New Perspectives in The Management of Peptic Ulcer Disease.

New Perspectives in The Management of Peptic Ulcer Disease.

Professor Javed Akram.

Mb, MEE(Can), MRCP(UK), FRCP(Glasg), FRCP(Edin), FRCP(London), FACP(USA), FASIM(USA), FACC(USA).

Professor Javed Akram.

Mb, MEE(Can), MRCP(UK), FRCP(Glasg), FRCP(Edin), FRCP(London), FACP(USA), FASIM(USA), FACC(USA).

Peptic Ulcer DiseasePeptic Ulcer Disease

A peptic ulcer is a break (an ulceration) in the protective mucous lining (mucosa) of the lower esophagus, stomach or duodenum

A peptic ulcer is a break (an ulceration) in the protective mucous lining (mucosa) of the lower esophagus, stomach or duodenum

Common MisconceptionsCommon Misconceptions

A peptic ulcer is NOT: A stress ulcer Chronic gastritis (a symptom as well as a disease state

that may lead to peptic ulcers) Dyspepsia (the symptoms that may or may not be

diagnosed as an ulcer)

Peptic Ulcers cannot be diagnosed solely on the basis of clinical presentation (Werdmuller et al. 1996)

A peptic ulcer is NOT: A stress ulcer Chronic gastritis (a symptom as well as a disease state

that may lead to peptic ulcers) Dyspepsia (the symptoms that may or may not be

diagnosed as an ulcer)

Peptic Ulcers cannot be diagnosed solely on the basis of clinical presentation (Werdmuller et al. 1996)

Dyspepsia.Dyspepsia.

Dyspepsia - Definition

A group of symptoms which alert clinicians to consider disease of the upper gastrointestinal tract

(British Society of Gastroenterology, 1996)(British Society of Gastroenterology, 1996)

Symptoms of Functional Dyspepsia

Nocturnal Nocturnal pain painLocalized Localized epigastric epigastric burning burning

BetterBetter with food with food

HeartburnHeartburn

RetrosternalRetrosternal burningburning

NauseaNausea

BloatingBloating

Early satietyEarly satiety

WorseWorse with food with food

Ulcer-like DominantUlcer-like Dominant Dysmotility-like Dominant Dysmotility-like Dominant

Quick Stats:Peptic UlcerQuick Stats:Peptic Ulcer

5-10% lifetime incidence 1-2% of people have ulcer at any given time $5.65 billion industry

5-10% lifetime incidence 1-2% of people have ulcer at any given time $5.65 billion industry

Peptic Ulcer Hospitalization RatesPeptic Ulcer Hospitalization Rates

Kurata JH. Kurata JH. Semin Gastrointest DisSemin Gastrointest Dis 1993:4 1993:4

RateRate per per

100,000100,000

Gastric UlcerGastric Ulcer Duodenal UlcerDuodenal Ulcer

70 75 80 85 900

20

40

60

80

100

Uncomplicated Uncomplicated

HemorrhageHemorrhage

Perforation Perforation

70 75 80 85 900

20

40

YearYear YearYear

30

10

Uncomplicated Uncomplicated

HemorrhageHemorrhage

Perforation Perforation

TypesTypes

Gastric Slightly more common in men and way more

common in elderly Most commonly located in the stomach’s lesser

curvature, antrum 1-3% associated with gastric carcinomas Basic defect is disruption of gastric mucosal

barrier (gastritis, duodenal reflux, H. pylori, NSAIDS)

Gastric Slightly more common in men and way more

common in elderly Most commonly located in the stomach’s lesser

curvature, antrum 1-3% associated with gastric carcinomas Basic defect is disruption of gastric mucosal

barrier (gastritis, duodenal reflux, H. pylori, NSAIDS)

TypesTypes

Duodenal Almost always located in the duodenal bulb More likely culprit in chronic disease No association with cancer

Duodenal Almost always located in the duodenal bulb More likely culprit in chronic disease No association with cancer

Risk FactorsRisk Factors

Smoking 33-100% more likely to develop duodenal ulcers Retards healing of identified ulcers J Akram& Colleagues ..E.J.of Gastrenterology.Nov2003)

Age and Sex Alcohol Diet

Milk Stress Ramadan fasting

Smoking 33-100% more likely to develop duodenal ulcers Retards healing of identified ulcers J Akram& Colleagues ..E.J.of Gastrenterology.Nov2003)

Age and Sex Alcohol Diet

Milk Stress Ramadan fasting

Risk FactorsRisk Factors

NSAIDS Responsible for majority of ulcers not caused

by H.pylori Greater risk for complications once ulcer

identified Risk of GU increases sixfold when taking

>three aspirin/day. Buffered coat has no advantage

NSAIDS Responsible for majority of ulcers not caused

by H.pylori Greater risk for complications once ulcer

identified Risk of GU increases sixfold when taking

>three aspirin/day. Buffered coat has no advantage

Prevalence of EndoscopicNSAID-Induced UlcerationPrevalence of Endoscopic

NSAID-Induced Ulceration

Mean Range Gastric Ulcer 15 % 10 to 30% Duodenal Ulcer 5 % 4 to 10 % Clinically Significant Ulcers 2% 1 to 4%

Mean Range Gastric Ulcer 15 % 10 to 30% Duodenal Ulcer 5 % 4 to 10 % Clinically Significant Ulcers 2% 1 to 4%

Risk Factors forSerious GI Adverse Events with NSAIDs: Relative Risks

Risk Factors forSerious GI Adverse Events with NSAIDs: Relative Risks

Rodriguez. Lancet. 1994; Guttham. Epidemiology. 1997; Shorr. Arch Intern Med. 1993; Piper. Ann Intern Med. 1991.

0 5 10 15

4.4 (2.0-9.7)

12.7 (6.3-25.7)

2.9 (2.2-3.8)

5.8 (4.0-8.6)

5.6 (4.6-6.9)

3.1 (2.5-3.7)

1.6 (1.4-2.0)

13.5 (10.3-17.7)

Corticosteroid use

Anticoagulant use

Low dose NSAIDLow dose NSAID

High dose NSAID

Age 70-80

Age 60-69

Age 50-59

Prior bleed

Relative RiskRelative Risk

NSAID

↑ Leukocyte-EndothelialInteractions

Capillary Obstruction

IschemicCell Injury

Proteases +Oxygen Radicals

Endo/EpithelialCell Injury

Mucosal Ulceration

Loss o

f PG

E 2 an

d PG

I 2 m

edia

ted in

hibiti

on

of ac

id se

cret

ion an

d cyto

prote

ctiv

e effe

ct

Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils

Peptic Ulcers and StressPeptic Ulcers and Stress

Experimental stress results in decreased upper gastrointestinal blood flow in animals

(Kauffman, 1997; Livingston 1993)

Effect of stress seems to be reversible (Levenstein et al., 1996)

Experimental stress results in decreased upper gastrointestinal blood flow in animals

(Kauffman, 1997; Livingston 1993)

Effect of stress seems to be reversible (Levenstein et al., 1996)

Peptic Ulcer and PersonalityPeptic Ulcer and Personality

Studies have found a strong association between dependency and peptic ulcers

Patients with peptic ulcer have significantly more personality disturbances than control subjects (Feldman et al.)

Ulcer patients also more inclined to pessimism and excessive dependence (Akram et al.)

Studies have found a strong association between dependency and peptic ulcers

Patients with peptic ulcer have significantly more personality disturbances than control subjects (Feldman et al.)

Ulcer patients also more inclined to pessimism and excessive dependence (Akram et al.)

Helicobacter pyloriHelicobacter pylori

Gram-negative spiral organism Most common and important risk factor for

duodenal ulcer Variable risk factor for gastric ulcers 10% healthy people under 30, 60% healthy

people over 60. Will cause disease in 15-20% of infected Eradication is the key

Gram-negative spiral organism Most common and important risk factor for

duodenal ulcer Variable risk factor for gastric ulcers 10% healthy people under 30, 60% healthy

people over 60. Will cause disease in 15-20% of infected Eradication is the key

Diagnosis of Peptic UlcerDiagnosis of Peptic Ulcer

DiagnosisDiagnosis Vague discomfort and feeling of gnawing hunger Duodenal usually has predictable food relationship (1-3 hrs after meal) Gastric ulcer relationship with food more variable Gastric ulcer-weight loss Duodenal ulcer-weight gain Watch for peptic ulceration/bleeding: melena, radiation of pain to

back/shoulder

Vague discomfort and feeling of gnawing hunger Duodenal usually has predictable food relationship (1-3 hrs after meal) Gastric ulcer relationship with food more variable Gastric ulcer-weight loss Duodenal ulcer-weight gain Watch for peptic ulceration/bleeding: melena, radiation of pain to

back/shoulder

Physical ExamPhysical Exam

Epigastric tenderness Rectal exam!!

Epigastric tenderness Rectal exam!!

StudiesStudies Radiography

Barium swallow with double contrast Duodenal-detects 40-80% Gastric-detects 65-80%

Endoscopy Gold standard Detects up to 95% gastroduodenal ulcers Generally considered the study of choice esp. for

large ulcers or those not clearly benign

Radiography Barium swallow with double contrast Duodenal-detects 40-80% Gastric-detects 65-80%

Endoscopy Gold standard Detects up to 95% gastroduodenal ulcers Generally considered the study of choice esp. for

large ulcers or those not clearly benign

Diagnosis of H. pyloriDiagnosis of H. pylori

Invasive (if patient requires endoscopy) Histologic testing (50-90% sensitive, 100%

specific) Rapid urease (CLO) test (95% sensitive and

95% specific)* Noninvasive

IgG antibody* Urea breath test (96% sensitive, 98% specific)

Invasive (if patient requires endoscopy) Histologic testing (50-90% sensitive, 100%

specific) Rapid urease (CLO) test (95% sensitive and

95% specific)* Noninvasive

IgG antibody* Urea breath test (96% sensitive, 98% specific)

ComplicationsComplications

Perforation Reoccurrence Obstruction Bleeding Cancer

Perforation Reoccurrence Obstruction Bleeding Cancer

Upper GI BleedingUpper GI Bleeding

A common medical conditionA common medical condition

250,000 – 500,000 admissions/year in US UGI bleeding incidence 100/100,000 adults

Incidence increases 20-30 fold from third to ninth decade of life

GI bleeding stops spontaneously in 80 %

250,000 – 500,000 admissions/year in US UGI bleeding incidence 100/100,000 adults

Incidence increases 20-30 fold from third to ninth decade of life

GI bleeding stops spontaneously in 80 %

Bleeding Stats:Mayo J.Akram etal 2001PJGEBleeding Stats:Mayo J.Akram etal 2001PJGE

TherapyTherapy

Goal is to heal the ulcer and prevent recurrence

Both can be accomplished by eradicating H. pylori if present

Treat the acute pain if necessary

Goal is to heal the ulcer and prevent recurrence

Both can be accomplished by eradicating H. pylori if present

Treat the acute pain if necessary

NonpharmacologicNonpharmacologic

There is no evidence that dietary modifications changes the course of the disease

Quit smoking Milk intake Faster healing, lower recurrence, lower

complications Discontinue NSAIDS COX2 Inhibitors?

There is no evidence that dietary modifications changes the course of the disease

Quit smoking Milk intake Faster healing, lower recurrence, lower

complications Discontinue NSAIDS COX2 Inhibitors?

Treatment of ulcersTreatment of ulcers Eradicate H. pylori Single antibiotic therapy does not work Compliance is key

More than 60% of the doses must be taken to ensure eradication

If eradicated, maintenance therapy not needed. If recurs, check for H. pylori again

If H. pylori not found, check again and treat with H2-receptor antagonists, PPI’s and sucralfate

Document healing of gastric ulcers with endoscopy

Eradicate H. pylori Single antibiotic therapy does not work Compliance is key

More than 60% of the doses must be taken to ensure eradication

If eradicated, maintenance therapy not needed. If recurs, check for H. pylori again

If H. pylori not found, check again and treat with H2-receptor antagonists, PPI’s and sucralfate

Document healing of gastric ulcers with endoscopy

ULCOCID(Sucralfate)

ULCOCID(Sucralfate)

Chemical Structure of Sucralfate Chemical Structure of Sucralfate

Sucrose Octasulphate Poly aluminum Hydroxide

Sucralfate

C12 H6 O11 [SO3 Al2 (OH)5] n H2 O

Sucrose Octasulphate Poly aluminum Hydroxide

Sucralfate

C12 H6 O11 [SO3 Al2 (OH)5] n H2 O

ULCOCID(Sucralfate)

ULCOCID(Sucralfate)

1. Non systemic

2. Cytoprotective

3. Acid related disorders

1. Non systemic

2. Cytoprotective

3. Acid related disorders

PHAMACOKINETICSPHAMACOKINETICS

ABS0RPTION Minimal absorption by GIT 3-5%

ABS0RPTION Minimal absorption by GIT 3-5%

EXCRETION Approximately 90% is excreted in the stool, very

small amount is excreted in the urine.

EXCRETION Approximately 90% is excreted in the stool, very

small amount is excreted in the urine.

INDICATIONS OF ULCOCIDINDICATIONS OF ULCOCID

Duodenal ulcers Gastric ulcers treatment of reflux and peptic oesophagitis H.pylori treatment of NSAID & aspirin induced GI symptoms and

mucosal damage. Prevention of stress ulcers and GI bleeding in critically ill

patients. Treatment of oral and oesophageal ulcers due to radiation

chemotherapy & sclerotherapy. Sucralfate enemas in ulcerative colitis & colonic

carcinomas

Duodenal ulcers Gastric ulcers treatment of reflux and peptic oesophagitis H.pylori treatment of NSAID & aspirin induced GI symptoms and

mucosal damage. Prevention of stress ulcers and GI bleeding in critically ill

patients. Treatment of oral and oesophageal ulcers due to radiation

chemotherapy & sclerotherapy. Sucralfate enemas in ulcerative colitis & colonic

carcinomas

AVAILABILITY OF DRUGAVAILABILITY OF DRUG

1. ULCOCID tablets ( containing 500 mg Sucralfate per tablet ).

2. ULCOCID tablets ( containing 1 g Sucralfate per tablet ).

3. ULCOCID Susp. 60 ml

( containing 1 g Sucralfate per 5ml).

1. ULCOCID tablets ( containing 500 mg Sucralfate per tablet ).

2. ULCOCID tablets ( containing 1 g Sucralfate per tablet ).

3. ULCOCID Susp. 60 ml

( containing 1 g Sucralfate per 5ml).

DOSAGE RECOMMENDATION OF ULCOCIDDOSAGE RECOMMENDATION OF ULCOCID

For Ulcer Patients Morning 2g Ulcocid Evening

For Non Ulcer Patients Morning 1 g Ulcocid Evening

For Ulcer Patients Morning 2g Ulcocid Evening

For Non Ulcer Patients Morning 1 g Ulcocid Evening

ULCOCIDULCOCIDULCOCID should always be

taken 1 hour before meals at bed time (Monotherapy)

Do not take antacids 1/2 hour before or after taking ULCOCID (Polytherapy).

ULCOCID should always be taken 1 hour before meals at bed time (Monotherapy)

Do not take antacids 1/2 hour before or after taking ULCOCID (Polytherapy).

ANTACIDS Vs ULCOCDANTACIDS Vs ULCOCDANTACIDS

Just symptomatic therapy. Intense antacid regimen required

for healing. Not safe for hypertensive or

cardiac patients. Non-Palatable. Not suitable for working class

because of frequent dose taken.

ANTACIDS Just symptomatic therapy. Intense antacid regimen required

for healing. Not safe for hypertensive or

cardiac patients. Non-Palatable. Not suitable for working class

because of frequent dose taken.

ULCOCID Ulcer healing occurs.

None

Palatable

Dosage is convenient.

ULCOCID Ulcer healing occurs.

None

Palatable

Dosage is convenient.

Ulcocid Vs H2- Receptor AntagonistsUlcocid Vs H2- Receptor Antagonists

Ulcocid Less side effects Can be administered to elderly. Smokers can use it. Does not effect hepatic

metabolism of drugs. Does not effect pulmonary

functions in patients with pre-existing broncho- pulmonary diseases.

Ulcocid Less side effects Can be administered to elderly. Smokers can use it. Does not effect hepatic

metabolism of drugs. Does not effect pulmonary

functions in patients with pre-existing broncho- pulmonary diseases.

H2-Receptor Antagonists More side effects Causes hallucination and delirium

in elderly Only for non- smokers. Does effect the metabolism of

drugs metabolized by Cytochrome P-450 path-way.

H2 – blockers may worsen the condition.

H2-Receptor Antagonists More side effects Causes hallucination and delirium

in elderly Only for non- smokers. Does effect the metabolism of

drugs metabolized by Cytochrome P-450 path-way.

H2 – blockers may worsen the condition.

Human Studies.Human Studies.Comparative evaluation of Sucralfate &

Cimetidine efficacy in treatment of chronic erosive gastritis.

The results of patients with chronic erosive gastritis treated with Sucralfate & Cimetidine were compared. The result of examinations indicate that chronic erosive gastritis is difficult to be heal; Sucralfate proved to be more efficient than Cimetidine.

Ref: Au:Kula-Z:Walasek-L So:Pizegl-Lek 1998; 51(2): 73-6

Comparative evaluation of Sucralfate & Cimetidine efficacy in treatment of chronic erosive gastritis.

The results of patients with chronic erosive gastritis treated with Sucralfate & Cimetidine were compared. The result of examinations indicate that chronic erosive gastritis is difficult to be heal; Sucralfate proved to be more efficient than Cimetidine.

Ref: Au:Kula-Z:Walasek-L So:Pizegl-Lek 1998; 51(2): 73-6

Meta-analysis:Human Studies.Meta-analysis:Human Studies.

Comparative evaluation of Sucralfate & Cimetidine efficiency in treatment of chronic erosive gastritis proved that Sucralfate is more efficient than Cimetidine.

Ref: Au: Kula-Z:Walasek-L So:Pizegl-Lek 1999; 51(2): 73-6

Comparative evaluation of Sucralfate & Cimetidine efficiency in treatment of chronic erosive gastritis proved that Sucralfate is more efficient than Cimetidine.

Ref: Au: Kula-Z:Walasek-L So:Pizegl-Lek 1999; 51(2): 73-6

ULCOCID Vs ACID PUMP INHIBITORS

ULCOCID Vs ACID PUMP INHIBITORS

Acid Pump Inhibitors Jaundice has been reported.

Hypoglycaemia, Wt. Gain.

Increased intragastric concentrations of viable bacteria during the T/M.

Acid Pump Inhibitors Jaundice has been reported.

Hypoglycaemia, Wt. Gain.

Increased intragastric concentrations of viable bacteria during the T/M.

Ulcocid No jaundice reported

None

None

Ulcocid No jaundice reported

None

None

Anti Helicobacter effects

Omeprazole Vs Ulcocid(With Clarithromycin and Metronidazole)

Anti Helicobacter effects

Omeprazole Vs Ulcocid(With Clarithromycin and Metronidazole)

75

80

85

90

95

100

4 WeeksHealing

H.Pylorieradication

OmeprazoleUlcocid

75

80

85

90

95

100

4 WeeksHealing

H.Pylorieradication

OmeprazoleUlcocid

Ulcocid Counters the Effect of H.Pylori on Gastric Mucosa

Ulcocid Counters the Effect of H.Pylori on Gastric Mucosa

H.PYLORI Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion Cell desquamation Mucosal microvessel

permeability Mucosal blood flow? Surface hydrophobicity Cell membrane permeability H+ Back diffusion.

H.PYLORI Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion Cell desquamation Mucosal microvessel

permeability Mucosal blood flow? Surface hydrophobicity Cell membrane permeability H+ Back diffusion.

ULCOCID Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion

Mucosal PGE2, Mucosal renewal Mucosal blood flow Surface hydrophobicity Cell membrane permeability H+ Back diffusion.

ULCOCID Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion

Mucosal PGE2, Mucosal renewal Mucosal blood flow Surface hydrophobicity Cell membrane permeability H+ Back diffusion.

HUMAN AND ANIMAL STUDIESHUMAN AND ANIMAL STUDIES

Invitro and clinical data suggest that triple therapy with SUCRALFATE is effective in eradicating HELICOBACTER PYLORI and reducing duodenal ulcer relapse.

Ref: Louw- Ja So:Scand-J-Gastroenterol-Suppl. 1998; 191:28-31

Invitro and clinical data suggest that triple therapy with SUCRALFATE is effective in eradicating HELICOBACTER PYLORI and reducing duodenal ulcer relapse.

Ref: Louw- Ja So:Scand-J-Gastroenterol-Suppl. 1998; 191:28-31

Human StudiesHuman Studies

Glycosulfatase activity of H. Pylori towards human gastric mucin; effect of Sucrafate.

Results demonstrate that H. Pylori, through its Glycosulfatase activity affects the sulphated mucin & glycero-gluco-lipid content of the protective mucous layer & that anti-ulcer drug Sucralfate is able to counteract the detrimental action of this enzyme.

Ref: Slomiany-BL; Piotrowski-J; Grabska-M; SLOMIANY-a So: Am-j-Gastroenterol. 1999 Sep; 87(9); 1132-7

Glycosulfatase activity of H. Pylori towards human gastric mucin; effect of Sucrafate.

Results demonstrate that H. Pylori, through its Glycosulfatase activity affects the sulphated mucin & glycero-gluco-lipid content of the protective mucous layer & that anti-ulcer drug Sucralfate is able to counteract the detrimental action of this enzyme.

Ref: Slomiany-BL; Piotrowski-J; Grabska-M; SLOMIANY-a So: Am-j-Gastroenterol. 1999 Sep; 87(9); 1132-7

ULCOCID INHIBITS THE EFFECT OF H.Pylori on gastric mucins

ULCOCID INHIBITS THE EFFECT OF H.Pylori on gastric mucins

0

200

400

600

800

1000

1200

Specific binding (dpm/assay)

Control 10 40 80

ULCOCID (mg/ml)

0

200

400

600

800

1000

1200

Specific binding (dpm/assay)

Control 10 40 80

ULCOCID (mg/ml)

ULCOCIDULCOCID Direct binding to ulcer

crater

Stimulates prostaglandin production

Enhances the surface active phospholipid mucosal barrier.

Direct binding to ulcer crater

Stimulates prostaglandin production

Enhances the surface active phospholipid mucosal barrier.

Stimulates growth factors

. Epidermal

. Transforming

. Fibroblast

Anti-helicobacter effects.

Stimulates growth factors

. Epidermal

. Transforming

. Fibroblast

Anti-helicobacter effects.

Recurrent Aphthous Stomatitis (RAS)Recurrent Aphthous Stomatitis (RAS)

Minor apthae Minor apthae

Recurrent Aphthous Stomatitis (RAS)Recurrent Aphthous Stomatitis (RAS)

Major apthae Major apthae

Sucralfate in apthous ulcers.F.Khan,A.Awan,J.Akram SMJ,Jun,2003

Sucralfate in apthous ulcers.F.Khan,A.Awan,J.Akram SMJ,Jun,2003

Statistically significantly better pain relief Earlier ulcer healing rates Better QOL

Statistically significantly better pain relief Earlier ulcer healing rates Better QOL

Sucralfate EnemaSucralfate Enema

Ulcerative Colitis Ca.Colon

Ulcerative Colitis Ca.Colon

HUMAN STUDIES HUMAN STUDIES

Management of bleeding in a patient with colorectal cancer:

SUCRALFATE an oral cytoprotective, used topically in a patient with colo-rectal cancer resulting in control of bleeding, less localized pain and more freedom & independence for the patient.

Ref: Au: Famcombe-M So: Support-care-cancer, 1993 May;1(3):159-60.

Management of bleeding in a patient with colorectal cancer:

SUCRALFATE an oral cytoprotective, used topically in a patient with colo-rectal cancer resulting in control of bleeding, less localized pain and more freedom & independence for the patient.

Ref: Au: Famcombe-M So: Support-care-cancer, 1993 May;1(3):159-60.

WHY ULCOCID ?WHY ULCOCID ?

Fast pain relief. Excellent healing rate. Equal good for smokers and non - smokers. Good for elderly. Equally good for ulcer and non - ulcer

patients. Economical

Fast pain relief. Excellent healing rate. Equal good for smokers and non - smokers. Good for elderly. Equally good for ulcer and non - ulcer

patients. Economical

Thank You.Thank You.