GIT_PP DRUGS

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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:

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:

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:

5НТ3 Д2, М1 5НТ3 LABIRYNTH M, H1

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:

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:

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:

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

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