DRUGSUSEDIN GASTROINTESTINALDISEASES

Dewi Selvina Rosdiana

Outline
Drugsusedinacidpepticdiseases Prokineticagent Antiemetic Antidiarrheals Laxatives Antispasmodic DrugusedformiscellaneousGIdisorder

DRUGUSEDINACIDPEPTICDISEASE
Acid neutralizing agents Acid production inhibitor H2 antagonist Proton-pump inhibitors Mucosal protective agents Other acid suppressant

Schematic model for physiologic control of hydrogen ion (acid) secretion by the parietal cells of the gastric fundic glands

Acidneutralizingagents:Antacids
Combination of Al(OH)3, Mg(OH)2, CaCO3 (+simethicone) Pharmacodynamics:
y Form salt and water y Promote mucosal defense by stimulation of PG production

Drug interaction:
y Inhibit absorption of digoxin, phenytoin, cimetidine, fluoroquinolone y Some Al can be absorbed

Acidneutralizingagents:Antacids

H2 receptorantagonists
Cimetidine, ranitidine, nizatidine, famotidine Pharmacodynamic: y Reduce acid secretion in 2 ways: competitive inhibition H2 receptor & modulate PCs response to gastrin & Ach y Reduce 90% (at night) and 60-80% (daytime)

H2 receptorantagonists
Pharmacokinetic: y rapidly absorbed in intestinal lumen y Undergo 1st pass metabolism F = 50% y T1/2: 1-4 hrs, and d.o.a depend on dose, 10 hrs in recommended dose y Elimination: hepatic metab., glomerular filtration filtration & renal tubular secretion y Cross the placenta, secreted into breast milk

H2 receptorantagonists
Safety: Extremely safe SE: diarrhea, constipation, headache, fatigue, myalgia Gynaecomastia Blood dyscrasi Avoid from pregnant and nursing women Drug interaction: cimetidine prolong half-lives drugs that are substrate for CYP: warfarin, theophylline, phenitoin, lidocaine, quinidine, b-blockers, Ca-channel blockers, benzodiazepines Compete with procainamide for renal tubular secretion

H2 receptorantagonists

Protonpumpinhibitors
Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole Pharmacodynamic: y Protonated & concentrated in PC canaliculi y The reactive cation binds covalently with H/K ATPase y Reduce 80-95%, needs 3-4 days to return

Protonpumpinhibitors
Pharmacokinetic: absorbed in intestinal lumen (available in enteric coated) y An acid-labile lipophylic prodrug: need acid environment to be activated easily diffuse into acidified compartment (PC canaliculi) y To be administered 1 hour before meal y Highly protein bound y Undergo 1st pass & hepatic metabolism y T1/2: 1,5 hr but acid inhibition last up to 24 hr y No renal elimination

Protonpumpinhibitors
Safety: Extremely safe SE: due to highly reduction acid Reduction in cyanocobalamin absorption Food-bound minerals (?) Increase risk of enteric infections Drug interaction Alter absorption of certain drugs

Protonpumpinhibitors

Mucosalprotectiveagents
Sucralfate: A complex of sucrose salt + sulfated AlOH
forms a paste that selectively cover ulcers/erosions Pharmacokinetic: y Almost unabsorbed y Breaking down into sucrose sulfate & Al salt Pharmacodynamic: y Forming physical barrier so that prevent further caustic damage stimulate mucosal PG & HCO3 secretion y Enhancing mucosal repair Drug interaction: y Inhibit absorption of digoxin, phenytoin, cimetidine, fluoroquinolone y Some Al can be absorbed

Mucosaldefenseenhancingagents
Bismuth compounds
Pharmacodynamic: = sucralfate Stimulate PG, mucus, bicarbonat secretion

Prostaglandin analog: misoprostol

A methyl analog of PGE1 Pharmacokinetic: y T1/2: 30 mnts 3-4 times daily Pharmacodynamic: stimulates mucus and bicarbonat secretion SE: diarrhea, abdominal cramp (10-20%), stimulate uterine contraction

Mechanism of action of drug used in acid peptic disease

PROKINETIC AGENTS
Agents that enhance coordinated GI motility and transits material in the GI tract Cholinomimetic Bethanechol Neostigmin methylsulfate Dopamine receptor antagonist Metoclopramide domperidon Serotonin (5-HT4) receptor agonist Cisapride, prucalopride Motilin agonist Macrolides: erythromycin

PROKINETIC AGENTS
Side effects: Metoclopramide Extrapyramidal effect Elevated prolactin level galactorrhea, gynaecomastia, menstrual disorder methaemoglobinemia Domperidone No extrapyramidal effect Cisaprid Fatal cardiac arrythmia (occasionally) torsades de pointes due to induced EAD

PROKINETIC AGENTS
Therapeutic use: GERD Impaired gastric emptying Postvagotomy Diabetic gastroparesis NGT-ed patients Dyspepsia syndrome (non-ulcers) Antiemetic Persistent hiccup (metoclopramide)

LAXATIVES(cathartics)
1. Stimulant laxatives: y Castor oil y Diphenylmethane derivatives: bisacodyl y Anthraquinone derivatives: Aloe, senna, cascara 2. Bulk forming laxatives: y Natural plant: bran, psyllium, methylcellulose y Synthetic fibers: calcium polycarbophil 3. Stool softener: y docusate y mineral oil y glycerin supp 4. Osmotic laxatives: y saline laxatives: magnesium citrate, sodium phosphate y unabsorbable sugars: sorbitol, lactulose

Mechanismofactionoflaxatives

ANTIEMETIC
1. Serotonin (5-HT3) receptors antagonist Ondansetron, granisetron, ramosetron, palanosetron, dolasetron 2. Dopamine antagonist: Metoklopramide, domperidon 3. H1-antagonist : Cyclizine, Promethazine, prochlorperazine, CPZ 4. Antikolinergics: Scopolamine 5. Cannabioid antagonist: Dronabinol

ANTIDIARRHEA
1. Opioid agonist 2. Colloidal bismuth compound 3. Kaolin (hydrated Mg-Al silicate) & pectin (indigestible KH) 4. Bile salt-binding resin 5. Octreotide

Pharmacodynamic Opioid (Loperamide, Diphenoxylate)

Inhibitpresynaptic cholinergic nerve,reduceperistalticactivity Increase transittime Decreasemasscolonic movements

antidiare

Sideeffects constipation,cramps,drowsiness, paralytic ileus,abdominalbloating. Diphenoxylate,butnotloperamide, produceeuphoria dan respiratory depression Darkstools,blackstaining ofthe tounge

Colloidalbismuth compound Kaolin&pectin

directantimicrobialeffectsand bindsenterotoxins

Havenosignificantadverseeffect adsorbentsofbacterialtoxins exceptconstipation. andfluid, therebydecreasingstool liquidityandnumber. Shouldnotbetakenwithin2hours ofothermedication binds bilesaltsandincreases fecalexcretionofbileacids Bloating,flatulence,constipation Fat malabsorption Shouldnotbetakenwithin2hours ofothermedication

Bilesaltbindingresin (Cholestiramine, Colestipol,colesevalam) Somatostatinlike (Octreotide)

reducesintestinalfluidsecretion Steatorrhea,nausea,bloating &pancreaticsecretion Fatsoluble vitamindeficiency slowsGImotility,inhibit Gallstoneformation, gallbladdercontraction hypo/hyperglycemia

ANTIPASMODIC
1. Anticholinergic Hyoscyamine, Dicyclomine 2. Serotonin (5-HT3) receptor antagonist Alosetron Indication: to prevent the pain and fecal urgency in patient with IBS treatment of diarrhea-predominant IBS

DrugusedformiscellaneousGIdisorder
1. Pancreatic enzymes: pancreatin, pancrelipase Chronic pancreatitis Malabsorption 2. Bile acids: ursodeoxycholic Gallstone dissolution 3. Antiflatulance: simethicone, herbal prep. (antifoaming agent)

References
McQuaidKR.DrugsusedinthetreatmentofGastrointestinaldiseases.In: KatzungBG,MastersSB,andTrevorAJ.Basicandclinicalpharmacology. 11th ed.Singapure.McGrawHill;2009.p.106798. WallaceJL,SharkeyKA.Pharmacotherapyofgastricacidity,pepticulcers, andgastroesophagealrefluxdisease.In:Goodman&Gilmans the pharmacologicalbasisoftherapeutics.12th ed.NewYork:McGrawHill; 2011.p.130921. WallaceJL,SharkeyKA.Treatmentofdisordersofbowelmotilityand waterflux;antiemetics;agentsusedinbiliaryandpancreaticdisease.In: Goodman&Gilmans thepharmacologicalbasisoftherapeutics.12th ed. NewYork:McGrawHill;2011.p.132349. PageC,CurtisM,WalkerM,HoffmanB.Integratedpharmacology.3rd ed. Spain.ElsevierMosby;2006.p.475507