Download Mechanism of action

Assist.Prof. Jinan Abdul-Amir S. Al-Hussaini
Pharmacology (Theoretical)
Lect.NO.(
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Pharmacology of digestive system
Stomachics:
These are the drugs which promote the functional activity of the stomach
by increasing secretion and motility.
Classification:
(1) Muscarinic agents: ex.: Ach, Carbachol.
(2) Dopamine antagonist: ex.: Metoclopramide hydrochloride.
(3) Alkaline stomachics: ex.: Carbonate salts, Bicarbonate salts.
(4) Bitters: ex.: Gentain, Nux vomica.
(5) Histamine agonists: ex.: Histamine, Betazole HCl (Histalog).
(6) Synthetic pentapeptide: ex.: Pentagastrin.
Mechanism of action:
(1) Muscarinic agents - it acts by :
*stimulating gastric receptors.
(2) Metoclopramide - it acts by :
a-Increase tone in the lower oesophageal sphincter.
b- Increase force and frequency of gastric antral contractions (gastrokinitic
effect).
c- Relaxes the pyloric sphincter.
d- Promotes peristalsis in the duodenum and jejunum resulting in
accelerated gastric emptying and upper intestinal transit.
Indications of Stomachics:
1- Hypochlorhydria and achlorhydria.
2- Anorexia.
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Carminatives or Antiflatulants:
These are the drugs which, when administered orally, cause the expulsion
of gases from the stomach.
Classification:
(1) Compounds which contain volatile oils: ex.: Powdered Aniseed, Ginger.
(2) Pure volatile oils: ex.: Terpentine oils, Peppermint oil.
(3) Substances obtained from volatile oils by cooling: ex.: Stearoptenes
Camphor, Stearoptenes Manthol.
(4) Volatile anaesthetics: ex.: Ether, Chloroform.
(5) Other volatile compounds: ex.: Alcohol.
(6) Miscellaneous: ex.: Simethicone.
Mechanism of action:
They have a mild irritant action on mucus membranes and tend to relax
the GIT musculature, particularly the cardiac sphincter of stomach, for a
period of up to 30 minutes which probably plays a large part in releasing
gases from the stomach.
Drugs for peptic ulcer:
Peptic ulcer occurs in that part of the GIT which is exposed to gastric
acid and pepsin, i.e., the stomach and duodenum. It result due to an
imbalance between the “aggressive” (acid and pepsin) and the “defensive”
(gastric mucus and the innate resistance of the mucosal cells) factors.
Classification:
Approaches for the treatment of peptic ulcer are:
(I)
**Antacids:
Neutralization of gastric acid:
These are the basic substances which neutralize gastric acid and raise the
PH of gastric contents.
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Mechanism of action:
1-They neutralize gastric acidity via reaction with gastric HCl to produce
salt and water.
2- They inactivate pepsin raising the gastric PH to at least 3-4 without
causing systemic alkalosis (since pepsin activity for peptic digestion is
optimal at PH 2-3).
Classification:
(A) Systemic antacids: ex.:
1- Sodium bicarbonate (NaHCO3):
This is still widely used by the lay people as it produces prompt relief
from heart burn and dyspepsia.
*Advantages:
a- it is immediately effective in neutralizing the HCL in the stomach because
of its high water solubility.
b- Duration of action is short.
*Disadvantages:
a- rapid liberation of CO2 may lead to gastric distention, perforation of
ulcer, and belching.
b- acid rebound.
c- metabolic alkalosis and disturbance of acid-base balance.
2- Sodium citrate.
3- Sodium acetate.
(B) Non-systemic antacids:
According to their capacity to increase gastric PH, they can be
subclassified into:
1- Buffer antacids: ex.: Aluminium hydroxide gel [Al(OH)3]. They limit the
rise of gastric PH below neutrality.
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2- Non-buffer antacids (Alkali antacid): ex.: Calcium carbonate [CaCO3],
Magnesium oxide [MgO], Magnesium carbonate [MgCO3], Magnesium
hydroxide [Mg(OH)2]. They potentially permit an elevation in PH above
neutrality.
3- Miscellaneous antacids: ex.: Sodium carboxymethyle cellulose.
*Advantages as general:
The non-systemic antacids are used either alone or in combination with
each other. They neutralize gastric, but not tend to cause systemic alkalosis
because they are insoluble basic compound and hence poorly absorbed, so
they don’t disturb acid-base balance in case of peptic ulcer, these drugs are
preferred.
*Disadvantages:
A- Aluminium hydroxide: This drug is a good adsorbent and adsorbs
toxins, gases, and bacteria.
Disadvantages:
1- Constipation which can be prevented by mixing of aluminium salts with
magnesium salts.
2- Decreases phosphate absorption by forming insoluble aluminium phosphate
in the intestine.
B- Magnesium hydroxide: Magnesium salts tend to be laxative and are
often found in combination with aluminium and calcium salts. The cathartic
effect results from soluble, but unabsorbed magnesium salts that remain in
the intestine, thus retaining water.
Disadvantages:
Normally about 20% magnesium is absorbed which is rapidly excreted
through kidney. However renal dysfunction or repeated dose can result in
dangerous degree of retention.
C- Calcium carbonate:
Disadvantages:
1- Slowly developing metabolic alkalosis.
2- Gastric acid rebound.
3- Hyperglycemia.
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Calciuria.
Metastatic calcification and urolithiasis.
Hypophosphatemia.
Constipation.
Indications of antacids:
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Gastric hyperacidity.
Peptic ulcer.
Gastritis.
Reflex oesophagitis.
Chronic renal failure (uremia).
Abnormal ulceration in cattle.
Ruminal acidosis from grain overload.
(II)
Drugs that inhibit gastric acid secretion:
(1) H2-receptors antagonists: they include:Cimetidine (Tagamet)® , Ranitidine, Nizatidine, Famotidine.
Mechanism of action:
These drugs bind selectively and competitively to the histamine H2receptors on the basolateral membrane of the gastric parietal cells. As well
as they inhibit gastric acid release from histamine by inhibiting acetyl
choline and gastrin-mediated acid secretion.
Indications:
1-duodenal ulcer.
2-benign gastric ulcer.
3-gastro-esophageal reflex disease.
4-erosive or ulcerative esophagitis.
5-upper gastrointestinal hemorrhage.
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Adverse effects:
Rare but they can cause *mental confusion, *hallucination, *bradycardia.
And because cimetidine is weak antiandrogenic, it may produce impotence
and gynaecomastia in male.
Contraindications:
*pregnancy.
*lactation.
Drug interactions:
Cimetidine inhibits the metabolism of phenytoin, theophylline, and
warfarin.
(2) Proton pump inhibitors: they include:Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole.
Mechanism of action:
These drugs are irreversible inhibitors of the proton pump (H+/K+ ATP
ase enzyme) on the parietal cell membrane resulting in a marked but
temporary suppression of gastric acid secretion to any stimulus including
food.
Indications:
1-severe and erosive esophagitis.
2-.duodenal ulcer and gastric ulcer.
3-prophylaxis of NSAIDs-induced ulcer.
4-also used incombination with antibiotics in the eradication of H. pylori and
in the treatment of Zollinger-Ellison syndrome.
Adverse effects:
*diarrhea.
*skin rash.
*headache.
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Drug interactions:
Omeprazole reduce the clearance and prolong the elimination of
diazepam, Phenytoin, and warfarin.
(3) Synthetic prostaglandins: e.g.: Misoprostol.
Mechanism of action:
Misoprostol has both acid inhibitory and mucosal protective properties. It
is believed to stimulate mucus and bicarbonate secretion and enhance
mucosal blood flow. In addition it binds to a prostaglandin receptor on
parietal cells, reducing histamine-mediated c-AMP production and causing
modest acid inhibition.
Indications:
*Peptic ulcer.
*NSAIDs-induced ulcer.
Adverse effects:
*diarrhea.
*abdominal pain.
Contraindications:
Misoprostol is Abortificient drug (stimulate uterine contraction), so it
should not be used during pregnancy.
Drug interactions:
No significant drug interactions are reported.
(III)
Drugs that do not directly inhibit gastric acid secretion.
(1) Colloidal bismuth compounds: they include:Bismuth subsalicylate, Bismuth subcitrate, Bismuth dinitrate.
Mechanism of action:
They do not directly inhibit acid secretion, however they do suppress H.
pylori infection and thus reduce the hypersecretion of acid induced by the
infection. In addition, they may form an insoluble protective layer over the
ulcer base preventing further damage by acid and pepsin.
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Indications:
1-non-specific treatment of dyspepsia and acute diarrhea.
2-prevention of traveler’s diarrhea.
3-eradication of H. pylori infection.
Adverse effects:
*blackening of the stool.
*darkening of the tongue.
Contraindications:
*renal insufficiency.
Drug interactions:
No significant drug interactions are reported.
(2) Sucralfate:
Is a salt of sucrose complexed to sulfated aluminium hydroxide.
Mechanism of action:
Similar to that of bismuth compounds.
Indications:
1-duodenal ulcer.
2-benign gastric ulcer.
3-dyspepsia caused by NSAIDs.
4-prevention of bleeding from stress-related gastritis.
Adverse effects:
*constipation.
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Contraindications:
Chronic renal failure because of the risk of aluminium absorption and
toxicity.
Drug interactions:
Sucralfate can reduce the absorption of a number of different drugs such
as phenytoin and tetracycline.
(IV)
Drug combinations to eradicate H. pylori:
Almost all patients with D.U. and many patients with G.U. are infected
with H. pylori that can be eradicated by both acid suppression and antibiotics
treatment. The effective regimens include:(A) proton pump inhibitors or ranitidine + bismuth citrate (as ranitidine
bismutrex) + clarithromycin + amoxicillin.
(B) Proton pump inhibitors or ranitidine + bismuth citrate + clarithromycin +
metronidazole.
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