Laxatives (or cathartics) = drugs used in treatment of constipation or to empty bowels for a medical reason © assoc. prof. PharmDr. Oldřich Farsa Ph.D. 2011 Classification of laxatives in accordance with mechanism and site of action 1. Osmotically acting laxatives (poorly absorbable salts, oligosaccharides, sugar alcohols) 2. Compounds i resorption of Na+ in large intestine => accumulation of water therein (castor oil Oleum ricini, anthraglycosides, triarylmethane derivatives) 3. Softening compounds (liquid paraffin) 4. Swelling (slime forming) compounds -non-absorbable polysaccharides (linen seed Semen lini, wheat bran, methylcelullose) General problems of laxatives possibility of addiction, necessity of chronic administration loss of electrolytes, namely K+ (important except others for motility of intestines) 1. Osmotic laxatives • cause osmotic accumulation of water in large intestine Poorly absorbable inorganic salts MgS04. 7H20 „bitter salt" Sen nag ran® gra (+ laxative herbs) Na2SO4.10 H20 „Glauber salt" Fortrans® plv. • also magistral iter preparations and mineral waters 1. Osmotic laxatives - continued Sugar alcohols ■ aplication p.o. or p.r. OH HO OH OH glycerol glycerine suppositories Suppositoria glycerini HO D-mannitol HO— — H H— —OH HO— — H HO — —H H — —OH H— —OH H — —OH H— —OH OH HO D-sorbitol syn. D-glucitol Yal® ret. sol. 1. Osmotic laxatives - continued Oligosaccharides lactose milk sugar 4-O-ß-D-galactopyranosyl-D-glucose OH HO OH lactulose 4-0-(3-D-galactopyranosyl-D-fructose •not absorbed, human has no enzyme for cleavage of it into monosaccharides •chronic constipation Duplalac® sir. 2. Compounds I resorption of Na+ in large intestine Triarylmethane derivatives •direct interaction with Auerbach's (or myenteric) plexus is presumed R = -COCH3 bisacodyl Fenolax®tbl. obd., Dulcolax®tbl. , Stadalax® Phenolphthalein tbl obd Confotto falqui®(+ Pruni fhjctus= R = _so Na sodjum picosu|fate dried plums as the source of K+) 0 Darmol® past. •faster onset of action •both compounds are prodrugs; the compound with 2 phenolic groups is active Synthesis of Phenolphthalein O O OH 3,3-bis(4-hydroxyphenyl)benzo[c]furane-1(3/-/)-on Phenolphthalein Castor oil •Ricini oleum virginale PhEur •oil obtained from seeds of Ricinus communis •mainly glycerol triester with ricinoleic acid (85 - 92 %) Anthraglycosides •aglycones based on an anthrone or or anthraquinone skeleton of plant origin (Aloe, Rheum, Cassia, Frangula...) •saccharide: mostly glucose; both C-0 and C-C glycosides OH O OH X •X = H2 1,8-dihydroxyanthrone = 1,8-dihydroxy-4a,10-dihydro-9a/-/-anthracene-9-on •linking of two molecules in positions 10 and 10'leads to tetrahydroxydianthrones X = 0 1,8-dihydroxyanthraquinone = 1,8-dihydroxy-4a,9a-dihydroanthraquinone * -OH in positions 1 and 8 are necessary for the activity, they can be present also in other positions 1,8-dihydroxyanthrone derivatives h oh aloin C-C glycoside cascaroside D from Rhamnus purshianus Krenn L. et al., Chem. Pharm.Bull.52, 391 (2004) from Rheum emodi Manitto P. et al.,, J.Chem. Soc. Perkin 14, 1577(1993) Tetrahydroxydianthrone and its derivatives OH OH q OH HO. HO O OH R1= H, R2= COOH, 10R, 10'R sennoside A O R1 R1= H, R2= COOH, 10R, 10'S sennoside B R1= H, R2= CH2OH, 10R, 10 'R sennoside C R1= OCCOOH, R2= COOH, 10R, 10'R sennoside E Eucarbon ® tbl. OH HO 1,8-dihydroxyanthraquinone derivatives •aglycones, glucose bound predominantly through a phenolic hydroxyl is the most frequent sugar component OH O OH O R1 R2 H CH3 chrysophanol syn. chrysophanic acid OH CH3 frangula emodin syn. emodin Cholagol®gtt. H CH2OH aloe emodin H COOH rhein Eucarbon ® tbl. Antidiarrhoics = drugs used for treatment of diarrhoea • causes of diarrhoea: GIT infections, intoxications, alergic inflammation, tumor • danger: water and electrolytes loss Classification of antidiarrhoics: • Adsorbents (activated charcoal, slime (mucilage) forming compounds (pectins, clays) • Adstringents (tanin, basic salts of Bi, compounds of AI and Ag) •„Intestinal disinfectants" - non-absorbable antibacterial chemotherapeutics acting in gastrointestinal tract • Intestinal peristaltic moderating compounds Adstringents Mg3[AI(OH)6]2 magnesium hexahydroxoaluminate •large surface •also effective adsorbent and antacide O^OH bismuth subgallate •also antibacterial activity Carbocit® (+ Carbo adsorbens) „Intestinal disinfectants" - non-absorbable antibacterial drugs phthalylsulfathiazole •non-absorbable N4-acylated sulfonamide •prodrug: free sulfathiazole is released in bacteria •mechanism of action: inhibition of dihydropteroate synthase Ftalazol@4bl ethacridine •in most lactate •mode of action: cation interacts with nucleic acids of a pathogen (intercalation) •magistraliter preparations „Intestinal disinfectants" - continued 5,7-dihalogenoquinolin-8-ol derivatives R1 R2 X1 x2 H H CI CI cloroxine syn. chloroxine [USAN] (CZ, SK) Endiaron® tbl. obd., also the substance for magistraliter preparations O CH, Br broxaldine (D.) H H clioquinol (USA) •myelooptic neuropathies CI Br bacteriostatic, fungistatic and antiprotozoal effects mechanism of action: forming of chelates with Me2+ important for microorganisms ^Intestinal disinfectants" - continued Rifaximin - poorly absorbable ansamycine antibiotic rifaximin rifampicin •poorly absorbable ATB for *ATB for treatment TBC treatment of infectious diarrhoea Normix® tbl. •mode of action: inhibition of DNA-dependent RNA-polymerase by forming of a stable complex with the enzyme => suppression of initiation of synthesis of bacterial RNA Intestinal peristaltic moderating compounds (also „antipropulsives") X -CN -CN -CON(CH3)2 Y -COOEt -COOH -OH Z H H CI diphenoxylate Reasec® tbl. (+ atropin) diphenoxine loperamid Imodium® cps. •structural similarity with methadone and pethidine (Tinctura opii was formerly used also as antidiarrhoic) •mechanism of action: interaction with opioid receptors in the intestine (supposed g,S - receptors; natural agonist is enkephaline) Intestinal peristaltic moderating compounds Comparison of structures of diphenoxylate, methadone and pethidine pethidine syn. meperidine diphenoxylate methadone Intestinal peristaltic moderating compounds Inhibitor of enkephalinase, i.e. indirect agonist of a-, 8-receptors racecadotril syn. acetorphan •clinical trials of the Phase III for acute diarrhoea in infants finished