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GLI ANTISECRETIVI, LA GASTROPROTEZIONE
E LE POLITERAPIE
Piero Portincasa. Giuseppe Palasciano
Clinica Medica “A. Murri”
UNIVERSITÀ degli STUDI
BARI
Regulation of acid secretion
Normal human stomach contains
approximately one billion parietal
cells that secrete 0.16 M HCl into
the gastric lumen.
3 principal physiological stimuli:
acetylcholine, histamine, gastrin
Regulation of acid secretion
Actions of antiulcer medications
Pharmacology
Antisecretory drugs
H2 receptor antagonists
Proton pump inhibitors
Antacids
Protective agents (sucralfate)
Indications
GERD
Peptic ulcer
H. pylori infection
Dyspepsia
Treatment and prevention of gastroduodenal ulcers associated with NSAIDs
Z-E syndrome
H2 receptor antagonists
GERD
Peptic ulcer (maintainance)
Dyspepsia
Subgroup of patients
Low cost
Good safety profile
H2-RA side effects
Absorption & distribution
Cross blood-brain and placental barrier (milk)
Hepato-renal metabolism
Influenced by liver / renal insufficiency
Clearance decreased in elderly
Adverse events (rare)
Gynecomastia – Impotence (C)
Immune and hematopoietic effects, B12 def. (C, R)
CNS symptoms confusion, hallucinations, seizures (C)
Hepatic dysfunction
ALT, acute hepatitis
Cardiac effects bradycardia, hypotention, prolonged QT
Renal effects hypercreatininemia, acute interstitial
nephritis (C)
Drug interactions (C)
Drug interactions - CIMETIDINE
Inhibits many isozymes of the cytochrome P450 enzyme system: CYP1A2 (moderate), 2C9 (weak), 2C19 (moderate), 2D6 (moderate), 2E1 (weak), 3A4 (moderate)
Alfentanil, Amiodarone, Atazanavir, Benzodiazepines, Beta-blockers, Calcium channel blockers, Carbamazepine, Carmustine, Cefpodoxime, cefuroxime, Citalopram, Clozapine, Cyclosporine, CYP1A2 substrates (aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine), CYP2C19 substrates (citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline), CYP2D6 substrates (amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine), CYP2D6 prodrug substrates (codeine, hydrocodone, oxycodone, and tramadol), CYP3A4 substrates (benzodiazepines, calcium channel blockers, cyclosporine, mirtazapine, nateglinide, nefazodone, sildenafil), Delavirdine, Dofetilide, Flecainide, Ketoconazole, fluconazole, itraconazole, Lidocaine, Metformin, Moricizine, Phenytoin, Procainamide, Propafenone, Quinolones, SSRIs, Sulfonylureas, Tacrine, Theophylline, Thioridazine, Warfarin, ETHANOL
Wolfe, MM, Sachs, G. Acid suppression: Optimizing therapy for gastroduodenal ulcer healing,
gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology 2000;
118(2 Suppl 1):S9.
The PPIs are the most potent
inhibitors of gastric acid
secretion available
Proton Pump Inhibitors (PPIs)
Omeprazole
Lansoprazole
Rabeprazole
Pantoprazole
Esomeprazole
Proton Pump Inhibitors (PPIs)
Omeprazole
Lansoprazole
Rabeprazole
Pantoprazole
Esomeprazole
Weak bases concentrated in the acidic compartments of the parietal cell.
Inactive prodrug is activated by the acid environment.
A reactive sulfhydryl group then forms a disulfide bond with a cysteine residue on the H-
K-ATPase pump (irreversible enzyme inactivation).
Proton Pump Inhibitors (PPIs)
The rate of conversion varies among the compounds and is inversely proportional to their pKa:
rabeprazole > omeprazole/esomeprazole = lansoprazole > pantoprazole.
Proton Pump Inhibitors (PPIs)
1. Most potent inhibitors of gastric acid secretion
2. Most effective when the parietal cell is stimulated to secrete acid
postprandially
3. PPIs should be administered before the first meal of the day
4. A second dose, which is occasionally necessary, should be
administered before the evening meal
5. PPIs should not be given concomitantly with H2-RA, PGs, or
other antisecretory agents (decreased activity)
THE GOLDEN RULES (1)
Proton Pump Inhibitors (PPIs)
1. SLOW: once-daily PPI dosing inhibits maximal acid output
by about 66% after 5 days
2. “ON DEMAND” therapy not as effective as with H2-RA
3. If FAST effect needed: use PPI x 2/day x 2-3 days
4. Restoration of acid secretion will likewise be delayed.
Maximal acid secretory capacity may not be restored for 24
to 48 hours after discontinuing PPIs
THE GOLDEN RULES (2)
Peptic ulcer, HP eradication
OM20 x 4wks (morning)>RAN300 or CIM800 (bedtime)
LAN30 x 4wks (morning)>RAN300 or FAM40 (bedtime)
PAN, RAB >RAN
Metanalysis: Holt DDS 1991; Poynard EJG 1995, Decker APT 1999
Gastric acid secretion in response to stimulation with gastrin- releasing peptide in subjects of different Helicobacter pylori status
PPIs VERY EFFECTIVE
Triplice
Quadruplice
“5+5”
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NSAIDs can cause Gastroduodenal
Injury (Raskin et al 1976)
NSAID damage to the gastric mucosa
Scanning electron micrographs of normal gastric mucosa (left) and
mucosal surface (right) 16 minutes after administration of aspirin
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Approximately 30M people worldwide benefit
from NSAIDs every day.
500M prescriptions every year - COSTS!
40% of NSAID users are over 60 years of age
NSAID use is rising due to:
- increasing availability without a prescription
- growing recognition of benefits in other disease areas
- the ageing population
NSAIDs are used extensively to
control Pain and Inflammation
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Osteoarthritis
Rheumatoidarthritis
Back painOther
Jones et al 1992
17%20%
6%
57%
Reasons for NSAID use
in the Elderly
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Acute Mucosal Lesions:~ Petequia~ Erosions~ Acute ulcers
Chronic / Deep GD Ulcers
Complications:~ GI Bleeding~ Perforation~ Obstruction
Gastrointestinal Lesions induced by NSAIDs
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PROTECTIVEFACTORS
Mucus layer
Ionic gradient
Bicarbonate layer
Prostaglandins
Surface epithelialcells
Mucosal bloodsupply
Aspirinand otherNSAIDs
H. pyloriPepsinGastric
acid
AGGRESSIVE FACTORS
Aspirin andother NSAIDs
Prostaglandinproduction
Bicarbonateproduction
Mucusproduction
Acidicenvironment
Neutral environment
Gastric acid plays a central role in NSAID-
associated Gastroduodenal damage
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Clinical
Intervention Endoscopic Studies Outcome Studies
H2 receptor Duodenal ulcer Duodenal ulcer
antagonists recurrence rebleeding
Helicobacter Pylori Duodenal ulcer Duodenal ulcer
eradication recurrence rebleeding
Oral Prostaglandin Endoscopic Upper GI
with NSAIDs gastroduodenal ulcer complication
Relationship between Endoscopic Studies and
Clinical Outcome studies
NSAIDs (including aspirin): Primary and Secondary prevention of gastroduodenal toxicity
NSAIDs
EfficacyNo GI side effects
GI side effects
Treatment
Primary prevention*
* Misoprostol
H2RA, PPIs, Coxibs
NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity
NSAIDs
EfficacyNo GI side effects
GI side effects
Treatment
Primary prevention
Important issues
Risk factors
Nonselective NSAIDs
Time, dose
Enteric-coated and buffered aspirin (no advantage)
H. Pylori
Selective COX-2 Inhibitors
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5-6
23
4-5Prior peptic ulcer disease
Increasing age: over 60 years
Male gender: men vs women
Alcohol
Smoking
Current use of:NSAIDs (x2)
anticoagulantscorticosteroids
serotonin-RIs
0 5 10
Relative risk
1.52
1.31.5
10
10-15
4-5
Risk factors for developing Gastroduodenal
Complications in NSAID usersAmerican College of Gastroenterology, 1998
10-15Several risk factors:
highest risk for NSAID-
induced GI toxicity (up
to 9% after 6 mo.
Low dose ibuprofen (RR 1.6, 95% CI 0.8-3.2) High dose ibuprofen (RR 4.2 (95% CI 1.8-9.8)
Low dose naproxen (RR 3.7 (95% CI 1.7-7.7) High dose naproxen (RR 6.0, 95% CI 3.0-12.2)
Low dose indomethacin (RR 3.0, 95% CI 2.2-4.2) High dose indomethacin (RR 7.0, 95% CI 4.4-11.2)
Richy, Ann Rheum Dis, 2004
Time dependent risk of gastrointestinal complications induced by NSAIDs use: a consensus statement using a meta-analytic approach
Time +
History of ulcers:
Test & treat
Asymptomatic – No History
Nothing or Test & treat if high
prevalence of HP
Before NSAIDs or aspirin low dose
?Inchiesta
“HP Fans”In MMG, MI e Specialistica
NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity
NSAIDs
EfficacyNo GI side effects
GI side effects
Treatment
Primary prevention
Treatment
Ulcer while on NSAIDs:
Stop NSAIDs (if possible)
Start antiulcer therapy
PPI>H2-RA or misoprostol or sucralfate
Test & Treat H. Pylori **
**Maastricht 2000
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Healing studies
Study No of Omeprazole Reference drug Treatmentpatients dosage and dosage duration
OMNIUM 935 20 mg od Misoprostol 4/8 weeks
40 mg od 200 g qid
ASTRONAUT 541 20 mg od Ranitidine 4/8 weeks
40 mg od 150 mg bid
* NSAID-associated gastroduodenal injury or symptoms
OMNIUM = Omeprazole vs Misoprostol for NSAID-Induced Ulcer Management
ASTRONAUT = Acid Suppression Trial: Ranitidine vs Omeprazole forNSAID-Associated Ulcer Treatment
New studies with Omeprazole in the acute
management of „acid NSAID disease‟
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Higher healing rates in NSAID-associated gastric
ulcer with Omeprazole compared with Misoprostol
Patients healed%
OMNIUM Hawkey et al 1997
0 4 weeksDuration of treatment
0
20
40
60
80
100
8
Omeprazole 20 mg od
Misoprostol 200 g qid
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Therapeutic gain with omeprazole at 8 weeks
20
Omeprazole provides therapeutic gains overMisoprostol and Ranitidine in the treatment
of NSAID-associated lesions anddyspeptic symptoms
0 5 10 15
Omeprazole 20 mg odvs ranitidine 150 mg bid
Omeprazole 20 mg odvs misoprostol 200 g qid
ASTRONAUTYeomans et al 1996, OMNIUM Hawkey et al 1998
Treatment - summary
A PPI is preferred in patients who must remain on NSAIDs or who have ulcers or multiple erosions
Maintenance therapy is also warranted in such patients
A guideline for the treatment and prevention of NSAID-induced ulcers. Members of
the Ad Hoc Committee on Practice Parameters of the American College of
Gastroenterology.
Lanza FL Am J Gastroenterol 1998 Nov;93(11):2037-46
NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity
NSAIDs
EfficacyNo GI side effects
GI side effects
Treatment
Primary prevention
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Omeprazole prevents ASA-induced gastroduodenal lesions
Omeprazole 40 mg od+ ASA 650 mg qid
Placebo + ASA 650 mg qid
0
20
40
60
80
100
Gastricprotection†
Duodenalprotection‡
Individuals protected %
*
**
* p<0.01 vs placebo
** p<0.001 vs placebo
Scheiman et al 1994
† Patients with less than 15 erosions, or bleeding or ulceration‡ Patients with less than 5 erosions or ulceration
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New studies with Omeprazole in theprevention of 'acid-NSAID disease'*
Prevention studies
* NSAID-associated gastroduodenal injury or symptoms
** Patients re-randomized from the healing parts of ASTRONAUT and OMNIUM
SCUR = Scandinavian Collaborative Ulcer Recurrence
OPPULENT = Omeprazole vs Placebo as Prophylaxis of ULcers and Erosions from
NSAID Treatment
Study No of Omeprazole Reference drug Treatmentpatients dosage and dosage duration
ASTRONAUT 432** 20 mg od Ranitidine 6 months150 mg bid
OMNIUM 732** 20 mg od Misoprostol 6 months200 g bidPlacebo
SCUR 177 20 mg od Placebo 3 months
OPPULENT 169 20 mg od Placebo 6 months
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Effective prophylaxis with Omeprazolein patients requiring NSAID therapy and with a
history of peptic ulcer disease or dyspepsia
SCUREkström et al 1996
monthsDuration of treatment
Omeprazole 20 mg od
Placebo
* Omeprazole vs placebo
p=0.0005
(log-rank test)
100
0 1 2 3
Patients in remission
%
*
0
20
40
60
8074%
48%
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Omeprazole is superior to Misoprostol and placebo in the prophylaxis of
'acid-NSAID disease'*
OMNIUM Yeomans et al 1996
Omeprazole20 mg od
Misoprostol200 g bid
Placebo
p=0.005p<0.0001(log-rank test)
*****
* NSAID-associated gastroduodenal injury or symptoms
***
**
0
20
40
60
80
100
Patients in remissionat 6 months%
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Cumulative Probability of Recurrent Bleeding (Chan et al, NEJM 2001)
0.0
0.1
0.2
0.3
1 2 3 4 5 60
Eradication therapy plus Naproxen
Omeprazole plus Naproxen
Months
Probability of
Recurrent
Bleeding
No. at risk
Omeprazole plus
Naproxen
Eradication therapy
plus Naproxen
75
75
75 75
71 68
74
61
65
55
64
53
62
50
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COX-2
“Inducible”
Prostaglandins
COX-1
“Constitutive”
(Housekeeping enzyme)
Prostaglandins
Mediate pain, inflammation and fever
NSAIDs
Protection of
gastric mucosaHemostasis
Kidney
& Brain
Mechanisms of Action of NSAIDs:
Current Hypothesis
Arachidonic acid
CO2H
How COX-2 Specific Inhibitors WorkCOX-1
IsoenzymeCOX-2
Isoenzyme
GI-protective
prostaglandin
No
side
Side
(COX-2
binding
site)
COX-2
specific drug
Arachidonic acid
not blockedArachidonic acid
blocked
Adapted from Hawkey. Lancet. 1999;353:307-314.
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COX-2 selectivity in human
whole blood
Drug COX-2 selectivity
Nabumetone 0.3
Indomethacin 0.4
Ibuprofen 0.2
Naproxen 0.1
Diclofenac 2
Meloxicam 2
Celecoxib 7
Valdecoxib 30
Rofecoxib 36
Etoricoxib 106
% P
ati
en
ts W
ith
Sc
ore
>2
Ibuprofen
800 mg tid
(n=51)
Vioxx
250 mg qd
(n=49)
Aspirin
650 mg qid
(n=17)
Endoscopy Study:7 Days dosing
* P<0.05 vs. placebo.† P<0.001 vs.Vioxx.
* †
Percent of Patients With Erosions or Ulcers
Lanza et al.(1999) Aliment Pharmacol Ther. 13, 761-767.
0
20
40
60
80
100
Placebo
(n=50)
71
12
94
8
* †
nsaid96/nk/ 49
P<0.01 for all groups compared with ibuprofen.
Placebo vs. Rofecoxib: P=NS.
Ge
om
etr
ic M
ea
n W
ith
84
% C
I
Week
Daily Faecal RBC Loss Over Time
Placebo Rofecoxib 25 mg
Rofecoxib 50 mg Ibuprofen 2.4 g
0
1
2
3
Baseline 1 2 3 4
Hunt et al. Am J Gastroenterol 1998;93:1671
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12 Week Placebo-ControlledEndoscopy Study
PlaceboRofecoxib 25 mgRofecoxib 50 mgIbuprofen 2400 mg
12-Week
% with ulcers
Hawkey Arthritis and Rheumatism 2000; 43: 370
50
0
10
20
30
40
7.34.7
28.5
8.1
nsaid96/nk/ 51
Rates of Myocardial Infarction
%
of patients
with MI
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0Rofecoxib
50 mg
VIGOR (RA)
Naproxen1000 mg
COXIBS – Adverse CV effects
Celecoxib for the prevention of sporadic colorectal adenomas.
Bertagnolli al. N Engl J Med. 2006 Aug 31;355(9):873-84.
CONCLUSIONS: These findings indicate that celecoxib is an effective agent
for the prevention of colorectal adenomas but, because of potential
cardiovascular events, cannot be routinely recommended for this indication.
Effect of Celecoxib on Cardiovascular Events and Blood Pressure in
Two Trials for the Prevention of Colorectal Adenomas.
Solomon et al. Circulation. 2006 Sep 5;114(10):1028-1035.
CONCLUSIONS: Celecoxib at 200 or 400 mg twice daily or 400 mg
once daily showed a nearly 2-fold-increased cardiovascular risk.
The trend for a dose-related increase in cardiovascular events and
blood pressure raises the possibility that lower doses or other
dose intervals may be associated with less cardiovascular risk.
Current recommendations for all patients receiving NSAIDs (1)
Review treatment indications and risk factors. Physicians should assess carefully the indications for NSAID treatment and thoroughly review risk factors for both GI and CV complications. CV risk factor modification, such as tobacco cessation and blood pressure, cholesterol, and, for diabetic patients, glucose control, is warranted in general, although unproven to specifically reduce NSAID- and coxib-associated CV risks.
Prescribe lower-risk agents. The decision to use COX-2 inhibitors requires a risk-benefit analysis that weighs the GI vs the CV risk in an individual patient.
Limit duration and dosage
Copyright ©2006 The American Gastroenterological Association
Current recommendations for all patients receiving NSAIDs (2)
Ask about and avoid combination NSAID therapy. Polypharmacy is common; many patients combine therapy, particularly ASA. The addition of ASA, however, may negate the GI-sparing effects of coxibs and remains an unproven means to decrease the risk of coxib-associated CV
Treat known H pylori. Routine H pylori testing should not be pursued in average-risk patients starting NSAID therapy. Patients with known H pyloriinfection, however, should undergo eradication.
Monitor patients taking both NSAIDs and coxibs for cardiovascular side effects.
Copyright ©2006 The American Gastroenterological Association
Current recommendations for all patients receiving NSAIDs (3)
Assess for and treat H pylori if present. The benefits of pursuing H pyloritesting and subsequent treatment is not proven, but may be worthwhile, particularly among those with a history of a previous ulcer or ulcer complication. Importantly, H pylori eradication alone is not sufficient in these patients, and cotherapy with gastroprotective treatment should be considered strongly.
Institute gastroprotection. Misoprostol (600 mg/day), if tolerated, or PPIs should
in high-risk patients. Nonselective NSAIDs plus PPIs are significantly safer than nonselective NSAIDs alone. H2-receptor antagonist therapy is inadequate. Coxib therapy alone similarly is beneficial in reducing GI risks, but with the possible trade-off of increasing CV risk. Addition of gastroprotection, although significantly beneficial, does not eliminate risk, particularly among patients at high risk for GI complications.
Copyright ©2006 The American Gastroenterological Association
Zollinger-Ellison syndrome
Small duodenal gastrinoma
Gastric body biopsy from a
patient with Z-E syndrome
Zollinger-Ellison syndrome
Effective goal (gastrinoma excision) only in 50% of cases
PPI x 2 /day before breakfast ((e.g. OME40, PANTO80)
Goal of medical treatment: symptom relief + ACID SUPPRESSION (BAO of 1-10 mmol/h)
If BAO>10 mmol/h then increase and divide in b.i.d. (OME 40 and 20/day)
Wolfe, Gastro 2000; Norton NEJM 1999
Treatment of GERD
PPIs control symptoms and heal esophagitis
Standard dose will work in 80-90% of patients
Maintainance: OME (PPI) =OME+CIS > RAN, CIS, RAN+CIS
Effective on complications of GERD (strictures, Barrett’s, extraesophageal symptoms)
Vigneri et al, NEJM 1995
Recommendations for PPI doses in the treatment of acid-related disorders
* As a general rule, duodenal ulcers should be treated for four weeks and gastric ulcers for eight weeks.
+Unapproved use.
Adapted from Wolfe, MM, Sachs, G, Gastroenterology 2000; 118:S9.
Direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease
Comparison of five PPIs (medical literature)
32 RCTs
Standard dose > low dose (healing)
Standard dose = low dose (maintainance)
Speed of symptom relief (ESO>LANSO>OME)
No clear superiority
Vakil N; Fennerty MB. Aliment Pharmacol Ther 2003 Sep 15;18(6):559-68
CONCLUSIONS: After the PPI therapeutic interchange from omeprazole to
lansoprazole, patients with GERD or heartburn previously stabilized while receiving
omeprazole experienced more severe symptoms and expressed decreased patient
satisfaction. These results suggest a need to monitor symptoms after similar
interchange programs.
Clinical and humanistic outcomes in patients with
gastroesophageal reflux disease converted from
omeprazole to lansoprazole.
Nelson WW; Vermeulen LC; Geurkink EA; Ehlert DA; Reichelderfer M
Arch Intern Med 2000 Sep 11;160(16):2491-6.
Center for Drug Policy and Clinical Economics, University of Wisconsin Hospital and Clinics,
600 Highland Ave, 1530, CSC F6/133, Madison, WI 53792, USA.
Are all PPIs similar in “stabilized patients?Maybe not.
Additional issues with PPIs (1)
Over-the-counter PPIs
Controversial (long-term prevention > acute symptoms)
Long-term safety
>15 years of use
prolonged hypergastrinemia, possible association of PPIs with gastric atrophy, and the effects of chronic hypochlorhydria
Intravenous formulations (bleeding, stress-related mucosal damage)
Costs (local differences)
Additional issues with PPIs (1)
Differences in drug metabolism and drug interactions
Cyt P450 enzymes, CYP2C19 (gene polymorphism)
Two mutations (Asians>Caucasians)
5% Homoz for mutation (delayed metabolism); 75% Homo for wild type gene (rapid metabolism); 20% Heteroz (intermediate metabolism)
Furuta et al, Ann Int Med 1998; Clin Pharm Ther 2002
EFFECT ON THERAPEUTIC EFFICACY?
PT: prothrombin time; Cmax: maximum plasma concentration (mg/mL); AUC: area under the curve.
Adapted from Gugler, R, Jensen, JC, Gastroenterology 1985; 89:1235; Diaz, D, Fabre, I, Daujat, M, et al, Gastroenterology 1990; 99:737; Meyer, UA, Eur J Gastroenterol
Hepatol 1996; 8 (Suppl 1):S21; Parsons, ME, Eur J Gastroenterol Hepatol 1996; 8 (Suppl 1):S15; Lew, EA, Aliment Pharmacol Ther 1999; 13 (Suppl 5):11; Lorf, T, et al,
Eur J Clin Pharmacol 2000; 55:733.
Comparison of drug interactions with PPIs
Principal cytochrome P450 enzymes involved in hepatic metabolism
The specific P450 enzymes involved in PPI metabolism and the potential for
interactions among these agents varies considerably
HIGH
HIGH
LOW
THEOPH
VERY LOW
Sir Luke Fildes, The Doctor (1891)The Tate Gallery – London, U.K.
GLI ANTISECRETIVI, LA GASTROPROTEZIONE E LE POLITERAPIE
Il MMG L’Internista
Lo Specialista
Il Farmacologo Il Ricercatore
