HARAMAYA UNIVERSITY HIWOT

FANA COMPREHESIVE
SPECIALIZED HOSPITAL

Department of Clinical Pharmacy

and Drug and Poison Information
Service (DPIS)
Gastrointestinal Disorders
Pharmacotherapy

By Salahadin A, BPharm
Outline(Integrated Therapeutics)

• Disease state definition

• Epidemiology
• Etiology and Review of relevant pathophysiology
• Diagnosis
• Clinical presentation
• Goals of therapy
• Pharmacotherapy
• Monitoring and Evaluation
Gastrointestinal Disorders
Pharmacotherapy

I. Gastrointestinal Tract(GIT)
Evaluation
 Evaluation of the GIT: Introduction

• GIT
– Composed of organs and tissues that have
diverse forms and functions
– Esophagus, stomach, small intestine, large
intestine, colon, rectum, biliary tract,
gallbladder, liver, and pancreas
• Patient history and physical examination remain
important for initial assessment, triage
• In addition diagnostic procedures are essential
in the evaluation of GI disorders
 Symptoms of Gastrointestinal
Dysfunction
• Heartburn, dyspepsia, abdominal pain,
nausea, vomiting, diarrhea, constipation,
and gastrointestinal bleeding
• Signs and symptoms of malabsorption,
hepatitis, and GI infection
• Warning symptoms include :
– weight loss, intractable vomiting, anemia,
dysphagia, and bleeding
– All clinicians should give due attention
Methods commonly used to assess
pts with GI complaints
• Include:
– Careful patient's history
– Comprehensive physical examination
– Routine laboratory tests
– Diagnostic studies and procedures
 Patient History
• Comprehensive pt history is the cornerstone
• A clear, detailed, chronologic account of the
patient's problems
• Should include:
– the onset of the problem
– the setting in which it developed
– factors that alleviate and aggravate the
problem
– its manifestations
 Patient History…..
• Lifestyle,…..diet and alcohol intake, use of
medications, …(non-steroidal anti-inflammatory
drugs)
• Travel and potential exposure to infection is
relevant
• Pain or discomfort must be characterized and
localized, and aggravating or relieving factors
ascertained.
• Altered bowel habit, particularly of recent onset, is
significant, as is recent nausea, vomiting or
anorexia (loss of appetite).
 Patient History…..
• Describe any vomitus and stool
– haematemesis, stool black and tarry (shows
upper GIT bleeding)…. stool fresh blood…
(lower GIT bleeding)
• Weight loss…. malabsorption, chronic
inflammation or cancer
• Liver, gallbladder, pancreas, stomach, small
intestine and colon disorders ….vague, poorly
localized symptoms.
• Family history…. inflammatory bowel disease or
colorectal cancer.
 General Questions in a GI History
• Tell me about the problem that you are experiencing.
When did it start? What were you doing when the
symptoms began?
• Your pain location? Please point to the area where you
feel pain.
• How rapidly did the pain come on? Is your pain constant
or intermittent? What factors exacerbate or alleviate your
pain? Does the pain awaken you at night?
• Have you had these symptoms in the past?
• What medications are you taking to help alleviate the
pain? How much do you take? Do these medications
work? ……………………….
 Drugs that May Cause GI Injury

GI mucosal injury Jaundice

• Aspirin
• Bisphosphonates
• Chemotherapeutic agents
• Corticosteroids
• Iron preparations
• NSAIDs
• Pancreatic enzymes
• Potassium chloride
• Warfarin
• Androgens
• Chlorpropamide
• Corticosteroids
• Erythromycin
• Estrogens
• Ethanol
• Gold salts
• Nitrofurantoin
• Phenothiazines
• Warfarin
 Drugs that May Cause GI Injury
Liver damage

• Acetaminophen • Verapamil
• Warfarin
• Allopurinol
• Zidovudine
• Amiodarone • Methotrexate
• Dapsone • Methyldopa
• Glyburide • Monoamine oxidase inhibitors
• Nevirapine
• Isoniazid • Nifedipine
• Ketoconazole • Nitrofurantoin
• Lovastatin • Phenytoin
• • Propylthiouracil
Tetracycline
• Rifampin
• Valproic acid • Salicylates
• Sulfonamides
 Drugs that May Cause GI Injury

Pancreatitis Pancreatitis cont’d….

• Corticosteroids • Opiates
• Didanosine • Pentamidine
• Estrogens • Sulfonamides
• Ethacrynic acid • Tetracycline
• Ethanol • Thiazides
• Furosemide
• Metronidazole
 Physical Examination
• A comprehensive evaluation of the patient
should be performed
General examination
• Skin turgor (dehydration)
• Skin and sclerae …pallor, jaundice and any
rash.
• Lymphadenopathy … node in the root of the
neck, may indicate gastric cancer.
 Physical Examination
• A careful examination of the abdomen
– Includes inspection, auscultation, percussion,
and palpation in this order
• Inspection:
– may reveal scars, hernias, bulges, or peristalsis
• Auscultation
– mainly focused on analysis of bowel sounds
and identification of bruits
– should be performed prior to percussion and/or
palpation
 Physical Examination

• Percussion of the abdomen

– allows for detection of tympany, measurement of
visceral organ size, and detection of ascites
• Palpation
– allow the clinician to identify tenderness, rigidity,
masses, and hernias
• Digital rectal examination
– used to detect rectal masses and tenderness, and to
assess muscle tone
– Stool on the examiner's glove obtained subjected to
testing for detection of occult blood
Laboratory and Microbiologic Tests
• Used to
– assess organ function
– screen for certain GI disorders
– evaluate the effectiveness of therapy
• Should be viewed largely as supportive to an
accurate history and physical examination
– e.g. CBC, A serum chemistry panel
• More specific lab blood tests can be done
• Microbiologic and related studies are useful in
evaluating patients
– Stool examination
Laboratory and Microbiologic Tests
Stool examination
• Volume, consistency, colour and the
presence of fat …..indicating malabsorption
• Microscope ….parasites, ova or cysts and
leucocytes or pus cells, which occur in
dysentery or intestinal inflammation
Laboratory and Microbiologic Tests
Blood Examination
• Blood count: RBC, platelet and white cell count and
red cell indices, levels of iron, ferritin, vitamin B12
and folic acid…..may be abnormal in malabsorption,
inflammatory bowel disease, liver disease, PUD,
intestinal cancer

• Clotting tests: prolonged PT may indicate synthetic

liver failure or vitamin K deficiency
Laboratory and Microbiologic Tests
Liver chemistry:
• Increased Alanine and aspartate transaminase
level …liver cell damage and ….increased alkaline
phosphatase (ALP) and ɣ-glutamyl transferase (ɣ
GT) ….biliary tract disease
• Inflammatory markers: Increased levels of C-
reactive protein (CRP) and a raised erythrocyte
sedimentation rate (ESR) may indicate inflammatory
bowel disease (IBD), acute pancreatitis or infection.
• Amylase and lipase levels: Acute pancreatitis
causes massively raised amylase or lipase levels
Diagnostic studies and procedures

• Radiology
– Radiologic procedures rely on differential
absorption of radiation of adjacent tissues to
highlight anatomy and pathology
• Two divisions
– Non-computer assisted radiologic
procedures
– Computer assisted radiologic procedures
Non-computer assisted radiologic procedures

 Upper GI Series Radiography

– Refers to the radiographic visualization of the
esophagus, stomach, and small intestine
– Instruct pts to refrain from eating or drinking 8 to
12 hours prior to testing, which allows the upper
GI tract to empty
– contrast agent(Barium sulfate and/or gastrograffin)
is administered to the patient at the beginning of
the study
– commonly uncovers gastric cancer, peptic ulcer
disease, esophagitis, gastric outlet obstruction,
and can be suggestive of Crohn's disease
Non-computer assisted radiologic procedures
 Lower GI Series Radiography
– used to examine the colon and rectum and is particularly
useful if a colonic obstruction is suspected
– Pts complaining of lower abdominal pain, constipation,
or diarrhea are often referred for a lower GI series, also
called a barium enema
– Patient preparation
• Instruct pts to refrain from eating or drinking 8 to 12 hours prior
to testing
• administering bowel-cleansing agents such as bisacodyl,
magnesium citrate, magnesium hydroxide, or polyethylene
glycol electrolyte (PEG) solution.
– detect and evaluate enterocolitis, obstructions,
volvulus, and mucosal and structural lesions
 Computer assisted radiologic procedures

• Imaging Studies
– Frequently used imaging procedures for evaluating
digestive disorders
• Transabdominal ultrasonography
• Computed tomography
• Radionuclide scanning
• Magnetic resonance imaging
• GI tract endoscopy
– used to examine the interior of a hollow viscus or
canal
Gastrointestinal Disorders
Pharmacotherapy

II. Gastroesophageal Reflux

Disease(GERD)
 Case Studies
• A 53-year-old man, who is otherwise healthy and
has a 20-year history of occasional heartburn,
reports having had worsening heartburn for the
past 12 months, with daily symptoms that disturb
his sleep
• He reports having had no dysphagia, GI bleeding,
or weight loss and in fact has recently gained 20
lb (9 kg)
• What would you advise regarding his evaluation
and treatment?
 GERD: Introduction
• Definition of GERD:
– A condition that occurs when the refluxed
stomach contents lead to troublesome
symptoms and/or complications
– Esophageal Vs Extraesophageal
 GERD: Introduction
• Esophageal GERD syndromes classified as
– symptom-based or tissue injury based
• Extraesophageal reflux syndromes
– GERD symptoms associated with disease processes
in organs other than the esophagus
– Patients with extraesophageal reflux syndromes may
present with reflux chest pain syndrome, laryngitis, or
asthma(Atypical symptoms)
 Epidemiology
• GERD occurs in people of all ages
– Most common in those older than age 40 years
• No major difference b/n men and women
except during pregnancy
• Prevalence depends on geographic region
• Important risk factors and co morbid conditions
– Family history, obesity, smoking, alcohol
consumption, certain medications and foods,
respiratory diseases
 Pathophysiology
• Key factor in the development of GERD is
– abnormal reflux of gastric contents from the stomach
into the esophagus
• Gastroesophageal reflux is associated with
– defective lower esophageal sphincter (LES) pressure
or function
• Aggressive factors that damage esophagus
up on reflux:
– gastric acid, pepsin, bile acids, and pancreatic
enzymes
 Complications
• Esophagitis
• Esophageal strictures
• Barrett esophagus
• Esophageal adenocarcinoma
• Esophageal bleeding
– Use of NSAIDs drugs or Aspirin is an additional risk
factor worsening of GERD complications
 Clinical Presentation
• Symptom-based esophageal GERD syndromes
(with or without esophageal tissue injury)
– Typical symptoms
• Heartburn
• Water brash (hypersalivation)
• Belching
• Regurgitation
– Alarm symptoms (may be indicative of complications)
– Dysphagia , Odynophagia
 Clinical Presentation
• Tissue injury–based esophageal GERD
syndromes (with or without esophageal
symptoms)
– Symptoms (May present with alarm symptoms such
as dysphagia, odynophagia or unexplained weight
loss.)
• Esophagitis
• Strictures
• Barrett esophagus
• Esophageal adenocarcinoma
 Clinical Presentation
• Extraesophageal GERD syndromes
– Symptoms (These symptoms have an association
with GERD, but causality should only be considered if
a concomitant esophageal GERD syndrome is also
present.)
• Chronic cough
• Laryngitis
• Asthma
• Dental enamel erosion
 Diagnostic tests for GERD
• Clinical history
• Barium radiography
• Endoscopy
• Ambulatory pH monitoring
– Identifies patients with excessive esophageal acid
exposure and helps determine if symptoms are acid
related.
• Empiric trial of a proton pump inhibitor as a
diagnostic test for GERD
 Treatment
• Desired Outcomes
– alleviate or eliminate the patient's symptoms
– decrease the frequency or recurrence and duration of
gastroesophageal reflux
– promote healing of the injured mucosa, and
– prevent the development of complications
• Therapy is directed at :
– augmenting defense mechanisms that prevent reflux
and/or
– decrease the aggressive factors that worsen reflux or
mucosal damage
 Therapeutic interventions in the mgt of
GERD disease

Pharmacologic interventions are

targeted at improving defense
mechanisms or decreasing aggressive
factors (LES, lower esophageal
sphincter).
 Two approach: Pharmacotherapy

• Step up approach:
– Starting with noninvasive lifestyle modifications and
patient-directed therapy and progressing to
pharmacologic management or anti-reflux surgery
• Step-down approach,
– starting with a proton pump inhibitor given once or twice
daily instead of an H2-receptor antagonist
– and then stepping down to the lowest dose of acid
suppression (either an H2-receptor antagonist or proton
pump inhibitor) needed to control symptoms
• Neither step up or down approach is superior
 Evidence-Based Treatment
Recommendations for GERD
• Lifestyle modifications
• Patient-directed therapy
– Nonprescription antacids, H2-receptor antagonists, and PPIs (2 weeks
limit if no response) for mild, infrequent heartburn/regur
• Acid-suppression therapy
– The preferred treatment for GERD
– PPIs provide more rapid relief of symptoms and are more effective at
healing the esophageal mucosa compared to H2RAs in patients with
moderate to severe GERD
• Promotility therapy (not as monotherapy)
• Maintenance therapy
– Most need continuous therapy to control sx and complications
• Antireflux surgery
Fig: Algorithm for Management of gastroesophageal reflux disease.
H2RA, H2-receptor antagonist; PPI, proton pump inhibitor.
Therapeutic Approach to GERD in Adults
• Intermittent, mild heartburn
– Lifestyle modifications plus
– patient-directed therapy
• Antacids: Maalox 30 mL as needed or after meals
and at bedtime and/or
• Nonprescription H2-receptor antagonists (taken up
to twice daily): Cimetidine 200 mg or
• Nonprescription proton pump inhibitor (taken once
daily): Omeprazole 20 mg
• If symptoms are unrelieved with lifestyle
modifications and nonprescription medications after
2 weeks, patient should seek medical attention.
 Therapeutic Approach to GERD in Adults

• Symptomatic relief of GERD

– Lifestyle modifications plus
– Prescription-strength acid-suppression therapy
• H2RA (for 6–12 weeks): Cimetidine 400 mg twice
daily or
• PPI(for 4–8 weeks): Omeprazole 20 mg once daily
• Treat with maintenance dose if sx recurs, std dose of
PPI or H2RA
• Mild GERD can usually be treated effectively with
H2RA
• Patients with moderate to severe symptoms should
receive a PPI as initial therapy
 Therapeutic Approach to GERD in Adults
• Healing of erosive esophagitis or treatment of
patients presenting with moderate to severe
symptoms or complications
– Lifestyle modifications Plus
– PPIs for 4–16 weeks (up to twice daily) Omeprazole 20
mg daily or
– High-dose H2RA(for 8–12 weeks): Cimetidine 400 mg
four times daily or 800 mg twice daily
– For atypical or alarm symptoms, obtain endoscopy
– Give a trial of a PPI. If symptoms are relieved, consider
MT(maintenace therapy)
– PPIs are the most effective MT for patients with atypical
symptoms, complications, and erosive disease
Therapeutic Approach to GERD in Adults
• Interventional therapies
– Antireflux surgery
• a viable maintenance alternative for select patients with
well-documented GERD.
– Endoscopic therapies
• Patients not responding to pharmacologic
therapy, including those with persistent atypical
symptoms, should be evaluated to confirm the
diagnosis of GERD
Gastrointestinal Disorders
Pharmacotherapy

III. PEPTIC ULCER DISEASE

(PUD)
 Learning Objectives
 Recognize differences between ulcers induced by Helicobacter
pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), and stress-
related mucosal damage (SRMD) in terms of risk factors,
pathogenesis, signs and symptoms, clinical course, and prognosis.
 Identify desired therapeutic outcomes for patients with H. pylori–
associated ulcers and NSAIDinduced ulcers.
 Identify factors that guide selection of an H. pylori eradication
regimen and improve adherence with these regimens.
 Determine the appropriate management for a patient taking a
nonselective NSAID who is at high risk for ulcer-related GI
complications (e.g., GI bleed) or who develops an ulcer.
 Devise an algorithm for the evaluation and treatment of a patient
with signs and symptoms suggestive of an H. pylori–associated or
NSAID-induced ulcer.
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 Case Study
 A 29 year old man presents with intermittent epigastric
discomfort, without weight loss or evidence of GI-
bleeding. He reports no use of aspirin or NSAIDs.
Abdominal examination reveals epigastric tenderness.
A serologic test for Helicobacter pylori is positive, and
he receives a 10-day course of triple therapy
(omeprazole, amoxicillin, and clarithromycin. Six
weeks later, he returns with the same symptoms.
 How should his case be further evaluated and
managed?

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 Peptic Ulcer Diseases
 PUD refers to a defect in the gastric or duodenal
mucosal wall that extends through the muscularis
mucosa into the deeper layers of the submucosa.
 Duodenal Ulcer(DU):
 Most common form of peptic ulcer
 Located in the proximal duodenum
 Incidence, death rates, need for surgery, and physician
visits have decreased by 50% over the past 30 years.
 Due to Eradication of H. pylori
 Unlike to GU Malignant DUs are extremely rare

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Peptic Ulcer Diseases…..
 Gastric Ulcer(GU)
 Less common than DU in absence of NSAIDs
 Found distal to the junction b/n the antrum and the
acid secretory mucosa
 Occur later in life (peak incidence 6th decade)
 Silent ……… presenting only after a complication
 More than half occur in males
 PUD can also occur in the
 Esophagus, secondery to GERD
 Small bowel adjacent to gastroenteric anastomoses

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 Epidemiology
 In the USA, PUD affects approximately 4.5 million
people annually with lifetime prevalence estimated
to be 11% to 14% in men and 8% to 11% in women.

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 Etiology
Multifactorial
Two most common causes of PUD are:
 Helicobacterpylori infection ( 70-80%)
 Non-steroidal anti-inflammatory drugs (NSAIDS)

 Others
 Stressful situations
 Smoking cigarettes
 Alcohol
 Genetic predisposition
 Zollinger-Ellison syndrome
 Medications: Corticosteroids, bisphosphonates, KCl,
chemotherapeutic agents
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 Effects of H. pylori on gastric Hormones

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Mechanisms by which NSAIDs may induce mucosal
injury

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 Etiology: Others
 Stress-Related Mucosal Damage
 Physiologically stressful situations that lead to SRMD include
sepsis, organ failure, prolonged mechanicalventilation,
thermal injury, trauma, and surgery
 Zollinger–Ellison Syndrome
 A gastrin-secreting tumor or gastrinoma (Zollinger-Ellison
syndrome) accounts for <1% of all PUs from uncontrolled
acid production
 Cigarette smoking is associated with a higher
prevalence of ulcers in patients infected with H. pylori;
however, it does not seem to increase the risk of
recurrence once H. pylori has been eradicated
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 Etiology: Others
 Dietary factors such as coffee, tea, cola, alcohol, and a
spicy diet may cause dyspepsia but have not been shown
independently to increase PUD risk.
 Medications: Corticosteroids, bisphosphonates, KCl,
chemotherapeutic agents, etc

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 Comparison of Common Forms of
PUD
Characteristic H. pylori Induced NSAID Induced SRMD

Condition Chronic Chronic Acute

Site of damage Duodenum > Stomach > duodenum Stomach >
stomach duodenum
Intragastric pH More dependent Less dependent Less dependent
Symptoms Usually epigastric Often asymptomatic Asymptomatic
pain
Ulcer depth Superficial Deep Most superficial

GI bleeding Less severe, single More severe, single More severe,

vessel vessel superficial mucosal
capillaries

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 PUD: Pathophysiology
 PU develop as a result of imbalance between:
Aggressive/Injurious factors e.g., gastric acid,
pepsin, bile salts, pancreatic enzymes and
 Defensive factors maintaining mucosal integrity
e.g., mucus, bicarbonate, blood flow,
prostaglandins, growth factors, cell turnover

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Figure 2. Balance between injurious and protective factors in peptic ulceration. Injurious factors
(on left-hand side) guide investigations; protective factors (on lower right-hand side) indicate
possible
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 Diagnosis of PUD
Diagnosis of ulcer
 either by upper GI radiography or upper endoscopy
Diagnosis of H. Pylori
 Non-invasive
 C13 or C14 Urea Breath Test- best test for detection of active
infection
 Stool antigen test, H. pylori IgG titer (serology)
 Invasive M icros oft
PowerPoint Pres entation

 Biopsy and Rapid Urease test

 It should be ensured that patients undergoing a breath test, stool antigen test,
or endoscopy are free from medication with PPIs or H2RAs for a minimum
of 2 weeks and antibiotics for 4 weeks prior to testing

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 Testing to Document H. Pylori Eradication
 Should be confirmed after end of therapy;
noninvasive testing with UBT is preferred, 4-8 weeks
after completion of therapy
 If ulcer recurs after eradication therapy, a more careful
search for reinfection or eradication failure should be
carried out by testing for presence of active infection
(e.g. by histologic examination & culture, together
with antibiotic-sensitivity test)

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 PUD Treatment: Goal
 Rapid relief of symptoms
 Healing of ulcer
 Preventing ulcer recurrences
 Reducing ulcer-related complications
 Reduce the morbidity and mortality

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 PUD Treatment: General Strategy
 Treat complications aggressively if present
 Determine the etiology of ulcer
 Discontinue NSAID use if possible
 Eradicate H. pylori infection if present or strongly
suspected, even if other risk factors (e.g., NSAID
use) are also present;
 Use antisecretory therapy to heal the ulcer if H.
pylori infection is not present

 Approach to the patient presenting with ulcer-like

70 symptoms. Next slide 06/21/2022
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 PUD Treatment: General Measures
 Lifestyle advice (e.g. diet, smoking, drinking)
 Alcohol, strong coffee or tea taken with moderation
 Late snacks are best avoided, b/c stimulate nocturnal
gastric secretion.
 Inform Pts to avoid foods that provoke or aggravate
Sxs
 Strongly discourage smoking and alcohol
 Warn pts against taking any medication : aspirin &
NSAIDs
 Anxiety and stress should be reduced if possible

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 PUD Treatment: Pharmacotherapy
 H2-Receptors antagonists
 Proton pump inhibitors
 Cyto-protective agents
 Prostaglandin agonists
 Antacids
 Antimicrobials for H. pylori eradication
 Such as clarithromycin, metronidazole, amoxicillin

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 Therapy of H. pylori Eradication
 Recommended for HP-infected patients with GU, DU, ulcer-
related complications
 First-line eradication therapy
a) PPI–based, three-drug regimen containing two antibiotics
 Usually clarithromycin and amoxicillin
 Reserving metronidazole for back-up therapy (e.g.,
clarithromycin–metronidazole in penicillin-allergic patients)
 PPI should be taken 30 to 60 minutes before a meal along with
the two antibiotics.
 Although treatment is minimally effective if used for 7 days, 10–
14 days of treatment is recommended
 Antisecretory drug may be continued beyond antimicrobial treatment in
patients with a history of complicated ulcer (e.g., bleeding or in heavy
smokers)
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 Therapy of H. pylori Eradication
b) Quadruple therapy using a PPI (with bismuth,
metronidazole, and tetracycline)
 achieves similar eradication rates as PPI based triple
therapy and permits a shorter treatment duration (7 days)
 However, this regimen is often recommended as second-
line treatment when a clarithromycin–amoxicillin regimen
is used initially.
 All medications except the PPI should be taken with
meals and at bedtime.

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Therapy of H. pylori Eradication
 Ifthe initial treatment fails to eradicate HP, second-line
empiric treatment should:
 use antibiotics that were not included in the initial regimen
 include antibiotics that do not have resistance problems
 use a drug that has a topical effect (e.g., bismuth)
 be extended to 14 days
 Thus, if a PPI–amoxicillin–clarithromycin regimen fails, therapy
should be instituted with a PPI, bismuth subsalicylate, metronidazole,
and TTC for 14 days
 Maintenance therapy with a PPI or H2RA is recommended for
high-risk pts with
 ulcer complications, pts who fail HP eradication, and those
with HP-negative ulcers.
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 Treatment of NSAID-induced ulcers
 Nonselective NSAIDs should be discontinued (when
possible) if an active ulcer is confirmed
 Most uncomplicated NSAID-induced ulcers heal with
standard regimens of an H2RA, PPI, or sucralfate if
the NSAID is discontinued
 If the NSAID must be continued, consideration should
be given to reducing the NSAID dose or switching to
acetaminophen, or a selective COX-2 inhibitor
 PPIs are the drugs of choice when NSAIDs must be
continued because potent acid suppression is required
to accelerate ulcer healing.
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 Treatment of NSAID-induced ulcers
 IfHP is present, treatment should be initiated with an
eradication regimen that contains a PPI.
 Patients at risk of developing serious ulcer-related
complications while on NSAIDs should receive
 prophylactic cotherapy with misoprostol or a PPI.
 Patients with ulcers refractory to treatment should undergo
upper endoscopy to confirm a nonhealing ulcer, exclude
malignancy, and assess HP status
 HP-positive patients should receive eradication therapy.
 In HP negative pts, higher PPI doses (e.g., omeprazole 40
mg/day) heal the majority of ulcers.
 Continuous PPI treatment is often necessary to maintain
healing.
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Prevention of Stress-Related Mucosal Damage
 Prevention of stress ulcers involves maintaining
hemodynamic stability to maximize mesenteric
perfusion and pharmacologic suppression of gastric
acid production.
 SUP is only indicated in intensive care unit (ICU)
patients with certain risk factors
 Indications for stress ulcer prophylaxis include
 Major trauma, major surgery, severe head trauma,
multiple organ failure, burns covering more than 25%
to 30% of body, severe sepsis, shock, mechanical
ventilation, coagulopathy, and high-dose steroid use
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 Long-Term Maintenance of Ulcer Healing
 Low-dose maintenance therapy with a PPI or H2RA
is only indicated in
 patients with severe complications secondary to PUD
such as gastric outlet obstruction or
 patients who need to be on long-term NSAIDs or high-
dose corticosteroids and are at high risk for bleeding.

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 Treatment of GI Bleeding
 The immediate priorities in treating patients with a
bleeding peptic ulcer are to achieve IV access, correct
fluid losses, and restore hemodynamic stability.
 Patients should be started on IV PPI therapy because
optimal platelet aggregation, partially inhibited
fibrinolysis, and better clot stabilization on the ulcer are
achieved when the gastric pH is greater than 6.
 IV PPI therapy should be continued for 72 hours because
most rebleeding occurs during this time followed by oral
PPI.
 Three-day PPI infusion therapy has been shown to be as
effective as twicedaily IV PPI therapy
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 Treatment of Refractory Ulcers
 Refractory ulcers are defined as ulcers that fail to heal
despite 8 to 12 weeks of acid suppressive therapy
 The presence of refractory ulcers requires a thorough
assessment, including
 evaluation of medication adherence,
 extensive counseling and questioning regarding recent over-
thecounter and prescription medication use, and
 testing for H. pylori using a different method than previously
done if testing was negative.

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 Treatment of Refractory Ulcers
 Treatment strategies
 Changing from H2RA therapy to a PPI should be considered
 esophagogastroduodenoscopy (EGD) with biopsy of the ulcer
to exclude malignancy
 H. pylori testing (if not done initially)
 serum gastrin measurement to exclude ZES, and gastric acid
studies
 Increasing the starting dose of PPI therapy may heal up to 90%
of refractory ulcers after 8 weeks of therapy

87 06/21/2022
 Evaluation of Therapeutic Outcomes
 Monitor pts for efficacy and safety of therapy
 Ulcer pain typically resolves in a few days when NSAIDs are
discontinued and within 7 days upon initiation of antiulcer
therapy.
 The persistence or recurrence of symptoms within 14 days after
the end of treatment suggests failure of ulcer healing or HP
eradication, or an alternative Dx such as GERD.
 High-risk pts on NSAIDs should be closely monitored for signs
and symptoms of bleeding, obstruction, penetration, and
perforation
 Follow-up endoscopy in pts with
 frequent symptomatic recurrence, refractory disease,
complications, or suspected hypersecretory states
88 06/21/2022
Gastrointestinal Disorders
Pharmacotherapy

IV. Viral Hepatitis

 Patient case
C.R., a 28-year-old man, presents to the ED with jaundice,
complaints of fatigue, and vague intermittent abdominal
pain for the past month. C.R. was diagnosed with hepatitis
B 2 years before admission. His social history includes IV
drug abuse and alcohol abuse (none for 2 years). Several
weeks ago, C.R. noted darkening of his urine and
yellowing of his eyes.

90
 Patient case…
Physical examination reveals a thin man in no apparent
distress. He is afebrile, and his BP, HR, and RR are
within normal limits. Moderate scleral icterus is noted.
The abdomen is soft and non-distended. The liver is
enlarged, and smooth with an edge palpable 5 cm below
the costal margin

The spleen is palpable. The cardiac, pulmonary,

neurologic, and extremity examinations all are within
normal limits.
91
 Patient case…
Lab test
PT, 15.4 sec , INR, 1.8; AST, 326 U/L ; ALT, 382 U/L ;
alkaline phosphatase, 142 U/mL ; total bilirubin, 4.2 mg/dL ;
and albumin, 2.8 g/dL .
Hepatitis serologic tests are positive for HBsAg, HBeAg, and
anti-HBc and negative for IgM, anti-HBc, IgM anti-HAV, and
anti-HCV.
1. What clinical findings does C.R. have that support the
diagnosis of chronic hepatitis B infection?
2. Does C.R. require treatment for chronic hepatitis secondary
to hepatitis B?
92
 Cause of Hepatitis
Hepatitis: inflammation of liver; presence of
inflammatory cells in organ tissue
Different causes
infectious (i.e, viral, bacterial, fungal, and parasitic organisms)
noninfectious (e.g, alcohol, drugs, autoimmune diseases)
A viral hepatitis is a inflammation of the liver due to
viral infection called hepatitis virus
There are five main types of viral hepatitis: A, B, C, D, E

93
 Acute and Chronic Hepatitis

Viral hepatitis can present as either an acute or chronic

illness.
Acute hepatitis is an illness with a discrete date of
onset with jaundice or increased serum
aminotransferase concentrations >2.5 times the upper
limit of normal.
Acute viral hepatitis infection is a systemic process and
lasts as long as, but not exceeding, 6 months.
Chronic hepatitis is an inflammatory condition of the
liver that involves ongoing hepatocellular necrosis for
94
6 months or more
 Hepatitis virus transmission
Hepatitis A and E are typically caused by ingestion of
contaminated food or water (feco-oral)…. shows
acute hepatitis
Hepatitis B, C and D are typically caused by contact
with contaminated blood or body fluids…..chronic
hepatitis (cirrhosis and hepatic cancer)

Viral hepatitis types B and C together, are the most

common cause of liver cirrhosis and cancer

95
 Epidemiology
An estimated 57% of liver cirrhosis and 78% of liver
cancer are due to hepatitis B virus (HBV and HCV
infection

About 150 million people are chronically infected with

HCV

Only 1 in 5 persons exposed to the hepatitis B and C

virus develops acute symptoms, but chronic infection
is common
96
 Pathogenesis
Both direct and indirect, immune mediated responses
instigated by the virus.
Direct cellular injury …..caused by the accumulation of
intact virus or viral proteins.
Host cellular and humoral immune responses are linked
to T lymphocytes, which enhance viral clearance from
hepatocytes and cause liver injury

host immune responses are more important than

virologic factors in the pathogenesis of liver injury.
97
 Diagnosis of hepatitis virus
Physical Exam
Low-grade fever
Significant vomiting and anorexia  tachycardia, dry
mucous membranes, loss of skin turgor

Icteric phase: icterus of the sclerae or mucous membranes

The skin may be jaundiced and may reveal urticarial
rashes.
Liver may be tender and diffusely enlarged with a firm,
sharp, smooth edge.
98
 Diagnosis…

Lab test
Elevation of serum transaminases not diagnostic, but
useful
ALT elevated more than AST
Acute Hepatitis: ALT > 1000
Chronic HCV: ALT is generally lower than 1000

Serum bilirubin: elevated…Bilirubin levels higher than

30 mg/dL indicate more severe disease.

99
 Serologic evaluation
Because the clinical manifestations and incubation
periods are similar among patients with hepatitis,
serologies are useful in diagnosing the type of viral
infection
Detecting specific;
antibodies against hepatitis A virus (anti-HAV),
hepatitis B surface antigen (HBsAg)
hepatitis C antibody (anti-HCV)
hepatitis B envelope antigen (HBeAg)
HBV-DNA
hepatitis D antibody (anti-HDV)

100
 Hepatitis A
Mild self-limited disease and confers lifelong immunity
to hepatitis A virus. Resolves with in 6 months
Transmission occurs primarily through the fecal–oral
route.
Highest attack rates in 5-14 year olds….children serve as
reservoir of infection
Symptoms and severity of HAV vary according to age.
Children younger than 6 years of age typically are
asymptomatic

101
Prevalence of infection is related to the
quality of the water supply, level of sanitation,
and age. 102
 Clinical manifestation
The host is usually asymptomatic during this stage of the
infection
Older children and adults have symptomatic disease with
jaundice occurring in >70% of cases.
Fatigue, weakness, anorexia, nausea, and vomiting.
Abdominal pain and hepatomegaly are common.
Less common symptoms include fever, headache, arthralgias,
myalgias, and diarrhea.
Within 1 to 2 wks patients may enter an icteric phase with
symptoms, including clay-colored stools, dark urine, scleral
icterus, and jaundice.
103
 Diagnosis: HAV
AST & ALT levels usually return to reference ranges over
5-20 weeks.
Serum Serology: presence of serum antigens and
immunoglobins

Anti-HAV IgM : positive at the time of onset of

symptoms; results remain positive for 3-6 months after the
primary infection
Anti-HAV IgG appears soon after IgM and generally
persists for many years….. indicative of previous exposure
and immunity to HAV
104
 Treatment and Prevention
Usually a self-limited disease that does not require a
specific therapy.
Patients should abstain from alcohol during the acute
phase of the disease

Potentially hepatotoxic medications should be avoided

during the acute phase of the illness
Prophylaxis can be administered before (pre-exposure
prophylaxis) or after exposure (post-exposure
prophylaxis

105
 Treatment and Prevention…
Immunoglobulin…passive immunization
• Pre-exposure(travelers to intermediate and high
HAV-endemic regions)….dose of 0.02 mL/kg of immunoglobulin
administered intramuscularly confers protection for <3 months,
and an IM dose of 0.06 mL/kg confers protection for 5 months.
• Could be used for post-exposure prophylaxis but not later than 2
wks…. 0.02 mL/kg IM dose as soon as possible.
Vaccine
Formulations of inactivated hepatitis A vaccine available
(Havrix and Vaqta)
Programs have targeted children as the most effective
means to control HAV.
106
 Hepatitis B
Approximately 5% of the world’s population is infected
with HBV.

It can occur in the form of chronic persistent hepatitis

asymptomatic or chronic active hepatitis – symptomatic
exacerbations of hepatitis
Causes Cirrhosis of Liver and Hepatocellular Carcinoma

107
108
 Concentration of Hepatitis B Virus in Various
Body Fluids

Low/Not
High Moderate Detectable

blood semen urine

serum vaginal fluid feces
wound exudates saliva sweat
tears
breastmilk

109
 Hepatitis B Virus : Modes of Transmission
 Sexual: Sex workers and homosexuals are particular at
risk.
 Parenteral: IVDA, health workers are at increased risk.

 Perinatal - Mothers who are HBeAg positive are much

more likely to transmit to their offspring than those who
are not.

110
 Clinical Manifestations
The clinical features of acute HBV infection are similar
to those described for HAV infection….nausea, vomiting,
anorexia, scleral icterus, and jaundice.
Extrahepatic manifestations, such as arthralgias, rash,
edema
Complication
most significant complication of acute HBV infection is acute
liver failure (onset of hepatic encephalopathy within 8 wks of
the onset of symptoms)

111
 Serology evaluation of HBV
I) HBsAg-- anti-HBs system
coating HBV
found in patients with acute or chronic HBV
infection and chronic carriers.
Detectable 1 to 2 weeks after infection…. Persist
for 1 to 6 wks in acute hepatitis
HBsAg can be found in : salive, urine, semina,
tears, sweat and breast milk
HBsAb - used to document recovery and/or
immunity to HBV infection.

112
 Serology evaluation of HBV…

II) HBeAg
Appears shortly after HBsAg
Secreted product of the nucleocapsid core of HBV
Indicates viral replication and infectivity
Anti-HBe is a marker of reduced infectivity

113
 Serology evaluation of HBV…

III) HBcAg—anti-HBc system

HBcAg can be found in the nuclei of liver cells, no free
HBcAg in serum
HBcAg is the marker of replication of HBV
Anti-HBc IgM is a marker of acute infection and acute
attack of chronic infection of HBV.
Anti-HBc IgG is the marker of past infection

114
 Progression

Acute HBV Infection:  90% resolve by themselves; less

than 1% develop fulminant hepatic failure

Chronic HBV Infection: 2-10% progress to chronic

state
90% in children under five progress to chronic state
5% to 10% of people progress to HCC

115
 Treatment
Progression of chronic hepatitis to cirrhosis is thought
to be related to continued replication of the hepatitis B
virus.

Seroconversion from HBeAg-positive to HBeAg-

negative (with appearance of antiHBe), reductions in
serum aminotransferase activity, elimination of
circulating HBV DNA
The most effective agents for treating chronic hepatitis
B have been interferons
116
 Treatment ….
Interferon
Method of action is the inhibition of viral replication of cells
thus assisting the immune system
Interferon alpha: SQ 5,000,000 U QD or 10, 000,000 U
3x weekly for 1 to 12 months.
Peg interferon available…180 mcg weekly
SQ

117
 Treatment ….
Adverse effects associated with standard and PegIFN-
a therapy are similar and quite common
Early side effects appear hours after administration
and resemble an influenza-like syndrome with fever,
chills, anorexia, nausea, myalgias, fatigue, and
headache.
Resolve after repeated exposure
Late side effects that may necessitate dose reduction
or discontinuation of therapy altogether.

118
 Treatment ….
In addition to IFN-a several antiviral agents for
treatment of chronic hepatitis B infection (lamivudine,
adefovir, entecavir, and telbivudine)

• Lamivudine –100 mg PO daily (anti HIV drug)

 a nucleoside analogue reverse transcriptase inhibitor.
 Well tolerated, most patients will respond favorably.
 However, tendency to relapse on cessation of
treatment, rapid emergence of drug resistance.
119
 Prevention…per-exposure
Vaccination
 The preferred vaccination schedule uses a three-
dose regimen. The first dose is followed 1 month
later by a second dose, and the third dose is
administered 6 months after the initial dose.
Recipients of blood products, household and
sexual contacts of HBV carriers, travelers to
HBV-endemic areas, injecting drug users, all
infants
Side effect is pain at the injection, Transient
febrile, nausea, rash, headache,myalgias, and
120 arthralgias
 Prevention…Post-exposure

Following exposure to HBV, prophylactic treatment

with hepatitis vaccination and passive immunization
with hepatitis B immunoglobulin (HBIG)
Percutaneous exposure: single dose of HBIG 0.06
mL/kg (3.4 mL) as an IM
Sexual contact: 0.06 mL/kg of HBIG as a single IM
dose within 14days of the last exposure
Infants born to mothers who are HBsAg positive
IM hepatitis B vaccine and HBIG (0.5 mL) within 12
hours of birth.
121
 Hepatitis C
HCV causes both acute and chronic infection. Acute HCV
infection is usually asymptomatic, and is only very rarely
associated with life-threatening disease.
About 15–45% of infected persons spontaneously clear the
virus within 6 months of infection without any treatment.

The remaining 55–85% of persons will develop chronic HCV

infection…..Of those with chronic HCV infection, the risk of
cirrhosis of the liver is between 15–30% within 20 years

122
 Highest incidence is among persons aged 20 to 39
years with a male predominance

HBV and HCV coinfection is common, results in more

severe liver disease than infection with either virus
alone, including increased risk of liver cancer

123
 Transmission
Percutaneous Transmission
Blood transfusion (5-10%)
Injection drug users (48-90%)

Non-percutaneous transmission …transmission

between sexual partners and from mother to child…..
Less contagious

124
 Clinical Manifestations

Most patients with acute HCV infection are

asymptomatic.

Patients with chronic HCV infection generally

complain of fatigue.

Nonspecific symptoms are similar to those seen with

HBV infection, including nausea, anorexia, abdominal
discomfort, and depression.

125
 Diagnosis: HCV
Serum detection of Anti-HCV; cannot distinguish acute
from chronic infection
Antibodies against core protein and nonstructural
proteins; may appear 3 – 5 months after infection

Confirmed by qualitative HCV RNA (PCR) assay with a

lower limit of detection of 50 IU/mL

126
 Treatment
Acute infection: if early identification is possible,
interferon therapy is rational.
Chronic active hepatitis.. Combination Peg interferon
and oral daily dose of ribavirin.
Peginterferon alfa-2a.. 180 mcg SQ per week.
Ribavirin is given in divided daily doses (twice per day):
the Ribavirin dose is 1000 mg for patients who weigh
≤75 kg or 1200 mg for those who weigh >75 kg.
Treatment with peginterferon plus ribavirin should be
administered for 24 weeks in patients
127
 Prevention
Pre-exposure Prophylaxis
No vaccines are effective against HCV

Post-exposure Prophylaxis
Immunoglobulin is no longer recommended for post-exposure
prophylaxis of hepatitis C infection because it is not effective
 Others; Screening of blood, organ, tissue donors, High-risk
behavior modification

128
 Hepatitis D
Only as co-infection with acute HBV or with superinfection
in chronic HBV carrier
Requires outer envelope of HBsAg for replication and
transmission
Can progress to chronic disease
Incubation Period 30 to 150 days

Serology
Hepatitis D antibody  (Anti-HDV)
Ab not always present in acute infection---requires repeating the
testing
Risk Factors - Same high risk groups as those for HBV
TX: IFN-alpha
129
 Hepatitis E
Enterically transmitted infection; fecal-oral route,
typically self-limited
Most outbreaks occur in developing countries.

Symptoms of acute hepatitis

Incubation period of hepatitis E virus is 2-9 weeks
Case fatality rate is 4%

130
 Hepatitis E: diagnosis
Serum, liver, and stool samples can be tested for HEV
RNA
Anti-HEV antibodies: IgM (acute) and IgG (chronic)

AST & ALT are elevated several days before the onset
of symptoms; return to normal within 1-2 months after
the peak severity of disease.
Treatment: supportive

131
Gastrointestinal Disorders
Pharmacotherapy

V. Cirrhosis and Portal

Hypertension
 Portal Hypertension and Cirrhosis: Introduction

Definition : Cirrhosis, or end-stage liver disease,

defined as
a diffuse process characterized by fibrosis and a
conversion of the normal hepatic architecture into
structurally abnormal nodules
Results increased resistance to blood flow in portal
hypertension and the development of varices and
ascites
 Hepatocyte loss and intrahepatic shunting of blood
results in diminished metabolic and synthetic function,
which leads to hepatic encephalopathy (HE) and
133 coagulopathy
 Portal Hypertension and Cirrhosis:
Introduction
Clinical consequences of cirrhosis include
impaired hepatocyte function, increased intrahepatic
resistance of portal hypertension, and hepatocellular
carcinoma
Circulatory irregularities such as splanchnic
vasodilation, vasoconstriction and hypoperfusion of the
kidneys, water and salt retention, and increased cardiac
output

134
 Pathophysiology and Etiology
Cirrhosis results in
Elevation of portal blood
pressure because of
fibrotic changes within
the hepatic sinusoids
Changes in the levels of
vasodilatory and
Vasoconstrictor
mediators, and
An increase in blood flow
to the splanchnic
vasculature
 Cont’d… patho
Fatty liver or steatosis from ethanol:
the first stage of liver injury - is characterized by lipid
deposition in the hepatocytes
 Steatosis is followed by liver inflammation
(steatohepatitis), hepatocyte death, and collagen
deposition leading to fibrosis
The specific mechanisms: not clear but suggestions
ethanol-induced oxidative stress on the liver
 Consequences:
Cirrhosis and the pathophysiologic
abnormalities that cause it result in
Ascites
Portal Hypertension
Esophageal varices
Hepatic encephalopathy, and
Coagulation disorders
 Clinical Presentation: Sn and Sx
· Anorexia, nausea, abdominal discomfort, weight loss,
and malaise
· Ascites, peripheral edema, jaundice, palmar erythema
· Gynecomastia, testicle atrophy, amenorrhea, pubical
hair lost
· Hepatomegaly, spleenomegaly, encephalopathy, and
bleeding
 Laboratory Findings
Initially elevated ALT and AST level but at the end stage
they can be normal or below normal
Elevated bilrubin most of the time
Low albumin level
Prolong prothrombin time (PT) and APTT
Elevated serum creatinine and blood urea nitrogen (BUN)
An elevation of prothrombin time was the single most
reliable manifestation of cirrhosis.
The combination of thrombocytopenia,
encephalopathy, and ascites had the highest
predictive value.
 Treatment: Cirrhosis

Goal of therapy

The major goals of treating patients with

cirrhosis include:
Slowing or reversing the progression of liver disease
Preventing superimposed insults to the liver
Preventing and treating the complications
Determining the appropriateness and optimal timing
for liver transplantation
 Portal Hypertension
Portal pressure is a function of flow and resistance to
that flow across the hepatic vasculature
Normal portal pressure is below 6mmHg, and in
cirrhotic patients may increase to 7 to 9mmHg
Portal hypertension:
results from both an increase in resistance to portal
flow
increased intrahepatic resistance due on
intrahepatic vasoconstriction, sinusoidal
compression, and fibrosis
 and also an increase in portal venous inflow
Caused by splanchnic vasodilation
 Portal Hypertension and Varices

Portal pressure increases to 5 mmHg more than the

pressure in the inferior vena cava
Development of varices and alternative routes of
blood flow
Risk of varices when portal pressure exceed the vena
cava pressure by > 12 mmHg
Hemorrhage from varices occurs in 25-40% of
cirrhotic patients
Each episode of bleeding carries a 30% risk of death
How Varices form
Portal hypertension causes blood
flow to be forced backward,
causing veins to enlarge and
varices to develop across the
esophagus and stomach from the
pressure in the portal vein
The backup of pressure also
causes the spleen to become
enlarged
 Management of varices
Involves three strategies:
Primary prophylaxis (prevention of the first
bleeding episode);
Treatment of acute variceal hemorrhage; and
Secondary prophylaxis (prevention of rebleeding in
patients who have previously bled)
 Primary Prophylaxis

Nonselective Beta -Adrenergic Blockade(Propranolol or

nadolol)
The mainstay of primary prophylaxis
reduce portal pressure by reducing portal venous inflow
via two mechanisms:
a decrease in cardiac output through beta1-adrenergic
blockade and a decrease in splanchnic blood flow
through beta2-adrenergic blockade.
HR not less than 55 beats/min & SBP not less than 90 mm
Hg
Adverse effects in 27% of patients
should be continued for life unless it is not tolerated
 BB in Varices…cont’d
Only nonselective β-blockers :
have an adrenergic dilatory effect in mesenteric arterioles ----
decrease in portal blood circulation and pressure
Propanolol & Nadolol :
 start: Propranolol 20 mg BID or 10 mg three times a day or
nadolol 20 mg once daily
dose titration to a reduction in resting heart rate of 20% to 25%,
an absolute heart rate of 55 to 60 beats/min, or the development
of adverse effects.
Selective β-blockers (e.g., atenolol and metoprolol) have little
effect on mesenteric arterioles
have not been shown to be effective in primary prophylaxis
Isosorbide-5-mononitrate: mentioned; alone vs with BB????
 Cont’d primary Px
Treatment Recommendations: Variceal Bleeding—Primary
Prophylaxis
Prophylaxis therapy with a nonselective beta -adrenergic
blocker
pts with small varices (< 5 mm) who have not bled &
have no criteria for increased risk of bleeding ……
controversy, most agree
Pts with small varices plus risk factors
medium to large varices (varices > 5 mm} & have not
bled plus high risk factor
endoscopic variceal ligation can be used instead of
BB
But not for low risk factor, unless intolerant or CI to
 Acute Variceal Hemorrhage
 An emergency and feared cxn of cirrhosis
 Treatment goals include:
 Volume resuscitation, acute treatment of bleeding, and
prevention of recurrence of variceal bleeding
Replenishment of blood volume and correction of
coagulopathy must be done with packed erythrocytes (to
increase Hb concentration to 10 g/dL) and fresh frozen plasma
and platelets
Protection of airway from aspiration of blood
Antibiotics to prevent SBP and G-ve systemic infection
Control of bleeding
 Prevention of rebleeding, and preservation of liver function
 Drug therapy: Acute variceal Bleeding

Drug Therapy
Drugs employed to manage acute variceal bleeding
include:
The somatostatin analogue octreotide or vapreotide and
Vasopressin, terlipressin,
 Work as splanchnic vasoconstrictors, thus decreasing
portal blood flow and pressure
Endoscopic Therapy may be indicated
 Endoscopic variceal band ligation (EVL)
 Drug therapy: Acute variceal Bleeding [2]

Infection Prophylaxis—Short-Term Antibiotics

Norfloxacin 400 mg BID for 7 days Vs no treatment
controls: Norfloxacin group
had a significantly lower incidence of SBP
No significant difference was seen in mortality
Guidelines recommend: 7 days of antibiotic prophylaxis
for prevention of SBP in patients with variceal
hemorrhage with oral norfloxacin (400 mg BID) or
ciprofloxacin IV (400 mg BID) if P.O. no possible
Ceftriaxone IV (1 g/day) for 7 days : FQ resistance high
 Secondary Prophylaxis/Prevention of Rebleeding
Secondary Prophylaxis: Prevention of Rebleeding
Prevent a recurrence of bleeding if survived first
episode of bleeding
Combination therapy with beta-adrenergic blockers
and chronic EVL : best option
Combo : BB + ISDN : unable to undergo EVL
initiation of β-blockers be delayed until after
recovery of the initial variceal hemorrhage
Block the patient’s acute tachycardia if pt
hypotension
Initiate: pt has had no bleeding for at least 24 hours
and before the patient is discharged from the
 Ascites and Spontaneous Bacterial Peritonitis
 Ascites is the accumulation of
fluid within the peritoneal cavity
Most common complication of
cirrhosis
Spontaneous bacterial peritonitis
(SBP)
is an infection of preexisting
ascitic fluid without evidence for
an intra-abdominal secondary
source such as a perforated viscus
 SBP is almost always seen in the
setting of end-stage liver disease
 Ascites mgt
Goals of therapy
To mobilize ascitic fluid
To diminish abdominal discomfort, back pain, and
difficulty in ambulation
To prevent major complications
Non pharmacological management
Na+ and water restriction, therapuetic paracentesis
Pharmacological management
Diuretics
Combination of spironolactone and furosemide
 Approach to the patient with Ascites and SBP

156
 Diuretics Therapy: Ascites

Diuretics Therapy: Choice of agent

High level of circulating aldosterone
Decrease execration and increase production
 Activation of RAS
 hepatic impairment prolongs the half life of aldosterone
 Low concentration of albumin
Spironolactone is rational choice
Dose 100 mg to 200 mg up to 400 mg
Combination with other diuretics, Furosemide
Spironolactone to furosemide ratio (100 : 40 mg)
Can be increased every 3 to 5 days simultaneously keeping
ratio
 Ascite Rx cont’d…
 Monitoring: diuretic therapy
Triamterene and amiloride : alternative to spironolactone if
intolerable side effects
goal is a weight loss of 0.5 to 1 kg/day
net fluid volume loss of about 0.5 to 1 L/day
If presented with both edema and ascites : initial fluid loss of
up to 1 L/day would be reasonable
Diuresis > 0.5 to 1 kg/day (0.5–1 L) : associated with volume
depletion, hypotension, and compromised renal function
Monitoring fluid intake and urine output
urine output should exceed fluid intake by about 300 to
1,000 mL/day
 Diuretic Complications and Management

Initiate: with single morning doses of spironolactone 100

mg and furosemide 40 mg administered orally
 Titrate diuretic therapy every 3 to 5 days using the 100
mg:40 mg ratio to attain adequate natriuresis and weight
loss
reasonable daily weight loss goal is 0.5 kg
Maximum daily doses are 400 mg spironolactone and
160 mg furosemide….. maintains normokalemia
D/C diuretic: experience uncontrolled or recurrent
encephalopathy, severe hyponatremia, renal insufficiency
 Cxn…cont’d..
Electrolyte And Acid-base Disturbances
Hyponatremia, hyperkalemia, metabolic alkalosis
Hyponatremia : temporary withdrawal of diuretics
and free water restriction
Hyperkalemia [in refractory ascites and impaired
renal function requiring high doses of
spironolactone]
Decreasing or holding spironolactone depending
on renal function and serum potassium
Metabolic alkalosis [hypokalemia] : Furosemide can
be temporarily withheld
Prerenal azotemia [over diuresis]: Gradual diuresis
 Drug therapy: SBP
 SBP
>92% of all cases of SBP are monomicrobial, with Escheria
coli (the most common isolate),Klebsiella species, Other G-ve
bacteria
G+ve organisms, Streptococcal (25%)
Anaerobic infection (rare <5%)
 Consider antibiotic coverage for these condition
Third-generation cephalosporin : DOC for SBP
 Prophylaxis against SBP
 Short-term antibiotic prophylaxis should be used for 7 days to
prevent SBP in cirrhosis patients with gastrointestinal
hemorrhage
Patients who survive an episode of SBP should receive long-
term prophylaxis with either daily norfloxacin or trimethoprim-
 SBP: Px…..cont’d..

Indications of Prophylaxis of Spontaneous Bacterial

Peritonitis
 Hepatic Encephalopathy (HE)

 Hepatic encephalopathy is a neuropsychiatry syndrome caused by

liver disease
 The principles of mgt are
To treat or remove precipitating causes
To reduce or eliminate protein intake and
To suppress production of neurotoxins by bacteria in the
bowel
The mainstay of therapy of HE involves measures to lower
blood ammonia concentrations and includes diet therapy,
lactulose, and antibiotics alone or in combination with lactulose
Lactulose (15-30 ml 8-hourly) administration lowers ammonia
levels in the blood in several ways
 HE… cont’d…
Lactulose lowers ammonia levels in the blood
creation of a laxative effect
reduces the time period available for ammonia
absorption
leaching of ammonia from the circulation into the
colon
 increasing bacterial uptake of ammonia by colonic
bacteria
reducing ammonia production by the small intestine
By interfering directly with the uptake of glutamine
by the intestinal wall and its subsequent metabolism
to ammonia
 HE… Rx…cont’d…
Metronidazole or Neomycin : inhibiting the activity of urease-
producing bacteria
decrease production of ammonia
Metronidazole initiated at 250 mg twice daily but titrated up to
four times daily
should not be considered first-line therapy
Indicated: who have not responded to diet and lactulose
therapy & if deemed necessary for improved outcome
Rifaximin 400 mg three times daily provides similar
effectiveness with less risk
Zinc replacement: decreasing ammonia levels and improving
symptoms of HE
 Evaluation of Therapeutic Outcomes

Monitoring Parameter
Ascites
 Daily assessment of weight
Spontaneous bacterial peritonitis
 Evidence of clinical deterioration (e.g., abdominal pain, fever,
anorexia, malaise, fatigue)
Variceal bleeding
 Child-Pugh score, endoscopy, CBC, evidence of overt bleeding
Hepatic encephalopathy
 Grade of encephalopathy, EEG, psychological testing, mental status
changes, concurrent drug therapy
Gastrointestinal Disorders
Pharmacotherapy

VI. Pancreatitis
Pancreatitis
 Patient case #1
A 49-year-old man was admitted with a nine-month
history of intermittent attacks of epigastric pain, jaundice
and fever. These attacks usually last up to several days
associated with nausea and vomiting. He was well in
between attacks and had no loss of weight
What is likely diagnosis for this patients?

169
 s

Ampulla
of Vater

Function of the pancreas is to release digestive enzymes

170 and insulin and glucagon .
 The Pancreas

Body –Forms
shell for stomach
to rest upon.

171
 Definition
Pancreatitis is an inflammation of the pancreas
Two forms:
Acute pancreatitis
Sudden…...mild to sever
often non-reoccurring …..90% self-limiting and
resolves in a wk
Do not progress to chronic form

Chronic Pancreatitis
ongoing occurrence of inflammation
marked by ON and OFF abdominal pain
172
 Epidemiology
300,000 case annually in US
10-20% are severe
Biliary and alcoholic cases account 90% ….biliary
pancreatitis being the most prevalent type.
Incidence among AIDS patients 4-22%
Incidence ……..increase w/ age.
Onset in the first decade suggests ….a hereditary cause,
infection (e.g., mumps), or trauma.

173
 Etiology - I GET SMASHED…
I -idiopathic………no etiology is identified
G -gallstone…..Gallstones may get stuck in the Ampulla of
Vater causing to backflow then into pancrease
E -ethanol (alcohol)….60-90% of patients have a history
of alcohol abuse…. Second next to gall stone for acute
case
T -trauma
S -steroids
M -mumps and other viruses (Epstein-Barrvirus,
Cytomegalovirus)
174
175
 Etiology - I GET SMASHED…
A -autoimmune disease (Systemic lupus erythematosus)
S -scorpion sting (e.g. Tityus trinitatis), and also snake
bites
H-hypercalcemia, hyperlipidemia and hypotermia
E - Endoscopic Retrograde Cholangio-
Pancreatography………a procedure that
combines endoscopy and fluoroscopy
D -Drugs………….four categories

176
 Etiology - I GET SMASHED…
Four Categories……………..drugs account for 2%
incidence
Drugs that exacerbate high triglycerides
Estrogens, steroids, isotretinoin, hydrochlorothiazide,
furosemide, and protease inhibitors
Drugs that cause hypersensitivity
Aminosalicylates, tetracycline, azathioprine, TMP/SMX, or
ACEI
Drugs that have a toxic effect
Valproic acid, statins, sulindac, metformin, and didanosine
Drugs that cause pancreatic spasm.
Opiates and octreotide are thought to cause spasms of the
177 sphincter of Oddi
 Pathophysiology
• The events that initiate an inflammatory process are still
NOT well understood

• Trypsinogen- (a proteolytic enzyme)is normally

released into the small intestine, where it is activated to
trypsin

• Acute pancreatitis involves premature activation of

trypsinogen in to trypsin with in the pancreas,
leading to activation of other digestive enzymes and
autodigestion of the gland
178
 Clinical manifestation#1
Abdominal pain:
may be continuous, intermittent or absent
Pattern is often atypical
RUQ or LUQ of the back
Diffuse throughout upper abdomen
Typical form:
Persistent , deep-seated,
Unresponsive to antacids
Worsened by alcohol intake or a heavy meal (especially
fatty foods)
Often need narcotics
Acute pancreatitis related to alcohol occur …..one to three
days after cessation of drinking.

179
 Clinical manifestation#2
Nausea and vomiting
Incidence………90 percent of patients
Duration……….may persists for many hours
Associated symptoms………. Restlessness, agitation, and
relief on bending forward
Patients with fulminant attacks may …… present in shock
or coma.
Painless disease….in only………….5 to 10%

Most the pain is severe……….Emergency department

visit and hospital admission is required

180
 Clinical manifestation #3
Pancreatic insufficiency
Weight loss
Fat malabsorption:
Steatorrhea: 15% of patients present with
steatorrhea and no pain… occur in chronic
pancreatitis(>90% of pancreas is lost)
Pancreatic diabetes:
Like DM1 needs insulin

181
 Complications
Necrotizing pancreatitis…….when pancreatic cell die
Leads to cyst or pocket like space
May lead into leakage of fluid containing toxins and enzymes
leaks from the pancreas through the abdomen. This can damage
blood vessels and lead to internal bleed
Respiratory Complications – due to irritation of
diaphragm
shallow breathing
inflammatory exudates, and dyspnea

182
 Complications
Ecchymotic discoloration of the flanks …….
 the escape of blood into the tissues from ruptured blood vessels

Grey-Turner's sign .
Bruise like …….b/n ribs and hip bones
The periumbilical region (Cullen's sign) ….
Retroperitoneal bleeding in patients with pancreatic necrosis.
Incidence: 1%......They reflect intra-abdominal
hemorrhage - a poor prognosis.

183
 Cullen’s sign

184
 Grey Turner’s sign

185
 Chronic pancreatitis
Chronic pancreatitis results from long standing
inflammation leading to irreversible parenchymal
destruction leading to pancreatic dysfunction
Chronic alcohol consumption , especially heavy
drinking remain leading cause
Leads to………Persistent, recurrent episodes of severe
pain
Symptoms;
Anorexia, nausea
Constipation, flatulence
Steatorrhea
Diabetes

186
 Prognosis
The overall mortality rate……..10-15%
May be as high as…………..30%
Patients with biliary pancreatitis tend to………
have a higher mortality rate than patients with alcoholic
pancreatitis.

In the first week of illness……………….most deaths

result from multi-organ system failure.
In subsequent weeks………………….infection plays a
more significant role

187
 Diagnosis#1
Physical exam
Palpable epigastric mass - pseudocyst
Less common features:
subcutaneous nodular fat necrosis (panniculitis),
thrombophlebitis in the legs, and polyarthritis.

Fat necrosis lesions……0.5 to 2 cm

tender red nodules, located over the distal extremities but may
occur elsewhere.

188
 Diagnosis #2
Laboratory Evaluation/ Pancreatic enzymes
Early in the course of acute pancreatitis……..
there is a breakdown in the synthesis-secretion coupling of
pancreatic digestive enzymes
i.e synthesis continues while there is a blockade of secretion.
As a result………….
digestive enzymes leak out of acinar cells through the basolateral
membrane to the interstitial space and….then the systemic
circulation.

189
 Diagnosis#3

 Amylase…Nonspecific !!!
Amylase levels > 3x normal very suggestive of acute
pancreatitis
May be Normal in chronic pancreatitis!!!

Enzyme level  severity

False (-)……..EtOH…………..or …………….Hyper-
TG
False (+) …….renal failure, other abdominal or salivary
gland process, acidemia

190
 Diagnosis#4
Serum amylase (70-200 u/mL)
Is the most frequently ordered test to diagnose acute
pancreatitis.
Rises within …6 to 12 hours of onset
Cleared fairly rapidly from the blood
half-life 10 hours
In uncomplicated attacks………..
serum amylase is usually elevated for three to five
days.

191
 Diagnosis#5
Serum Lipase (0 – 160 U/mL)
Less frequently ordered than amylase b/s…...Difficult to
perform and lacked precision
Inclusion of co-lipase in the assay of commercially
available kits has improved… diagnostic accuracy.

Sensitivity…………85 to 100 percent

However………..nonspecific elevations of lipase have
been reported in almost as many diseases as amylase.

192
 Diagnosis#6
Other inflammatory markers will be elevated

ALT > 3x normal  gallstone pancreatitis

96% specific but …………only 48% sensitive

Depending on severity may see:

  Ca WBC
  Hct BUN
 glucose
 Bilirubin…..25% pancreatic edema leads to compression of the
bile duct

193
 Diagnosis#7
Radiographic Evaluation
US or CT
show enlarged pancreas with stranding, abscess, fluid
collections, hemorrhage, necrosis or pseudocyst
MRI…………..the newest
Better visualization of fluid collections
Endoscopic/Ultrasonography …………
even newer but used less
Useful in obese patients

194
 Management
Supportive care is very important part of the management
Control of Pain……..Narcotic analgesics
Maintain Fluid/electrolyte balance
Correction of malabsorption with ………….adequate
enzyme replacement and nutrition
Remove offending agent ………..if possible

195
 Non-pharmacological#1
No oral food ………….until pain free…..pancreatic rest
Avoid fatty food to decrease pancreatic stimulation
Nasojejunal suction for patients with emesis
TPN may be needed
Aggressive volume repletion with IVF
Keep an eye on fluid balance/sequestration and electrolyte
disturbances
Avoidance of alcohol/other offending agents
Prevention of Shock – hemodynamic stability
* Administer Blood, Plasma expanders,
Albumin
196 * LR solution
 Non-pharmacological #2
Treatment Endoscopic therapy
controls pain in some patients who have a prominent stricture in
the proximal pancreatic duct.
dilation is followed by ……………stent placement across the
stricture.
Pain improves in ………….55 to 100% of selected patients with
an isolated proximal stricture during 2 to 69 months of follow-
up.
Surgery…………….
If all measures fail to relieve pain, which is superior to
endoscopic drainage

197
 Pharmacological#1
Treatment- Pain control
Cause …………Pancreatic ductal hypertension
secondary to pancreatic outflow obstruction
Medications:
Acetaminophen or NSAIDs
Opiate analgesics
Meperidine 50-100 mg Q3to 4 hrs IV… max dose
600mg/day
Hydrocodone, 10 mg every 6 hours as needed

198
 Pharmacological#2
Meperidine ……….. Pethidine
Favored over morphine
Human studies showed that morphine caused …….an increase in
sphincter of Oddi pressure.
Despite these data there is no ………..clinical evidence to suggest
that morphine can aggravate or cause pancreatitis or cholecystitis.

Problem with Meperidine

normeperidine accumulation after repeated doses of
meperidine……………. in renal failure
seizures - neuromuscular irritation

199
 Pharmacological#3
Pain Control - Fentanyl IV
An alternative agent ………..if large doses of meperidine
needed
ADR…………..Respiratory function depression

Drug Interaction………..
Concurrent use of a calcium channel blocker and a
beta-adrenergic blocker with fentanyl has resulted in
severe hypotension.

200
 Pharmacological#4
Treatment Hyperlipidemia
high TG >500 mg/dl should be treated……………..
Fibric acid derivatives, ……Gemfibrozil, fenofibrate
Niacin, and omega-3 fatty acids.
High doses of a strong statin ……………
simvastatin, atorvastatin, rosuvastatin also…….lower
triglycerides, by as much as approximately 50%.
e.g., atorvastatin starting at 10 to 20 mg/day

201
 Pharmacological#5
The somatostatin analogue …octreotide
Mechansim………….
inhibits pancreatic secretion and has visceral
analgesic effects.
Octreotide may also ………..
have a role in the management of refractory
pancreatic fistulas or pseudocysts.

202
 Pharmacological#6
Oral pancreatic enzymes
Pancreatic steatorrhea …….stool becomes smelly
A reduction in dietary fat
Pancreatic Enzyme
25,000 to 30,000 units of lipase per meal
H2-receptor antagonists or proton pump inhibitors
Increase effectiveness of enzyme therapy for malabsorption
and steatorrhea
Also for stress ulcer

203
204
 Pharmacological#7
Treatment autoimmune chronic pancreatitis
Steroids……dramatic response within 4 weeks.
Prednisolone is initiated at …………
30 to 40 mg/day for 1 to 2 months and
tapered by 5 mg every 2 to 4 weeks.

Maintenance dose…………..
5-10 mg/day of prednisolone needed to prevent relapse.

205
 Complication: Infection
Acute necrotizing pancreatitis…….
 leading cause of morbidity and mortality
 Incidence……… 30%
 Patients who develop infection tend to have more
extensive necrosis compared to those in whom the
necrotic tissue remains sterile.

Occurs late……..
in the course of necrotizing pancreatitis

206
 Complications: Infection
Many areas for concern…………..
abscess, pancreatic necrosis, infected pseudocyst,
cholangitis,
SEPSIS may occur
Use of broad-spectrum antimicrobials
Multiple organisms…..bowel flora
Prophylactic antibiotics………is NOT recommended
Necrotizing pancreatitis
Significantly increases morbidity & mortality
Usually found on CT with IV contrast

207
 Pancreatitis: Infection
Organisms…………..gut-derived
Escherichia coli, Pseudomonas, Klebsiella, and
Enterococcus spp.
Initiate with in 48 hrs and continue for 2 to 3 wks..
Imipenim –cilastatin 500mg TID
FQ + metronidazole … 2nd line
Fungal infection /Gram positive……. Uncommon

prophylactic antibiotic use for more than 10 to 14

days…….Is not recommended.

208
 Complications: Pseudocysts
Defined as accumulation of pancreatic fluid in a cavity
like structure
Incidence……….25%
More common with alcoholic pancreatitis
Resolves spontaneously in most cases
Persistent pain or continued high amylase levels may be
present for 4-6 wks afterward
Cyst may become …….
infected, rupture, hemorrhage or obstruct adjacent structures
Asymptomatic, non-enlarging pseudocysts can be…… watched
and followed with imaging
Symptomatic, rapidly enlarging or complicated pseudocysts…
need to be decompressed
209
210
 Complications - Others
Pulmonary
Atelectasis, pleural effusion, pneumonia and ARDS
can develop in severe cases
The diaphragm gets involved
Other……..Metabolic disturbances
hypocalcemia, hypomagnesemia
GI bleeds…..Stress gastritis
Fistula formation…abnormal protrusion

211
 References
1) Marie A. Chisholm-Burns.Pharmacotherapy
Principles & Practice. Chisholm-burns Ma, editor:
The McGraw-Hill Companies, Inc. ; 2008.
2) Joseph T. DiPiro P, Executive Dean and Professor, South
Carolina College of Pharmacy, University of South
Carolina. Pharmacotherapy A Pathophysiologic
Approach. Seventh Edition ed.: McGraw-Hill; 2008.
3) Koda-Kimble MAY, Lloyd Yee. Applied Therapeutics:
The Clinical Use Of Drugs, 9th Edition. Koda-Kimble
MAY, Lloyd Yee, editor: Copyright ©2009 Lippincott
Williams & Wilkins; 2009.

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