Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Dr. Carl Rosow, Dr. David Standaert and Prof. Gary Strichartz

MesalamineMesalamine forfor InflammatoryInflammatory BowelBowel DiseaseDisease PaulPaul DieffenbachDieffenbach andand AliAli ShoebShoeb OutlineOutline

„ ClinicalClinical CaseCase ofof UlcerativeUlcerative ColitisColitis „ MesalamineMesalamine PharmacodynamicsPharmacodynamics „ MesalamineMesalamine PharmacokineticsPharmacokinetics „ SaferSafer MesalmineMesalmine FormulationsFormulations „ ConclusionConclusion TheThe ClinicalClinical CaseCase ClinicalClinical PresentationPresentation

„ 2020 yearyear--oldold womanwoman presentspresents withwith bloodybloody diarrheadiarrhea andand crampycrampy Normal abdominal pain. Photo removed for abdominal pain. copyright reasons.

„ ProctosigmoidoscopyProctosigmoidoscopy revealsreveals edematousedematous,, friablefriable,, ulceratingulcerating sigmoidsigmoid coloncolon withoutwithout Patient

normalnormal vascularvascular Photo removed for markings.markings. copyright reasons. UlcerativeUlcerative ColitisColitis

„ ChronicChronic,, relapsingrelapsing inflammatoryinflammatory bowelbowel diseasedisease primarilyprimarily presentingpresenting inin youngyoung adultsadults (peak(peak incidenceincidence 2020--2525 y/oy/o femalefemale >> male)male)

„ ExactExact causecause unknownunknown –– possiblypossibly duedue toto

overactiveoveractive TTH2 immuneimmune responseresponse inin thethe largelarge intestineintestine (loss(loss ofof tolerancetolerance toto normalnormal flora?)flora?) PathologicalPathological FeaturesFeatures ofof UCUC

•Gross • Edematous, reddened, friable surface – often visible ulceration Photo removed for • Isolated islands of regenerating copyright reasons. mucosa form pseudopolyps • Continuous distribution from rectum towards proximal colon • Microscopic • Diffuse, mononuclear inflammatory infiltrate • Frequent microscopic ulcerations into lamina propria and submucosa, Photo removed for but not extending to deeper layers copyright reasons. • Risk of epithelial dysplasia and adenocarcinoma after many years of chronic disease MesalamineMesalamine ForFor UlcerativeUlcerative Colitis?Colitis?

„ 55--aminosalicylicaminosalicylic acidacid ((mesalaminemesalamine)) isis effectiveeffective inin rheumatoidrheumatoid arthritis.arthritis.

Chemical diagram of „ 5-aminosalicyic acid, mesalazine ObservationObservation thatthat aa removed for copyright reasons. mesalaminemesalamine formulationformulation amelioratesameliorates ulcerativeulcerative colitiscolitis inin patientspatients withwith rheumatoidrheumatoid arthritisarthritis leadlead toto newnew indicationindication forfor thethe drug.drug. MesalamineMesalamine

PharmacodynamicsPharmacodynamics DiverseDiverse MechanismsMechanisms ofof ActionAction

„ MesalamineMesalamine isis notnot aa productproduct ofof rationalrational drugdrug designdesign!!

„ TherapeuticTherapeutic actionaction ofof mesalaminemesalamine isis multifactorial:multifactorial:

„ AntiinflammatoryAntiinflammatory

„ ImmunosuppressiveImmunosuppressive AntiinflammatoryAntiinflammatory RoleRole

„ MesalamineMesalamine isis aa salicylatesalicylate (like(like aspirin).aspirin). SuggestsSuggests influenceinfluence onon synthesissynthesis ofof inflammaoryinflammaory lipidlipid mediatorsmediators

Cell Membrane Phospholipids

Phospholipase A2 Phospholipase A2

Platelet Activating Factor Arachidonic Acid

Lipoxygenase Cyclooxygenase

Leukotrienes (LTB4) Prostaglandins (PGE2) Lipoxins Thromboxane Prostacyclin AntiinflammatoryAntiinflammatory RoleRole

„ MesalamineMesalamine inhibitsinhibits thethe enzymaticenzymatic activityactivity ofof CyclooxygenaseCyclooxygenase,, LipoxygenaseLipoxygenase,, andand PAFPAF synthesis.synthesis.

Cell Membrane Phospholipids

Phospholipase A2 Phospholipase A2

Platelet Activating Factor Arachidonic Acid

Lipoxygenase Cyclooxygenase

Leukotrienes (LTB4) Prostaglandins (PGE2) Lipoxins Thromboxane Prostacyclin ImmunosuppressiveImmunosuppressive RoleRole

„ MesalamineMesalamine promotespromotes thethe releaserelease ofof adenosineadenosine,, whichwhich impairsimpairs leukocyteleukocyte functionfunction andand activation.activation.

„ MesalamineMesalamine interferesinterferes withwith ILIL--1,1, ILIL--2,2, TNFTNF--αα synthesis.synthesis. TheseThese cytokinescytokines areare crucialcrucial forfor thethe activationactivation andand proliferationproliferation ofof cellscells mediatingmediating thethe inflammatoryinflammatory process.process.

„ MesalamineMesalamine depressesdepresses antibodyantibody synthesissynthesis byby plasmaplasma cells,cells, whichwhich maymay limitlimit antibodyantibody--mediatedmediated diseasedisease process.process. MesalamineMesalamine

Delivery,Delivery, Metabolism,Metabolism, ExcretionExcretion DrugDrug TargetingTargeting andand Delivery:Delivery: TheThe problemproblem

„ EfficacyEfficacy ofof mesalaminemesalamine dependsdepends onon achievingachieving aa highhigh concentrationconcentration atat diseasedisease site.site.

„ UlcerativeUlcerative ColitisColitis mainlymainly affectsaffects thethe coloncolon..

„ UnformulatedUnformulated mesalaminemesalamine isis absorbedabsorbed inin thethe smallsmall intestineintestine (80%)(80%) DrugDrug TargetingTargeting andand Delivery:Delivery: TheThe ProdrugProdrug SolutionSolution ---- SulfasalazineSulfasalazine

„ SulfasalazineSulfasalazine isis aa prodrugprodrug containingcontaining mesalminemesalmine boundbound toto thethe antibioticantibiotic sulfapyridinesulfapyridine viavia anan azoazo bond.bond. TheThe formulationformulation reducesreduces absorptionabsorption inin thethe smallsmall intestine.intestine.

Diagram removed for copyright reasons.

In the terminal ileum and colon, coliform bacteria cleave the azo bond using an azoreductase enzyme releasing the therapeutically active metabolite (mesalamine) at the site of inflammation. SulfasalazineSulfasalazine MetabolismMetabolism andand ExcretionExcretion

„ 20%20% ofof SulfasalazineSulfasalazine dosedose isis absorbedabsorbed byby thethe smallsmall intestine.intestine. AbsorbedAbsorbed SulfasalazineSulfasalazine isis excretedexcreted inin bilebile oror urine.urine.

„ MesalamineMesalamine moietymoiety isis generallygenerally notnot absorbedabsorbed byby thethe largelarge intestine.intestine. TheThe smallsmall amountamount thatthat isis absorbedabsorbed isis excretedexcreted inin thethe urine.urine.

„ 60%60% ofof SulfapyridineSulfapyridine moietymoiety isis absorbedabsorbed byby largelarge intestine,intestine, metabolizedmetabolized byby liver,liver, andand excretedexcreted inin urine.urine. SulfasalazineSulfasalazine ToxicityToxicity

„ SulfaSulfa groupsgroups cancan bebe allergenicallergenic causingcausing rashrash,, feverfever,, andand hepatichepatic dysfunction.dysfunction.

„ ReactionsReactions correlatedcorrelated withwith sulfasulfa groupgroup serumserum concentrationsconcentrations.. SerumSerum concentrationconcentration relatedrelated toto hepatichepatic metabolismmetabolism andand renalrenal excretion.excretion.

Phase I: Phase II: Oxidation Acetylation Reduction Methylation Plasma Hydrolysis Conjugation Kidney

Liver

Phase I and II hepatic drug metabolism facilitates drug renal excretion SlowSlow AcetylatorAcetylator PhenotypePhenotype

„ 50%50% ofof caucasianscaucasians andand africanafrican--americansamericans havehave alteredaltered hepatichepatic PhasePhase IIII drugdrug metabolismmetabolism duedue toto missingmissing isoformisoform ofof NN--acetylationacetylation enzymeenzyme NATNAT--22..

„ ThisThis ““slowslow acetylationacetylation”” phenotypephenotype impliesimplies decreaseddecreased sulfapyridinesulfapyridine clearanceclearance.. SoSo what?what? PharmacokineticsPharmacokinetics ofof ““SlowSlow AcetylatorAcetylator”” PhenotypePhenotype ChalkChalk--TalkTalk SaferSafer MesalamineMesalamine FormulationsFormulations MesalimineMesalimine DimerizationDimerization

Sulfapyridine Mesalamine

Mesalamine Mesalamine Chemical diagrams removed for copyright reasons.

4-aminobenzoyl-β- Mesalamine alanine

These mesalamine formulations are poorly absorbed by the small intestine and require colonic bacteria for cleavage of the azo bond and release the mesalamine moiety. Asacol:Asacol: pHpH--DependantDependant MesalamineMesalamine ReleaseRelease

Cutaway schematic of large and small intestines removed for copyright reasons.

Asacol is formed by coating mesalamine with pH-sensitve coating. Coating dissolves when pill reaches terminal ileum where the pH is > 7.

How does Pentasa differ from Asacol Both Pentasa and Asacol are prescription forms of mesalamine. The difference between Asacol and Pentasa is in the outer chemical coating. Oral Pentasa has a unique formulation. The active ingredient is contained in coated microgranules, which enables a prolonged release of the active substance throughout the intestinal tract, from duodenum to the rectum. Therefore the Pentasa preparation is more useful for Crohn's patients who often have inflammation of the small intestine. The average small bowel transit time is approximately 3-4 hours in healthy volunteers. Asacol is a delayed release enteric-coated tablets which generally releases the active ingredient only in the colon. While there are always clinical exceptions, Asacol is generally suitable for patients with colitis only (ulcerative colitis or Crohn's colitis), but not disease involving the small intestine. Pentasa:Pentasa: SustainedSustained ReleaseRelease ofof MesalamineMesalamine

„ Pentasa is formed by packaging mesalamine in permeable microgranules.

„ Permeable microgranules allow for Diagram removed for mesalamine release throughout the copyright reasons. intestinal tract.

„ Pentasa is more appropriate for Crohn’s Disease because of its diffuse intestinal tract distribution. ConclusionConclusion

„ TherapeuticTherapeutic actionaction ofof MesalamineMesalamine isis multifactorialmultifactorial:: AntiinflammatoryAntiinflammatory andand Immunosuppressive.Immunosuppressive.

„ DeliveryDelivery toto coloncolon isis crucialcrucial forfor efficacyefficacy:: AccomplishedAccomplished byby mesalaminemesalamine conjugationconjugation toto makemake aa prodrugprodrug (Sulfasalazine(Sulfasalazine andand BalsalazineBalsalazine),), oror byby pHpH--sensitivesensitive coatingcoating (Asacol).(Asacol).

„ DecreaseDecrease inin drugdrug metabolismmetabolism andand clearanceclearance contributescontributes toto toxicitytoxicity:: ““SlowSlow AcetylatorAcetylator”” phenotypephenotype leadsleads toto aa decreasedecrease inin sulfapyridinesulfapyridine clearanceclearance andand anan increasesincreases inin itsits serumserum concentration.concentration. ElevatedElevated sulfapyridinesulfapyridine serumserum concentrationsconcentrations increaseincrease riskrisk forfor adverseadverse allergicallergic reactions.reactions.