H2-antagonists Pharmacological actions Pharmacokinetics Adverse effects Interactions Therapeutic uses

1. H2 - ANTAGONISTS
Mr. Vishal Balakrushna Jadhav
Assistant professor (Pharmacology)
School of Pharmaceutical Sciences (SOPS), Sandip University, Nashik
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2.  H2 -antagonists
 Pharmacological actions
 Pharmacokinetics
 Adverse effects
 Interactions
 Therapeutic uses
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Overview of Discussion

3.  First class of highly effective drugs for acid-peptic disease, but have been
surpassed by proton pump inhibitors (PPIs).
 Agents includes cimetidine, ranitidine, famotidine and roxatidine.
 Cimetidine, ranitidine and roxatidine Interacts competitively, while
famotidine interacts competitive-noncompetitively with H2 receptors to
antagonize actions of histamine. They do not interacts with H1 receptors.
 Cimetidine was the first H2 blocker to be introduced clinically and is
described as the prototype, though other H2 blockers are more commonly
used now.
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H2 -antagonists

4.  The histamine H2-receptor antagonists act selectively on H2 receptors, but
they have no effect on H1 receptors. They are competitive antagonists of
histamine and are fully reversible.
 H2 blockade Cimetidine and other-
 Block histamine-induced gastric secretion, cardiac stimulation (prominent
in isolated preparations, especially in guinea pig), uterine relaxation (in rat)
and bronchial relaxation (H2 blockers potentiate histamine induced
bronchospasm).
 Attenuate fall in BP due to histamine.
 Are highly selective: have no effect on H1 mediated responses or on the action
of other transmitters/autacoids.
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Pharmacological actions

5.  Gastric secretion- H2-receptor antagonists-
 Markedly inhibit gastric secretion→ all phases (basal, psychic, neurogenic,
gastric) of secretion are suppressed dose-dependently, but the basal nocturnal
acid secretion is suppressed more completely.
 Attenuate secretory responses to histamine and other stimuli such as ACh,
gastrin, insulin, alcohol, and food → reflects the permissive role of histamine
in amplifying responses to other secretagogues.
 Reduces the volume, pepsin content and intrinsic factor secretion→ most
marked effect is on acid secretion.
 Do not interfere with normal vit B12 absorption→ no vit. B12 deficiency occurs
even after prolonged use.
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6.  Have antiulcerogenic effect→ usual ulcer healing doses produce 60 to
70% inhibition of 24 hr acid output. Gastric ulceration due to stress and
drugs (NSAIDs, cholinergic, histaminergic) is prevented.
 Do not have any direct effect on gastric or esophageal motility or on lower
esophageal sphincter (LES) tone.
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7.  Cimetidine is adequately absorbed orally→ bioavailability is 60–80% due to
first pass hepatic metabolism. Absorption is not interfered by presence of food
in stomach.
 It crosses placenta and reaches milk, but penetration in brain is poor because
of its hydrophilic nature.
 About 2/3 of a dose is excreted unchanged in urine and bile, the rest as
oxidized metabolites. The elimination t½ is 2–3 hr.
 Dose reduction is needed in renal failure.
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Pharmacokinetics

8.  Cimetidine is well tolerated by most patients→ mild adverse effects
includes headache, dizziness, bowel upset, dry mouth, and rashes occur.
 Cimetidine (but not other H2 blockers) has antiandrogenic action→
displaces dihydrotestosterone from its cytoplasmic receptor, increases
plasma prolactin and inhibits degradation of estradiol by liver.
 High doses given for long periods have produced gynaecomastia, loss of
libido, impotence and temporary decrease in sperm count. Transient
elevation of plasma aminotransferases; but hepatotoxicity is rare.
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Adverse effects

9. Cimetidine inhibits several cytochrome P-450 isoenzymes and reduces hepatic
blood flow. it inhibits the metabolism of drugs like warfarin, diazepam,
phenytoin, quinidine, carbamazepine, theophylline, imipramine etc. so that
they can accumulate to toxic levels (as shown in figure)-
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Interactions

10. Metabolism of propranolol and diazepam is also retarded, but this may not be
clinically significant.
All H2 antagonists may reduce the efficacy of drugs that require an acidic
environment for absorption, such as ketoconazole.
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11. H2 blockers are used in conditions to suppress gastric acid secretion. Used
in appropriate doses, all available agents have similar efficacy. However, The
use of these agents has decreased with the advent of PPIs (have higher
efficacy and equally good tolerability). The indications are-
1. Peptic ulcers
2. Stress ulcers and gastritis
3. Zollinger-Ellison syndrome
4. Gastroesophageal reflux disease (GERD)
5. Prophylaxis of aspiration pneumonia
6. Other uses
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Therapeutic uses

12. 1. Peptic ulcers
H2 blockers are effective in promoting the healing of duodenal and gastric
ulcers. However, recurrence is common if H. pylori is present and the
patient is treated with these agents alone. Patients with NSAID-induced
ulcers should be treated with PPIs or misoprostol, because these agents
heal and prevent future ulcers more effectively than H2 blockers.
2. Stress ulcers and gastritis
Induced by acutely stressful situations like hepatic coma, severe burns and
trauma, prolonged surgery, prolonged intensive care, renal failure, asphyxia
neonatorum, and mucosal ischaemia with acid secretion→ gastric erosions
and bleeding→ Intravenous infusion of H2 blockers given, however because
of tolerance, PPIs are the drugs of choice. 12

13. 3. Zollinger-Ellison syndrome It is a gastric hypersecretory state due
to a rare tumour secreting gastrin. H2 blockers in high doses control
hyperacidity and symptoms in many patients, but PPIs are the drugs of
choice. Definitive treatment is surgical.
4. Gastroesophageal reflux disease (GERD) H2 blockers afford
symptomatic relief and facilitate healing of esophageal erosions, but are less
effective than PPIs→ thus indicated only for mild cases of GERD.
5. Prophylaxis of aspiration pneumonia H2 blockers given preoperatively
(preferably evening before also) reduce the risk of aspiration of acidic gastric
contents during anaesthesia and surgery.
6. Other uses H2 blockers have adjuvant beneficial action in certain cases of
urticaria who do not adequately respond to an H1 antagonist alone.
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