Management of PUD,
H. pylori infection
4th Med Pharmacology
27/10/05
Introduction
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PUD = ulceration of gastroduodenal mucosa (usually
extending through muscularis mucosa)
Prevalence 5-10%
50% of these have recurrence within 5 yrs
Discovery of H. pylori of great importance
diagnostically & therapeutically in PUD (Nobel prizeMarshall & Warren)
H. pylori cultured from stomach of ~90% DU pts &
~80% GU pts
Eradication of H. pylori ↓ recurrence of PUD by ~7590%
Pathogenesis of PUD
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Not fully understood, but 3 major factors identified
Factor
Treatment approach
Infection with gram-negative H.
pylori
Eradication of H. pylori infection,
e.g. triple tx
↑ gastric HCl secretion
↓ HCl secretion or neutralizing it,
e.g. H2 antagonists, pirenzepine,
antacids
Inadequate mucosal defence against
gastric HCl
Agents that protect gastric mucosa,
e.g. sucralfate
Importance of treating PUD
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Gastric ulcers:
5% malignant
Endoscopic biopsy at time of initial diagnosis recommended &
repeat endoscopy after 6-8 wks tx
Surgical tx for nonhealing GU
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Duodenal ulcers:
Usually not malignant
If pt asymptomatic do not need to prove ulcer healing
Many heal without tx
H2-receptor antagonists, sucralfate & high dose antacids shown
to ↑ rate of healing and % of ulcers that heal. Drug tx has 7085% incidence ulcer healing at 6 wks cf placebo (~40%)
Importance of treating PUD (contd)
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Complications of PUD
1)
GI bleeding
Gastric outlet obstruction
Perforation
Penetration into pancreas
Intractability
2)
3)
4)
5)
Stomach
Stomach
Duodenum
Non-pharmacological measures to treat PUD
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Diet
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Stop smoking
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Avoid aspirin/NSAIDs. Enteric coating or anti-ulcer tx may ↓
mucosal damage from aspirin. In pts with strong indications for
NSAID tx treating with PPI, H2-R antagonists, sulcralfate or
misoprostil may relieve symptoms. Tx with a COX 2 selective
NSAID [CI CVS problems]
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Avoid C2H5OH
Drugs used
to treat PUD
Antimicrobial H2-Histamine Prostaglandins
Agents
R Blockade
Amoxicillin
Bismuth
Clarithromycin
Metronidazole
Tetracycline
Cimetidine
Famotidine
Nizatidine
Ranitidine
Misoprostol
PPI
Lansoprazole
Omeprazole
Antimuscarinic
Agents
Pirenzepine
Antacids
Al(OH)3
[Mg(OH)2]
CaCO3
Mucosal
Protective
Agents
Bismuth
Sulcralfate
H. pylori Eradication
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1)
2)
3)
4)
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If GU/DU identified by upper endoscopy/radiographic study
need to determine if H.pylori present
Diagnostic tests include:
Serologic testing
C-13 urea breath test
Urease assay (Clotest)
Culture/histological analysis of endoscopic biopsy
Majority of PU can be healed with H2-antagonists/PPI alone,
but relapse of sx occur in up to 80% pts within 1 yr cf 8% if
treated with H.pylori eradication tx.
Current recommendations for tx of H. pylori
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Test for H.pylori before starting eradication tx
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If H. pylori test is positive, use eradication tx
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If H. pylori test is negative, treat with lansoprazole
(Zoton) 30mg OD. Use for 4 wks for DU, 8 wks for
GU. May use lansoprazole 15mg OD to prevent relapse
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Eradication of H. pylori
Eradication defined as negative tests for the bacterium
4 wks or more after the end of tx
Current recommendations for tx of H. pylori
1st line eradication tx for H.
pylori
2nd line tx
Preferred tx= PPI PO + Clarithromycin
500mg BD PO + Amoxicillin 1 gm BD
PO for 7 days
PPI + Bismuth 120mg QDS PO +
Metronidazole 500mg TDS PO +
Tetracycline 500mg QDS PO for 7 days
If Penicillin allergic= PPI +
Clarithromycin 500mg BD PO +
Metronidazole 400mg BD PO for 7 days
E.g. of PPI: Lansoprazole 30mg BD PO
Subsequent failures handled on
individual basis with advice from
gastro/micro
H. pylori eradication
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1 week triple-therapy regimens eradicate H.. Pylori in
>90% cases. Usually no need for continued
antisecretory tx unless ulcer complicated by
bleeding/perforation
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2 week triple-therapy offer higher eradication rates cf 1
week but SE common & poor compliance
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2-week dual-therapy with PPI & antibacterial produce
low rates of H. pylori eradication & not recommended
H. pylori eradication
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Treatment failure may be due to
- Resistance to antibacterial drugs
- Poor compliance
Drug
Side effects
Bismuth
n&v, unpleasant taste, darkening of tongue & stools, caution in renal
disease
Metronidazole n&v, unpleasant taste, ↓effectiveness OCP, care with lithium/warfarin
Amoxicillin
& tetracycline
GI side effects, ↓ effectiveness OCP, pseudomenbranous colitis
Lansoprazole
↓ effectiveness OCP
H2-receptor antagonists
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MOA: Competitively block binding of histamine to
H2 R, ↓ intracellular cAMP & secretion of gastric
acid. Reversible
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Egs: Cimetidine, ranitidine, famotidine & nizatidine
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Effective for acute/chronic DU & benign GU.
Recurrence common after tx with H2-R antagonists
alone is stopped.
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Mainly renal excretion
H2-receptor antagonists
Drug
Side effects
Cimetidine
-reversible impotence, gynaecomastia & ↓
sperm count (high doses) (nonsteroidal
antiandrogen)
-mental status abnormalities-confusion,
hallucinations (elderly/renal impairment)
-leukopenia & thrombocytopenia (rare)
-cytochrome P450 inhibitor (e.g. impairs
metabolism of warfarin, theophylline &
phenytoin)
Ranitidine, fanotidine, nizatidine
-Impotence, gynaecomastia & confusion
less frequently than cimetidine.
-Little interference with cytochrome P450
-Reversible drug-induced hepatitis with all
H2-antagonists
Proton-pump Inhibitors (PPI)
•
MOA: blocks parietal cell H+/K+ ATPase enzyme system
(proton pump) ↓ secretion of H+ ions into gastric lumen
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Heals erosive oesophagitis more effectively than H2antagonists. Used in antimicrobial regimens to eradicate H.
pylori
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SE: n&v, diarrhoea, dizziness, headaches, gynaecomastia &
impotence (rare), thrombocytopenia, rashes
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Dose: 20mg/day omeprazole in acute tx of DU
Mucosal Protective Agents
1)
Sulcralfate
MOA: Binds to positively charged proteins present on damaged mucosa
forming a protective coat
Useful in “stress ulceration”
As effective as H2-R antagonists/high dose antacids in healing of DU
SE: Constipation
↓absorption of cimetidine, digoxin, phenytoin & tetracycline
2)
Bismuth
MOA: Antimicrobial action. Also inhibit pepsin activity, ↑mucus secretion
& interact with proteins in necrotic mucosal tissue to coat & protect the
ulcer crater
Antacids
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MOA: Weak bases that react
with gastric acid to form
H20+salt. ↓pepsin activity as
pepsin inactive at pH>4
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Symptom relief,
liquids>tablets
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E.g. Maalox = [Mg(OH)2] +
Al(OH)3
Drug
Side effect
[Mg(OH)2]
severe osmotic
diarrhoea (therefore
combined with
AlOH)
Al(OH)3
↓phosphate,
↓absorption of
tetracycline,
thyroxine &
chlorpromazine,
constipation
CaCO3
↑Ca in blood &
urine (high doses)
Antimuscarinic drugs
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Not successful b/c of general unwanted antimuscarinic effects
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Muscarinic R stimulation ↑ GI motility & secretory activity
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Pirenzipine: Some selectivity due to affinity for & blockade of M1-receptors
in autonomic ganglia (low affinity for M2-receptors of smooth muscle of
ileum & bladder)
In stomach appears to inhibit transmission in parasympathetic enteric ganglia.
Used as adjunct in refractory PUD & Zollinger-Ellison syndrome
Poorly absorbed from GIT and excreted mainly unchanged in urine & bile
Doesn’t cross BBB
SE: Dry mouth, visual disturbances, agranulocytosis & thrombocytopenia
Prostaglandin analogues
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Endogenous prostaglandins (PGE2 & I2) contribute to GI mucosa integrity by
-stimulation of mucus & bicarbonate secretion
-maintenance of blood flow (allows removal of luminal H-ions)
-prevention of luminal H-ions from diffusing into the mucosa (e.g. in response to
C2H5OH)
-↓ of gastric acid secretion
-helping to repair damaged epithelium
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Gastric & duodenal mucosal damage & chronic PU associated with the use of
NSAIDs may derive from interference with the cytoprotective action of
prostaglandins
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Misoprostol = synthetic prostaglandin E1 analogue
Prevents NSAID induced ulcers & heals chronic GU & DU
SE: Abdo pain, n&v, diarrhoea, abortifacient (produces uterine contractions)
NSAID-associated ulcers
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GI bleed & ulceration can occur with NSAIDs. If possible withdraw NSAID
if ulceration. Consider alternative analgesia
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If at risk of ulcer a PPI, H2-R antagonist or misoprostol may be considered
for protection against NSAID-associated ulcers. Colic & diarrhoea may limit
use of misoprostol
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If NSAID treatment needs to continue
-treat ulcer with PPI & on healing of ulcer continue with PPI
-treat ulcer with PPI & on healing switch to misoprostol for maintenance tx
Caution COX-2 inhibitors & CVS events
Because of concerns re CVS safety, COX-2 inhibitors should only be used in
preference to standard NSAIDs only when specifically indicated & after
assessment of CVS.
Pts receiving COX-2 inhibitor & who have IHD or cerebrovascular
disease should be switched to alternative asap
Associated Gastric Conditions
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Zollinger-ellison syndrome
Rare gastrin-secreting, non-ß islet cell tumour of the pancreas or duodenum →gastric
acid hypersecretion
2/3rd Zollinger-ellison tumours malignant
MEN-1 associated with Zollinger-ellison syndrome in ¼ cases
Presents with DU (single/multiple) + diarrhoea
Tx: Control of ↑acid with H2-R antagonists & PPI at much higher doses than those
used for PUD
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Non-ulcer dyspepsia
Syndrome of persistent ulcer-like symptoms in absence of radiographic & endoscopic
abnormalities
May be explained by motor abnormalities, microscopic inflammation, H. pyloriassociated gastritis & associated psychiatric disease
Tx: Empiric. Some may benefit from psychoactive agents e.g. TCADs
GORD
GORD = Symptoms of “heartburn”
General advice includes AVOIDING
Drug Tx
Meals
antacids=+/-alginic
at night, lying down after meals
Elevate head of bed
Heavy lifting, tight clothing, bending
Being overweight
Smoking (nicotine relaxes lower
oesophageal sphincter)
Aggravating substances (spicy foods,
C2H5OH)
Drugs which encourage reflux (e.g.
antimuscarinic, smooth muscle relaxants,
theophylline)
acid
Pro-kinetic agent, e.g. metoclopramide
H2-antagonist
PPI
If severe sx when tx stopped, or bleed from
oesophagitis or stricture maintenance tx with
PPI or surgery may be necessary
GI haemorrhage
Risk factors for ↑ morbidity/mortality
1)
Age > 60yrs
2)
Additional co-morbid illness/es
3)
Bright red haemetemesis & ↓ BP
4)
Large (>2 cm ulcers)
5)
Shock
6)
Recurrent bleed
Need to maintain adequate circulatory volume in order to localise bleeding site
and institute tx
Management of upper GI haemorrhage
1) Resuscitation and stabilisation
Assess haemodynamic status
Frequent vital signs HR & BP
Blood for FBC, coag, grp & cross-match
GI haemorrhage (contd)
2) Tx
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IVF. Hypovolaemia is usually the cause of the ↓BP so should initiate
restoration of intravascular volume. Vasopressors generally not indicated.
Blood transfusion if bleeding massive, ongoing or severe
Coagulopathy may require FFP
Thrombocytopenia may require platelet transfusion
ET intubation to prevent aspiration
CVP monitoring to guide fluid replacement
Early consult with gastroenterologist, surgeon, or invasive radiologist when
significant haemorrhage, continued instability or active bleeding
3) Upper GI bleeding diagnosed by
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OGD (diagnostic &/or therapeutic)
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Arteriography
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Upper GI barium study
Treatment of different lesions
Peptic ulcer haemorrhage
Most stop bleeding spontaneously
1)
Endoscopy – thermal coagulation, injection tx, haemostatic clips
2)
Surgery – e.g. if failure of endoscopic tx, haemodynamic instability despite
resuscitation, recurrent haemorrhage, shock, continued bleed requiring > 3
units/day. Tx include oversewing of artery + truncal vagotomy + pyloroplasty,
antrectomy, gastrojejunostomy (Billroth procedure), highly selective vagotomy
3)
Arterial angiotherapy (arterial vasopressin/embolisation)
4)
Intravenous PPI. Better able to maintain gastric pH > 6 & protect ulcer clot from
fibrinolysis
5)
H2-antagonists. Not in active bleed. ?effective in ↓recurrent bleed
Treatment of different lesions
Mallory-Weiss tear:
Mucosal tear at GO junction. Most stop spontaneously. May need therapeutic
endoscopy or arterial angiography
Aortoenteric fistula:
Usually aorto-duodenal. Usually hx previous aortic graft surgery. Tx: surgery
Stress ulceration:
Pts with head injuries, burns, major trauma, shock, sepsis, respiratory failure,
coagulopathy.
Prophylactic tx with H2-R antagonists, sucralfate & antacids in pts at risk