Clinical Use of Drugs : Pharmacotherapy GI Disorders

Upper GI Disorders

GI Anatomic region

Gastric Acid Secretion

Neuronal

sight, smell, taste cholinergic pathway

Physical
strecth acetylcholine & gastrin

Hormonal
Stimulate parietal cells to secrete gastric acid Proton pump (H+/K+- ATPase)

Gastrin Acetylcholine Histamine

Acid Secretion

Physiological & Pharmacological Gastric Acid Secretion

Pharmacotherapy of Acid Related Disorders

Acid-suppressing drugs Proton-pump Inhibitors (PPIs) Five PPIs available in clinical use : Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole, & Pantoprazole

Similar in their pharmacological properties

All PPIs have equivalent efficacy at comparable doses PPIs diminish daily production of acid by 80 95% most potent gastric suppressors

PPIs prodrugs, require activation in acid environment tetracyclic sulfenamide unable to diffuse back to canalicular membrane Activated form of PPIs covalently bound to H+/K+-ATPase Acid secretion resume after newly formed H+/K+-ATPase molecules Prolong acid suppression (24 48 hours) PPIs block final steps of acid secretion

Effective in acid suppression regardless of other stimulating factors Dosage form : Enteric coated drugs, enteric coated granules, enteric coated tablets, powdered in combination with bicarbonate to prevent degradation by acid in the stomach

Pharmacokinetics : Rapidly absorbed, highly protein bound, extensively metabolized by hepatic CYPs

CYP2C19 & CYP3A4 CYP2C19 genotype

Asian vs Caucasian or African American (23% vs 3%)

Chronic renal failure does not lead to accumulation of PPIs with once-a-day dosing Hepatic impairment substantially reduce clearence of esomeprazole and lansoprazole

Adverse Effects & Drug Interactions

Most common : nausea, abdominal pain, flatulence, & diarrhea

Subacute myopathy, arthralgia, headache, & rash

Inhibition of CYP2C19, slower the clearence of phenytoin, disulfiram, & other drugs metabolized the same enzymes) Increase expression of CYP1A2 (increase clearence of imipramine, antipsychotic drugs, tacrin, & theophylline) Loss of gastric acidity affect bioavailability of ketoconazole, ampicillin esters, & iron salts Chronic use hip fracture, possibly decreasing Ca2+ absorption

Adverse Effects & Drug Interactions

Most common : nausea, abdominal pain, flatulence, & diarrhea

Subacute myopathy, arthralgia, headache, & rash

Inhibition of CYP2C19, slower the clearence of phenytoin, disulfiram, & other drugs metabolized the same enzymes) Increase expression of CYP1A2 (increase clearence of imipramine, antipsychotic drugs, tacrin, & theophylline) Loss of gastric acidity affect bioavailability of ketoconazole, ampicillin esters, & iron salts Chronic use hip fracture, possibly decreasing Ca2+ absorption

Therapeutic Use

Promote healing of gastric & duodenal ulcers Gastroesophageal reflux disease (GERD) Hypersecretory conditions : ZolingerEllison syndrome Prevention of recurrence of NSAID associated gastric ulcers

H2 Receptor Antagonists

H2RAs competitive inhibitors of H2 receptor on basolateral membrane of parietal cells Available drugs : Cimetidine, Ranitidine, Famotidine, Nizatidine

Differ in pharmacokinetics & propensity to cause drug interations

H2RAs predominantly inhibit basal acid secretion suppressing nocturnal acid secretion

Pharmacokinetics

Rapidly absorbed, peak serum concentration achieved within 1 3 hours Small percentage of H2RAs are protein-bound Liver disease per se is not indication for dose adjustment Excreted by kidneys through filtration & tubular secretion reduce dose on patients with reduced creatinine clearence

Adverse Effects & Interactions

H2RAs generally well-tolerated

Low incidence of AEs : diarrhea, headache, fatigue, muscular pain, & constipation Neurologic : headache, dizziness, drowsiness, lethargy, hallucination, psychosis)
Cimetidine at high doses inhibit testosterone binding to androgen receptors & inhibition of CYP reduce hydroxylation of estradiol Galactorrhea in women, and gynecomastia, reduced sperm counts & impotence in men

Long-term use :

Blood dyscrasia including thrombocytopenia have been reported H2RAs cross the placenta & excreted in breast milk

Therapeutic Uses

Promote healing of gastric & duodenal ulcers Treat uncomplicated GERD Prevent occurrence of stress ulcers

Agents that Enhance Mucosal Defences

Prostaglandin Analog : Misoprostol Synthetic analog of PGE1 Gastric acid secretion inhibition Dose related

100 200 ug significantly inhibit basal secretion ( up to 95%) or food stimulated secretion ( 85% inhibition)

Cytoprotective role of prostaglandin toward gastric acidity

Stimulate Gi pathway decreasing cAMP & gastric acid secretion Stimulate mucin & bicarbonate secretion Increase blood flow

Recommended dose for ulcer prophylaxis : 200 ug four times a day

Frequent dosing limited its use inconvenience

Misoprostol can cause exacerbation of inflammatory bowel disease Contraindicated in pregnancy increase uterine contractility

Therapeutic Use To prevent NSAID-induced mucosal injury

Sucralfate

Sulfated polysaccaride Octasulfate of sucrose

Inhibit pepsin-mediated hydrolisis of mucosal proteins contributes to mucosal erosion & ulceration In acid environment (pH<4), sucralfate cross-linking viscous & sticky polymer that adhere to epithelial cells & ulcer crater up to 6 hours after single dose Stimulating secretion of PGs & growth factors

Therapeutic Use

In critically patients, sucralfate may offer advantage over PPIs & H2RAs in preventing stress ulcers Condition associated with mucosal inflammation / ulceration which is not responsive to acid suppression such as oral mucositis (radiation & aphtous ulcer), bile reflux gastropathy

Bismuth Salts

Binding to and protecting mucosal lesion Enhancing cellular protective mechanims Antimicrobial effects, primarily againts H.pylori Frequently use in combination with other antibiotics to eradicate H.pylori

Prokinetic agents
Metoclopramide & Betanechol Stimulate motility of upper GI & increase LES (lower esophageal sphincter)

Patients with delayed gastric emptying or refractory to other available treatment options

General Guidelines of medical management of Gastroesophageal Reflux Disease (GERD)

Meta-analysis of H2-receptor antagonists on Functional (Non-Ulcer) Dyspepsia

Meta-analysis of H2-receptor antagonists on Functional (Non-Ulcer) Dyspepsia

Comparison of Prokinetic, Acid Suppression, and Antianxiety Therapies in Functional Dyspepsia

Both Mosapride and Famotidine significantly improved the symptoms of Functional Dyspepsia within 2 weeks and the improvement was maintained for 8 weeks after the beginning of the study (p < 0.001)

Meta-analysis : Helicobacter pylori eradication improve symptoms in non-ulcer dyspepsia ?

PPIs vs AH2 : Effect on persistent or rebleeding of peptic ulcer

In patients with peptic ulcer and H. pylori infection, prolonging therapy with proton pump inhibitor after a triple therapy for 7 days with a proton pump inhibitor and two antibiotics is not necessary to induce ulcer healing

Step-Up vs Step-Down Therapy in New-Onset Dyspepsia

Double-blind, randomized controlled trial

Step-up therapy : started with antacids, switched to H2-receptor antagonists, and then ended with proton pump inhibitors (PPIs) Step-Down therapy : reversed order

Step-Up therapy somewhat more cost effective than a step-down approach, but effectiveness of treatment and adverse events are similar.

Nausea & Vomiting

Patophysiology of Emesis Nausea, the imminent need to vomit

Associated with gastric stasis Labored movement of thoracic & abdominal muscles before vomiting Forceful of GI contents caused by GI retroperistalsis Act of vomiting require coordinated contraction of abdominal muscles, pylorus, antrum, raised gastric cardia, diminished lower esophageal sphincter, & esophageal dilatation Neurotransmitter receptor : cholinergic, histaminic, serotonergic, dopaminergic, opiate, neurokinin, & benzodiazepin receptors

Retching,

Vomit

Chemoreceptor trigger zone (CTZ)

Specific etiologies of Nausea & Vomiting

Emetogenicity of Chemoterapeutic Agents

Emetogenicity of Chemoterapeutic Agents

Presentation of Nausea & Vomiting

Treatment
Non pharmacologic Dietary restriction if appropiate Stable physical position Psychological & behavioral intervention

Relaxation Bio-feedback Self-hypnosis Cognitive distraction Guided imagery Systematic desentization

Etc

Pharmacological intervention

Pharmacological Intervention
Factors that enable clinician to discriminate the choices of antiemetic must be recognized, : The suspected etiology of symptoms Frequency, duration, & severity of the episodes The ability of patients to use oral, rectal, injectable or transdermal medication The success of previous antiemetic medication

Laxative, Cathartics, & Therapy of Constipation

Fluid content is principal determinant of stool content (70 85% contain water) 8 9 L of fluid enter small intestine 1 1.5 L crossing ileocaecal valve, colon extracts most of remaining fluid 100 ml of fecal water daily Secretory changes, bowel movement, transit time, extent of absorption determine the consistency of stool

Neurohormonal mechanisms, pathogens, drugs might alter processes above Up to 60% of patients with constipation have normal colonic transit Predominant factors underlying constipation often not obvious therapy remain empiric & non specific

Laxation : evacuation of formed fecal material from rectum) Catharsis : evacuation of unformed, usually watery fecal material from the entire colon

The terms frequently used interchangebly

Mode of Action of Laxative :

Enhancing retention of intraluminal fluid by hydrophilic or osmotic mechanims Decreasing the net absorption of fluid by effects on small- and large-bowel fluid & electrolyte transport Altering motility by either inhibiting segmenting (nonpropulsive) contractions or stimulating propulsive contractions

Antidiarrheal agents

Oral rehydration solution is the cornerstone of therapy for patient with acute illness resulting significant diarrhea Pharmacotherapy should be reserved for patients with persistence symptoms

Selected Antidiarrheal Agents