) or dehydration. Most of these diarrhoea-related deaths are due to infectious diseases such as gastroenteritis, cholera, typhoid fever, giardiasis, dysentery and even HIV/AIDS and about 760,000 of these deaths are in children under the age of 5, in this category of people it is the second leading cause of death.2,3

Figure 2: A World Map with countries in which racecadotril is actively marketed coloured blue
Figure 3: Mu opioid receptor

Figure 4: Kappa opioid receptor
Figure 5: Delta opioid receptor
Its mechanism of action, i.e. how it works, is that it inhibits a family of enzymes called the enkephalinases which break down enkephalins, which are a type of endorphin.

The opioids and their receptors

The endorphins are a class of peptides (sort of like miniature protein molecules) that bind to the opioid receptors which are the receptors that give opioids (narcotic painkillers) like morphine their characteristic effects. The opioid receptors come in three major varieties  μ (mu), κ (kappa) and δ (delta), each with different physiologic roles, i.e. they produce differing effects on the body, when activated. The mu subtype is responsible for most of the therapeutic and side effects of morphine and other opioids you probably know (like methadone, heroin, pethidine, codeine, oxycodone and fentanyl). The delta subtype seems to be involved in some of the antidepressant effects of opioids, some of their effects on breathing rate, their ability to induce seizures, some of their ability to relieve pain (although not most of their ability to relieve pain as most of it is found in the mu subtype) and some of their constipating effects. The kappa subtype is involved in some of the painkilling effects of opioids, their potential to induce hallucinations and delusions, their negative effects on mood and some of their constipating, pupil-constricting and sedating effects.4-6

The enkephalins are a type of endorphin that binds specifically to the delta opioid receptors, although they do bind, to a lesser extent, to the mu subtype. There are two types of enkephalins — met-enkephalin (which has the amino acid sequence: tyrosine-glycine-glycine-phenylalanine-methionine) and leu-enkephalin (sequence: tyrosine-glycine-glycine-phenylalanine-leucine), respectively.4-6
Figure 6: Met-enkephalin

Figure 7: Leu-enkephalin

Racecadotril, is a prodrug, which means that it isn't active in itself, but it first needs to be metabolised into a substance called thiorphan, in order to exert its therapeutic effects. Thiorphan, in turn, inhibits enkephalinases.
Figure 8: Thiorphan
Racecadotril is believed to exert its effects solely in the periphery; that is, outside of the brain and spinal cord.7

It's been in clinical use in France, for over twenty years; although only recently (past few years) has it been approved for clinical use in the U.K.8,9 It's been found effective in treating diarrhoea caused by a number of different things; including:

  • Gastroenteritis 
  • Dysentery
  • Cholera


Figure 9: Codeine
Figure 10: Diphenoxylate
Figure 11: Loperamide
Of course, there are other treatments available for opioids codeine, diphenoxylate and loperamide, which primarily work by activating the mu opioid receptor in the intestines and while they all work just as well as racecadoctril they have other limitations. For one, codeine has the problem that in some people (up to 20% of the population), due to their genetics, it may either have too strong (potentially leading to death or addiction) or too little an effect on them. Likewise codeine can, even in people that can safely and usefully use it, cause mental clouding and drowsiness, which can be incapacitating. As for diphenoxylate it's only ever sold in combination with atropine (the active ingredient in the deadly nightshade) and hence comes with the additional side effects of this ingredient, such as dry mouth, blurred vision, dizziness and difficulty passing urine. Loperamide, on the other hand, has a few potential drug interactions, such as with the medications quinidine (a drug for certain neurological disorders, heart rhythm irregularities and malaria) and ivacaftor (a drug for cystic fibrosis). See loperamide is an opioid that lacks the ability to cross the blood-brain barrier (BBB) and hence only has effects on body areas outside the brain and spinal cord. It is a very fat-soluble drug (in fact it's about the most fat soluble opioid I know of) but its activity to limited to the periphery due to the fact that it's transported by a pump called the P-glycoprotein (PGP; MDR1), which ferries drug molecules across the BBB from the brain and spinal cord to the rest of the body. Another advantage that racecadotril has over other opioid antidiarrhoeals is that it produces significantly less side effects; in fact, in clinical trials in which it was compared to placebo (i.e. a fake drug, like a sugar pill), it was found that the frequency of side effects in the group receiving the active drug was, if anything, less than in the group receiving the placebo.10-15
Figure 12: Atropine

The likely reason for this is that the delta opioid receptors mostly regulate the absorption of water and electrolytes from the intestines, hence reducing the excessive excretion of these substances, experienced by those with diarrhoea; whereas the mu opioid receptors regulate the rate of gastrointestinal transit, that is, the rate at which the food moves through the various components of the digestive tract. Consequently loperamide, diphenoxylate/atropine and codeine are more prone to causing constipation compared to racecadotril.10-15

It turns out that enkephalinase inhibitors exist naturally in the body, in fact human saliva contains a potent peptide enkephalinase inhibitor called opiorphin exists (sequence: glutamine-arginine-phenylalanine-serine-arginine); on a dose-by-dose basis opiorphin is a stronger painkiller than morphine when injected directly into the spinal cord of mice. Although it's worth noting that it's not able to produce any effects in humans by merely swallowing it or applying it to one's wounds as the substance has great difficulty crossing the BBB, plus it is rapidly degraded in the acidic conditions of the stomach into its base amino acids.16-21
Figure 13: Opiorphin

Brand names:

Belgium: Tiorfix
Brazil: Tiorfan
Chile: Hidrasec, Resorcal
China: Du La Bao (杜拉宝), Feng Hai Ting (丰海停), Hidrasec (海兰赛), Mo Ni Ka (莫尼卡)
France: Diarfix, Tiorfan, Tiorfanor, Tiorfast
Germany: Tiorfan¤
Greece: Hidrasec
India: Ad-DT, Ad-Sachet, Ad, Aquasec, Cadotril, Dirasec, Dotril, Enuff, Floradot, Hydral, Lomorest, Nodi.
Indonesia: Hidrasec¤
Italy: Tiorfix
Mexico: Hidrasec
Netherlands: Hidrasec
Philippines: Hidrasec
Portugal: Tiorfan
Spain: Tiorfan
Thailand: Hidrasec
United Kingdom: Hidrasec
Venezuela: Hidrasec

Reference list:

  1. Brayfield, A, ed. (13 December 2013). "Racecadotril"Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 May 2014.
  2. "Diarrhoeal disease". World Health Organization. United Nations. April 2013. Retrieved 6 May 2014.
  3. Guandalini, S; Frye, RE; Tamer, MA (10 April 2014). "Diarrhea". In Liacouras, CA; Windle, ML; Schwarz, SM; Cuffari, C. Medscape Reference. WebMD. Retrieved 6 May 2014.
  4. Brayfield, A, ed. (14 January 2014). "Opioid Analgesics". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 May 2014.
  5. Rang, HP; Dale, MM; Flower, RJ; Henderson, G (2011). Rang & Dale's Pharmacology (7th ed.). Edinburgh, UK: Churchill Livingstone. ISBN 978-0-70-203471-8.
  6. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  7. "SPC-DOC_PL 39418-0003.PDF" (PDF). Medicines and Healthcare Products Regulatory Agency. Bioprojet Europe Ltd. 26 December 2012. Retrieved 6 May 2014.
  8. "ESNM12: Acute diarrhoea in children: racecadotril as an adjunct to oral rehydration". Evidence summary: new medicine. National Institute for Health and Clinical Excellence. 12 March 2013. Retrieved 6 May 2014.
  9. "ESNM11: Acute diarrhoea in adults: racecadotril". Evidence summary: new medicine. National Institute for Health and Clinical Excellence. 12 March 2013. Retrieved 6 May 2014.
  10. Matheson, AJ; Noble, S (April 2000). "Racecadotril.". Drugs 59 (4): 829–35; discussion 836–7. doi:10.2165/00003495-200059040-00010. PMID 10804038.
  11. Huighebaert, S; Awouters, F; Tytgat, GN (February 2003). "Racecadotril versus loperamide: antidiarrheal research revisited.". Digestive Diseases and Sciences 48 (2): 239–50.doi:10.1023/A:1021989606317. PMID 12643598.
  12. Szajewska, H; Ruszczyński, M; Chmielewska, A; Wieczorek, J (September 2007). "Systematic review: racecadotril in the treatment of acute diarrhoea in children." (PDF). Alimentary Pharmacology & Therapeutics 26 (6): 807–13. doi:10.1111/j.1365-2036.2007.03444.x. PMID 17767464.
  13. Tormo, R; Polanco, I; Salazar-Lindo, E; Goulet, O (August 2008). "Acute infectious diarrhoea in children: new insights in antisecretory treatment with racecadotril.". Acta Paediatrica 97(8): 1008–15. doi:10.1111/j.1651-2227.2008.00830.x. PMID 18462465.
  14. Lehert, P; Chéron, G; Calatayud, GA; Cézard, JP; Castrellón, PG; Garcia, JM; Santos, M; Savitha, MR (September 2011). "Racecadotril for childhood gastroenteritis: an individual patient data meta-analysis.". Digestive and Liver Disease 43 (9): 707–13. doi:10.1016/j.dld.2011.03.001. PMID 21514257.
  15. Mehta, S; Khandelwal, PD; Jain, VK; Sihag, M (November 2012). "A comparative study of racecadotril and single dose octreotide as an anti-secretory agent in acute infective diarrhoea.".The Journal of the Association of Physicians of India 60: 12–5. PMID 23767196.
  16. Rosa, M; Arsequell, G; Rougeot, C; Calle, LP; Marcelo, F; Pinto, M; Centeno, NB; Jiménez-Barbero, J; Valencia, G (February 2012). "Structure-activity relationship study of opiorphin, a human dual ectopeptidase inhibitor with antinociceptive properties.". Journal of Medicinal Chemistry 55 (3): 1181–8. doi:10.1021/jm2012112. PMID 22224710
  17. Rougeot, C; Robert, F; Menz, L; Bisson, JF; Messaoudi, M (August 2010). "Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects." (PDF). Journal of Physiology and Pharmacology 61 (4): 483–90. PMID 20814077
  18. Yang, QZ; Lu, SS; Tian, XZ; Yang, AM; Ge, WW; Chen, Q (February 2011). "The antidepressant-like effect of human opiorphin via opioid-dependent pathways in mice.". Neuroscience Letters 489 (2): 131–5. doi:10.1016/j.neulet.2010.12.002. PMID 21145938
  19. Wisner, A; Dufour, E; Messaoudi, M; Nejdi, A; Marcel, A; Ungeheuer, MN; Rougeot, C (November 2006). "Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways." (PDF). Proceedings of the National Academy of Sciences of the United States of America 103 (47): 17979–84. doi:10.1073/pnas.0605865103. PMC 1693858. PMID 17101991
  20. Tian, XZ; Chen, J; Xiong, W; He, T; Chen, Q (July 2009). "Effects and underlying mechanisms of human opiorphin on colonic motility and nociception in mice.". Peptides 30 (7): 1348–54. doi:10.1016/j.peptides.2009.04.002. PMID 19442408
  21. Popik, P; Kamysz, E; Kreczko, J; Wróbel, M (November 2010). "Human opiorphin: the lack of physiological dependence, tolerance to antinociceptive effects and abuse liability in laboratory mice.". Behavioural Brain Research 213 (1): 88–93. doi:10.1016/j.bbr.2010.04.045. PMID 20438769.

1 comment:

  1. Treat your baby's what is diarrhea with Probiotics and ensure they are diarrhea-free for the next couple months!