PHARMACOLOGICAL TARGETS IN GASTROESOPHAGEAL REFLUX DISEASE

NAVIGATION
Introduction Gastrointestinal tract and wall Clinical relevance Gastric motility and Gastric glands Gastroesophageal reflux disease (GERD) Acid secretion and regulation Pharmacological targets for (GERD) Recent drugs Conclusion

GASTROINTESTINAL TRACT

GASTROINTESTINAL WALL

CLINICAL RELEVANCE

NEURONAL PLEXUSES
diabetes mellitus connective tissue disorders

FUNCTIONAL GI MOTILITY

CLINICAL RELEVANCE
ALTERED PERISTALSIS
Pregnancy Obstruction

IMPROPER MIXING OF FOOD

DAILY GI SECRETIONS
JUICES SALIVA GASTRIC PANCREATIC VOLUME 1000ml 1500ml 1000ml 6-7 1-3.5 8-8.3 7-8 PH

BILE,BRUNNERS 1200ml

INTESTINES TOTAL

2000ml 6700ml

7.5-8

CLINICAL RELEVANCE

QUANTITY OF SECRETION PHASES OF SECRETION

GASTRIC GLANDS

MUCOUS NECK CELLS

PARIETAL CELL

Acid regulation

OVERVIEW
Chronic relapsing condition Significant morbidity Estimated lifetime prevalence of 2535 % 44% have heartburn once a month 14% have weekly symptoms 7 % have daily symptoms

Mechanism

Free Flow

Reflux Disease

Pathogenesis

DIETARY FACTORS

 Caffeine
Peppermint Spicy foods Fatty foods

Citrus fruits
Chocolate Tomato Alcohol

DIAGNOSIS

History Response to a PPI Radiologic findings Endoscopy Ambulatory pH monitoring

HISTORY

 Pyrosis (Heartburn) regurgitation or both. High specificity, low sensitivity

ATYPICAL SYMPTOMS
Atypical chest pain Hoarseness Nausea Cough Odynophagia Globus sensation Onset after age 45 Recurrent laryngitis Subglottic stenosis

RESPONSE TO PPI

 Omeprazole 40 mg BID X 14 days as specific and sensitive for diagnosis as 24 hour ph monitoring Failure to respond warrants further investigation of patients symptoms

RADIOLOGY

ENDOSCOPY

AMBULATORY pH MONITORING

Diagnostic gold standard

COMPLICATIONS

Esophagitis Strictures Ulcerations Barretts esophagus Adenocarcinoma

COMPLICATED GERD

Dysphagia Odynophagia Early satiety GI bleeding Iron deficiency anemia Vomiting Weight loss

MANAGEMENT

LIFESTYLE MODIFICATION

LIFESTYLE MODIFICATION

LIFESTYLE MODIFICATION

PPI

H2RA

ANTACIDS

PROKINETIC DRUGS

ANTIREFLUX SURGERY

NEWER DRUGS

LIFESTYLE MODIFICATIONS
Head of bed elevated by six inches Decreased fat intake Smoking cessation Weight loss Avoidance of recumbency for 3 hours post-prandially Avoidance of large meals

PROTON PUMP INHIBITORS

 OMEPRAZOLE

RABEPRAZOLE

ESOMEPRAZOLE

PANTOPRAZOLE

LANSOPRAZOLE

TENATOPRAZOLE

PHARMACODYNAMICS

Acid secretion

Acid regulation

PRODRUG

ABSORBED INTO SYSTEMIC CIRCULATION

DIFFUSES INTO PARIETAL CELLS

ACCUMULATES IN SECRETORY CANALICULI

ACTIVATED TO TETRACYCLIC SULFENAMIDE

BINDS COVALENTLY TO ACID - PUMP

IRREVERSIBLY INHIBITS THE PUMP

ACID SECRETION IS SUPPRESSED

BOTH BASAL AND STIMULATED

 Provides acid suppression for 24-48 hours Acid secretion resumes after new enzyme synthesis Block final step in acid secretion Metabolized by CYP2C19, CYP3A4 Dose reduction is recommended for esomeprazole and lansoprazole in hepatic disease

PHARMACOKINETICS

Prodrugs Administered 30 minutes before food Are highly plasma bound Maximal acid secretion suppression requires several doses Single daily dosing may need 2-5 days Lansoprazole is preferred in pregnancy

ADVERSE EFFECTS

Nausea Abdominal pain Constipation Flatulence Diarrhea

Hypergastrinemias Gastrointestinal tumors Carcinoid tumors Vitamin B12 malabsorption Campylobacter infection

INTRACTIONS

Decrease clearance of Disulfiram Phenytoin Decrease bioavailability of Ketoconazole Ampicillin Esters Iron salts Increase clearance of Imipramine Tacrine Theophylline

H2 RECEPTOR ANTAGONISTS

CIMETIDINE

FAMOTIDINE

RANITIDINE

NIZATIDINE

PHARMACOKINETICS

Rapid oral absorption Peak concentration achieved in 1-3 hours Absorption enhanced by food Small % are protein bound Major site for excretion is kidney Hemodialysis nor peritoneal dialysis clears significant amount of drug

ADVERSE EFFECTS

Head ache Diarrhea Drowsiness Fatigue Muscular pain Constipation

Galactorrhea Gynacomastia Impotence Reduced sperm count Thrombocytopenia

INTRACTIONS

 Cimetidine inhibits CYP1A2,P2C9,P2D6 Ranitidine inhibits CYP hepatic Famotidine and Nizatidine have no significant drug intractions Slight increase in blood alcohol

TOLERANCE AND REBOUND PHENOMENON

 Decreased therapeutic effect Tolerance can develop within 3 days Resistant to increased doses of medication May be due to secondary hypergastrenemia

PPI
-MORE POTENT -IRREVERSIBLE INHIBITOR -GIVEN BEFORE FOOD -METABOLISED IN LIVER -REDUCES BOTH SECRETION

H2RA
-LESS POTENT -REVERSIBLE INHIBITORS -GIVEN WITH FOOD -HEPATIC 10% -35% -REDUCES BASAL SECRETION

PPI
-

H2RA
-

EXTENSIVELY PROTEIN BOUND

SMALL % PROTEIN BOUND

-TOLERANCE SEEN

-TOLERANCE NOT SEEN

-HEALING RATES AT 4 WEEKS IS 80% -STRICTURES RESPOND BETTER -HEALING RATES AT 4 WEEKS IS 50% -STRICTURES RESPOND POORLY

PROKINETIC DRUGS

 Metoclopramide Domperidone Cisapride

METOCLOPRAMIDE

PHARMACODYNAMICS

 Increases gastric motility Action is independent of vagal innervations LES tone is increased No effect on gastric secretion

D2 selective antagonist 5HT4 receptor agonist 5HT3 antagonist Sensitization of muscarinic receptors on smooth muscle

PHARMACOKINETICS

Rapidly absorbed orally Crosses blood brain barrier Half life is 4-6 hours Secreted in milk Partly conjugated in liver Excreted in urine

ADVERSE EFFECTS

Sedation Dizziness Diarrhea Muscle dystonias Galactorrhoea Gynacomastia

INTRACTIONS

Hastens absorption of Aspirin Hastens absorption of Diazepam Decreases absorption of Digoxin Bioavailability of Cimetidine is reduced Abolishes the therapeutic effect of Levodopa

DOMPERIDONE

 Chemically related to haloperidol Pharmacologically related to Metaclopramide Crosses BBB poorly EPS are rare Oral bioavailability is 15% Plasma t is 7.5 hours Cardiac arrhythmias can develop on rapid iv injection

ANTACIDS

SODIUM BICARBONATE SODIUM CITRATE MAGNESIUM SALTS ALUMINIUM HYDROXIDE GEL MEGALDRATE CALCIUM CARBONATE SIMETHICONE

SODIUM BICARBONATE

Water soluble Acts instantaneously Short duration Absorbed systemically May produce alkalosis Produce CO2 in stomach Rebound acid production can occur

CALCIUM CARBONATE

Very potent Rapidly acting Releases CO2 and causes discomfort Can cause hypercalcaemia,calcium stones,calciuria,alkalosis Can cause milk alkali syndrome with milk

ANTACIDS COMBINATIONS

 Fast (mag salts) slow (alum salts) Laxative (mag salts) constipation (alum salts) Gastric emptying is hastened (mag salts) delayed (alum salts) Toxicity is counteracted

SIMETHICONE

 Is a surfactant Decreases foaming Is indicated in many antacid preparations

INTRACTIONS

Decreases absorption of
Tetracycline Iron salts Fluroquinolones Ketoconazole H2 blockers Ethambutol Isoniazid

RECENT DRUGS

DEXLOXIGLUMIDE
LOXIGLUMIDE

Cholecystokinin A receptor antagonist Improves gastric emptying Suppresses transient relaxation of LES Investigations in Europe are suggestive of its use in GERD

TEGASEROD

Amino guanidine indole Partial 5-HT4 agonist Negligible affinity for receptor subtypes Stimulates motility in GI tract Should be taken on empty stomach 98% plasma bound t is 11hours Diarrhea and headache are side effects No significant cardio-toxicity reported No clinically relevant drug interactions

PRUCALOPRIDE
SPECIFIC 5-HT4 RECEPTOR AGONIST

MOSAPRIDE
5-HT4 RECEPTOR AGONIST

ATI-7505
5-HT4 AGONIST AND AN ANALOGUE OF CISAPRIDE

AKU 517
REVERSIBLE INHIBITOR OF ACID - PUMP

SORAPRAZAN
ACID PUMP INHIBITOR

XP-19986
A TRANSPORTED PRODRUG OF R-BACLOFEN

CONCLUSION

REFERENCES

1)THE PHARMACOLOGICAL BASIS OF THERAPEUTICS GOODMAN AND GILMANS 2)CLINICAL PHARMACOLOGY BENNETT
AND BROWN

3)MATINDALE 33rd EDITION 4)LIPPINCOTS ILLUSTRATED PHARMACOLOGY 5)BERTRAM KATZUNG 10 EDITION 6)GENERAL PHARMACOLOGICAL PRINCIPALS KD TRIPATHI

7) HARRISONS TEXT BOOK OF INTERNAL MEDICINE 8) DAVIDSONS PRINCIPLES AND PRACTICE OF MEDICINE 9) API TEXT BOOK OF INTERNAL MEDICINE 10)TEXT BOOK OF PREVENTIVE MEDICINE PARK 11)CURRENT MEDICAL DIGNOSIS AND TREATMENT 12)BASICS OF PHYSIOLOGY GYTON 13)TEXT BOOK OF PHYSIOLOGY-GANONG

14)GASTROENTROLOGY AND HEPATIC DISEASES VOLUME 1-NORMAN DAVID 15)GRAYS ANATOMY 16)BIOLOGICAL HEALTH DEPARTMENT CALIFORNIA STATE UNIVERSITY 17)CASE STUDIES AIIMS NEW DELHI 18)DEPARTMENT OF GASTROENTROLOGY UMC MANGALORE