Drugs used in inflammatory bowel disease and biological and immune therapy of IBD

Prof. Hanan HagarPharmacology Department

College of Medicine

Chronic inflammatory bowel diseasesChronic inflammatory bowel diseases

(IBD)(IBD)

IBD is IBD is is a group of is a group of inflammatory conditions conditions of the of the colon and and small intestine. .

auto-immune disordersauto-immune disorders The major types of IBD are The major types of IBD are Crohn's disease

and and ulcerative colitis (UC). (UC).

Differences between Crohn's disease and UC

Crohn's disease Ulcerative colitis

Location affect any part of the GIT, from mouth to anus

Restricted to colon & rectum

Distribution Patchy areas of inflammation (Skip

lesions)

Continuous area of inflammation

Depth of inflammation

deep into tissues Shallow, mucosal

Complications Strictures, Obstruction

Abscess, Fistula

Toxic mega colon

Colon cancer

Crohn's diseaseUlcerative colitis

Causes of IBDsCauses of IBDs

Not known.Not known. Abnormal activation of the immune Abnormal activation of the immune

system.system. The susceptibility is genetically inherited.The susceptibility is genetically inherited.

SymptomsSymptoms

VomitingVomiting Abdominal painAbdominal pain DiarrheaDiarrhea Rectal bleeding.Rectal bleeding. Weight lossWeight loss

ComplicationsComplications

1.1. AnemiaAnemia

2.2. Abdominal obstruction (Crohn’s disease)Abdominal obstruction (Crohn’s disease)

3.3. Mega colonMega colon

4.4. Colon cancerColon cancer

There is There is no cure no cure for IBDs but treatment for IBDs but treatment options are restricted to controlling options are restricted to controlling symptoms, maintaining remission, and symptoms, maintaining remission, and preventing relapse. preventing relapse.

Treatment of IBDTreatment of IBD

Treatment of IBDTreatment of IBD

1.1. 5-amino salicylic acid compounds (5-ASA).5-amino salicylic acid compounds (5-ASA).

2.2. GlucocorticoidsGlucocorticoids

3.3. Immunomodulators Immunomodulators

4.4. Biological therapy (TNF-Biological therapy (TNF-αα inhibitors). inhibitors).

5.5. Surgery in severe conditionSurgery in severe condition

5-amino salicylic acid compounds (5-ASA) 5-amino salicylic acid compounds (5-ASA)

AminosalicylatesAminosalicylates

Topical Topical anti-inflammatory drugsanti-inflammatory drugs 5-ASA itself is absorbed from small intestine.5-ASA itself is absorbed from small intestine. Different formulations are used to overcome Different formulations are used to overcome

rapid absorption of 5-ASA from the proximal rapid absorption of 5-ASA from the proximal

small intestinesmall intestine Azo compoundsAzo compounds Mesalamine compoundsMesalamine compounds

Azo compoundsAzo compounds

Compounds that contain 5-ASA and Compounds that contain 5-ASA and connected by azo bond connected by azo bond (N=N)(N=N) to to sulfapyridine moiety, another molecule of sulfapyridine moiety, another molecule of 5-ASA or to inert compound.5-ASA or to inert compound.

Sulfasalazine: Sulfasalazine: 5-ASA + sulphapyridine 5-ASA + sulphapyridine

Olsalazine:Olsalazine: 5-ASA + 5-ASA5-ASA + 5-ASA

Balsalazide:Balsalazide: 5-ASA + inert carrier 5-ASA + inert carrier

Azo compoundsAzo compounds

Azo structure reduces absorption in small Azo structure reduces absorption in small intestineintestine

In the terminal ileum and colonIn the terminal ileum and colon, bacterial , bacterial flora release flora release azoreductaseazoreductase that cleaves the that cleaves the azo bond azo bond (N=N)(N=N) and releases 5-ASA. and releases 5-ASA.

Sulfasalazine (Azulfidine)Sulfasalazine (Azulfidine)

Pro-drugPro-drug A combination of 5-ASA and sulfapyridineA combination of 5-ASA and sulfapyridine Is given orally.Is given orally. Little amount is absorbed Little amount is absorbed (10%)(10%) In the terminal ileum and colonIn the terminal ileum and colon, sulfasalazine is , sulfasalazine is

broken by azoreductase into:broken by azoreductase into: 5-ASA (not absorbed, 5-ASA (not absorbed, active moietyactive moiety)) Sulphapyridine (absorbed, Sulphapyridine (absorbed, side effectsside effects))

Mechanism of action of sulfasalazineMechanism of action of sulfasalazine

5-ASA has anti-inflammatory action due to:5-ASA has anti-inflammatory action due to: inhibition of prostaglandins and leukotrienes.inhibition of prostaglandins and leukotrienes. decrease neutrophil chemotaxis.decrease neutrophil chemotaxis. Antioxidant activity (scavenging free radical Antioxidant activity (scavenging free radical

production).production).

Side effects of sulfasalazineSide effects of sulfasalazine

Crystalluria.Crystalluria. Bone marrow depression Bone marrow depression Megaloblastic anemia.Megaloblastic anemia. Folic acid deficiency (should be provided).Folic acid deficiency (should be provided). Impairment of male fertility Impairment of male fertility ((OligospermiaOligospermia).). Interstitial nephritis due to 5-ASA.Interstitial nephritis due to 5-ASA.

Mesalamine compoundsMesalamine compounds

Formulations designed to deliver 5-ASA in Formulations designed to deliver 5-ASA in

terminal small bowel & large colonterminal small bowel & large colon

MesalamineMesalamine formulations are formulations are Sulfa free Sulfa free well toleratedwell tolerated have less side effects have less side effects useful in patient sensitive or allergic to sulfa useful in patient sensitive or allergic to sulfa

drugs.drugs.

Mesalamine compoundsMesalamine compounds

Oral formulationsOral formulationsAsacol:Asacol: 5-ASA coated in pH-sensitive resin that5-ASA coated in pH-sensitive resin thatdissolved at pH 7 (dissolved at pH 7 (controlled releasecontrolled release).).

Pentasa:Pentasa: time-release microgranules that releasetime-release microgranules that release5-ASA throughout the small intestine (5-ASA throughout the small intestine (delayeddelayedreleaserelease).).

Rectal formulations Rectal formulations CanasaCanasa (suppositories)(suppositories)RowasaRowasa (enema)(enema)

Clinical uses of Clinical uses of 5-amino salicylic acid compounds 5-amino salicylic acid compounds

Induction and maintenance of remission Induction and maintenance of remission

in mild to moderate ulcerative colitis & in mild to moderate ulcerative colitis & Crohn’s disease (Crohn’s disease (First line of treatmentFirst line of treatment).).

Rheumatoid arthritisRheumatoid arthritis (Sulfasalazine only)(Sulfasalazine only) Rectal formulations are used in active distalRectal formulations are used in active distal

UC UC ulcerative ulcerative proctitisproctitis and and proctosigmoiditis. proctosigmoiditis. 

GlucocorticoidsGlucocorticoids

Prednisone, prednisolonePrednisone, prednisolone (orally)(orally) Higher rate of absorption Higher rate of absorption More adverse effects compared to rectal More adverse effects compared to rectal

administrationadministration

Hydrocortisone Hydrocortisone ((enema or suppository)enema or suppository):: Less absorption rate than oral.Less absorption rate than oral. Minimal side effects & Maximum tissue Minimal side effects & Maximum tissue

effectseffects..

Budesonide:Budesonide:

A potent synthetic compoundA potent synthetic compound Given orally Given orally (controlled release tablets)(controlled release tablets) so so

release drug in ileum and colon.release drug in ileum and colon. Low oral bioavailability (10%).Low oral bioavailability (10%). Is subject to Is subject to first pass metabolismfirst pass metabolism Used in treatment of active forms of moderate Used in treatment of active forms of moderate

to severe UC & Crohn’s disease involving to severe UC & Crohn’s disease involving ileum and proximal colon.ileum and proximal colon.

Mechanism of action of glucocorticoidsMechanism of action of glucocorticoids

Inhibits phospholipase A2Inhibits phospholipase A2

Inhibits gene transcription of NO synthase, Inhibits gene transcription of NO synthase,

cyclooxygenase-2 (COX-2)cyclooxygenase-2 (COX-2)

Inhibit production of inflammatory Inhibit production of inflammatory

cytokinescytokines

Decrease antigen-antibody reaction Decrease antigen-antibody reaction

Uses of glucocorticoids

Induction of remission in moderate & severe moderate & severe

active IBD.active IBD.

Not used for maintaining remission.Not used for maintaining remission.

Oral glucocorticoidsOral glucocorticoids is commonly used in is commonly used in

active condition. active condition.

Rectal glucocorticoidsRectal glucocorticoids are preferred in IBD are preferred in IBD

involving rectum or sigmoid coloninvolving rectum or sigmoid colon

Uses of glucocorticoids

Asthma Rheumatoid arthritis immunosuppressive drug for organ transplants Antiemetics during cancer chemotherapy

Immunomodulators Immunomodulators

Are used to induce remission in IBD in Are used to induce remission in IBD in active,active,severe conditionssevere conditions or steroid resistant patients.or steroid resistant patients.

Immunomodulators include:Immunomodulators include: MethotrexateMethotrexate Purine analogs:Purine analogs:

(azathioprine & 6-mercaptopurine).(azathioprine & 6-mercaptopurine).

Purine analogs Purine analogs (azathioprine & 6-mercaptopurine)(azathioprine & 6-mercaptopurine)

AzathioprineAzathioprine is a pro-drug of 6-mercaptopurineis a pro-drug of 6-mercaptopurine Inhibits purine synthesisInhibits purine synthesis Induction and maintenance of remission Induction and maintenance of remission

in IBDin IBD

Adverse effectsAdverse effects::

Bone marrow depression: Bone marrow depression: leucopenia, leucopenia,

thrombocytopenia. thrombocytopenia. Gastrointestinal toxicity.Gastrointestinal toxicity. Hepatic dysfunction.Hepatic dysfunction. Complete blood count & liver function Complete blood count & liver function

teststests are required in all patients are required in all patients

MethotrexateMethotrexate

a folic acid antagonist a folic acid antagonist Inhibits Inhibits dihydrofolate reductasedihydrofolate reductase required required

for folic acid activationfor folic acid activation Orally, S.C., I.M.Orally, S.C., I.M. UsedUsed to induce and maintain remission in to induce and maintain remission in

inflammatory bowel diseases. inflammatory bowel diseases. Rheumatoid arthritisRheumatoid arthritis CancerCancer

Adverse effects of methotrexateAdverse effects of methotrexate

Bone marrow depressionBone marrow depression Megaloblastic anemiaMegaloblastic anemia

Monoclonal antibodies used in IBD(TNF-α inhibitors)

Infliximab Adalimumab Certolizumab

InfliximabInfliximab

a chimeric mouse-human monoclonal antibody a chimeric mouse-human monoclonal antibody 25% murine – 75% human.25% murine – 75% human. TNF-α inhibitors Inhibits soluble or membrane –bound TNF-α Inhibits soluble or membrane –bound TNF-α

located on activated T lymphocyteslocated on activated T lymphocytes Given intravenously as infusion (5-10 mg/kg).Given intravenously as infusion (5-10 mg/kg). has long half life (8-10 days) has long half life (8-10 days) 2 weeks to give clinical response2 weeks to give clinical response

Uses of infliximabUses of infliximab

In moderate to severe active Crohn’s In moderate to severe active Crohn’s disease and ulcerative colitis disease and ulcerative colitis

Patients not responding to Patients not responding to immunomodulators or glucocorticoids.immunomodulators or glucocorticoids.

Treatment of rheumatoid arthritisTreatment of rheumatoid arthritis PsoriasisPsoriasis

Side effectsSide effects

Acute or early adverse infusion reactions Acute or early adverse infusion reactions (Allergic reactions or anaphylaxis in 10% of (Allergic reactions or anaphylaxis in 10% of patients).patients).

Delayed infusion reaction Delayed infusion reaction (serum sickness-(serum sickness-like reaction, in 5% of patients).like reaction, in 5% of patients).

Pretreatment with diphenhydramine, Pretreatment with diphenhydramine, acetaminophen, corticosteroids is acetaminophen, corticosteroids is recommended.recommended.

Side effects (Cont.)Side effects (Cont.)

Infection complication Infection complication (Latent tuberculosis, (Latent tuberculosis, sepsis, hepatitis B).sepsis, hepatitis B).

Loss of response to infliximab over time Loss of response to infliximab over time due due to the development of antibodies to infliximabto the development of antibodies to infliximab

Severe hepatic failure.Severe hepatic failure. Rare risk of lymphoma. Rare risk of lymphoma.

Adalimumab (HUMIRA)Adalimumab (HUMIRA)

Fully humanized IgG antibody to TNF-αTNF-α Adalimumab is TNFα inhibitor It binds to TNFα, preventing it from activating

TNF receptors Has an advantage that it is given by

subcutaneous injection is approved for treatment of, moderate to

severe Crohn’s disease, rheumatoid arthritis, psoriasis.

Summary for drugs used in IBD

5-aminosalicylic acid compounds Azo compounds:

sulfasalazine, olsalazine, balsalazide Mesalamines:

Pentasa, Asacol, Rowasa, Canasa Glucocorticoids prednisone, prednisolone, hydrocortisone, budesonideImmunomodulators

Methotrexate Purine analogues:

Azathioprine &6-mercaptopurineTNF-alpha inhibitors (monoclonal antibodies)

Infliximab – Adalimumab - Cetrolizumab

Thank you

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