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

1. 1DEPARTMENT OF PHARMACOLOGY

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

3. A. 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.
B. 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.
C. 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.
D. Treatment approaches include,
A. Eradicating the H. pylori infection
B. Reducing secretion of gastric acid with the use of PPIs or H2-receptor
Antagonists,
C. Providing agents that protect the gastric mucosa from damage, such as
Misoprostol and sucralfate.
PEPTIC ULCER
3DEPARTMENT 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
4DEPARTMENT 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
5DEPARTMENT OF PHARMACOLOGY

6. MECHANISM OF ACTION
6DEPARTMENT OF PHARMACOLOGY

7. A. ANTIMICROBIALAGENTS
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)
7DEPARTMENT 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.
8DEPARTMENT 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
9DEPARTMENT 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. 10DEPARTMENT 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.
a. Chronophysiology
b. Chronopathology
c. Chronopharmacology
Chronopharmacology consist of,
11DEPARTMENT 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
12DEPARTMENT 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
13DEPARTMENT OF PHARMACOLOGY

14. 14DEPARTMENT OF PHARMACOLOGY

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.
15DEPARTMENT 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.
16DEPARTMENT 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.
17DEPARTMENT OF PHARMACOLOGY

18. 18DEPARTMENT OF PHARMACOLOGY
II. GASTRIC MUCOSAL DEFENSE
i. 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.
ii. That attention has been directed to alterations in mucosal defense factors in the
Pathogenesis of acid-peptic disorders.
iii. These factors include gastric epithelial cell mucous and bicarbonate secretion,
prostaglandin production, gastric mucosal blood flow, etc..

19. 19DEPARTMENT OF PHARMACOLOGY

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.
20DEPARTMENT 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
21DEPARTMENT 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.
22DEPARTMENT 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.
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24. 24DEPARTMENT OF PHARMACOLOGY