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GIT: structure and function:

GIT: structure and function

The pharmacologically treatable impairments of the GIT:

The pharmacologically treatable impairments of the GIT reflux esophagitis peptic ulcers delayed gastric emptying constipation and spastic pain (colic) diarrhea infections inflammation

Peptic ulcer is a benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin. :

Peptic ulcer is a benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin. Predisposing factors: excess in production of acid an intrinsic defect in the barrier functions of the mucosa chronic colonization of the gastric and duodenal mucosa with Helicobacter pylori Therapeutic strategies: reduce the acid exposure of the mucosa improve the integrity of mucosal barrier

«No acid, no ulcer» Drugs that decrease acid secretion:

«No acid, no ulcer» Drugs that decrease acid secretion Parietal cell Secretion is decreased due to blockade of Н2- R М3-R G-R inhibition of К+Н+-АТPase adenylate cyclase

Drugs used to decrease gastric secretion:

Drugs used to decrease gastric secretion 1. Н2-blockers (I- III generations): cim e tidine (I), ran i tidine (II), fam o tidine, nis a tidine, rox a tidine (III) 2. Inhibitors of the proton pump (IPP), or К+Н+АТPase inhibitors: om e prazole, lanz o prazole, rab i prazole 3. М-cholinergic antagonists (м1): pir e nzepine 4. Inhibitors of the adenylate cyclase , or PGE1- analogs: misopr o stol 5. Gastrin-antagonists ( pr o glumide ), Somatostatine-analogs ( octr e opide )

Н2-blockers: main features:

Н2-blockers: main features Onset of action in 1hr , duration of action from 6 (cimetidine) to 12 (all the rest) hrs Suppress both basal and stimulated HCl secretion, do not affect secretion of pepsinogen Тolerance is insignificant USES : for prevention of heartburn in patients with gastric and duodenal peptic ulcer, reflux- esophagitis, gastritis, hypergastrinemia (Zollinger- Ellison syndrome), for prevention of gastric juice aspiration in anesthetized patients

H2-blockers: adverse effects (maximal for cimetidine ):

H2-blockers: adverse effects (maximal for cimetidine ) 1. Inhibition of liver microsomal enzymes: metabolism of some drugs is decreased, toxic effects possible - TCA, BDZs, theophylline , some antiepileptics Long-term treatment may cause hyper - prolactinemia ( results in gynecomastia, impotence, galactorrhea) and ricochet hypersecretion after abrupt discontinuation Dyspepsia, diarrhea, headaches (3%), rare ly : leucopenia, skin rash Contraindicated for children, pregnant, and nursing women.

Н2-blockers: PK:

Н2-blockers: PK Bioavailability is about 50% Distribute throughout the body (breast milk and fetus including) Renal elimination is the most important route, only famotidine is more dependent on liver metabolism (60%) Dosing : after meals 1 tablet 1 -2 times a day, ( cimetidine 3-4 times a day ) . For duodenal ulcer add 1 tablet before night.

IPP: mechanism of action:

IPP: mechanism of action Prodrugs: inactive in neutral and alkalinic media In acidic media (parietal cells) IPP are metabolize d into sulfenamide , irreversible inhibitor of Н+К+АТPase, which suppresses basal and stimulated secretion (~ 1 hr ) NOTE: prevent premature activation in the GIT, as sulfenamide (cation) is not absorbed

IPP: main features:

IPP: main features Most effective M ost selectiv e Not active in neutral (or low acidic) media ( not compatible with Н2-blockers, or antacids!) Inactivated by HCl in case of broken coating ( do not disrupt the enteric coating!) Administration : 1 tablet in the morning 1 hr before meals


IPP: USES Gastro-intestinal reflux disease, erosive esophagitis (drug of choice) Hypergastrinemia, Zollinger-Ellison syndrome Peptic gastric or duodenal ulcers, esp. if refractory to Н2-blockers Pr evention and treatment of NSAIDs-induced gastropathy as a substitute for H2-blockers or misoprostol

IPP: adverse effects:

IPP: adverse effects 1. S afe in short-term treatment (less than 3 months): rarely diarrhea, head-ache, weakness 2. Omeprazole interferes in the oxidation of warfarin, phenytoin, diazepam, cyclosporine 3. In long-term treatment with high doses - hyperplasia of ECL-cells Contraindications : pregnant or nursing women, children before 12 years of age

Other antisecretory drugs: uses:

Other antisecretory drugs: uses 3. М-cholinergic antagonists: pirenzepine (м1) is a moderately effective antisecretory drug . It m ay be used as an adjunct in pts refractory to standard therapy , or in p t s with concomitant spasmodic conditions ( pancreatitis, cholelithiasis, nephrolithiasis ) . 4. Inhibitors of the adenylate cyclase, or PGE1- analogs: misoprostol is used in pts at risk of NSAIDs-induced gastropathy as preventive or treatment agent (CI: pregnancy, uterine or intestine bleeding)

Mucosal Protective Agents (Cyto-, or Gastroprotectors):

Mucosal Protective Agents (Cyto-, or Gastroprotectors) 1.Collodial Bismuth compounds: De-nol, P entabismole 2.Complex of aluminium hydroxide and sulfated sucrose: Sucralfate Mechanism of action F orm ing a complex gel with mucus, they create physical barrier defending mucus NB! Needs acidic pH for activation: do NOT combine with H2-blockers or antacids Weak antihelicobacter action

Relapses of peptic and duodenal ulcers,chronic gastritis (60%) are due to Helicobacter pylori:

Relapses of peptic and duodenal ulcers,chronic gastritis (  60%) are due to Helicobacter pylori After eradication of H.pylori recurrence rates <15%. Тriple therapy (80-90% erad.) Bi +metronidazole+tetracycline during 2 weeks 2 line regimen:quadrotherapy Bi+ metronidazole+amoxicillin/ clarytromicin+omeprazole during 2 weeks

АNTACIDs neutralize HCl in the gastric lumen MORE RAPIDLY than antisecretory agents:

АNTACIDs neutralize HCl in the gastric lumen MORE RAPIDLY than antisecretory agents Produce rapid action ( NB ! S ystemic) NaHCO3 СaCO3 Produce less rapid action ( NB! Non-systemic) Al(OH)3 Si- соmpounds Mg(OH)2 (act more rapidly, than Al(OH)3) Complex antacids: ” А lmagel”(“...-A” “...- Nео”), “Maalox”(“...+”)

АNTACIDs: side effects:

АNTACIDs: side effects carbonates(Ca esp.) activate gastrin receptors and antral HCl secretion ( ricochet ) carbonates are absorbed and can produce transient metabolic alkalosis excessive intake of NaHCO3 can produce hyper natriemia (unwanted in patients with HT & CHF)  Mg-, Al- blood levels might be dangerous in patients with renal insufficiency prolonged intake of Al-compounds may decrease P absorption - anemia, osteoporosis, encephalopathy may decrease bioavailability of other drugs (esp. gel preparations)


АNTACIDs: USES Antacids with systemic action should be used ONLY for heartburn attack ! Antacids with less/no systemic action: for prolonged treatment of gastritis, peptic ulcers, reflux-esophagitis, dyspepsia. Rate/speed of neutralization effect  -------------------------------------------------- NaHCO3 CaCO3=Mg(OH)2Al(OH)3 ----------------------------------------------------  Duration of effect

Antacids: main features:

Antacids: main features Should be d osed according to the neutralizing capacity Should be taken in 1 and 3 hours after meals 4 to 6 times a day. Food prolongs antacid stay in the stomach, thus enhancing acid neutralization Target: to keep рН>3,5-4 most of the day Liquid forms act quicker Duration of treatment of gastric peptic ulcer 8-12 weeks, duodenal ulcer - 4-6 weeks Al(OH)3 causes constipation; Mg(OH)2 - diarrhea (osmotic and due to cholecystokinin). Complex drugs like Maalox, Almagel reduce this side effect Avoid concurrent administration with other drugs!

Emetics & Antiemetics :

Emetic s & Antiemetics

Slide 23:


Classification of Emetics::

Classification of Emetic s : 1) centrally acting (D-R of the CTZ) : аpomorphine; 2) peripherally acting (activate vagus due to gastric irritation): ZnSO4, CuSO4 (1%), Ipecacuanha sirop

Emetics :

Emetics Emetics are used for the treatment of acute enteral poisoning, usually in outpatients. They should be administered as soon as possible, usually not later than 1 hour after poison ingestion. About 30% of poison is removed from GIT due to drug-induced vomiting. After this gastric lavage or/and activated charcoal should be used

CI for Emetics :

C I for Emetics poisoning by strong acids or alkalies, or volatile solvents unconcsious patients , HT, CAD, cerebra l atherosclerosis, risk of pulmonary bleeding apomorphine:in children before 7 y. of age NB! Emetics are ineffective in patients with severe CNS depression

Antiemetic drugs and uses:

Antiemetic drugs and uses 1. М-cholinergic blockers : scopolamine Motion sickness 2. D2- blockers : metoclopramide, domperidone haloperidol, droperidol Drug-induced emesis 3. Н1-blockers: diphenhydramine , diprazine Motion sickness, morphine-induced emesis 4. 5-НТ3-blockers: оndansetron, granisetron МАХ effective for X-ray-, or chemotherapy-induced emesis, postoperation emesis

Prokinetic drugs: cisapride (5-HT4), domperidone (D2), metoclopramide (D2):

Prokinetic drugs : cisapride (5- HT4), domperidone (D2), metoclopramide ( D2)

LAXATIVES (cathartics, purgatives, evacuants):

LAXATIVES (cathartics, purgatives, evacuants) USES chronic atonic constipation acute constipation acute enteral poisonings p reparation GIT for diagnostic, therapeutic, or surgical procedures

Laxatives: mechanisms of action:

Laxatives: mechanisms of action

Laxatives: classification :

Laxatives: classification 1 . Оsmotic : 1.1. MgSO4, NaSO4 (10-25%)*, fortrans;* 1.2. Lactulose, macrogol-4000 (forlax) 2. Bulk: (hydrophyllic colloids): аgar, меthylcellulose , bran 3. Fecal softeners/emollients: docusate sodii, castor oil, mineral oil/liquid paraffine* (3g/kg), glycerine suppositories 4. Stimulants/irritants: 4.1.synthetic: phenolphthalein, pikosulphate, bisakodyl 4.3. аntraglycosides: some herbal remedies

Аntraglycosides of Rheum, Frangula, Joster, Senna («glaxena», «senadе»):

Аntraglycosides of Rheum, Frangula, Joster, Senna («glaxena», «senadе»)

Laxatives: side effects:

Laxatives: side effects Abdominal colic pain Uterine contractions, increased tone E lectrolyte depletion, hypokalemia, hypomagnemia T olerance (if 3-4 doses/day are insufficient) « I nert» bowel formation For chronic constipatio n: Do not use laxatives for a long time If necessary - drugs of groups # 1.2, 2, 3, in refractory cases – # 4 Do not use more often than 2 times a week

Laxatives: contraindications:

Laxatives: contraindications Abdominal pain of unknown origin A cute inflammation in GIT GIT, or uterine bleeding P regnant and nursing women I n patients with spastic constipation W ith antibiotics of broad spectrum


АNTIDIARRHEAL DRUGS USES Non-infectious diarrhea (irritable bowel syndrome) Travellers’ diarrhea Diarrhea in patients with mild intestine infection NB! NO «alert signs»: fever, blood in feces, symptoms of intoxication (weakness, headache, muscle aches)


АNTIDIARRHEAL DRUGS: CLASSIFICATION and side effects Ag OR : loperamid e (imodium), codeine, diphenoxylate («lomotil»: + atropine) Сramps, sleepeness, vertigo, in small children - risk of respiratory depression Аbsorbents : kaolin, pectin, hydrated aluminium silicate, activated charcoal, attapulgite Antisecretory : bismuth subsalicylate, indomethacin Antifoaming drugs are used for meteorism: simeticone (espumisan), activated charcoal

Choleretics: cholesecretics and cholekinetics :

Choleretics: cholesecretics and cholekinetics 1.Increasing bile s ecretion а)plant derivatives : preparations of Mays, Dog Rose, Immorthel, «cholaflux», «allochol» б) synthetic: nicodine, oxaphenamide 2. Increasing bile efflux а) cholekinetics (in atonic gall): sorbite, xylite, MgSO4 (20-25%) b ) antispasmodics : М-Ant, No-spa (drotaverine), aminophylline, « B aralgin» (metamizole + 2 synthetic antispasmodics)

Choleretics: cholesecretics** & cholekinetics*:

Choleretics: cholesecretics ** & cholekinetics * USES: H epatobiliary dyskinesia * chronic hepatocholecystitis ** chronic pancreatitis Contraindications оbturation of hepatobiliary ducts jaundice acute inflammation of the GIT acute cholecystitis


HEPATOPROTECTORS SILIBILIN АDEMETHEONIN ESSENTIAL PHOSPHOLIPIDS Treatment and prophylaxis of liver toxicicity (in alcoholics and oth.) Long-term treatment Effectiveness needs more evidence to be proved