DRUGS USED IN GIT DISEASES

DR FIRMALINO

Groups

• A. Drugs Used in Acid Peptic Diseases• B. Drugs Promoting Gastrointestinal Motility• C. Anti Emetic Drugs• D. Pancreatic Enzyme Replacement Products• E. Laxatives• F. Drugs Used For Dissolution of Gallstones• G. Drugs Used In The Treatment of Chronic

Inflammatory Bowel Disease• H. Drugs Used in Therapy Of Portal Systemic

Encephalopathy

Gastric acid secretion

Peptic Ulcer Disease

Endoscopy

A. Drugs Used In Acid Peptic Disease

• Antacids– Weak bases– Reduce gastric acidity– Reduce pepsin activity– Has mucosal protection by stimulating prostaglandin

production• Kinds– magnesium hydroxide Mg (OH)2– aluminum hydroxide Al (OH)2– sodium bicarbonate NaHCO3– calcium carbonate

Mechanism of antacid

Clinical uses of antacids• 1. if given 1 hr after a meal, it neutralises gastric acid for 2 hrs• 2. if a second dose is given 3 hrs after the meal, it maintain

the effect for up to 24 hrs• 3. promotes healing of duodenal ulcer• 4. role in gastric ulcer is less clear• 5. may be used to relieve the pain of esophagitis, duodenal &

gastric ulcer• 6. tablet antacid are generally weaker in neutralizing capability• a. not recommended for treatment of active peptic ulcer

disease

Adverse reactions

• magnesium– diarrhea– hyper magnesemia

• aluminum– constipation– hypophosphatemia

• combine these 2 to avoid each other’s side effect

Gastric Antisecretory Drugs

• 3 normal agonist / stimulants to gastric acid secretion– Histamine– Acetylcholine– Gastrin

• H2 receptor antagonist– Cimetidine– Ranitidine– Famotidine– Nizatadine

Pharmacodynamics/Pharmacokinetics

• Decrease food stimulated acid secretion by 90%• Less effective in nocturnal secretion• Also for heartburn & dyspepsia• Effective for promoting healing of duodenal &

gastric ulcer & preventing recurrence• Also for Zollinger Ellison syndrome & gastric

hypersecretory states like systemic mastocytosis• Preferably given at bedtime for 4 wks

Toxicity• Cimetidine– confusion– reversible gynecomastia – increase prolactin & estrogen

• rare w/ ranitidine & famotidine

– has hepatotoxic microsomal metabolism of some drugs like warfarin, theophylline, diazepam, phenytoin• less w/ ranitidine• no effect w/ famotidine & nizatadine

• Famotidine– headache

• All drugs– hematologic

Gynecomastia

Anti Muscarinic Agents

• Cholinoceptor antagonist– Rarely used since the gastric receptor is least

sensitive to it– Adjunct only

• Example– pirenzepine– atropine (hyoscyamine)– scopolamine (hyoscine)– ipratropium

Parasympatholytic effect

• pupil dilatation, bronchodilatation• tachycardia, dry mouth• decrease gastric acid secretion• decrease intestinal motility

Proton Pump Inhibitors

• Irreversibly inhibits gastric parietal cell proton pump H+/K+ AT pase by 100%

• 4 drugs– Omeprazole– Lanzoprazole– Rabaprazole– Pantoprazole

Indications (4-8 wks tx)

• Gastric ulcer • Duodenal ulcer • Gastro esophageal reflux disease GERD• Esophagitis• Superior to H2 antagonist & misoprostol in dealing

w/ NSAID induced ulcer• Zollinger Ellison Syndrome• Multiple Endocrine Neoplasia• Systemic Mastocytosis

Toxicity

• Develop gastric carcinoid tumors in rats but not in man

Somatostatin analog

• Growth hormone inhibiting hormone• octreotide• Inhibit gastric acid & pancreatic secretion• Tx of Gastrinoma (Zollinger Ellison Syndrome• May decrease portal pressure & reduce

variceal hemorrhage

Mucosal Protective Agents

• Sucralfate– Aluminum sucrose sulfate– Selective binding to necrotic ulcer tissue & act as

barrier to acid,pepsin,bile– Directly absorbs bile salt– Stimulate prostaglandin synthesis– Not absorbed– Requires acid pH to be activated therefore should

not be used w/ antacid,proton pump inhibitors,H2 receptors antagonist

Mucosal Protective Agents

• Colloidal Bismuth Compounds– Also binds an ulcer tissue,coat it & protect it from

acid & pepsin– inhibition of pepsin– stimulate mucus production– increase prostaglandin synthesis– possible antimicrobial effect on H.pyloni especially

if combined w/ metronidazole & tetracycline– ulcer healing up to 98%

Kinds of Colloid bismuth

• bismuth subsalicylate• tripotassium dicitrate bismuthate – toxicity-minimal

• Carbenoxolone– Synthetic derivative of glycyrrhizic acid (from

licorice)

Mechanism of action of colloid bismuth

• Increase mucus production, increase secretion & increase viscosity

• Has aldosterone like effect, thus causes– Hpn, fluid retention, hypokalemia

• Concurrent use of spironolactone controls fluid retention but also abolished ulcer healing effect

• Use w/ thiazide prevent Na retention w/o abolishing ulcer healing effect

Prostaglandin Synthetic Analog

• Produced by gastric mucosa & inhibits gastric secretion in high doses by inhibition of histamine related cAMP production– Example – Misoprostol ( Cytotec)

• Prevents ulcer induced by NSAID• Toxicity– Diarrhea– Uterine contraction - abortion

Antibiotics

• Ampicillin• Amoxicillin• Clarithromycin• Metronidazole• Tetracycline

Dr Warren / Dr Marshall

• 1979 – Dr Warren, a pathologist, noted H. Pylori in Gastric ulcer biopsy

• 1984 – Dr Marshall swallowed H. Pylori and developed gastritis / ulcer. He treated himself w/ antibiotics and he improved

• 2005 – both were awarded the Nobel Prize & 1 million dollars for their work

Combination therapy

• Not recommended – no proven benefit• Especially if combined w/ a proton pump

inhibitor like omeprazole, the H2 receptor antagonist even inhibit omeprazole

Refractory Disease

• 20% - failure rate especially w/ elderly & smokers

• What to do– Increase the dose– Prolong treatment >4 wks – Shift to another H2 antagonist– Shift to proton pump inhibitor– Add antibiotics for H.pylori - Clarithromycin,

ampicillin

DRUGS PROMOTING INTESTINAL MOTILITY

• Cholinomimetic effect• Agents– Bethanechol – Metoclopramide– Cisapride

• Metoclopramide– Dopamine antagonist – thus the anti emetic effect

in cancer tx, emergency surgery labor, delivery– Enters CNS

• Cisapride– Does not enter CNS; increase colon motility– For gastro esophageal reflux

Metoclopramide / Cisapride

• Both causes release of acetylcholine from cholinergic neurons in enteric myenteric plexus

• Also sensitizes intestinal smooth muscle to Ach.• Do not increase gastric & pancreatic secretion• Hasten esophageal clearance, increase lower

esophageal sphincter pressure• Increase gastric emptying• Shorten small bowel transit time

Clinical use

• Metocloparamide facilitates small bowel intubation

• Diabetic gastroparesis• Post vagotomy• Gastroesophageal reflux• Can decrease heart burn

Toxicity

• cisapride – can cause ventricular arrhythmia

• Metoclopramide– Somnolence– Nervousness– Dystomia– Parkinson/tardive dyskinesia– Increase pituitary prolactine release, galactorrhea,

menstrual disorder

Other drugs• Erythromycin

– Macrolide antibiotic– Prokinetic effect in stomach – increase motility– For diabetic gastro paresis & intestinal pseudo obstruction

• Alosetron– 5 HT antagonist– Under research for irritable bowel syndrome

• Tegaserod– 5 HT partial agonist– w/ similar benefit

• 5 HT– 5 hydroxytyptamine Or serotonin– vasoconstrictor– intestinal smooth muscle stimulant & increase motility

ANTI EMETIC DRUGS

• Emesis or vomiting is just a manifestation of a wide variety of conditions– Pregnancy – Motion sickness– GIT obstruction– Peptic ulcer– Drug toxicity (cancer chemo Tx)– MI– Renal failure– Hepatitis

Major anti emetic drugs

• H1 antihistamines• Phenothiazines• Metoclopramide• Ondansetron• Marijuana• Corticosteroid• Benzodiazepine

H1 Antihistamines

• diphenhydramine , hydroxyzine• has antimuscarinic & sedative effects• particularly effective for nausea & vomiting of

motion sickness due to depression of the vestibulo cerebeller pathway (like the anticholinergic scopolamine)

Phenothiazines

• blocks dopamine receptors in chemoreceptor vomiting trigger zone in the brain

• kinds– prochlorperazine– promethazine

• has limited use due to its sedative effect• toxicity– sedation– dystonia – reversed by diphenhydramine

Other anti emetic• Metoclopramide - also a dopamine antagonist like phenothiazine• 5 HT (hydroxytryptamine) inhibitors

– ondansetron, granisetron, dolasetron– good for cancer chemotherapy

• Neurokinin antagonist– under research for delayed emesis & vomiting due to high dose

chemotherapy• Marijuana – tetrahydrocannabinol & dronabinal

– also for vomiting of cancer chemotherapy• Corticosteriod

– dexamethasone, methylprednisolone– mechanism against vomiting is unknown

• Benzodiazepine– sedative/hypnotic drug used to control anticipatory nausea &

vomiting

PANCREATIC REPLACEMENT PRODUCTS

• Steatorrhea may occur in pancreatic insufficiency when lipase output is lower by 100% of normal

• Pancreatic enzyme replacement when given orally is inactivated by gastric acid pH below 4.0 thus only about 8% of this ingested lipase reaches the distal duodenum

• Kinds– Pancreatin– Pancrelipase

• Maybe supplemented w/ cimetidine thus lowering gastric acid secretion & preserve the enzyme

• Toxicity– Renal uric acid stone formation(the enzyme has

high purine content)• Lactose intolerance

LAXATIVES

• Kinds– Irritants/stimulants– Bulking laxatives– Stool softener

Constipation

Irritant/Stimulant laxatives• Castor oil– hydrolyzed in upper small intestine to ricinoleic

acid, a local irritant that increase motility• Cascara, Senna, Aloes– contain emodin alkaloid that cause colon

stimulation 6-8 after ingestion• Phenolphthalein,• Bisacodyl - Dulcolax supp / tab)• colonic stimulants– Sodium Picosulfate(Laxoberal tab, liquid)

Bulking laxatives• Hydrophylic colloids, Prepared from indigestible parts of

fruits, vegetable seeds, Forms gels in the large intestines, distending it & stimulating peristalsis– Kinds – Agar, Psyllium seeds (Metamucil sachet), Methylcellulose,

Bran/vegetable fiber• Saline cathartics – non absorbable salts that holds water &

cause distension & peristalsis like Mg citrate & Mg hydroxide• Polyethelene glycol• Lactulose (duphalac)• synthetic disaccharide (galactose-fructose)

– not absorb• osmotic laxative(attracts water)

– Sorbitol – also non absorbable

Stool Softeners

• Emulsify stool & soften it • Kinds– Mineral oil– Glycerin suppository– Dioctyl sodium sulfosuccinate(docusate)

Diarrhea

ANTIDIARRHEAL

• Opioids– Inhibit acetylcholine release at presynaptic opioid

receptors & stops intestinal motility• Kinds– Diphenoxylate - weak analog of Meperidine– Loperamide – related to haloperidol

• Contraindication– Ulcerative colitis – may cause toxic megacolon

ANTIDIARRHEAL

• Adsorbent– Kaolin/pectin

DRUGS USED FOR DISSOLUTION OF GALLSTONES

• Only for cholesterol gallstones• Kinds– Chenodiol– Ursodiol

• Both can dissolve cholesterol gallbladder stone 5mm within 2 years therapy

• Cannot dissolve stones with >4% calcium

• Controversial • `If stone contains <4% calcium, it cannot be seen

on xray as radio opaque and therefore not readily diagnosed– Patient may have recurrence if treatment is stopped

and may need to be treated for life– If stone causes obstruction before it can be dissolved,

it becomes a surgical emergency• Ursodiol is also being used for primary biliary

cirrhosis

DRUGS USED FOR TREATMENT OF CHRONIC INFLAMMATORY BOWEL DISORDERS

• Ulcerative Colitis • Crohn’s disease• Kinds– Corticosteroid – Immunosuppressive drugs– Salicylates – 5 amino salicylic acid, Mesalamine

• Mechanism– Affects arachidonic acid pathway in pathogenesis of

inflammation– Inhibits prostaglandin and leukotriene production

Other kinds

• sulfasalazine/Sulfapyridine– toxicity – Mallaise, headache, abdominal

discomfort, serum sickness, bone marrow suppression

• olsalazine – may cause watery diarrhea• balsalazide• all salicylates are given orally or by retention

enema

Immunosuppressive agents

• Corticosteroid • Hydrocortisone• Prednisone• Oral or retention enema

Cytotoxic drugs

• Azathioprine, Cyclosporine, Mercaptopurine– Helpful in fistulas associated with Crohn’s– Toxicity• drug induced pancreatitis

Infliximab

• Treatment for imflammatory bowel disorder• A monoclonal antibody directed at TNF, a

protein known to cause inflammation in Crohn’s• Toxicity– nausea– serum sickness– serious infection– malignancy(lymphoma)– very expensive $2000/infusion

DRUGS USED IN PORTAL SYSTEMIC ENCEPHALOPATHY

• NEOMYCIN– Non absorbable antibiotic– LACTOSE laxative

• Mechanism unclear– Reduced by bacteria to lactic acid/acetic acid

which traps ammonia and other toxins in intestines causing the encephalophaty

• END