GASTROINTESTINAL & ANTI-EMETIC DRUGS - Drugs used to treat GERD (Gastro-Esophageal Reflux Disease) & Peptic ulcer

Classification

Anti-Microbial Agents

Optimal therapy for Patients with Peptic Ulcer disease who infected with

Helicobacter Pylori....

Urea Breath Test: Exhaled 13CO2 analyzed...presence of H.Pylori increase ratio of

13CO2-12CO2 in Expired breath...H.pylori release UREASE hydrolyzes labeled Urea

into 13CO2

Triple therapy consist of PPI, Metronidazole/Amoxicillin, Clarithromycin

Quadruple therapy PPI, Metronidazole, Tetracycline, Bismuth subsalicylate

GERD not associated with H.pylori

H2-Receptor Antagonists

Gastric acid secretion by parietal cells of mucosa stimulated by ; Histamine, Ach,

Gastrin. Receptor binding results in activation of Protein Kinase....stimulate H+/K+-

ATPase proton pump ...secrete H+ in exchange for K+ into lumen of Stomach.....Gastric acid production

MOA= H2-receptor anatagonists block action of Histamine at all H2-receptor ... Competetively bind to H2-Receptor----- reduce intracellular conc. ATP....inhbit gastric acid secretion

Potently inhibit 90% Basal, Food-stimulated, Nocturnal secretion of gastric acid after single dose......Cimetidine is prototype.....competetive inhibitor & fully reversible

T.E= treat Peptic Ulcer (Duodenal & Gastric ulcer), Acute Stress Ulcer, GERD,

P.K= Cimetidine is Enzyme inducer...dose reduced in renal/hepatic failure...

S.E=headache, dizziness, diarrhea, muscular pain...Cimetidine have NonSteroidal Antiandrogen effects, cause Gynecomastia, Galactorrhea

Ketoconazole depend upon gastric acid secretion, co-administration decrease activity

Proton Pump Inhibitor PPIs

MOA= weak base bind to Serine residue of H+/K+ ATPase proton pump by forming stable covalent bond.....decrease secretion of Hydrogen ion (H+) into the lumen...it is the final step of gastric acid secretion...it takes 18hr to resynthesize enzyme

Omeprazole is the first drug...Enzyme inhibitor...all are prodrugs...with acid-resistant coating...coating remove in Alkaline medium, duodenum, produce weak Base...inhibit

Basal & Stimulated Gastric Acid secretion by >90%

T.E= treat Active Doudenal ulcer, Stress ulcer, Prophylaxis of Erosive Esophagitis..

Zollinger-Ellison syndrome; Gastrin producing tumor cause Hypersecretion of HCI

treat GERD.....30-60min before breakfast or heavy meal

S.E= increased risk of fracture of Hip, Wrist, Spine, ↑ diarrhea & Clostridium Difficile colitis

Drug interactions= with Clopidogrel; ↓ effectiveness of Clopiddogrel, ↑ CVS side

effect ... with Vit B12; ↓ Abs.b/c acid required for its Abs.......↑pH decrease Abs.of

CaCO3 so pt. used Calcium citrate as a source of Ca++...

Prostaglandins

PG -E inhibit secretion of HCI, secretion of Mucus & Biarbonate(Cytoprotective action)

Misoprostol used for Gastric ulcer induced by NSAID.... contraindiated in pregnancy

AntAcids

Weak bases that react with Gastric Acid to form water & salt to diminish acidity.. .... Pepsin is inactive at pH>4, so ↓ pepsin activity

Chemistery= vary widely in chemical composition, Na+ content, Acid-neutralizing capacity, palatability, price....

Acid-neutralizing ability; depend on capacity to neutralize HCI & stomach empty or full.

AI(OH)3, Mg(OH)2, CaCO3, NaHCO3

T.E= promote healing of Duodenal ulcer, symptomatic relief of Peptic ulcer & GERD,

Last-line agent used for Acute Gastric Ulcer....CaCO3 used in Osteoporosis

S.E= AI(OH)3 cause Constipation, Mg(OH)2 cause Diarrhea, NaHCO3 cause

Alkalosis & liberate CO2 cause Flatulence,blenching....Phosphate binding to AI(OH)3

cause Hypophosphatemia....Na+ avoid in Hypertension and CHF....Mg, Ca, Na avoid in

renal impair

Mucosal Protective Agents

Cytoprotective agents; enhance mucous protection prevent mucosal injury, ↓ inflammation, healing ulcer

Sucralfate= complex of Aluminium Hydroxide & Sulfated Sucrosebind to +Ve group of Protein in normal & necrotic Mucosa......

MOA= by forming Complex gel with Epithelial cells...create physical barrier that impair diffusion of HCI...prevent degradation of mucus by Pepsin & acid.....Stimulate PG release & mucus,Bicarbonate output.....inhibit Peptic digestion...

T.E= Healing of Duodenal ulcer....prevent recurrence...require acidic pH for activation...not Administered with PPIs, H2-Antagonist, Antacid

Bismuth Subsalicylate= inhibit Pepsin, ↑ secretion of mucus, anti-microbial action, interact with Glycoprotein in necrotic mucosal tissue to coat & protect ulcer crater.......

Drugs used to control Chemotherapy- Induced Emesis

Anti-emetics:

Vomiting

1) Chemotrigger zone (CTZ) located in area Postrema...outside the B.B.B... respond directly in the blood or CSF..

2) Vomiting center in reticular formation of medulla...respond to input from GIT & Pharynx

Emetic Action of Chemotherapeutic agent

Chemotherapeutic agent directly stimulate CTZ or Vomiting center...several receptor i.e Dopamine D2, Serotonin 5-HT3 play critical role....

Chemotherapeutic agent damage GIT & release Serotonin from

ENTEROCHROMAFFIN cells which activate 5-HT3 in CTZ or vomiting center

Phenothiazines

Prochlorperazine= block D2 receptor... effective against Flourouracil & Doxorubicin...

cause Hypotension, Extrapyramida effects

5-HT3 Receptor Blocker

Longer duration of action.... Selective anatagonist of 5-HT3 receptor... Ondansetron & Granisetron effective against Cisplatin-emetic action...Hydroxydolasetron active metabolite of Dolasetron....Headache side effect..

Prolong QT-interval with Dolasetron

Metoclopramide= Prokinetic agent... used against Cisplatin emetic action... side effects include sedation, diarrhea, extrapyramidal effects

Butyrophenone

Droperidol & Haloperidol= block D1,D2 receptor.. Droperidol used for SEDATION in endoscopy & surgery...Prlong QT-interval...effective against Cisplatin emetic action

Corticosteroid

Cause hyperglycemia & insomnia in Diabetes mellitus

Substance P/Neurokinin-1 Receptor Blocker

Aprepitant: target Neurokinin & block Substance-P in brain... Administer with Dexamethasone & Palonosetron ...Enzyme inducer CYP3A4... Cause Constipation

Anti-Diarrheal

Increased motility of GIT & decreased Abs of Fluid

Anti-motility agent Diphenoxylate + Atropine Loperamide

Adsorbents Aluminium hydroxide Methylcellulose

Agents that modify Fluid & Electrolyte Bismuth subsalicylate Transport

Antimotility agent

Diphenoxylate & Loperamide= analogue of Meperidine... have Opioid like action.

Activate Opioid Receptor in ENS to inhibit Ach release... Decrease Peristalsis ...

S.E; Drowsiness, Abdominal cramp, Megacolon...not used in pt. with colitis Adsorbents

AI(OH)3 & Methycellulose= act by adsorbing intestinal toxins or micro-organsim .... Or

by coating intestinal mucosa

Agents that modify Fluid & Electrolyte Transport

Bismuth Subsalicylate= Used for Traveler‟s diarrhea...decrease fluid secretion in bowel... due to salicylate & coating action.... S.E; Black tongue, Black stool

LAXATIVES

Laxatives used for constipation to accelerate the movement of food through GIT

Irritants & Stimulants Bisacodyl, Castor oil, Senna

Bulk Laxative Methylcellulose , Psyillium

Saline & Osmotic Laxative Magnesium citrate, Magnesium hydroxide,

Polyethylene glycol, Lactulose

Stool softener Docusate

Lubricant Glycerin suppositories, Mineral oil

Chloride channel Activator Lubiprostone

Irritants & Stimulants

Senna = active ingredient of Sennoside.... Glycoside... cause water & electrolyte secretion in bowel... useful in Opioid induced constipation

Bisacodyl=potent stimulant of Colon... available in Suppositories & Enteric coated... side effect Abdominal cramp , atonic colon

Castor oil= Breakdown small intestine into Ricinoleic acid..irritant to stomach.. ↑peristalsis .. avoid in pregnancy cause uterine contraction

Bulk laxative

Hydrophilic colloid ... form Gels in large intestine... cause water retention & intestinal distension... ↑ Peristalsis...used with caution in pt. with Intestinal obstruction

Saline & Osmotic laxative

Non-absorbable salts... hold water in intestine by Osmosis... increase intestinal activity & defecationin hrs.... PEG used as Colonic Lavage...

Lactulose cause Osmosis... degrade in Colon by Colonic bacteria into lactic,formic, acetic acid... this increase osmotic pressure

Stool softener

Surfactant become emulsified wth stool... produce softer feces... not used with mineral oil cause Abs of mineral oil

Lubricants

Facilitate pessage of stool mineral oil take orally in UPRIGHT position to avoid Aspiration & Abs. of oil

Chloride Channel Activator

Lubipristone= increase fluid secretion ... activate CI- channel.... Used for CHRONIC CONSTIPATION....