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DRUGS FOR

GASTROINTESTI
NAL TRACT
DISEASES
BANDOLA, Angelica
BONGAT, Michelle Ann
FRANCISCO, Zyrelle
GARRIDO, John Paul
NACION, Allea Joyce

GASTROINTESTINAL
TRACT
A group
of organs
working
together

Convert
food ->
energy

Digest
food and
process
waste
http://www.mayoclinic.org/gastrointestinal-tract/img-20007468

GASTROINTESTINAL
DRUGS

This chapter describes
drugs used to treat:
1) Peptic ulcers and
Gastroesophageal Reflux
Disease (GERD)
2) Chemotherapy-induced
emesis
3) Diarrhea
4) Constipation
5) Inflammatory bowel disease

PHASES OF GASTRIC SECRETION Phase Cephalic (stimulate) Gastric  (stimulate) Stimuli Pathway Sight. taste or  1)Vagus thought of food (M3 receptors) 2)Histamine(H2 rece ptor) 3)Gastrin Food in the stomach 1)Stretch: local refle x  (M3  receptors) 2)Chemical substanc es in food  (gastrin) 3)Increase pH: Inhibi tion of  somatostatin (GHIH)  release . smell.

ANATOMY OF STOMACH .

PHYSIOLOGY OF THE STOMACH WHAT DO MECHANICAL I DO WHEN YOU EAT? DIGESTION CHEMICAL www.docsity.com .

STOMACH SECRETES… Hydrochloric acid (HCl) • digestive acid secreted by parietal cells in the stomach Mucus • protects the stomach lining from both HCl and digestive enzymes Intrinsic factor • a glycoprotein that facilitates gastric absorption of vitamin B12 Bicarbonate • – a base that is a natural mechanism to prevent hyperacidity .

STOMACH SECRETES… (con’t) Pepsinogen • an enzymatic precursor to pepsin.com/anatomy-book/contents/m46517. an enzyme that digests dietary proteins Prostaglandins • serve a variety of anti-inflammatory and protective functions http://philschatz.html .

DRUGS FOR GASTROINTESTINAL DISORDERS Gastroesophageal reflux disease (GERD) Peptic Ulcer Inflammatory Bowel Disease .

.STATISTICSGERD 6 % of adult population experience GERD 20 % http://www.com/health/gerd/statistics#2 Will experience weekly symptoms within 12 months.healthline.

4M Prescriptions were written for GERD in the United States on an annual basis $2 billion Are lost productivity each week of the year because of the symptoms of GERD. http://www.MEDICAL COST OF GERD 64.healthline.com/health/gerd/statistics#2 .

com/health/gerd/facts-statistics-infographic#4 .healthline.MEDICAL COST OF GERD http://www.

com/health/gerd/statistics#2 .62% > of all hospitalizations for GERD in 2005. Women are more likely to be hospitalized for GERD symptoms than men.  http://www.healthline.

PEPTIC
COMMON
ULCER

10-15%
OF THE POPULATION

Ulcer rates are declining for young
men and increasing for older
individuals
http://www.myvmc.com/diseases/peptic-ulcer-disease-pud/

WHAT IS PEPTIC ULCER
(PUD) ?
• is an ulcer of 
an area of 
the gastrointestinal
tract
exposed to the 
acid and 
pepsin secretion
• Gastritis → precursor 
to PUD and it is clinic
ally difficult to differe

WHAT IS PEPTIC ULCER (PUD) ?

Stomach 
(Gastric ulcer)

Duodenum 
(Duodenal ulcer
)

Esophagus 
(Esophageal ulc
er)

Meckel's Diverticu
lum 
(Meckel's Divertic
ulum ulcer)

 vom iting Infrequent or absent remis sions • Small % become cancerou s  • Severe ulcers may erode t hrough  stomach wall .DUODENAL VS GASTRIC ULCERS DUODENAL  GASTRIC • Age: 25‐75 years • Gnawing or burning uppe r abdomen pain relieved b y food but reappears 1‐ 3 hrs  after meals • Worse pain when stomac h empty • Bleeding occurs with deep erosionHematemesis-Melena  • Age: 55‐65 years • Relieved by food but pain  may  persist even after eating • Anorexia. weight loss.

WHY ULCERATION OCCUR S?  High [H+] in the Gastric lum en Stomach: a number of mech anisms • Mucus secretion: slows ion diffusi on • Prostaglandins: I2 and E2 • (alcohol. and other drug s) • Bicarbonate ions • High Blood Flow (nitric oxide)  Because of imbalance . aspirin.

ethanol & tobacco Stress and increased hydrochloric acid (HCl) secretion Inadequate mucosal defense against gastric acid Imbalance .MAIN CAUSES OF PEPTIC ULCER DISEASE Infection with gram-negative Helicobacter pylori Use of nonsteroidal anti-inflammatory drugs (NSAIDs).

IMBALANCE PRIMARILY BETWEEN  AGGRESSIVE FACTORS AND DEFENSIVE FACT ORS Aggressi Defensiv ve e factors factors bile Acid pepsi n HCO3 mucu s .

H. Pylori • Gram (‐) rod with flagella • most common cause of  PUD Transmission route fecal‐ oral • Secretes urease → convert urea to ammonia • Produces alkaline environ ment  enabling survival in stoma ch • Almost all duodenal and 2/ 3  gastric ulcer pt’s infected  .

Barry J Marshall & J. pylori & its role in peptic ulcer . Robin Warren discovered of H.

.

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 pylor i • More often in  duodenum • Often superficial • Less severe GI bleeding Ulcers associated with NSAIDs • More often in stomach • Often deep more severe GI  bleeding Sometimes  asymptomatic . PYLORI  AND NSAID‐INDUCED ULCER Ulcers associated with H.DIFFERENTIATING BETWEEN H.

pylori infection Reducing secretion of gastric acid with the use of PPIs or H2-receptor antagonists Providing agents that protect the gastric mucosa from damage.TREATMENT APPROACHES Eradicating the H. such as misoprostol and sucralfate .

GASTROESOPHAGEAL REFLUX DIS EASE  (GERD) Common and GI m otility disorder Acid contents reflux b ack into esophagus Intense burning.   • and  strictures – Barrett’s esophagus Improves with life style  management .  esophageal ulcers.  som etimes belching Commonly associa ted  with obesity Acidity of Gastric c ontents –most  common factor Can lead to esoph agitis.

.

ANTIMICROBIAL AGENTS • For patients with peptic ulcer disease (duodenal or gastric ulcers) who are infected with H.serology and urea breath tests . endoscopic biopsy of the gastric mucosa b. pylori • H. various noninvasive methods . pylori is diagnosed via: a.

ANTIMICROBIAL AGENTS
• Eradication of H. pylori
rapid healing of
active ulcers and low recurrence rates
• Successful eradication of H. pylori (80% to 90%) is
possible with various combinations of antimicrobial
drugs.
 Triple therapy – therapy of choice
PPI combined with amoxicillin (metronidazole may be
used in penicillin-allergic patients) + clarithromycin
 Quadruple therapy – considered in areas with high
resistance to clarithromycin; results in a 90% or greater
eradication rate
PPI + bismuth subsalicylate + metronidazole +
tetracycline

Treatment with a Single
Antimicrobial Drug

Much less effective
Results in antimicrobial
resistance
Not recommended

Substitution of antibiotics Do not substitute ampicillin for amoxicillin or doxycycline for tetracycline .

H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION Acetylcholin e Gastric acid secretion is stimulated by: Histamine Gastrin .

H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION Receptormediated binding of acetylcholine. histamine. or gastrin Activation of protein kinases Stimulates the H+/K+adenosine triphosphatas e (ATPase) proton pump Secrete hydrogen ions in exchange for K+ into the lumen of the stomach .

.

and nocturnal secretion of gastric acid • Cimetidine • Ranitidine • Famotidine • Nizatidine .H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION Competitively blocking the binding of histamine to H2 receptors → these agents reduce the secretion of gastric acid Potently inhibit (greater than 90%) basal. foodstimulated.

H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION Histamine H2receptor antagonists • Act selectively on H2 receptors in the stomach • Have no effect on H1 receptors • Competitive antagonists of histamine and are fully reversible. .

H2-RECEPTOR H2-RECEPTOR ANTAGONISTS ANTAGONISTS AND AND REGULATION REGULATION OF OF GASTRIC GASTRIC ACID ACID SECRETION SECRETION Cimetidine • First histamine H2receptor antagonist • Its utility is limited by its adverse effect profile and drug– drug .

Famotidine & Nizatidine • Use of these agents has decreased with the advent of PPIs • Effective in promoting the healing of duodenal and gastric ulcers • Recurrence is common if H.Ranitidine.H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION Cimetidine . pylori is present and the patient is treated with these agents alone .

H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION Patients with NSAID-induced ulcers Should be treated with PPIs (because these agents heal and prevent future ulcers more effectively than H2 antagonists Given as an intravenous infusion to prevent and manage acute stress ulcers associated with high-risk patients in intensive care units (tolerance may occur) .

especially for • • • • .Effective for the treatment of heartburn (GERD) Low doses of H2 antagonists OTC Act by stopping acid secretion May not relieve symptoms for at least 45 minutes • Antacids → quickly and efficiently neutralize stomach acid. action is only temporary • PPIs → now used preferentially in the treatment of GERD.

ranitidine. and famotidine -intravenous formulations • t ½ ↑ in patients with renal dysfunctio → dosage adjustments are needed .H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION After oral administration → distribute widely throughout the body (including into breast milk and across the placenta) Excreted mainly in urine Cimetidine.

such as .H2-RECEPTOR ANTAGONISTS AND REGULATION OF GASTRIC ACID SECRETION ADVERSE EFFECTS • H2 antagonists → well tolerated • Reduce the efficacy of drugs that require an acidic environment for absorption.

CNS EFFECTS Occur primarily in elderly patients and after intravenous administration Confusion & altered mentation .

Cimetidi ne Endocrine effects acts as a nonsteroidal antiandrogen (Cimetidine) Gynecomas tia Galactorrhe as .

phenytoin. and Clopidogrel .Endocrine effects acts as a nonsteroidal antiandrogen (Cimetidine) Interfere with Inhibits several cytochrome P450 isoenzymes the metabolism of many other drugs. such as warfarin.

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Dexlansopr azole Esomeprazo le Lansoprazol e Omeprazole Pantoprazol e Rabeprazol e .

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Bind to the H+/K+.ATPase enzyme system (proton pump) Suppress the secretion of hydrogen ions into the gastric lumen Membrane-bound proton pump → final step in the secretion of gastric acid Require active pumps to be effective .

. and acid secretion is inhibited during this time.PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Prodrugs with an acid-resistant enteric coating → protect them from premature degradation by gastric acid • Coating is removed in the alkaline duodenum → prodrug. a weak base. is absorbed → transported to the parietal cell → converted to the active drug → forms a stable covalent bond with the H+/K+-ATPase enzyme • It takes about 18 hours for the enzyme to be resynthesized.

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Standard doses→ inhibit both basal and stimulated gastric acid secretion by more than 90% Omeprazole + sodium bicarbonate • Faster absorption • OTC & Rx .

Esomeprazole and Lansoprazole • OTC • Shortterm treatment .PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Omeprazole.

THERAPEUTIC USES Superior to the H2 antagonists in suppressing acid production and healing ulcers Prophylaxis Preferred drugs for stress ulcer treatmen t and for the treatment: • GERD • Erosive esophagitis • Active duodenal ulcer • Pathologic hypersecre tory .

Zollinger.Ellison Syndrome Gastrin-producing tumor causes hypersecretion of HCl .

pylori . H2 antagonists reduce the activity of the used withpump proton antimicrobial regimens to eradicate H.partially effective for GERD symptoms Reduce the risk of bleeding from ulcers caused by aspirin and other NSAIDs Used for prevention or treatment of NSAID-induced ulcers BID / PPI (morning) + H2 Antagonist (night) improve symptom control If an H2-receptor antagonist is needed should be taken well after the PPI.PPIS: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP OD .

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Pharmacokinetics • Effective orally • Maximum effect .should be taken 30 to 60 minutes before breakfast or the largest meal of the day .

can be taken without regard to food .PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Dexlansopraz ole • Has a dual delayed release formulation .

excreted in urine and feces . long duration of action (due to covalent bonding with the H+/K+ATPase enzyme) Metabolites . intravenous formulations Plasma half-life of these agents . lansoprazole.only a few hours.PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Esomeprazole. and pantoprazole – also avail in.

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Adverse effects • Generally well tolerated • Omeprazole and Esomeprazole .decrease the effectiveness of clopidogrel (inhibit CYP2C19 and prevent the conversion of clopidogrel to its active metabolite) • concomitant use of PPIs + clopidogrel not recommended because of a possible increased risk of cardiovascular events .

impair the absorption of calcium carbonate Calcium citrate • effective option for calcium supplementation in patients on acid suppressive therapy (absorption of the citrate salt is not affected by gastric pH) .PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Increase the risk of fractures duration of use is 1 year or greater Prolonged acid suppression with PPIs (and H2 antagonists) → low vitamin B12 • because acid is required for its absorption in a complex with intrinsic factor Elevated gastric pH .

Hypomagnesi a ↑ incidence of pneumonia .PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP Diarrhea & Clostridium difficile colitis Patients must be counseled to discontinue PPI therapy and contact their physician if they have diarrhea for several days.

PROSTAGLANDINS Prostaglandi nE • Produced by the gastric mucosa • Inhibits secretion of acid • Stimulates secretion of mucus and bicarbonate .

PROSTAGLANDINS Deficiency of prostaglandins involved in the pathogenesis of peptic ulcers .

such as elderly patients and those with previous ulcers • C/I: pregnancy ( stimulate uterine contractions and cause miscarriage) • Adverse Effects • Dose-related diarrhea and nausea most common .PROSTAGLANDINS Misoprostol • analog of prostaglandin E1 • approved for the prevention of NSAIDinduced gastric ulcers • Prophylactic use of misoprostol • should be considered in patients who are taking NSAIDs and are at moderate to high risk of NSAID-induced ulcers.

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antacids also reduce pepsin activity Efficacy of an antacid depends on its capacity to neutralize gastric HCl and on whether the stomach is full or empty (food delays stomach emptying allowing more time for the antacid to react) .ANTACIDS Weak bases that react with gastric acid to form water and a salt to diminish gastric acidity Pepsin (a proteolytic enzyme) is inactive at a pH greater than 4.

Commonly used antacids are combinations of salts of Aluminum and Aluminum Magnesium hydroxide Magnesium hydroxide Calcium carbonate . not recommended for long- .Systemic absorption can produce transient metabolic alkalosis.reacts with HCl to form CO2 and CaCl2 Sodium bicarbonate .

aid in .used as calcium supplements for the treatment Aluminum of osteoporosis hydroxide + Mg hydroxide .ANTACIDS THERAPEUTIC USES Symptomati c relief of peptic ulcer disease and GERD Promote healing of duodenal ulcers Calcium carbonate preparations .

ANTACIDS ADVERSE EFFECTS Aluminum hydroxide Magnesium hydroxide .

Adverse effects may occur in patients with renal impairment .ANTACIDS Preparations that combine these agents aid in normalizing bowel function.

and healing existing ulcers .MUCOSAL PROTECTIVE AGENTS “Cytoprotective compounds” These agents have several actions that enhance mucosal protection mechanisms Preventing mucosal injury. reducing inflammation.

sucralfate creates a physical barrier that protects the ulcer from pepsin and acid. • Effective for the treatment of duodenal ulcers and prevention of . allowing the ulcer to heal.MUCOSAL PROTECTIVE AGENTS Sucralfate • Aluminum hydroxide + sulfated sucrose → binds to positively charged groups in proteins of both normal and necrotic mucosa • By forming complex gels with epithelial cells.

and it does not heal gastric ulcers . but it can interfere with the absorption of other drugs by binding to them PPIs H2 antagonists Antacid Does not prevent NSAID-induced ulcers.MUCOSAL PROTECTIVE AGENTS Should not be administered with Well tolerated.

MUCOSAL PROTECTIVE AGENTS Bismuth subsalicylate • Component of quadruple therapy to heal peptic ulcers • Has antimicrobial actions • Inhibits the activity of pepsin • Increases secretion of mucus .

LIFESTYLE CHANGES TO EASE SYMPTOMS.. .

.

Ranitidine B.QUESTION #1  Patient Allea Nacion went to your drug store and wants to take a H2 EXPLANATION? antagonist before All H2 antagonist except famotidine she takes alcohol to avoid gastric ANSWER? inhibit gastric first pass  irritation. Roxatidine D. Tiznidine . A.  Which H2 metabolism of  antagonist will you ask her to take? ethanol and WHY? increase its bioavailability. Famotidine C.

C. Antacids may not B. a patient comes to your pharmacy of heart burn. Antibacterial .ANSWER? QUESTION #2 EXPLANATION: Antacids neutralize the already sec Zyrelle Francisco. What retedcomplaining acid in the stomach. relieve symptoms at Anti-inflammatory least for 45 min.  drug can relieve her pain? All other drugs act by stopping acid secretion and so  A. Analgesic WHY? D.

 B. Famotidine in A.Question #3 EXPLAINATION: H2 antagonists cross  A pregnant placenta andlady are(first alsotrimester) comes to you with ulcer disease. is not teratogenic? Safety of Proton pump inhibitors not established Sucralfate C. pregnancy. Ranitidine Misoprostol causes D. Misoprostol abortion. Sucralfate ANSWER? . Which drug secreted inpeptic breast milk.

DRUGS USED TO TREAT INFLAMMATORY BOWEL DISEASE .

Chron’s disease Ulcerative colitis .

celgene.http://www.com/ulcerative-colitis-and-crohns-sing-different-tunes/ .

healthline.STATISTICS – CROHN’S DISEASE S T E G WHO ’S N H O CR ? E S A E DIS http://www.com/health/crohns-disease/facts-statistics-infographic#6 .

healthline.com/health/crohns-disease/facts-statistics-infographic#6 .MEDICAL COST OF CROHN’S DISEASE http://www.

000 people.000 DOCTOR’S VISITS/YEAR Northern Europe North America 30.5 to 24.000 HOSPITALIZATIONS/ YEAR http://www.com/diseases/ulcerative-colitis-inflammatory-bowel-disease/ .myvmc. : 250.STATISTICS OF ULCERATIVE COLITIS 0.5 COMMONLY cases per 100.

Therapeutic Pyramid T Disease severity Severe h e r a Surgery p Natalizumab y Cyclosporine Responsiven ess Refractory TNF antagonist Intravenous corticosteroid Moderate Mild TNF antagonist Oral corticosteroids Methotrexate Azathioprine/6-Mercaptopurine Budesonide (ileitis) Topical corticosteroids (proctitis) Antibiotics 5.Aminosalicylates Responsive .

Azathioprine and 6-Mercatopurine Methotrexate Anti-Tumor Necrosis Factor Therapy Anti-Itegrin Theraphy . responsiveness. and drug toxicity: Aminosalicylates Glucocorticoids Purine Analogs.Drugs used in IBM They are chosen on the basis of disease severity.

but is thought to involve: • • • • Reduced cytokine formation Reduced free radical formation Inhibited prostaglandin production Inhibited leucocyte chemotaxis 5-aminosalicylic acid (5-ASA) .Aminosalicylates 5-aminosalicylic acid (5-ASA) – active component • Aka Mesalamine Its mechanism of action is not entirely understood.

Aminosalicylates Clinically approved drugs:  Sulfazalazine ◦ Oral use  Mesalazine ◦ Available as  Enteric-coated tablets (for ileal Crohn’s disease)  Slow release tablets (for proximal bowel Crohn’s)  Enemas. suppositories (for distal colonic disease)  Used when sulfasalazine can not be tolerated  Olsalazine  Balsalazide ◦ prodrug of 5-ASA .

Location of Oral Mesalamine Release Stomach Jejunum Ileum Colon Sulfasalazine Colazal ® (balsalazide) Dipentum® (olsalazine) Asacol® (mesalamine) delayed-release tablets Lialda® (mesalamine) Mesalamine delayed release tab Pentasa® (mesalamine) controlled-release capsules .

 For px with distal colonic disease → suppository or enema is appropriate. .  Maintenance treatment with a 5-ASA → effective for sustaining remission in UC but is of questionable value in CD.Aminosalicylates Clinical Uses:  The mainstay tx → mild to moderately active ulcerative colitis and Crohn's disease (induction).

alopecia . peripheral neuropathy • blood disorders • skin reactions – lupus like syndrome. nausea. StevensJohnson syndrome. hepatitis. diarrhea Idiosyncratic (rare) • acute pancreatitis.Aminosalicylates Adverse Effects: Dose-related (10-45%) • headache. epigastric pain.

G6PD deficiency (haemolysis) .Slow acetylator status ( risk of hepatic and blood disorders) .Aminosalicylates Contraindications /Cautions  5-ASA .Salicylate hypersensitivity  Sulfapyridine + 5-ASA = Sulfasalazine(cleaved in colon by colonic bacteria) .

Glucocorticoids DRUGS: ineffectiv  Prednisone and Prednisolone e ◦ oral/ enema   maintaining remission ◦ enemas. or suppositories inducing remission Hydrocortisone Budesonide efficaciou s ◦ (poorly absorbed – used for iliocaecal CD/ UC) . foam.

• • Budesonide . potent synthetic analog of prednisolone subject to rapid first-pass hepatic metabolism → low oral bioavailability. • (Entocort) → controlled-release oral formulation that releases the drug in the distal ileum and colon. Prednisolone • intermediate duration of action – OD.Glucocorticoids • are the most commonly used oral Prednisone and glucocorticoids.. • used to maximize colonic tissue effects and minimize systemic absorptio • via topical treatment of active inflammatory Hydrocortisone bowel disease in the rectum and sigmoid colon.

Glucocorticoids Clinical Uses:  used in the tx of patients w/ moderate to severe active inflammatory bowel disease.  Active disease → initial oral dosage of 40–60 mg/d of prednisone or prednisolone .

Glucocorticoids Clinical Uses:  For the tx of IBD involving the rectum or sigmoid colon → rectal glucocorticoids are preferred because of their lower systemic absorption.  Oral controlled-release budesonide (9 mg/d) is → the tx of mild to moderate Crohn’s disease involving the ileum and proximal colon .

Glucocorticoids Adverse Effects: .

◦ Onset of benefit → several weeks up to six months. induce T cell apoptosis by modulating cell (Rac1) signalling . ◦ Dose-related BM suppression is uniformly observed Azathioprine ◦ MOA: inhibit ribonucleotide synthesis.PURINE ANALOGS:   Azathioprine/6-Mercaptopurine (6MP) Azathioprine & 6-MP ◦ The most extensively used immunosuppressive agents.

AZA/6-MP Metabolism 6-TG 6-TU XO AZA 6-MP TPMT 6-MMP Circulation nucleotides DNA RNA HPRT 6-TImP TPMT 6-MMP ribonucleotides Intracellula Purine synthesis .

Azathioprine/6-MP Indications: Steroid Active sparing agents disease CD/UC Maintenance General of remission CD/UC treatment x 3-4years .

Azathioprine/6-MP in IBD Efficacy/Issues Intolerance/Risks     Effective in 50 – 70% of patients with IBD 30% failure due to intolerance (15%) or no response (15%) Metabolism issues TPMT      Bone marrow suppression Pancreatitis Hepatotoxicity Nausea Myalgias Other Risks ◦ Lymphoma – 4 fold ◦ Infection .

occur at 2-3 weeks.weekly FBC x 8 weeks .Azathioprine/6-MP Adverse effects:  Flu-like symptoms (20%) .warn patients reg: sore throat/fever . cease on withdrawal  Hepatotoxicity.3 monthly thereafter .determined by TPMT activity . pancreatitis (<5%)  Leucopenia (3%) – myelotoxicity .

Azathioprine/6-MP Drug Interactions: Allopurinol reduces xanthine oxide catabolism of the purine analogs active 6-thioguanine nucleotides severe leukopenia .

SC.METHOTREXATE • A folic acid derivative that interfere with folic acid metabolism (folic acid antagonist) • A cytotoxic agent with multiple characteristics and maybe describe as an antimetabolite. or IM . and in cancer • Given PO. • Beneficial in a number of chronic inflammatory diseases including Crohn’s disease and rheumatoid arthritis.

At high doses used for chemotherap y : inhibit cellular proliferation At low doses used in the treatment of inflammator y bowel diseases (12-25 .

Mechanism of action Folate Folate Dihydrofolat e reductase Methotrexate Active transpor Productio t n of Methotrexatethymine and purines Tetrahydrofola Dihydrofolat te e (FH2) Dihydrofolate (FH4) reductase Cytotoxicity .

Clinical Uses • Used to induce and maintain remission in patients with Crohn’s disease • For remmision: Patients are treated with 15-25 mg of methotrexate once a week by subcutaneous injection • If after 8-12 weeks the result is satisfactory the dose is reduced to 15mg/wk .

Adverse Effects Liver toxicity Megaloblastic anemia Alopecia Mucositis GO BACK .

Anti – tumor Necrosis Factor Therapy Tumor Necrosis Factor (TNF) Produced by innate immune system. the adaptive immune system and non immune cells One of the key proinflammatory cytokines in inflammatory bowel disease .

Mechanism of action MACROPHAGE Help er T cell type 1 α-Tumor Necrosis Factor (TNF-α) CYTOTOXIC METABOLITES .

Anti – tumor Necrosis Factor Therapy Two biologically active forms: 1. Membrane-bound TNF .Soluble TNF 2.

2. CERTOZULIMAB Composed of the antibody binding fragment (Fab) of humanized monoclonal antibody against TNF conjugated to polyethylene glycol. unlike other agents.Three monoclonal antibodies to human TNF: 1. which works by blocking the protein that causes the inflammation in the body. ADALIMUMAB A TNF blocker. 3. INFLIXIMAB Reduce signs and symptoms of moderate to severe Crohn’s disease in which there are passageways when the inflammation penetrates beyond the wall of small intestines. it does not contain the constant fragment of immunoglobulin (Fc) . Useful in treatment of moderate to severe inflammatory diseases such as Crohn’s disease.

and 4 weeks 400 mg at 0.Anti – TNF antibodies used in inflammatory bowel disease Inliximab Adalimumab Certolizumab Class Monoclonal antibody Monoclonal antibody Monoclonal antibody % human 75% 100% 95% Structure IgG1 IgG1 Fab fragment attached to PEG (Lacks Fc portion) Route of administration Intravenous Subcutaneous Subcutaneous Half-life 8-10 days 10-20 days 14 days Induction dose 5 mg/kg at 0. and 4 weeks Maintenance dose 5 mg/kg every 8 weeks 40 mg every 2 weeks 400 mg every 4 weeks . 2. 2. 80 mg and 40 mg at 0. 2 and 6 weeks 160 mg.

Clinical uses
• Acute and chronic treatment of
moderate to severe Crohn’s disease
• Infliximab approved acute and chronic
treatment of moderate to severe
ulcerative colitis
• After induction of 5-10 mg/wk at 0, 2,
and 6 weeks, 70% of patients have a
clinical response and 1/3 achieved a
clinical remission

Adverse Effects

Infection (due to suppression of the helper
T cell type 1 (TH1) inflammatory response)
includes: Bacterial sepsis, tuberculosis, invasive
fungal organism, reactivation of Hepatitis B,
listeriosis and other opportunistic infections.

Reactivation of tuberculosis
 Upper respiratory infection (sinusitis,
bronchitis and pneumonia)
 T-cell lymphoma

Adverse Effects cont.
Antibodies to the
antibody (ATA)

Clinical response
Development of
acute infusion
reaction

develops in patients
given episodic anti-TNF
therapy than regular
scheduled injections

Prevalence of ATA INFLIXIMAB CERTOLIZUMAB ADALIMUMAB 14% 48% 38% GO BACK .

sense whether adhesion has occurred.Anti-Integrin therapy Integrin Family of proteins that function Consists of heterodimers that contains mechanically two subunits: alpha & beta attach the cell cytoskeleton to the extracellular matrix (ECM).  .

NATALIZUMAB Approved dosage is 300 mg every 4 weeks by intravenous infusion patients should not be on other BLOCKS immune suppressant agent .Natalizumab Useful in induction and clinical response to α.4 subuni remission in patients having t Inflammatory Bowel Diseases Vs.

Adverse effects • Progressive multifocal leukoencephalopathy (due to reactivation human polyomavirus –JC virus) • Acute infusion reactions • Small risk of opportunistic infections Go back to table of contents .

(2012).retrieved from: http://www.org/Taxonomy/RelatedDoc uments. USA.munsonhealthcare.References: Amdbook.org. Basic and Clinical Pharmacology. indication and adverse effects of TNF-inhibitors.2016. 11 th ed.  Katzung.pg 1100-1115  Munson.org/content/figure-3-alpha-and-beta-su bunits-integrins-are-transmembrane-proteins retrieved: October 8.Integrins are transmembrane protein.Pharmacology.encyclopedia. al(2009). al. (2014). et. 2016.Methotrexate.com(2012). McGraw-Hill Companies.amdbook.retrieved from:http ://www.aspx?id=0&sid=1&ContentTypeId=3&ContentID=403 21 retrieved October 8.  .retrieved from: http://www.com/medicine/drugs/pharmacology/ methotrexate retrieved: October 8. et.  Encyclopedia. 2016.