Inflammatory Bowel Diseases Pharm 2 HK look at pictures

Severity of Crohn's Disease mild to moderate

Ambulatory, few symptoms

Crohn's Disease Maintenance what have a low success rate

Aminosalicylates

Infliximab

Anti-Tumor Necrosis Factor Agent IV Mostly animal

Hydrocortisone

(IV,rectal) Corticosteroid Used for IBD

You are contacted by one of the new GI medical fellows regarding the use of infliximab for a patient with a history of Crohn disease (CD) and no other medical conditions. The patient is currently taking mesalamine (Pentasa) 1 g by mouth four times daily, azathioprine 100 mg by mouth once daily, esomeprazole 40 mg by mouth once daily, lisinopril 20 mg by mouth once daily, entecavir 1 mg by mouth once daily, and acetaminophen 325 mg by mouth twice daily. Which recommendation is best for you to provide the GI fellow regarding infliximab therapy for this patient? A. Premedicate with an antihistamine, acetaminophen, and corticosteroids before the first dose. B. Obtain additional information regarding this patient's medical history before prescribing therapy. C. Assess cardiac function by obtaining an echocardiogram before administration. D. Order a tuberculosis (TB) test to rule out TB before administration.

B.

What medication has precautions of predisposition to infection that may occur with all anti-TNF agents, Benefit-risk should be evaluated for those with chronic infections?

Biologic agents

Crohn's Disease Maintenance what are not effective

Corticosteroids 50% of patients are dependent Budesonide 6mg daily for three months

Cyclosporine

Immunosuppressant Improvement of symptoms within 2-3 days Usual duration of 7-10 days

6-Mercaptopurine (Purinethol)

Immunosuppressant Agent

Azathioprine (Imuran, Azasan)

Immunosuppressant Agent Converted to 6-mercaptopurine

What Targets the excessive immune response of both UC and Crohn's disease and Inhibits the synthesis of protein, RNA and DNA and therefore decrease production of inflammatory mediators?

Immunosuppressant Agents

What agents should be used for maintenance therapy for IBD. Reserved for those whose condition is not responding to other therapies and used to spare the use of corticosteroids?

Immunosuppressant Agents

What has an Active metabolites with long half lives?

Immunosuppressant Agents

What is Used as adjunctive treatment of both UC and Crohn's disease, with aminosalicylates to maintain remission and Allow dose reduction or elimination of steroids use?

Immunosuppressant Agents

Methotrexate

Immunosuppressant Agents Well documented effectiveness in steroid dependent Crohn's An antimetabolite with proposed mechanisms of action in Crohn's Disease. Used to induce and maintain remission of Crohns . *available IM and PO (not effective in UC)* No benefit to IM over oral if normal GI function

What can be used for unresponsive patients or corticosteriod dependent patients in UC remission

Immunosuppressants

What medication targets the excessive immune response of both UC and Crohn's disease and *disrupts purine incorporation into DNA and therefore decrease production of inflammatory mediators?*

Immunosuppressants (Purine Analogs)

DI of Immunosuppressants?

Increased levels with allopurinol causing increased neutropenia

Crohn's Disease Moderate to Severe treatment for Fistulizing or perianal disease with Remission in 80% at 8 weeks

Infliximab

______ is also indicated for moderate-severe Ulcerative Colitis In patients who have failed first line therapy with mesalamine or steroids.

Infliximab

Monitoring for Adalimumab?

Neuro and mental status exam

What is the treatment for Mild-Moderate Crohn's Disease?

Oral aminosalicylates (Mesalamine products) Budesonide (Prednisone and methylprenisolone third line) Antibiotics (Metronidazole/ Ciprofloxacin) Corticosteroids (higher efficacy than budesonide but higher risk of AE)

__________ have low efficacy for UC and CD. ______ are not recommended?

Probiotics and Antibiotics -may be considered for reducing fistula drainage in CD/infections

What is a curative procedure for UC?

Proctocolectomy (CD has no curative surgery)

extent of extensive disease of UC

Proximal to splenic flexure Requires systemic

CI of Sulfasalazine?

Salicylate allergy and *Sulfa allergy*

Monitoring for Mesalamine?

Severe GI disturbances

UC classification: more than 6 stools per day with blood; systemic disturbance (ex: fever, tacky, anemia) and ESR greater than 30

Severe UC

Prednisone, Decadron

(PO) Corticosteroid Used for IBD

Methylprednisolone

(PO-Medrol) & (IV-Solu-Medrol) Corticosteroid Used for IBD

Crohn's Disease Special Populations

*Geriatric* Co-morbid disease make difficult diagnosis and treatment *Pediatric* Failure to thrive *Pregnancy* Active IBD - premature and low birth weight Safety of drug classes

What medications need to be avoided in elderly?

*More prone to SE!* medications that can exacerbation heart failure (TNF), Corticosteroids enhancement of osteoporosis, Greater risk of infection with immunosuppressants

When treating IBD with corticosteroids Use for ____then taper the dosage. Taper over ____, depending on dosage, length. __ corticosteroid therapy for 3-10 days for severs cases, then change to oral

1-2 months weeks IV

DI of Sulfasalazine? (3)

1. Increased effects of hypoglyemics and anticoags 2. Increased risk of myelosupression with use of Azathioprine, Mercaptopurine 3. Inhibition of digoxin absorption

Anti-Tumor Necrosis Factor Agents The Median time to response is ____

2 weeks

Anti-Tumor Necrosis Factor Agents. Chronic, regularly scheduled treatment maintains a response in more than 60% of patient and disease remission in 40% Depending on the agent, the dose is given either every __ , ___ or ___

2 weeks 4 weeks 8 weeks

Crohn's Disease Maintenance Immunosuppressants ___ remission rate Azathioprine or 6-MP 2.5mg/kg

45%

Crohn's Disease Maintenance ___ remission at a year with Infliximab

46%

Anti-Tumor Necrosis Factor Agents: Ulcerative Colitis Maintenance therapy has a ___% continued clinical response

50%

oral aminosalicylates ___ response rate sulfasalazine 4-6 grams/day Mesalamine products For Crohn's Disease Mild-Moderate

50%

Ulcerative Colitis Maintenance -Remission rate

50% patients on oral therapy and 70% of untreated patients

Immunosuppressant Agents ___% patients achieve remission Up to __% of patients remain in remission

50-60 80

Budesonide 9mg daily for up to 8 weeks ___ success (not for sites distal to ascending colon) for Crohn's Disease Mild-Moderate

50-60%

Anti-Tumor Necrosis Factor Agents. Symptomatic improvement in __% of patients Including those who are dependent on steroids and failed purine analogs and methotrexate

60%

Crohn's Disease Maintenance what is the chance of relapse within two years?

80%

A potent and very selective 5-HT3 antagonist rapidly absorbed by the GI tract with a high binding affinity Short-term treatment of women with severe, chronic, diarrhea-predominant IBS who have failed to respond to conventional IBS therapy Very restricted use (restricted providers) due to severe GI events due to constipation, including death due to ischemic colitis

Alosetron (Lotronex)

What is the Gold standard for mild to moderate IBD (induction and maintenance) May improve symptoms within 1 week of initiation

Aminosalicylates Prodrug cleaved by gut bacteria into 5-aminosalilcylate and sulfapyridine metabolites

Colozal

Aminosalicylates Balsalzide Capsule Colon Gold standard mild to moderate IBD

Asacol®

Aminosalicylates Mesalamine Distal ileum & colon Tablet Gold standard mild to moderate IBD

Rowasa®

Aminosalicylates Mesalamine Rectum, Terminal colon Enema Gold standard mild to moderate IBD

Pentasa®

Aminosalicylates Mesalamine Rectum, Terminal colon Small Bowel & colon Enema, Capsule Gold standard mild to moderate IBD

Dipentum®

Aminosalicylates Osalazine Tablet Colon Gold standard mild to moderate IBD

Azulfidine®

Aminosalicylates Sulfasalazine Tablet Colon Gold standard mild to moderate IBD

Major drug classes used for IBD?

Aminosalicylates Glucocorticoids Immunosuppressants Tumor necrosis factor inhibitors

What has *Anti-inflammatory* affects, Theories include reduce prostaglandin and leukotriene production, scavenge free radicals and inhibits TNF?

Aminosalicylates (5-ASA)

What Low dose tricyclic antidepressants may be beneficial for abdominal pain associated with IBS?

Amitriptyline or desipramine 10-50mg/day No effect on mood at these doses

Binding of TNF to TNF Receptors activates the release of the pro-inflammatory cytokines from macrophages as well as other immune modulating effects These agents bind to the TNF with a high affinity and prevent the TNF from binding to the TNF Receptors. This suppresses the cytokine release

Anti-Tumor Necrosis Factor A lot of cytokines are released in response to TNF

What do you give a patient who has failed conventional therapy for severe Crohn's ? All have an indication for severe Crohn's who have failed conventional therapy.

Anti-Tumor Necrosis Factor Agent

Adalimumab

Anti-Tumor Necrosis Factor Agent Subcutaneous 100% human

Certolizumab

Anti-Tumor Necrosis Factor Agent Subcutaneous Pegylated humanized Fab Freagment

Where does Crohn's Disease occurs?

Any part of the GI tract Small intestine (common), terminal ileum & cecum

ADR for Vedolizumab?

Arthralgia, bronchitis, cough, back pain, rash, pruritus, sinusitis, nasopharyngitis, nausea, pyrexi, URTI, fatigue, influenza, oropharyngeal pain, pain in extremities

Crohn's Disease Severe to Fulminant assess all patients for

Assess patient for masses, obstruction, abscess

Ulcerative Colitis Mild-Moderate Extensive 3rd line

Azathioprine or 6-mercaptopurine

C.C. is a 53-year-old man with CD for the past 12 years who is hospitalized because of disease relapse. Colonoscopy is consistent with moderate to severe disease located in the colon and terminal ileum. He has not responded to a 5-day course of intravenous methylprednisolone, and on review of C.C.'s medical record and a discussion with him, you determine he was taking prednisone 40 mg orally once daily for 12 days before this hospital admission. His severe symptoms continue; temperature is 101.3°F, blood pressure 131/81 mm Hg, and heart rate 68 beats/minute. He has normal kidney and liver function, and a workup for infectious disease is negative. Which therapy would be best to initiate? A. Metronidazole 500 mg orally three times daily. B. Infliximab 5mg/kg intravenously. C. Azathioprine 100 mg orally once daily. D. Hydrocortisone 100 mg intravenously every 8 hours.

B.

Monitoring for Infliximab?

BP and HR

Adverse effects of Immunosuppressant Agents?

Bone marrow suppression, pancreatitis, liver dysfunction, rash, arthralgia, fatigue, nausea, flu-like symptoms, hypersensitivity reactions, hepatotoxicity (rare), lymphoma infection Overall well tolerated but must monitor the patient (CBC, SCr, BUN, LFTs)

Crohn's Disease Moderate to Severe treatment for Terminal ileum/ascending colon

Budesonide

Crohn's Disease Moderate to Severe treatment

Budesonide (terminal ileum/ascending colon) Prednisone Infliximab (fistulizing or perianal disease) Remission in 80% at 8 weeks Perianal fistulae simple: infliximab and abx complex: above, surgery or immunosuppressive

Monitoring for Methotrexate?

CBC, SCr, BUN, LFTs, baseline CXR, pregnancy test for females

What are Long term use adverse effects of corticosteroids?

Cataracts, hypertension, *elevated blood sugar*, osteoporosis, infection risk, acne, mood/sleep disturbances, suppressed immunity, increased susceptibility to fungal and bacterial infections, edema

What medications are only approved for adults?

Cipro, vedolizumab, certolizumab, and natalizumab

Budesonide (Entocort EC)

Corticosteroid Used for IBD PO Capsules Long acting formulation, limited absorption from GI tract More localized effect Less systemic side effects Steroid of choice in Crohn's Disease Short term efficacy less than other steroids *Only steroid that can be used long term* More potent than prednisone

IBD Anti-inflammatory effect with systemic or local administration Immunosuppression and prostaglandin inhibition Role in therapy Used in conjunction with other medications Used alone to treat acute exacerbations *(ONLY DURING INDUCTION)*

Corticosteroids

Ulcerative Colitis Maintenance -Remission who can take a corticosteriods?

Corticosteroids are not an option for remission in ANY patients

What is located in the transmural inflammation of GI tract and may involve any segment of the GI tract from mouth to perianal area, patchy "cobblestones", and has complications of fistulas, perforations, strictures, and malabsorption?

Crohn's *mainly location*

What does this describe? Depth of ulceration Submucosa or deeper Inflammation Patchy, 'cobblestone' Fistulas, perforations, strictures common Malabsorption present

Crohn's Disease

What medication has a role in inhibiting the production and release of Interleukin 2 and is restricted to use in pts with fulminate or refractory symptoms of UC who failed other therapies?

Cyclosporine

_______1-2 weeks after therapy with any Anti-Tumor Necrosis Factor agent

Delayed serum sickness-like reaction

extent of UC Distal disease

Distal to splenic flexure Topical or systemic treatment

T/F? Bleeding, fever, weight loss, anemia and persistent severe pain are symptoms of IBS.

FALSE IBD

T/F Dosage adjustments must not be considered

FALSE! they must be considered

Severity of Crohn's Disease moderate to severe

Fail treatment Fever, weight loss, abd pain, vomiting, obstruction

IBS Management: Constipation predominant types of laxitives?

Fiber can lead to increased bloating and abdominal discomfort Osmotic laxatives, such as milk of magnesium, can soften stool and may increase stool frequency without bloating

Monitoring parameters of Sulfasalazine?

Folate, CBC, LFTs, BUN, SCr

Immunosuppressant Agents have a _____delay of onset for therapeutic benefit from therapy.

Four month

UC classification: More than 10 bowel movements per day, continuous bleeding, toxicity, abd tenderness and dissension, blood transfusion requirement, and colonic dilation on abd plain films?

Fulminant UC

What is the last line agent for Biologic agents?

Golimumab

What medication if indicated for moderate to severely active disease in those patients with steroid dependency or those whose conventional therapies have failed?

Golimumab (humanized monoclonal TNF antibody)

What are Mesalamine, Aminosalicylates A/E

HA, N/V, rash, pancreatitis, paradoxical exacerbation, interstitial nephritis. Pain with symptomatic worsening of IBD at initiation of therapy

ADR of Adalimumab?

Heart failure, optic neuritis, demyelination

Crohn's Disease Severe to Fulminant treatment

Hospitalization (assess for mass, obstruction, abscess) IV corticosteroids (prednisone) Infliximab Adjunctive therapy (Nutritional support, fluid/electrolytes)

Ulcerative Colitis Severe to Fulminant Whats the treatment?

Hospitalization for IV corticosteroids and hydration if unresponsive to other therapies Hydrocortisone 300mg/day Methylprednisolone 60mg Infliximab 5mg/kg Cyclosporine 2-4mg/kg/day continuous IV for 7-10 days

Drug Interactions with Mesalamine, Aminosalicylates?

Increased risk of myelosuppression with Azathioprine,Mercaptopurine

DI of Mesalamine?

Increased risk of myelosuppression with Azathiprine, Mercaptopurine

Goal of pregnancy tx

Induce and maintain remission of IBD prior to contraception (active TBD may cause prematurity and low birth weight)

Anti-Tumor Necrosis Factor Agents: Ulcerative Colitis ______produces a response in 70% of patients One-third achieve a full clinical remission

Induction therapy

ADRs for Biologic Agents?

Infection, PML- opportunistic demyelinating brain disorder with 50% mortality, fatigue, HA, depression, arthralgia

in UC what is continuous, confluent throughout the GI tract

Inflammation

___________, _____________, and __________ are indicated for UC: mild to moderate extensive disease: Refractory to standard therapies, in patients who have failed first line therapy with Mesalamine or steroids?

Infliximab, Adalimumab, and Golimumab

_____ reactions are common with infliximab

Infusion, infections

Stimulate the type 2 chloride channel in the small intestine to increase intestinal fluid secretion and improve fecal transit Approved for use in women with constipation predominant IBS 8mcg twice daily (dose for chronic constipation is 24 mcg BID) Category C - avoid use in women of child bearing age

Lubiprostone (Amitiza)

ADR for Certolizumab?

Lymphoma

What comes in different formulations (enema, tablets, and capsules) and is most widely used in practice?

Mesalamine

Ulcerative Colitis Maintenance -Remission what are you giving for distal dz

Mesalamine enemas 3 x week

Ulcerative Colitis Maintenance -Remission what are you giving for proctitis

Mesalamine suppositories 1 gram daily

An antimetabolite with proposed mechanisms of action in Crohn's Disease: Interfere with the inflammatory actions of interleukin-1 Increase release of adenosine, an endogenous anti-inflammatory autacoid. May stimulate death of activated T lymphocytes.

Methotrexate

What medication is an abortifacient and is pregnancy category X?

Methotrexate

What 2 medications need to be avoided in pregnancy?

Metronidazole and Ciprofloxacin

What are the commonly used antibiotics

Metronidazole, ciprofloxacin

For Crohn's Disease Mild-Moderate antibiotics

Metronidazole/ciprofloxacin up to 50% response

UC classification: fewer than 4 stools per day with our without blood, without systemic disturbance and with a normal ESR?

Mild UC

UC classification: More than 4 stools per day with minimal signs of toxicity

Moderate UC

ADR of Sulfasalazine?

N/V, HA, rash, anemia, pneumonitis, hepatotoxicity, nephritis, thrombocytopenia, lymphoma, pancreatitis, paradoxical exacerbation

______ associated with disease flares in UC

NSAIDS

What is a humanized monoclonal antibody against cell adhesion molecule alpha4-integrin and prevents inflammatory WBCs from migrating into tissue?

Natalizumab

What medication is only available through a restricted distribution program (TOUCH) and cannot be combined with other immunosuppressants?

Natalizumab Must taper off steroids within 6 months

Methotrexate adverse effects?

Nausea, fatigue/malaise, hepatotoxicity, pancreatitis, bone marrow suppression, hypersensitivity, pneumonitis, pulmonary fibrosis, teratogen, increased risk of infection

Adverse effects of Cyclosporine?

Nephrotoxicity risk is increased with high doses, longer use, older age. Renal fx will improve once discontinued Hypertension, low magnesium, nausea/vomiting, opportunistic infections, seizures

Ulcerative Colitis Mild-Moderate Extensive 2nd line

Oral corticosteroids Prednisone 40-60mg a day Infliximab 5mg/kg IV weeks 0, 2, 5

Ulcerative Colitis Mild-Moderate Extensive 1st line

Oral sulfasalazine (4-6grams)or oral mesalamine (4.8grams)

Ulcerative Colitis Maintenance -Remission what are you giving for extensive dz

Oral sulfazalazine (2-4 grams) or mesalamine (1.6-2.4 grams) Should not be on chronic steroids

Severity of Crohn's Disease Severe to fulminant

Persistent symptoms, systemic toxicity Cachexia, obstruction, tenderness

BBW for Natalizumab?

Risk of progressive multifocal leukoencephalopathy, a potentially fatal opportunistic viral infection (typically apparent in those with prior immunosuppressant exposure or with a duration of infusion longer than 2 years)

Contraindications for Mesalamine, Aminosalicylates?

Salicyclate allergy

Monitoring for Biologic Agents?

Signs of hepatotoxicity, baseline MRI, mental status, signs of PML

Crohn's Disease Moderate to Severe treatment for Simple perianal fistulae treatment simple and complex

Simple: infliximab and antibiotics Complex: above, surgery or immunosuppressive

Crohn's Disease Perianal lesions

Skin tags, hemorrhoids, fissures, fistulae

What must be supplemented with folic acid in pregnancy?

Sulfasalazine

Ulcerative Colitis Severe to Fulminant what may require surgical intervention

Systemic toxicity or colonic dilation

What must be tested prior to the initation of therapy of biologic agents?

TB, Hep B or C educate patients to avoid live vaccines during therapy It can reactive TB, HPV, and sepsis

T/F? Inflammatory Bowel Disease Typically involves periods of remission and exacerbation?

TRUE

Induction therapy

The first in a series of therapeutic measures taken to treat a disease. Steroids

What are are superior to both topical corticosteroids and oral aminosalicylates with More rapid response, 90% response rate in Ulcerative Colitis Mild-Moderate Distal

Topical aminosalicylates (enema/suppository)

Ulcerative Colitis Mild-Moderate Distal treatments

Topical aminosalicylates (enema/suppository) Oral aminosalicylates Topical corticosteriods Topical mesalamine Use of topical and oral mesalamine together Oral prednisone 40-60 mg

An adjunctive therapy is nicotine patch; smoking reduces symptoms of _______

UC

UC Superficial

Ulceration or erosion Crypt abscesses Pseudopolyps

What does this describe? Depth of ulceration Superficial Inflammation Commonly continuous Risk of toxic megacolon Pseudopolyps common Colon cancer risk

Ulcerative Colitis

What is located limited to mucosal layer of colon and/or rectum, commonly continuous inflammation, and complications of severe bleeds and fulminant colitis/toxic megacolon?

Ulcerative Colitis

name 2 Inflammatory Bowel Diseases.

Ulcerative Colitis and Crohn's disease

Ulcerative Colitis Moderate to Severe when do you add a steroid?

Unresponsive to maximal doses of sulfasalazine or mesalamine derivatives, add steroid (prednisone) Up to 1mg/kg/day Similar efficacy to sulfasalazine/mesalamine but beneficial effects may occur more rapidly with steroids

Anti-Tumor Necrosis Factor Agents: Adverse Effects?

Up to 6% of patient have a serious event Infection due to suppression of inflammatory response Serious infection or reactivation of infections such as: tuberculosis, hepatitis B, fungal infections More common if also taking steriods More common but less serious infections include sinusitis, bronchitis, pneumonia Infusion reactions are common with infliximab Delayed serum sickness-like reaction 1-2 weeks after therapy with any agent Severe hepatic reactions Worsening of Congestive Heart Failure Increased risk of Lymphoma with treatment Risk of lymphoma from untreated IBD alone!

What biologic agent is used for UC and CD in moderately to severely active disease who have had an inadequate response, lost response, were intolerant to other agents?

Vedolizumab

What is a humanized monoclonal antibody that is an integrin receptor antagonist and effective for inducing and maintaining clinical response and remission, improving endoscopic appearance of the mucosa and achieving steroid free remission?

Vedolizumab

When treating IBD with corticosteroids Effects are usually within ________

a week

What adjunctive therapy do you give to Initially rule out any infectious etiology and Modify host flora to interrupt the inflammatory response

antibiotics

3 adjunctive therapies

antibiotics nicotine patch (UC) probiotics

____ if patient with progressive disease with Ulcerative Colitis Maintenance in Remission

colectomy

Crohn's Disease Inflammation can penetrate to

deep layers of GI tract strictures, fissures

Anti-Tumor Necrosis Factor Agents Approximately 1/3 of patients lose response over time. This is possibly due to ____________

development of antibodies to the TNF antibody

T/F you should discontinue drug therapy for IBD during pregnancy?

false!

Severity of Ulcerative Colitis? >10 stools, continuous bleeding, systemic toxicity

fulminant

When do you initiate immunosuppressants for an acute flare?

if it can help maintain the future remission, will not help the immediate exacerbation since delay inefficacy

Ulcerative Colitis Moderate to Severe Inadequate response with the combination therapy consider adding an ______

immunosuppressant Azathioprine or Mercaptopurine

Crohn's Disease ____ is discontinuous Intermixed with normal areas, cobblestone pattern

inflammation

Ulcerative Colitis Maintenance -Remission give Intermittent ____ dosing (5mg/kg IV Q8 weeks)

infliximab

IBS Management: Diarrhea predominant. Antidiarrheals such as _______ can decrease frequency and urgency

loperamide

Anti-Tumor Necrosis Factor Agents Approximately 1/3 of patients _____. This is possibly due to development of antibodies to the TNF antibody

lose response over time

Severity of Ulcerative Colitis? Up to 4 bloody/watery stools a day; no systemic

mild

Severity of Ulcerative Colitis? >4 bloody/watery stools/day Possible anemia, weight loss, nausea-vomiting

moderate

Long term use of corticosteroids is not recommended but if used _________! and for what?

monitoring is required BP, fasting lipids, glucose, vitamin D, bone density

What you can Add _____ at low doses to improve remission rates

oral mesalamine

What is an adjunctive therapy that Modify host flora to alter inflammatory response

probiotics

Severity of Ulcerative Colitis?> 6 stools, anemia/tachycardia, elevated ESR

severe

Ulcerative Colitis treatment depends on

severity and extent of disease

When treating IBD with corticosteroids Restrict use to _____?

short-term management of active disease (< 3 months)

What can cause these adverse effects? Increase glucose levels, insomnia, anxiety, fluid retention (edema)

treating IBD with corticosteroids