2011 Updates in Therapeutics:

The Pharmacotherapy Preparatory Review and

Recertification Course
Gastrointestinal Disorders
Brian A. Hemstreet, Pharm.D., BCPS
University of Colorado School of Pharmacy

Conflict of Interest Disclosures

Dr. Hemstreet has conducted research sponsored

by Astra Zeneca.

Learning Objectives
1. Review and apply national guideline treatment strategies for
the following gastrointestinal (GI) disorders: gastroesophageal
reflux disease (GERD), peptic ulcer disease (PUD), ulcerative
colitis, Crohns disease, viral hepatitis, chronic liver disease,
upper GI bleeding, constipation, diarrhea, irritable bowel
syndrome (IBS), nausea, vomiting, pancreatitis, prevention of
stress related mucosal disease (SRMD).
( )

2. Recommend appropriate pharmacologic and

nonpharmacologic interventions for the treatment of GERD.

3. Differentiate between clinical signs, symptoms, risk factors,

and treatment of both Helicobacter pylori and nonsteroidal
anti-inflammatory drug (NSAID)-associated PUD.

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Learning Objectives
4. Discuss the role of pharmacologic intervention in the
treatment of nonvariceal upper GI bleeding.

5. Review the clinical differences in signs, symptoms,

and treatment of Crohns disease and ulcerative
colitis.
colitis

6. Identify the common manifestations of chronic liver

disease and their treatment.

7. Review the treatment of both acute and chronic viral

hepatitis.

Learning Objectives

8. Recognize pertinent information for educating

patients and prescribers regarding the appropriate use
of pharmacologic agents for various GI disorders.

9. Recommend appropriate pharmacologic and

nonpharmacologic interventions for diarrhea and
constipation.

10. Review recommendations for the treatment and

prevention of nausea and vomiting.

Learning Objectives

11. Discuss the clinical and treatment differences

between acute and chronic pancreatitis.

12. Discuss the role of ppharmacologic

g intervention in
the treatment of IBS.

13. Understand commonly encountered statistical

tests and concepts using GI disorders as examples.

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Patient Case # 1
HPI: 75 year old male with continued daily GERD
symptoms despite non-pharmacologic treatment and
twice daily lansoprazole therapy for 5 months
PMH: GERD (3 yrs), Parkinsons Disease
Diagnostics: endoscopic evaluation reveals normal
appearing mucosa

What is the best course of action for the treatment and

evaluation of this patient?

Handout Page 77

Gastroesophageal Reflux Disease

Clinical definition
A condition which develops when reflux of stomach
contents causes troublesome symptoms and/or
complications

troublesome symptoms are based on interference

with normal daily activities or well-being

Typical Symptoms
Pyrosis, regurgitation

Treatment of GERD
Nonpharmacologic/Lifestyle modifications
Targeted

Antacids
Acid suppression
Proton Pump Inhibitors
Histamine-2 Receptor Antagonists
Promotility Agents
Proper patient education
Surgical intervention

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Patient Case #1

A. Add metoclopramide, reassess in 3 months

B. Educate on proper use of lansoprazole and refer for

manometryy

C. Add metoclopramide and refer for surgical

intervention

D. Add famotidine and reassess in 4 months

Patient Case # 2
HPI: 68 year old female with heme positive stools anemia
and abdominal pain.

PMH: Type 2 DM, Peripheral neuropathy

MEDS: metformin,
tf i aspirin,
i i gabapentin,
b ti OTC ketoprofen
k t f

Diagnostics: endoscopy reveals 1 cm gastric ulcer, H.

pylori negative via CLO Test

Appropriate treatment for her PUD?

Handout Page 84

Peptic Ulcer Disease (PUD)

Classification
Duodenal ulcer
Gastric ulcer

Etiologies
Helicobacter pylori (carcinogen)
NSAIDs

Symptoms
Epigastric pain, nausea, anorexia, belching
May be temporally related to food intake

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NSAID Associated PUD
NSAIDs have topical and systemic adverse GI effects
COX-2 vs. COX-1 effects

Risk Factors
Age >60, History of PUD +/- complications
Corticosteroids, anticoagulants, low dose aspirin, aspirin,
NSAID dose
Contributing factors
H. pylori, Smoking, CVD, RA, SSRIs

Management of NSAID-Associated PUD

Remove and reevaluate need for NSAID and/or
aspirin
Test for H. pylori and treat if positive

Acid suppression
PPI ffor 88-12
12 weeks
k

Misoprostol

COX-2 Inhibitors
Cardiovascular risks
Use with aspirin

Patient Case #2

A. Ranitidine 150 mg twice daily for 4 weeks

B. Lansoprazole 30 mg, amoxicillin 1000 mg,

clarithromycin 500 mg twice daily for 10 days

C. Lansoprazole 30 mg daily for 8 weeks

D. Misoprostol 200 mcg 4 times daily for 8 weeks

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 Patient Case #3
HPI: 42 year old male with sharp epigastric pain for 6
weeks. Pain is worse with eating and is present
approximately 5 days per week. Some relief with
OTC antacids.

MEDS: antacids as needed

Allergies: Penicillin (rash)
UBT for H. pylori is positive

What is most appropriate treatment at this time?

Handout Page 84

Diagnosis of H. pylori
Invasive testing (endoscopic)
Histology
Rapid urease (affected by antisecretory agents)
Culture

Non-invasive testing
Serologic (IgG)
Urea breath test (affected by antisecretory agents)
Fecal antigen (affected by antisecretory agents)

Treatment of H. pylori
Triple therapy
PPI + amoxicillin or metronidazole + clarithromycin
10-14 days of treatment (14 preferred)
Efficacy affected by previous macrolide exposure

Quadruple Therapy
PPI + Bismuth + Metronidazole + Tetracycline
1st line, PCN allergy, previous macrolide exposure, failure
of triple therapy
10-14 days of treatment

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Patient Case #3

A. Amoxicillin, clarithromycin, omeprazole for 10

days
B. Cephalexin, clarithromycin, omeprazole for 10
days
C. Bismuth, tetracycline, metronidazole,
omeprazole for 14 days
D. Levofloxacin, metronidazole, omeprazole for 10
days

Case #4
Scenario: Retrospective cohort study
Comparators:
New NSAID vs. naproxen and ibuprofen
Results:
No significant differences in safety
Author argument:
New agent was promoted as safer and therefore used
preferentially in patients with higher risk for adverse
GI events

Handout Page 88

Bias
Bias: Source(s) of variation that distort a
studys findings in one direction

Several different types

May affect different aspects of study

Prevention
Rigorous study design, methodology, data
collection, and analysis

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Case #4

A. Recall bias

B. Misclassification bias

C. Interviewer bias

D. Channeling bias

Patient Case #5
HPI: 35 year old male with ulcerative colitis
(majority of colon). Experiences 5-6 bloody bowel
movements per day when prednisone is reduced to
less than 40mg/day.

MEDS: Balsalazide 6.75 g/day, prednisone 40

mg/day

What would be an appropriate modification of his

drug regimen at this time?

Handout Page 98

Inflammatory bowel disease

Ongoing inflammation of the GI mucosa

Crohns Disease
Ulcerative Colitis

Exact cause is unknown

Defects in intestinal barrier/immune system

Possible exacerbating factors: NSAIDs, smoking,

luminal bacteria, dietary
Remission and relapse

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 Clinical Findings Ulcerative Colitis Crohns Disease
Bowel Involvement Rectum/Colon Mouth to Anus
Perianal Involvement No Yes
Depth Superficial Submucosa/deeper
Pattern of inflammation Continuous Patchy
Histology Crypt abscesses Granulomas
Fistula,
Fi t l perforation,
f ti or N
No Y
Yes
Strictures
Toxic megacolon Yes No
Colorectal cancer Yes Uncommon
Malnutrition Rare Yes
Pseudopolyps Common Fairly Common

Drug Treatment Options

5-Aminosalicylates Immunomodulators
Sulfasalazine Azathioprine
Mesalamine 6-Mercaptopurine
Olsalazine Methotrexate
Balsalazide Cyclosporine
Tacrolimus
Antibiotics
Metronidazole Biologics
Ciprofloxacin Infliximab
Adalimumab
Corticosteroids Certolizumab
Natalizumab

IBD Treatment Guidelines

Severity UC Crohns

Mild-Moderate Aminosalicylate Aminosalicylate or

Budesonide (ileal)

Moderate to Corticosteroid Corticosteroid (short-term)

Severe (short-term) +/-
+/- TNF- inhibitor
Infliximab OR
OR Azathioprine/6-MP
Azathioprine/6-MP OR
Methotrexate

Natalizumab (last line)

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Patient Case #5

A. Change balsalazide to sulfasalazine

B. Initiate therapy with methotrexate IM weekly

C. Initiate infliximab and taper prednisone

D. Add mesalamine suppository

Patient Case #6
HPI: 25 year old female with Crohns disease.
Presents with a 2 day history of crampy abdominal
pain, fever, fatigue, and 10-12 bloody stools per day.
MEDS: Pentasa 250mg #4 caps 2 times/day
Vitals: Temp 101, HR=110, RR=18, BP = 118/68

What would be an appropriate therapeutic choice at this

time?

Handout Page 98

Patient Case #6

A. Increase dose of Pentasa to 4 grams/day

B. Cyclosporine 4 mg/hr continuous infusion

C. Surgery consult for immediate colectomy

D. Hydrocortisone 100 mg IV q 8 hours

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Patient Case #7
HPI: 56 year old male with 2 day history of
confusion, disorientation, somnolence, and reduced
oral intake.
PMH: Cirrhosis (Class B), Low back pain, chronic
renall iinsufficiency,
ffi i hypertension
h t i
MEDS: oxycodone, temazepam, propranolol
Which recommendation is best at this time for
treatment of this patients hepatic encephalopathy?

Handout Page 106

Complications of Cirrhosis

Variceal bleeding Ascites

Morbidity Hepatorenall
H
Infection
Mortality Syndrome

Hepatopulmonary
Encephalopathy
Syndrome

Hepatic Encephalopathy

Definition: central nervous system disturbance

secondary to hepatic insufficiency resulting in a
broad range of neuropsychiatric manifestations

Nitrogenous substances (ammonia) play a large

role

Clinical features: mental status changes, coma,

asterixis

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Treatment

Removal of exacerbating factors

Constipation
GI bleeding
Infection
Dehydration
Hypokalemia
Hypotension
CNS active drugs

Treatment

Reduction in nitrogen load

Lactulose
Non absorbable disaccharide
A t andd chronic
Acute h i
Antibiotics
Neomycin
Rifaximin
Metronidazole

Patient Case #7

A. Discontinue propranolol and start gentamicin

B. Start oral lactulose and discontinue oxycodone and

temazepam

C. Start oxazepam for alcohol withdrawal prophylaxis

D. Start oral neomycin and discontinue propranolol and

oxycodone

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Patient Case #8

HPI: 36 year old female with 36 hours symptoms

consistent with UGIB. EGD reveals several large
esophageal varices that are banded.

PMH Cirrhosis,
PMH: Ci h i alcohol
l h l abuse,
b MI

In addition to the endoscopic band ligation

which therapy is most appropriate at this time?

Handout Page 106

Variceal Bleeding

Varices: Collateral vessels formed secondary to

increased resistance to blood flow within the liver

Bleeding risk
25-35% of patient with cirrhosis
30-50% mortality per bleed

High recurrence rate

~70% within first month of bleed

Treatment of Variceal Bleeding

Stabilization + IV fluids
Endoscopic interventions
Sclerotherapy
Band ligation
Medical Management
Vasopressin + nitroglycerin
Octreotide
Antibiotics

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Prevention of Variceal Bleeding
Pharmacologic +/- endoscopic
Primary prevention
Small varices + high bleeding risk
Medium/Large varices
Non selective beta blockers

Secondary prevention
All patients with history of bleeding
Non selective beta blockers
Endoscopic (band ligation)

Patient Case #8

A. Initiate nadolol 20mg orally once a day x 3 days

B. Initiate vasopressin continuous infusion x 2 days

C. Initiate octreotide 50 ug bolus, then 50 ug/hr for 5

days

D. Initiate pantoprazole 80mg bolus, then 8mg/hr x 72

hours

Patient Case #9
HPI: 45-year old woman with history of IVDA. Diagnosed
8 months ago with HBV. Treatment naive. No ascites or
encephalopathy.
Diagnostics:
AST 650 IU/ml, ALT 850 IU/ml
HBSAg (+), HBeAg (+), YMDD mutation
HBV DNA 107, 000 IU/ml
Biopsy: severe necroinflammation/bridging fibrosis
What is the most appropriate course of action at this
time?

Handout Page 119

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Viral Hepatitis
Hepatitis A, B, C, D, E
Acute
Chronic
Hepatitis B
Hepatitis C
Disease > 6 months

Prevention
Active vs. passive immunization

Hepatitis B

DNA Virus, Genotypes A-H

Transmission
Parenteral, bodily fluids, sexual contact, perinatal

Detect via serologies, symptoms, LFTs

Patients with active disease will be HBsAg (+)

Treat patients with chronic disease

> 2 x ALT, HBV DNA > 20,000 IU/ml

Chronic Hepatitis B Treatment

Need to distinguish if HBV:
is HBeAg positive or negative
Harbors the YMDD mutation of the DNA polymerase

First Line Therapies

Interferon/PEG-interferon alpha
Reverse transcriptase inhibitors
Entecavir, tenofovir
Lamivudine, telbivudine, adefovir

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Patient Case #9

A. No treatment; Recheck HBV DNA in 6 months

B. Initiate PEG-IFN + ribavirin

C. Initiate lamivudine 100 mg/day

D. Initiate tenofovir 10 mg/day

Patient Case #10

A new enzyme immunoassay for HCV RNA has been
developed.

Sensitivityy = 95%
Specificity = 92%

If the prevalence of hepatitis C in a cohort of 500

patients is 40% what is the positive predictive value of
this new test?

Handout Page 119

Predictive Value
Predictive value:
Helpful to predict likelihood of a disease in an individual

Positive predictive value (PPV)

Indicates the proportion of individuals who actually have
the disease when the diagnostic test indicates presence of
that disease

Negative predictive value (NPV)

Indicates the proportion of individuals who are truly free of
the disease when the diagnostic test indicates absence of
that disease

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Positive Predictive Value

Steps for calculating PPV (%)

1. Construct a 2 x 2 table utilizing data
2. Work horizontally on table
3. 100 x TP*/(TP + FP**)
*TP = True positives
**FP = False positives

Predictive value is affected by disease prevalence

Positive Predictive Value

Result Infection No-infection Total

Positive 190 24 214

g
Negative 10 276 286

Total 200 300 500

190/(190 + 24) x 100

Patient Case #10

A. 75%

B. 89%

C. 92%

D. 96%

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Patient Case #11
HPI: 38 year old male with chronic hepatitis C
(genotype 1) currently undergoing treatment with
pegylated interferon + ribavirin. Evaluated at 12 week
follow up appointment after starting treatment.

LABS:
AST 90 IU/ml (350 IU/ml), ALT 64 IU/ml (420 IU/ml)
HCV RNA 3500 IU/ml (450,000 IU/ml)

What is the most appropriate course of action at

this time?

Handout Page 119

Hepatitis C
RNA Virus
Genotypes 1-6 (1-3 most common is US)
Several subtypes
Genotype 1 most resistant to drug treatment
Transf sion IV dr
Transfusion, drug
g ab
abuse,
se transplant

Major cause of chronic liver disease

60-80% progression following acute infection
#1 reason for transplant

Treatment of Chronic Hepatitis C

Rapid Viral Response (RVR)
Undetectable HCV RNA at week 4 of treatment

Early Viral Response (EVR)

> 2 log in viral load or undetectable at 12 weeks

End of Treatment Response (ETR)

Undetectable HCV RNA at the end of the total treatment

period

Sustained viral response (SVR)

Undetectable HCV RNA 24 after finishing treatment

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 Treatment of Chronic Hepatitis C
Pegylated Interferons:
Pegasys: 180ug SQ Q Week (abdomen/thigh)
Peg Intron: 1-1.5 ug/kg/week SQ

Genotype 1: Pegasys + ribavirin in 2 DD

1200 mg/day
g y (>75kg)
( g)
1000 mg/day (<75kg)

Genotype 1: Peg-intron + ribavirin in 2 DD

800 mg/day (< 65kg)
1000 mg/day (65-85 kg)
1200 mg/day (85-105 kg)
1400 mg/day (>105 kg)

Treatment of Chronic Hepatitis C

Genotypes 2 and 3
Pegylated interferon +
Ribavirin 800 mg/day in 2 DD

Treatment Duration
Genotype 1:
48 weeks if EVR
72 weeks if no EVR, but undetectable HCV RNA at 24
weeks
Genotypes 2 and 3: 24 weeks

Patient Case #11

A. Discontinue therapy and monitor for symptoms

B. Continue treatment for an additional 12 weeks

C. Decrease dose of ribavirin to 800 mg/day

D. Continue treatment for and additional 72 weeks

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 Patient Case #12
HPI: 55 year old man with chronic alcohol abuse and
chronic pancreatitis, weight loss (135 lb), and
steatorrhea.
LABS: Albumin 2.1 g/dl, Fecal fat 20g/day
Medications: morphine CR, oxycodone IR as needed
What is the most appropriate course of action at
this time?

Handout Page 132

Overview
Pancreatitis

Acute
Mild-Severe Inflammation
Generally reversible exocrine and/or
endocrine function
Rarely progresses to chronic
Pain, N/V, sepsis, organ dysfunction
Chronic
Longstanding pancreatic injury
Fibrosis/destruction of tissue
Irreversible exocrine and/or endocrine
function
Pain, steatorrhea, malnutrition,
diabetes

Acute Pancreatitis

Largely supportive Care

Pain management
Antiemetics
Nutritional support
Enteral
Hyperglycemia
Antibiotics
Infection, abscess, or necrosis

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Chronic Pancreatitis
Complication Targeted Comments
Therapies
Pain Narcotic +/ non- Acetaminophen and/or NSAIDs
narcotic therapies Long acting narcotic preparations + IR
breakthrough
Pancreatic enzymes Caution with acetaminophen and narcotics
if alcohol use is continued
Maldigeston and Pancreatic enzymes Start around 30,000-40,000
30 000 40 000 lipase units
Malabsorption per meal; dose for snacks
Do not crush or chew
Max 2500 u/kg/dose; 10,000 u/kg/day
Titrate to steatorrhea + weight gain
Porcine based so avoid if pork allergy

Fat soluble vitamins ADEK

Diabetes Insulin Long acting + short acting

Oral intake may be variable

Patient Case #12

A. Increase morphine CR to 60 mg twice daily

B. Initiate dronabinol to improve appetite

C. Initiate pancrelipase 30,000 units/meal

D. Add a multivitamin to his regimen

Patient Case #13

HPI: 32 year old woman with crampy abdominal
pain, bloating and constipation diagnosed with IBS-C.

LABS: within normal limits

Medications and allergies: none
What is the most appropriate course of action at
this time?

Handout Page 132

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Irritable bowel syndrome
Common functional GI disorder
Categories
IBS-D
IBS-C
IBS-M
Features
Change in frequency and/or stool appearance
Pain, bloating
Relief with defecation

Therapies Comments
Hyoscyamine, Target pain due to spasm and also treat diarrhea
dicyclomine Initial or adjunctive therapy for IBS-D or IBS-M
Tricyclic Target pain and diarrhea
antidepressants Generally reserved for IBS-D
Low doses
SSRIs, SNRIs Target pain and often have promotility action in IBS-D
Can also treat comorbid depression and anxiety

Lubiprostone
p Indicated for IBS-C in women > 18 yyears
Main adverse effect is nausea, more expensive option

Loperamide Adjunctive for IBS-D, but does not treat pain

Probiotics Some potential improvement in global symptoms and pain
Alosetron Indicted for IBS-D in women > 18 years failing other therapies
Must be enrolled in prescribing program
Risk of ischemic colitis

Tegaserod Indication: IBS-C; available on emergency use only due to CV risk

Rifaximin Some data to support improvement in bloating

Patient Case #13

A. Amitriptyline 50 mg/day

B. Senna 2 tablets twice daily

C. Tegaserod 6 mg twice daily

D. Citalopram 20 mg once daily

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Patient Case #14
HPI: 30 year old pregnant woman (14 weeks) with
myalgias, watery diarrhea (4-5), vomiting x 1.

LABS: influenza (-), WBC 8000 x 103

Medications: prenatal vitamin
Allergies: none
What is the most appropriate course of action at
this time for this patients diarrhea?

Handout Page 132

Management of Diarrhea
Remove correct underlying cause
Identify drug-induced causes

Rehydration
ORS
Parenteral

Dietary modification

Antidiarreheal Preparations
Therapies Comments
Loperamide OTC and prescription products, tablet and liquid
OTC indicated in age > 6
Pregnancy category B
Opioids (diphenoxylate, Generally reserved for more severe cases
tincture of opium) Increased risk of CNS adverse effects
Bismuth subsalicylate OTC tablet and liquid preparations
Avoid:
Patients < 12 years of age
Pregnancy
Salicylate allergy
Signs/symptoms of bleeding or mucous
Stool and tongue discoloration
Chelation interactions
Lactase Suspected or diagnosed lactose intolerance
Probiotics Data in AAD, IBD, IBS, radiation induced

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Patient Case #14

A. Loperamide

B. Bismuth subsalicylate

C. Lactase

D. Pyridoxine

THE END

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