Drugs acting on the gastrointestinal tract

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Drugs acting on the gastrointestinal tract

• Prof. MUDr Jirina Martínková PhD,
• 2006/2007

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Drugs used to inhibit or neutralise gastric
secretion

to reduce acid secretion and peptic ulceration
(both duodenal and gastric), reflux,
oesophagitis (in which gastric juice causes
damage to the oesophagus) Reasons why
peptic ulcers develop - increased mucosal
irritation , mucosal-damaging mechanisms
enhanced acidity (acid, pepsin,stress, alcohol,
cigarette smoking) - decreased
mucosal-protecting mechanisms of the stomach -
NSAIDs consumption PGS
synthesis is diminished (PGE 1-2
stimulates mucus and bicarbonate secretion
decreases acid secretion and causes
vasodilation), PGI2 inhibits acid,
stimulates mucus and bicarbonate secretion -
infection of the stomach mucosa with Helicobacter
pylori (chronic gastritis)
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Drugs used to inhibit or neutralise gastric
secretion

• Fig. 1

Regulation of acid secretion by parietal cells is
important in peptic ulcer. The secretion is an
isotonic solution of HCl (150 mmol/L) with a pH
less than 1. The Cl- is actively transported into
canaliculi in the cells which communicate with
the lumen of the gastric glands and thus with the
lumen of the stomach. This Cl- secretion is
accompanied by K, which is than exchanged for H
from within the cell by a PP. Carbonic
anhydrase catalyses the combination of carbon
dioxide and water to give carbonic acid, which
dissociates into H and bicarbonate ions. The
latter exchanges across the basal membrane for
Cl- Three main stimuli act on the parietal
cells - gastrin (a hormon) - ACH (a
neurotransmitter) - histamine (a local hormone)
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GASTRIC PARIETAL CELL
intersticial fluid
M - muscarinic receptor PGR - prostaglandin E2
receptor ECHB enterochromaffin cells Gs a Gi -
G-proteins cAMP - cyclic AMP Ac - adenylyl
cyclase PK - proteinkinase PGE - prostaglandins
E C - synport carrier for Cl- a K P antiport,
which exchanges Cl- and HCO-3 PP
proton-pump
bazolaterall membrane
apical membrane
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Drugs used to inhibit or neutralise gastric
secretion

• ANTACIDS
• HISTAMINE H2-RECEPTOR ANTAGONISTS
• PROTON-PUMP INHIBITORS
• TREATMENT OF HELICOBACTER PYLORI INFECTION
• DRUGS THAT PROTECT THE MUCOSA

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Drugs used to inhibit or neutralise gastric
secretion ANTACIDS

• act by neutralising gastric acid and thus raising
  the gastric pH. This has the effect of inhibiting
  peptic activity, which practically ceases at pH
  5. They vary widely in their potency
• The antacids in common use are salts of magnesium
  and aluminium
• Magnesium trisilicate, aluminium hydroxide,
  alginates
• given 1 and 3 hours after each meal and at
  bedtime
• used in dyspepsia
• symptomatic relief in peptic ulcer,
• A. can be effective in promoting healing of
  duodenal ulcers, their benefit in gastric ulcers
  is less clear
• oesophageal reflux

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Drugs used to inhibit or neutralise gastric
secretion HISTAMINE H2-RECEPTOR ANTAGONISTS

• The histamine H2-antagonists competitively
  inhibit histamine action at all H2 receptors,
  their main clinical use is as inhibitors of
  gastric acid secretion.
• They inhibit histamine - gastrin - and
  ACH-stimulated acid secretion both basal and
  food stimulated by 90 and promote healing of
  duodenal ulcers
• Relapses are likely to follow when treatment with
  H2 receptors antagonists is stopped
• Drugs
• (cimetidin- a CYP450 inhibitor) ranitidine
  famotidine
• Adverse effects diarrhea, dizziness, muscle
  pain, transient rashes

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Drugs used to inhibit or neutralise gastric
secretion PROTON-PUMP INHIBITORS

• Inhibit the terminal step in the acid secretory
  pathway the proton pump which results in
  markedly inhibition of both basal and stimulated
  gastric acid secretion
• Being weak bases, they accumulate in the acid
  environment of the canaliculi of the stimulated
  parietal cells where they are activated. This
  preferential accumulation in areas of very low
  pH, such as occur uniquely in the secretory
  canaliculi of gastric parietal cells, results in
  a specific effect on these cells
• Given orally (as capsules containing
  enteric-coated granules) they are absorbed and
  distributed into the parietal cells and then
  accumulate in the canaliculi (a single daily dose
  affects acid secretion for 2-3 days)

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Drugs used to inhibit or neutralise gastric
secretion PROTON-PUMP INHIBITORS

• omeprazole lanzoprazole pantoprazole

Adverse effects (not very common) headache,
diarrhea, rashes
used in - peptic ulcer - reflux
oesophagitis - as one component of
therapy for
Helicobacter pylori infection -
Zollinger-Ellison syndrome (a rare condition
caused by
gastrin-secreting tumours)
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Drugs used to inhibit or neutralise gastric
secretion TREATMENT OF HELICOBACTER PYLORI
INFECTION

• H.pylori is implicated in the production of
  gastric and, more particularly, duodenal ulcers
  and is a risk factor for gastric cancer
• Combination therapy with three drugs is employed
  to eradicate H.pylori like
• omeprazole amoxicillin metronidazole
• or
• omeprazole clarithromycin amoxicillin
  (tetracycline) bismuth chelates
• Elimination of the bacillus can produce long-term
  remission of ulcers but reinfection can occur

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Drugs used to inhibit or neutralise gastric
secretion DRUGS THAT PROTECT THE MUCOSA

• enhance the mucosal protection mechanisms
• and/or provide a physical barrier over the
  surface of the ulcer

Bismuth chelate has toxic effects on the
bacillus mucosal-protecting effects coating
the ulcer base, adsorbing pepsin, enhancing
local PG synthesis, stimulating bicarbonate

secretion Adverse effects nausea, vomiting,
blackening of the tongue and faeces usedas one
component of therapy for H.pylori infection
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Drugs used to inhibit or neutralise gastric
secretion DRUGS THAT PROTECT THE MUCOSA

• Sucralfate
• A complex of aluminium hydroxide and sulfated
  sucrose, which in the presence of acid acquires a
  strong negative charge and binds to positively
  charged groups in protein
• forms complex gels with mucus -
  decreasing mucus degradation and Hions diffusion
• stimulates bicarbonate secretion
  and PGs production

Adverse effects Constipation (in 15 of
patients treated) Less common dry mouth,
headache, rashes S.reduces the absorption
of a number of other drugs including
fluorochinolone antibiotics, theophylline,
tetracycline, digoxin
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Drugs used to inhibit or neutralise gastric
secretion DRUGS THAT PROTECT THE MUCOSA

• Misoprostol
• A stable analogue of PGE1 which inhibits gastric
  acid secretion, both basal and stimulated by food
  or histamine by a direct action on the parietal
  cells. It increases mucosal blood flow and
  augments the secretion of mucus and bicarbonate
• Adverse effects
• diarrhea, abdominal cramps, uterine contractions
• used to prevent gastric damage that can occur
  with chronic use of NSAIDs

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URINARY BLADDER - INNERVATION
Symp (L1-L4)
parasymp (S2-S4)
motor innervation (L2 S2)