PHARMACOTHERAPPY OF INFLAMATORY

BOWEL DISEASE፡ PRESENTATION

GROUP 1NAME ID NO
ABDISA TADESSE PH/135/13
ABINET ALEMAYEHU PH/210/13
ABREHAM DEBEBE PH/139/13
ALEMAYEHU FIKADU PH/140/13
ANSAR NUREDIN PH/142/13
AWEL AMAN PH/143/13
BEDASO HURBU PH/144/13
BEREKET ABETUN PH/146/13
BEREKET GETACHEW. PH 147/13
BETELHEM MEKONEN. PH/148/13
objectives
 Characterize the pathophysiologic mechanisms underlying inflammatory bowel

disease(IBD).

 Recognize the signs and symptoms of IBD, including major differences between

ulcerative colitis and Crohn’s disease.

 Identify appropriate therapeutic outcomes for patients with IBD.

 Describe pharmacologic treatment options for patients with acute or chronic

symptoms of ulcerative colitis and Crohn’s disease.

 Recommend appropriate monitoring parameters and patient education for selected

drug regimens for treating symptoms of IBD.

IBD
 There are two forms of inflammatory bowel disease (IBD):
 ulcerative colitis (UC), a mucosal inflammatory condition
confined to the rectum and colon.
 Crohn’s disease, a transmural inflammation of gastrointestinal
(GI) mucosa that may occur in any part of the GI tract.
 The etiologies of both conditions are unknown, but they may
have a common pathogenic mechanism.
ETIOLOGY
 The exact cause of IBD is not fully understood
 Processes thought to be involved in its development include
 genetic predisposition
 dysregulation of the inflammatory response within the GI tract,
or perhaps environmental or antigenic factors.
 The fact that a positive family history is a strong predictor of IBD
supports the theory that genetic predisposition may be responsible in
many cases.
 infectious agents
PATHOPHYSIOLOGY

 Ulcerative colitis
 The inflammatory response in UC is propagated by atypical type 2
helper T cells that produce proinflammatory cytokines
 interleukin-1 (IL-1), IL-6, and
 tumor necrosis factor(TNF).
 The role of an immune response to intestinal bacteria in the
development of UC may not be as strong a contributing factor CD.
 NSAID use is also implicated in disease flares in patients with UC.
uc
 The inflammatory process within the GI tract is limited to the colon and
rectum in patients with UC.
 Most patients with UC have involvement of the rectum(proctitis) or both
the rectum and sigmoid colon (proctosigmoiditis)
 Inflammation involving the majority of the colon is referred to as pancolitis.
 Left-sided disease, inflammation extending from the rectum to the splenic
flexure.
 A small number UC involve mild inflammation of the terminal ileum,
referred to as “backwash ileitis.”
…
 The pattern of inflammation in UC is continuous and confluent
throughout the affected areas of the GI tract.
 The inflammation is also superficial and does not typically extend
below the submucosal layer of the GI tract.
 The formation of crypt abscesses within the mucosal layers of the GI
tract is characteristic of UC and may help to distinguish it from CD.
 The inflammatory response may progress in severity, leading to
mucosal friability and significant GI bleeding.
complications
 Local complications (involving the colon) occur in the majority of patients
with UC.
 minor complications(hemorrhoids, anal fissures, and perirectal abscesses).
 A major complication is toxic megacolon.
 high fever, tachycardia, distended abdomen, elevated white blood cell
count, and a dilated colon.
 The risk of colonic carcinoma is much greater in patients with UC as
compared with the general population.
Hepatobiliary complication

Fatty liver pericholangitis, chronic active hepatitis , cirrhosis, sclerosing

cholangiti, cholangiocarcinoma, and gallstones .
 Arthritis(asymptomatic and migratory) few large joints, knees, hips,
ankles, wrists, and elbows.
 Ocular complications (iritis, episcleritis, and conjunctivitis) occur in some
patients.
 Skin and mucosal lesions (erythema nodosum, pyoderma gangrenosum,
aphthous ulceration, and Sweet syndrome).
crohn,s disease
 As with UC, the immune activation seen in CD involves the release of many
proinflammatory cytokines.
 Cytokines thought to play major roles in CD are derived from T-helper type 1
cells and include interferon-γ, TNF-α, and IL-1, IL-6, and IL-12.
 TNF-α is a major contributor to the inflammatory process seen in CD.
 activation of macrophages
 procoagulant effects in the vascular endothelium, and
 increases in production of matrix metalloproteinases in mucosal cells.
cd
 The role of an immune response directed against endogenous
bacteria as the initiating factor is more evident in CD, (apparent
strong T-helper 1 activation against bacteria).
 NSAIDs.
 The role of dietary antigens in the development of CD compared to
UC is also another potential initiating factor
 entire GI tract may be affected in CD. (the small
intestine(terminal ileum and cecum) are almost always affected).
Complications cd…
 Small bowel stricture with subsequent obstruction is a complication that
may require surgery.
 Fistula formation is common and occurs much more frequently than UC.
 Arthritis, iritis, skin lesions, and liver disease often accompany Crohn
disease.
 Nutritional deficiencies are common with Crohn disease (weight loss, iron
deficiency anemia, vitamin B12 deficiency, folate deficiency,
hypoalbuminemia, hypokalemia, and osteomalacia).
Clinical presentation

General

• Patients with CD or UC may present with similar symptoms.

• Some patients present with extra-intestinal manifestations

before GI symptoms occur.

• In approximately 10% of cases it may not be possible to

distinguish between UC and CD.

These patients are described as having “indeterminate colitis.”

…

 Symptoms

Ulcerative colitis: Diarrhea (bloody, watery, or mucopurulent),

rectal bleeding, abdominal pain/cramping, weight loss and
malnutrition, tenesmus, constipation (with proctitis)

Crohn’s disease: Diarrhea (less bloody than UC), rectal

bleeding (less than UC), abdominal pain/cramping, weight loss
and malnutrition (more common than UC), fatigue/malaise
 Signs

• Ulcerative colitis: Fever, tachycardia (with severe disease),

dehydration, arthritis, hemorrhoids, anal fissures, perirectal

abscesses

• Crohn’s disease: Fever, tachycardia (with severe disease),

dehydration, arthritis, abdominal mass and tenderness,

perianal fissure or fistula

 Laboratory Tests

• Ulcerative colitis: Leukocytosis, decrease hematocrit/hemoglobin, elevated

erythrocyte sedimentation rate (ESR), guaiac-positive stool, (+) perinuclear
antineutrophil cytoplasmic antibodies (pANCA; up to 70% of patients)

• Crohn’s disease: Leukocytosis decrease hematocrit/hemoglobin, elevated

ESR, guaiac-positive stool
 (+) anti–Saccharomyces cerevisiae antibodies (up to
 50% of patients), hypoalbuminemia with severe disease
Clinical presentation…UC

Mild UC (four bloody or watery stools per day without systemic signs
of toxicity or elevation of ESR).

Moderate disease (more than four stools per day with evidence of
systemic toxicity).

Severe disease( more than six stools per day and evidence of anemia,
tachycardia, or an elevated ESR).

Lastly, fulminant UC (more than 10 stools per day with continuous

bleeding, signs of systemic toxicity, abdominal distention or
tenderness, colonic dilation, or a requirement for blood transfusion)
…CD

Patients with mild to moderate CD: typically ambulatory and have no

evidence of dehydration, systemic toxicity, loss of body weight, or abdominal

tenderness, mass, or obstruction.

Moderate to severe disease :patients who fail to respond to treatment for

mild to moderate disease, or those with fever, weight loss, abdominal pain or

tenderness, vomiting, intestinal obstruction, or significant manemia.

Severe to fulminant CD : persistent symptoms or evidence of systemic

toxicity despite outpatient corticosteroid treatment, or presence of cachexia,

rebound tenderness, intestinal obstruction, or abscess.

treatment
Goals of Treatment:
 designed to target the underlying inflammatory response.
 both management of active disease and prevention of disease relapse
 Resolution of acute inflammatory processes
 resolution of attendant complications (eg, fistulas or abscesses),
 alleviation of systemic manifestations (eg, arthritis), maintenance of
remission from acute inflammation

 surgical palliation or cure.

…
When designing a drug regimen for treatment of IBD, several factors should be
considered
 patient’s symptoms,
 medical history,
 current medication use,
 drug allergies, and
 location and severity of disease.
 A thorough patient history may also help to identify a family history of
IBD or potential exacerbating factors, such as tobacco or NSAID use.
Nan pharmacologic therapy
No specific dietary restrictions(avoidance of high-residue
foods in pts with strictures may help to prevent obstruction).

Nutritional strategies in patients with long-standing IBD may

 vitamin and mineral supplementation.
 Administration of vitamin B12, folic acid, fat-soluble
vitamins, and iron may be needed to prevent or treat
deficiencies.

In severe cases,enteral or parenteral nutrition may be needed to

achieve adequate caloric intake.
 Patients with IBD(CD) risk for bone loss.
 malabsorption or
 an effect of repeated courses of corticosteroids.
 Patients with IBD should receive a baseline bone density measurement prior to
receiving corticosteroids.
 Vitamin D and calcium supplementation should be used in all patients receiving
long-term corticosteroids.
 Oral bisphosphonate therapy may also be considered in patients receiving
prolonged courses of corticosteroids or in those with osteopenia or osteoporosis.
 Surgical intervention
 fistulae or abscesses, or in
 patients with medically refractory disease.
 Ulcerative colitis is curable( total colectomy).
 Pts with UC(colectomy reduces the chance of developing colorectal
cancer).
 Pts with CD may have affected areas of intestine resected.
 CD may recur following surgical resection.
 Repeated surgeries (malabsorption of nutrients and drugs consistent with
development of short-bowel syndrome)
Pharmacologic therapy
 aminosalicylates, glucocorticoids
 immunosuppressive agents (azathioprine, mercaptopurine,
cyclosporine, and methotrexate),
 antimicrobials (metronidazole and ciprofloxacin),
 agents to inhibit tumor necrosis factor-α (TNF-α) (anti–TNF-α
antibodies)
 leukocyte adhesion and migration (natalizumab and vedolizumab).
 Sulfasalazine combines a sulfonamide (sulfapyridine) antibiotic and
mesalamine (5- aminosalicylic acid) in the same molecule.
aminosalicyclates
 most commonly used drugs

 designed to deliver 5-aminosalicylate (5-ASA, mesalamine) to areas of

inflammation within the GI tract.

 mesalamine, it appears to have favorable anti-inflammatory effects.

These effects may include

 reducing prostaglandin and leukotriene production,

 inhibiting bacteria-induced chemotaxis & scavenging of free radicals.

Topical suppositories and enemas are designed to deliver mesalamine directly to the
distal colon and rectum
 The prototypical aminosalicylate is sulfasalazine, mesalamine linked by a
diazo bond to the carrier molecule sulfapyridine.
 Sulfasalazine is associated with various adverse effects, most

due to the sulfapyridine component.

 headache, dyspepsia, nausea, vomiting, and fatigue.
 Idiosyncratic effects & bone marrow suppression, reduction in sperm
counts in males, hepatitis, and pulmonitis.
 Hypersensitivity reactions may occur in patients allergic to sulfonamide-
containing medications
 The use of non-sulfapyridine–based aminosalicylates has

led to greater tolerability.

Although the adverse effects are similar to those of sulfasalazine, they

occur at a much lower rate.
 Olsalazine, in particular, is associated with a higher incidence

of secretory diarrhea.

These agents can also be used safely in patients with a reported

sulfonamide allergy
corticosteroids
 Potent anti-inflammatory properties and are used in active IBD to
rapidly suppress inflammation.
 modulating several cell types involved in the inflammatory process.
 improve symptoms and disease severity rapidly, they should be
restricted to short-term management of active disease.
 Long-term use of systemic corticosteroids is
 cataracts, skin atrophy, hypertension, hyperglycemia,
 adrenal suppression, osteoporosis, and increased risk of
infection, among others
…
Immunosuppressants

Agents targeting the excessive immune response or cytokines

Antibiotics
 Metronidazole and ciprofloxacin
 Metronidazole : pouchitis (inflammation of surgically-created intestinal
pouches) and patients with CD who have had ileal resection or have
perianal fistulas.
 Ciprofloxacin refractory active CD.(diarrhea, and long-term use of
metronidazole is associated with the development of peripheral neuropathy.
Tt… of UC

Mild to Moderate Active UC

 First-line therapy of mild to moderate disease involves oral or topical
aminosalicylate derivatives.
 Topical suppositories and enemas are preferred for active distal UC
(left-sided disease and proctitis), as they deliver mesalamine directly to
the site of inflammation.
 Topical mesalamine is superior to both topical corticosteroids and oral
aminosalicylates for inducing remission in active mild to moderate UC.
Moderate to severe

 Steroids have a place in the treatment of moderate to severe

UC or in those who are unresponsive to maximal doses of oral
and topical mesalamine.
 Oral prednisone 40 to 60 mg daily is recommended for adult.
 TNF-α inhibitors are an option for patients with moderate to
severe disease who are unresponsive to ASAs, corticosteroids,
or other immunosuppressive agents.
Severe or intractable disease

 Patients with severe UC symptoms require hospitalization.

 If the patient is unresponsive to oral or topical mesalamine and oral corticosteroids

 intravenous corticosteroids should be initiated Hydrocortisone 300 mg/day

given in three divided doses or

 methylprednisolone 60 mg daily for 7 to 10 days are the preferred therapies

 Infliximab 5 mg/kg is also an option for severe UC.

 Cyclosporine 2 to 4 mg/kg per day given as a continuous intravenous infusion

should be reserved for patients unresponsive to 7 to 10 days of intravenous

corticosteroid therapy.
Tt of crohn’s disease
 Mild to moderate active CD

 Induction of remission of mild to moderate active CD (oral ASA)

 Sulfasalazine 4 to 6 g per day is most effective for patients with colonic

involvement, with response rates of 50%.

 Budesonide 9 mg orally once daily for up to 8 weeks may be used for

mild to moderate active CD ( terminal ileum or ascending colon) 50% to

60% of patients

 Metronidazole or ciprofloxacin can be used in pts who do not respond to

oral ASA.
Moderate to severe…
 Oral corticosteroids, such as prednisone 40 to 60 mg daily.

 Budesonide 9 mg orally once daily may be used for moderate

active CD( terminal ileum or ascending colon).

 Infliximab is an effective alternative to corticosteroid therapy

(fistulizing or perianal disease)

 simple perianal fistulae, antibiotics and infliximab are appropriate tt options

Complex perianal fistulae(multiple openings, stricture, or penetration into the

vaginal wall).
 surgical intervention but may also be amenable to treatment with antibiotics,
infliximab, azathioprine, or 6-MP
severe
 hospitalization for appropriate treatment.
 Patients should be assessed for possible surgical intervention (abdominal
distention, masses, abscess, or obstruction are present).
 Intravenous daily doses of corticosteroids equivalent to prednisone 40 to 60 mg
are recommended as initial therapy to rapidly suppress severe inflammation.
 If there are no contraindications, infliximab 5 mg/kg followed by 5 mg/kg at
weeks 2 and 6 may be used
 There is no evidence that infliximab is either safe or effective for fulminant
disease.
Summary : tt of IBD
Reference
 Pharmacotherapy principle and practice text book.
 Pharmacotherapy a pathophysiology approach 10th
edition.
 Koda kimble and young's applied therapeutics

the clinical use of drugs 10th edition