Targets for Development of Anti-ulcer Agents
-
Upload
vamsirajasekhar -
Category
Documents
-
view
176 -
download
0
Transcript of Targets for Development of Anti-ulcer Agents
TARGETS FOR DEVELOPMENT OF ANTI-ULCER AGENTS
ByVamsi rajasekhara reddy
M-Pharmacy 1st Year(Pharmaceutical Chemistry)
CONTENT
FACTORS FOR ULCERATION PHYSIOLOGY OF ACID SECRETION TARGETS OF ANTIULCER AGENTS MECHANISM OF ACTION SIDE EFFECTS
PATHOGENIC FACTORS FOR ULCERATION Imbalance between the aggressive and the defensive factors.Acid secreted by parietal cells is aggressive factor.Gastric mucosa, bicarbonate secretion, prostaglandins nitric oxide are defensive factors
Helicobacter pylori infection.
ACID SECRETION BY STOMACH
Gastric acid secreted by parietal cells. Basolateral membrane of these cells contain 3 main
stimulantsGastrin (from G cells)Histamine (from enterochromaffin cells)Acetylcholine (from vagal efferent)
These stimulants stimulate proton pump Stimulated proton pump translocates from cytoplasmic
vesicles to the secretory canaliculus of the parietal cells Uses energy derived from hydrolysis of ATP, to transport H+
out of parietal cells in exchange for K+
Hydrogen ions combine with Chloride ions to form hydrochloric acid(HCl)
Hydrochloric acid is secreted in to gastric lumen.
Secretion of acid by parietal cells
TARGETS
H2 receptor eg: Cimetidine, Ranitidine, Famotidine Proton Pump eg: Omeprazole, Lansoprazole, Pantoprazole
M1 receptor eg: Pirenzipine, propantheline, Oxyphenonium
Gastrin receptors eg:Misoprostol, Enprostil, Rioprostil
Cell wall eg:sucralfate
Stomach eg: Antacids ( sodium bicarbonate, Magnesium hydroxide )
Helicobacter pylori eg:Amoxycillin, Clarithromycin, Metronidazole
H2 RECEPTOR
ranitidine cimetidine
SAR
Imidazole ring exist in two tautomeric forms. In these form – I to be necessary for maximal H2 antagonist activity.
When R is substituted with methyl group, the activity is potentiated
The other heterocyclics like furan, thiazole enhance the potency and selectivity of H2 receptor antagonism
The ring and terminal nitrogen should be separated by four carbon atom for optimum activity. The shorter chain decrease the activity.
The side chain should contain an electron with drawing substituents and an Isosteric thioether (- S-) link in place of methylene group (- CH2) leads to more active compound.
The terminal nitrogen should be polar, non basic substituents for maximal activity.
Synthesis of Cimetidine
Histamine H2 Receptor Antagonist
Reversible competitive inhibitors of H2
receptor
Highly selective, No action on H1 or H3
receptors
Very effective in inhibiting nocturnal acid secretion ( as it depends largely on Histamine )
Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetyl choline and histamine)
H2 Blockers–Side effects & Interactions
Extremely safe drugs
Mental status changes may occur
Cimetidine inhibits metabolism of estradiol and increase prolactin level
Cimetidine increases concentration of Warfarin, Theophylline, Phenytoin, Ethanol.
PROTON PUMP
Examples
N
CH3CH3
HOH2C
OCH3
SOCl2N
CH3CH3
ClH2C
OCH3
NH2
NH2H3CO
C S
H5C2O
KSN
NH
H3CO
SH+
N
CH3
CH3 OCH3
CH2N
NH
H3CO
S
O
OH
Cl
NaOH
NCH3
CH3
OCH3CH2N
NH
H3CO
S
O
Omeprazole
2 chloromethyl 3,5 dimethyl 4 methoxy pyridine
5 methoxy 2 mercaptobenzimidazole
4 methoxy O
phenylene diamine
potassium ethylxanthate
Proton Pump Inhibitors
Most effective drugs in antiulcer therapy Irreversible inhibitor of H+ K+ ATPase Prodrugs requiring activation in acid environment Weakly basic drugs & so accumulate in canaliculi
of parietal cell Activated in canaliculi & binds covalently to
extracellular domain of H+ K+ ATPase Acid secretion resumes only after synthesis of
new molecules
Poton Pump Inhibitors – Kinetics
Given as enteric coated granules in capsule or enteric coated tablets
Pantoprazole also given intravenously
Half life – 1.5 hrs
Since it requires acid for activation - given 1 hr before meals
Other acid suppressing agents not coadministered
P.P.I. – Side effects & InteractionsExtremely safe drugs
Causes hypergastrinemia which leads to carcinod tumor in rats
But no evidence of such tumors in man
Inhibit CYP 450 & hence metabolsim of warfarin, phenytoin, etc
Pantoprazole & Rabeprazole have no significant interactions
M1 RECEPTORS
N
NH2
Cl
+Cl
O
O2N -H C l
N
NH
ClO
O2N
H2
Raney Ni
N
NH
ClO
NH2
2 0 0 °C
-H C l
N
NH O
NH
ClCOCH2Cl
N(CH3)3
N
NO
NH
OClH2C
-HCl
NH N CH3
N
NO
NH
ON
N
CH3
3-Amino
-
Chloropyridine2 Nitrobenzoyl chloride
M1 RECEPTOR ANTAGONIST
Block M1 receptor at enterochromaffin cells
Donot cross Blood Brain Barrier
Nonselective
Blurred vision, dry mouth, urinary retention
Delay gastric emptying
Eg: Propantheline, Oxyphenonium, Pirenzepine, Telenzepine
GASTRIN RECEPTORS
PROSTAGLANDIN ANALOGUES
Produced in gastric mucosa Inhibits gastrin release Enhances mucosal blood flow Stimulates secretion of mucus and bicarbonates NSAID associated gastrointestinal injury Need multiple daily dosing Diarrhoea, abdominal cramps, uterine
contractions
Eg: Misoprostol, Enprostil Rioprostil
CELL WALL
Mucosal Protective Agents
Sucralfate
Colloidal Bismuth compounds
Sucralfate
In acidic pH polymerises to viscous gel that adheres to ulcer crater
Taken on empty stomach 1 hr. before meals
Salt of sucrose complexed to sulfated aluminium hydroxide
Concurrent antacids, H2 antagonist avoided
( as it needs acid for activation )
Colloidal Bismuth Compounds
Coats ulcer, stimulates mucus & bicarbonate secretion
Direct antimicrobial activity against H.pylori
May cause blackening of stools & tongue
Not used for long periods – bismuth toxicity
Available compounds : Bismuth subsalicylate – in USA Bismuth subcitrate – in Europe Bismuth dinitrate
STOMACH
ANTACIDS
Weak bases that neutralize acid
Also inhibit formation of pepsin
(As pepsinogen converted to pepsin at acidic pH)
Present day antacids :
Aluminium Hydroxide
Magnesium Hydroxide
Duration of action : 30 min when taken in empty stomach
2 hrs when taken after a meal
Side effects : Al3+ antacids – constipation (As they relax gastric
smooth muscle & delay gastric emptying)
Mg2+ antacids – Osmotic diarrhoea .
In renal failure Al3+ antacid – Aluminium toxicity
Antacid – Interactions Adsorb drugs and form insoluble complexes that are not absorbed
HELICOBACTER PYLORI
Eradication of H.pylori
Triple Therapy
The BEST among all the Triple therapy regimen is
Omeprazole / Lansoprazole - 20 / 30 mg
Clarithromycin - 500 mg
Amoxycillin / Metronidazole - 1gm / 500 mg
Given for 14 days followed by P.P.I for 4 – 6 weeks Short regimens for 7 – 10 days not very effective
Some other Triple Therapy Regimens are
Bismuth subsalicylate - 2 tab
Metronidazole - 250 mg
Tetracycline - 500 mg
Ranitidine Bismuth citrate - 400 mg
Tetracycline - 500 mg
Clarithromycin / Metronidazole - 500 mg
Quadruple Therapy
Given when Triple Therapy fails
Omeprazole / Lansoprazole - 20 / 30
Bismuth subsalycilate - 2 tabs
Metronidazole - 250
Tetracycline - 500
FUTURE PROSPECTS
Reversible proton pump inhibitors are currently underdevelopment by the company Astra-Zeneca.
Development of vaccine for Helicobacter pylori is currently being explored.
REFERENCE:
“FOYE’S PRINCIPLES OF MEDICINAL CHEMISTRY” 1019-1024
Essentials of MEDICAL PHARMACOLOGY “K D Tripathi” 587-598
Clinical Pharmacology by “P N Bennett M J Brown” 561-568 An Introduction to Medicinal Chemistry by “Graham L.
Patrick” 642-670 Principles of Pharmacology by H L Sharma K K Sharma”
386-399 http://aac.asm.org/cgi/content/full/48/12/4582?maxtoshow
=&HITS=10&hits=10&RESULTFORMAT=&fulltext=cimetidine+synthesis&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
http://aac.asm.org/cgi/content/full/51/3/831 http://jac.oxfordjournals.org/cgii/content/full/59/1/160
THANK YOU