Chronopharmacology of peptic ulcer

peptic ulcer,classification of peptic ulcer drugs,chronopharmacology,circadian rythm chronopharmacology of peptic ulcer.

1. CHRONOPHARMACOLOGY OF PEPTIC ULCER 1 DEPARTMENT OF PHARMACOLOGY

2. CONTENTS PEPTIC ULCER MOA OF PEPTIC ULCER BIOLOGICAL RYTHMS CHRONOPHARMACOLOGY OF PEPTIC ULCER 2 DEPARTMENT OF PHARMACOLOGY

3. Peptic ulcer occurs in that part of the gastrointestinal tract ( g.i.t .) which is exposed to Gastric acid and pepsin, i.e. the stomach and duodenum. Ulcer is caused by eradication of the stomach mucosa ,In duodenal ulcer acid Secretion is high in about half of the patients, reduction of acid secretion which is the Main approach to ulcer treatment. The etiology of peptic ulcer is not clearly known.It results probably due to an Imbalance between the aggressive (acid, pepsin, bile and H. pylori)and the defensive (Gastric mucus and bicarbonate secretion , prostaglandins,innate resistance of the Mucosal cells) factors . Treatment approaches include, Eradicating the H. pylori infection Reducing secretion of gastric acid with the use of PPIs or H2-receptor Antagonists, Providing agents that protect the gastric mucosa from damage, such as Misoprostol and sucralfate . PEPTIC ULCER 3 DEPARTMENT OF PHARMACOLOGY

4. CLASSIFICATION OF PEPTIC ULCER ANTIMICROBIAL AGENTS Amoxicillin Bismuth compounds Clarithromycin Metronidazole Tetracycline H2 – HISTAMINE RECEPTOR BLOCKERS Cimetidine Famotidine Nizatidine Ranitidine PROTON PUMP INHIBITORS (PPIs) Dexlansoprazole Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole 4 DEPARTMENT OF PHARMACOLOGY

5. PROSTAGLANDINS Misoprostol ANTIMUSCARINIC AGENTS Dicyclomine ANTACIDS Aluminum hydroxide Calcium carbonate Magnesium hydroxide (milk of magnesia) Sodium bicarbonate MUCOSAL PROTECTIVE AGENTS Bismuth subsalicylate Sucralfate 5 DEPARTMENT OF PHARMACOLOGY

6. MECHANISM OF ACTION 6 DEPARTMENT OF PHARMACOLOGY

7. ANTIMICROBIAL AGENTS Successful eradication of H. Pylori (80% to 90%) is possible with various combinations of Antimicrobial drugs. Currently, triple therapy consisting of a PPI combined With Amoxicillin plus clarithromycin is the therapy of choice. UREA BREATH TEST (For detecting of H.pylori ) 7 DEPARTMENT OF PHARMACOLOGY

8. B. H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION MOA : Competitively blocking the binding of histamine to H2 receptors. THERAPEUTIC USES : Peptic ulcer,acute stress ulcer,GERD . PHARMACOKINETICS: Oral administration, the H2 antagonists ,distribute widely Throughout the body (including into breast milk and across the placenta) and are excreted Mainly in urine. ADVERSE EFFECTS: gynacomastia and galactorrhea (continuous release/discharge of Milk),Other central nervous system effects such as confusion. C.PPIS: INHIBITORS OF THE H+/K+-ATPASE PROTON PUMP MOA: The PPIs bind to the H+/K+- ATPase enzyme system (proton pump) and suppress The secretion of hydrogen ions into the gastric lumen. THERAPEUTIC USES: Stress ulcer,GERD . PHARMACOKINETIC: PPIs should be taken 30 to 60 minutes before breakfast or the Largest meal of the day, Although the plasma half-life of these agents is only a few hours, Metabolites of these agents are excreted in urine and feces . 8 DEPARTMENT OF PHARMACOLOGY

9. ADR: Nausea, diarrhea , GI distubance,bone fractures. D. PROSTAGLANDINS Prostaglandin E, produced by the gastric mucosa, inhibits secretion of acid and stimulates secretion of mucus and bicarbonate ( cytoprotective effect). GERD 9 DEPARTMENT OF PHARMACOLOGY

10. ANTACIDS The main aim of the antacid is to increase the acid secretion in the stomach Normal stomach PH level is 3, while decrease or increase this PH level eradication can occur Antacid drugs are maintain the PH level of the stomach If PH level is low in the since(PH1.5), which can maintain the optimum PH level EXAMPLES: Aluminum hydroxide, Magnesium hydroxide (milk of magnesia) Sodium bicarbonate. 10 DEPARTMENT OF PHARMACOLOGY

11. CHRONOPHARMACOLOGY Chronopharmacology is concern with the variations in the pharmacological action of Various drugs over biological timings & endogenous periodicities. In medicine three disciplines are taken acoount according to time. Chronophysiology Chronopathology Chronopharmacology Chronopharmacology consist of, 11 DEPARTMENT OF PHARMACOLOGY

12. CHRONOPHARMACOKINETICS It deals with the study of the temporal changes in the pharmacokinetics of the drugs with respective time. Study of absorption, distribution, metabolism, and excretion of drug according to the time of the day or year. CHRONESTHESY The rhythmic changes in susceptibility or sensitivity of a target system to a drug. CHRONERGY Rhythmic changes of both the desired [effectiveness] and undesired [toxicity, tolerance] effects on the organism as a whole. CHRONOTHERAPEUTICS Application of chronobological principle to the treatment of diseases. CHRONOPHARMACEUTICS Branch which designs and develops a drug delivery system in accordance with biological rhythm to optimize the treatment of disease 12 DEPARTMENT OF PHARMACOLOGY

13. BIOLOGICAL RHYTHMS Circadian: Lasting for about 24 hours. (Sleep wake cycles) Infradian : Cycles longer than 24 hours. (Menstrual cycle) Ultradian : Cycles shorter than a day. (Neuronal firing time) Seasonal: Seasonal affective disorders 13 DEPARTMENT OF PHARMACOLOGY

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15. CHRONOKINETIC PK&PD variation Gatric motility is double in day time than night(morning 12.00AM) Plasma concentration are higher in day than in night Hepatic blood flow has been shown to be greater at 8.00am and metabolism to be Reduced during the night. CHRONO PK - ABSORPTION Depends on the gastric emptying time,PH,motility and gastrointestinal blood flow Liphophilic drugs are better absorbed at morning Eg : valproic acid,indomathacin,ketoprofen CHRONO PK – DISTRIBUTION Blood flow depends on several regulatory factors,including sympathetic and Parasympathetic system. A diurnal increase and nacturnal decrease the blood flow and local tissue blood flow may Explain a possible differences in drug distribution depending on the dosing time. 15 DEPARTMENT OF PHARMACOLOGY

16. CHRONO PK – METABOLISM Depend on liver enzyme activity & hepatic blood flow High extraction ratio : metabolism depend on blood flow Low extraction ratio : metabolism depends on enzyme activity Hepatic flow high in the morning,metabolism reduced in the night CHRONO PK – ELIMINATION Elimination rate has high in the morning than the night CHRONO PHARMACOLOGY OF PEPTIC ULCER Peptic ulcer is defined as the erosin happen in the lumen of stomach The human stomach is capable of secreting hydrochloric acid in concentrations that Create a greater than 2 million fold gradient in hydrogen ion concentration between the Gastric lumen and tissue vascular compartments. 16 DEPARTMENT OF PHARMACOLOGY I.GASTRIC ACID SECRETION

17. Under fasting conditions, acid is secreted in relatively low amounts to maintain an Intragastric pH of approximately 1.5. This low-level rate is termed basal acid secretion. A circadian rhythm in basal gastric acid secretion has been reported in healthy men with Active duodenal ulcer disease. The rate of basal acid secretion is highest between 9 pm and midnight Increase in acid secretion, meals are generally associated with a transient elevation in Intragastric pH due to the buffering effect of the meal. Thus, during the daytime hours, intragastric pH fluctuates, especially at mealtimes. During the nighttime hours, in the absence of food, intragastric pH remains low. Which the gastric mucosa is most vulnerable to damage and also most susceptible to Acid inhibiting treatment strategies This gatric acid secretion has more in the early morning or late night period based on The Circadiun rythm , so our aim to Given the drug at late night period then only get The proper result. 17 DEPARTMENT OF PHARMACOLOGY

18. 18 DEPARTMENT OF PHARMACOLOGY II. GASTRIC MUCOSAL DEFENSE The major therapeutic aim in most peptic ulcer regimens is to reduce gastric acidity. A significant percentage of patients (10-20%) fail to respond to acid-suppressing Medical or surgical treatments. That attention has been directed to alterations in mucosal defense factors in the Pathogenesis of acid-peptic disorders. These factors include gastric epithelial cell mucous and bicarbonate secretion, prostaglandin production, gastric mucosal blood flow, etc..

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20. Circadian alterations in gastric emptying rates may result in delayed absorption of many oral Medications administered during the evening. The delay is reflected by lower maximum Plasma concentrations ( Cmax ) and longer times-to-peak drug plasma concentrations ( Tmax ) Showed lower when administered during the evening, compared to the morning. 20 DEPARTMENT OF PHARMACOLOGY

21. A constant infusion of ranitidine over a period of 24 h does not lead to a constant Effect,the increase in gastric pH by ranitidine was less during the nightly than during the Daytime hours of drug infusion. Indicating that there might be a partial nocturnal Resistance to H2-receptor blockade. H2 BLOCKERS 21 DEPARTMENT OF PHARMACOLOGY

22. PROTON PUMP INHIBITORS(PPI) The proton pump inhibitors provide superior 24-h acid suppression when compared with The H2-blockers proton pump inhibitors are more effective if administered during the Morning hours as compared with evening dosing. 22 DEPARTMENT OF PHARMACOLOGY H2-blockers should be administered after the final meal of the day to achieve optimum protection during the nocturnal time period.

23. REFERENCES LippincottIllustrated Reviews: Pharmacology Sixth Edition Essentials of Medical Pharmacology Seventh Edition, KD TRIPATHI Ex-Director-Professor and Head of Pharmacology,Maulana Azad Medical College and associated LN and GB Pant Hospitals New Delhi, India,JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD,New Delhi • London • Philadelphia • Panama B.Lemmer etal ., Chronopharmacology : time, a key in drug treatment, Ann Biol Clin (1994), 52, 1-7 © Eisevier , Paris. Biological Rhythms, © Professor Alan Hedge, Cornell University, August 2013. Björn Lemmer etal ., Review on Chronopharmacology and controlled drug release 10.1517/17425247.2.4.667 © 2005 Ashley Publications Ltd ISSN 1742-5247 667 Ashley Publications,www.ashley-pub.com . S. W. SANDERS* and J. G. MOOREt,J ., GASTROINTESTINAL CHRONOPHARMACOLOGY: PHYSIOLOGY, PHARMACOLOGY AND THERAPEUTIC IMPLICATIONSPharmac . Ther . Vol,54, pp. 1-15, 1992 Printed in Great Britain. All rights reserved. 23 DEPARTMENT OF PHARMACOLOGY

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