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Drugs Used in Acid-peptic Disease

Drugs Used in Acid-peptic Disease

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Published by: anaeshkl on Apr 07, 2012
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01/22/2013

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Types
drugs that
neutralise gastric acid (antacids)
reduce gastric acid secretion
via proton pump inhibition
via effects on histamine, cholinergicand prostaglandin receptors
enhance mucosal defences throughcytoprotective or possibly antimicrobialactivities
ANTACIDS
mechanism of action
weak bases react with gastric hydrochloric acid to formsalt and water, reducing gastric acidity
reduction of pepsin activity at above pH 4.0
mucosal protection through stimulation of prostaglandin production or through binding of injurious substance
principal constituent
magnesium or aluminium hydroxide, alone or incombination with sodium bicarbonate or a calcium salt
combinations have been developed tomaximise effectiveness and minimiseinconvenience
the net buffering capacity is determined by the ability toneutralise gastric acid and the duration of medication’sresidence in the stomach
tablet formulations are generally weak in their neutralising capacity
not recommended for the treatment of active peptic ulcer 
adverse effects
change in bowel habits
cation absorption (sodium, magnesium,aluminium, calcium)
only significant in patients with renalimpairment
systemic alkalosis
drug interactions
interaction with other drugs used in acid-peptic disease
 both proton pump inhibitor and sucralfaterequire acidic medium for activity
may adsorb drugs in gastrointestinal tract, thus reducingabsorption
digoxin, iron, itraconazole, ketoconazole,quinolones (ciprofloxacin, norfloxacin,enoxacin), tetracycline
speed gastric emptying, thus delivering drugs toabsorption sites in the intestines more quickly
magnesium hydroxide + aluminium hydroxide alkalinizeurine to alter excretion of drugs sensitive to urinary pH
salicylates
GASTRIC ANTI-SECRETORY DRUGS
gastric acid secretion is under the control of 3 principalagonists
histamine
acetylcholine
gastrin
final common pathway
through the proton pump, H+/K+ ATPase
modalities
H
2
antagonists
antimuscarinic agents
 proton pump inhibitor 
physiologic control of H+ secretion
pharmacologic control of H
+
secretionH
2
RECEPTOR ANTAGONISTS
inhibitors of the action of histamine at H
2
-receptors onthe gastric parietal cells inhibiting acid secretion andhence volume of gastric secretion
classification
competitive, surmountable, reversible
cimetidine, ranitidine, famotidine, nizatidine
unsurmountable, irreversible long-acting
tiotidine, loxtidine
Drugs used in acid-peptic disease
 NC Hwang 2009
 
structure
all structurally dissimilar 
cimetidine contains an imidazole ring and isstructurally similar to histamine
ranitidine contains a furan ring
famotidine and nizatidine contain a thiazolering
imidazole, furan, thiazole, serve as an aromatic nucleusof histamine H2-receptor antagonists
furan and thiazole derivatives are more potentthan imidazole derivative cimetidine
mechanism of action
direct effect of H
2
receptor blockade
reduction in parietal cell cAMP concentrationsattenuate the intracellular activation of proteinkinases by gastrin and acetylcholine
effects
over 90% reduction in basal food-stimulated,and nocturnal secretion of gastric acid after asingle dose
 blockade of cardiac and mast cell H
2
receptor-mediated effects not clinically significant
ranitidine and nizatidine increase antralcontractility
direct effects on smooth musclecholinergic receptors
indirect effects by increasingcholinergic neurotransmission(possibly via inhibitory action onacetylcholinesterase)
indications
in acid-peptic disease, especially duodenal ulcer, thesedrugs reduce symptoms and accelerate healing, and prevent recurrences
in Zollinger-Ellison syndrome
in gastro-oesophageal reflux disease
pharmacokinetics
cimetidine
rapidly absorbed from intestine
85% bioavailability
19% bound to plasma protein
Vd 1 L/kg
clearance 8 ml/min/kg, decreased in uraemia
β
2 hours, increased in uraemia
50% excreted unchanged in urine, 13% assulphoxide
ranitidine
rapidly absorbed from intestine
50% bioavailability, increased in cirrhosis
15% bound to plasma protein
Vd 1.3 L/kg
clearance 10 ml/min/kg
β
2 hours, increased in uraemia, cirrhosis
70% excreted unchanged in the urine
famotidine
rapidly absorbed from intestine
50% bioavailability, increased in cirrhosis
15% bound to plasma protein
Vd 1.3 L/kg
clearance 7 ml/min/kg
β
4 hours, increased in uraemia, cirrhosis
70% excreted unchanged in the urine
nizatidine
rapidly absorbed from intestine
90% bioavailability, increased in cirrhosis
30% bound to plasma protein, mainly
α
1
acidglycoprotein
Vd 1.2 L/kg
clearance 10 ml/min/kg,
β
1.5 hours, increased in uraemia, cirrhosis
more than 90% of an oral dose is excreted inthe urine within 12 hours, 60% unchanged
ANTIMUSCARINIC AGENTS
rarely used, if at all, as adjuncts to H2-receptor antagonists
 pirenzipine, is relatively selective for gastric M1muscarinic receptors
PROTON PUMP INHIBITORS
omeprazole, lansoprazole, rabeprazole, pantoprazole,esomeprazole
all are substituted benzimidazoles that reversibly inhibitsthe gastric parietal cell proton pump, H
+
/K 
+
ATPase
omeprazole is a racemic mixture of R-and S-isomers
esomeprazole is the S-isomer of omeprazole
all administered as a lipophilic prodrugs
to protect the acid-labile prodrug from rapid destructionwithin the gastic lumen, they are formulated as acid-resistant enteric coated formulations
mechanism of action
after passing through the stomach and entering thealkaline intestinal lumen, the enteric coating dissolvesand the prodrug is absorbed
as lipophilic weak bases with pKa 4-5, diffuse rapidlyacross lipid membranes into acidified compartment, suchas the parietal cell canaliculus
in acidic environment the prodrug is activated
activation hindered by presence of H
2
receptor antagonists
within the acid compartment, the prodrug rapidly becomes protonated, converts into active, reactivethiophilic sulphonamide cation, and is concentrated >1000 fold within the parietal canaliculus
the sulphonamide reacts with H
+
/K 
+
ATPase, forms acovalent disulphide linkage, irreversibly inactivates theenzyme
H
+
secretion is reduced, but not gastric volume
Drugs used in acid-peptic disease
 NC Hwang 2009

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