Peptic Ulcer Disease (PUD)

Transcription

1 Peptic Ulcer Disease (PUD) Therapeutics II 2004 Kristi L. Thebald, Pharm.D., BCPS (pager) (ffice phne) Required Reading: Berardi RR. Peptic ulcer disease. In: DiPir JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Psey LM, editrs. Pharmactherapy: a pathphysilgic apprach. 5 th ed. New Yrk: McGraw-Hill; p Ability Outcmes: Assess a patient with PUD. Evaluate drug therapy in a patient with PUD. Select/Recmmend drug therapy fr a patient with PUD. Mnitr fr expected therapeutic utcmes and ptential adverse effects assciated with drug therapy fr PUD. Educate patients, care givers and health care prfessinals regarding drug therapy used in the management f PUD. Cllabrate with peers t devise a patient-specific therapeutic plan fr the management f PUD. Cmmunicate the infrmatin pertinent t the management f PUD in a clear, cncise and rganized manner. Cntent Questins: 1. List the etilgies and risk factrs fr PUD. 2. List the established and pssible risk factrs fr NSAID-induced ulcers and upper GI cmplicatins. 3. Understand the pathphysilgy f PUD, fcusing n the rle f Helicbacter pylri and NSAIDs. 4. Differentiate between the typical clinical manifestatins f dudenal and gastric ulcers. 5. Explain when the varius diagnstic tests fr Helicbacter pylri are indicated and the advantages and disadvantages f each. 6. Understand the treatment apprach t Helicbacter pylri-assciated ulcers. 7. Understand the cnventinal treatment apprach t dudenal and gastric ulcers. 8. Understand the treatment apprach t NSAID-induced ulcers. 9. Knw the mechanisms f actin, ADRs and drug interactins fr the agents used in the management f PUD. 10. Describe when maintenance therapy is indicated fr patients with PUD. 11. Explain treatment strategies t prevent NSAID-induced ulcers.

2 Peptic Ulcer Disease (PUD) Intrductin/Epidemilgy Apprximately 10% f Americans develp PUD during their lifetime Cmparable prevalence between men and wmen In persns ver age 65, PUD assciated with 16% f hspitalizatins and deaths Apprximately % f ulcers recur within 1 year f initial ulcer healing with cnventinal antiulcer regimens. Eradicatin f H. pylri reduces the risk f recurrence t less than 10% in 1 year. Definitin f PUD The underlying tendency t develp mucsal ulcers at sites that are expsed t acid and pepsin Etilgies Helicbacter pylri 15% f patients infected with H. pylri develp clinical manifestatins f an ulcer Mst cmmnly assciated with dudenal ulcers Nnsteridal anti-inflammatry drugs (NSAIDs) Gastrdudenal ulcers ccur in 15-30% f regular NSAID users and may develp within a week r with cntinued treatment (6 mnths r lnger) Clinically imprtant GI events ccur in 3-4.5% f arthritis patients taking NSAIDs and 1.5% will have a serius cmplicatin Mst cmmnly assciated with gastric ulcers Critical illness (stress-related mucsal damage) Zllinger-Ellisn syndrme (hypersecretin f gastric acid) Viral infectins (cytmegalvirus) Vascular insufficiency (crack-ccaine assciated) Radiatin/chemtherapy Rare genetic subtypes Idipathic Risk Factrs fr PUD Cigarette smking (impairs ulcer healing, prmtes ulcer recurrence and increases likelihd f cmplicatins) Caffeine-cntaining fds, milk, alchl and spicy fds increase acid secretin and cause dyspepsia but d nt appear t increase the risk fr ulcer frmatin Genetic predilectin Stressful life events may exacerbate PUD Risk Factrs fr NSAID-Induced Ulcers and Upper GI Cmplicatins Established risk factrs Pssible risk factrs

3 Pathphysilgy H. pylri Spiral-shaped, ph sensitive, gram (-), micraerphilic bacterium with flagella Survives in the acidic envirnment f the stmach thrugh its ability t prduce urease Urease hydrlyzes urea in the gastric juice and cnverts it t ammnia and CO 2 Neutralizing effect f ammnia frms a micrenvirnment that prtects the rganism frm acid Cntributes t mucsal injury by 3 mechanisms Direct mechanisms Bacterial enzymes, virulence factrs and adherence Alteratins in the immune/inflammatry respnse Hypergastrinemia leading t increased acid secretin NSAIDs Cause gastric mucsal damage by 2 mechanisms Direct r tpical irritatin f the gastric epithelium Systemic inhibitin f endgenus GI mucsal prstaglandin synthesis

4 Membrane phsphlipids Phsphlipase A 2 Arachidnic acid COX-1 Cnstitutively expressed COX-2 Induced at inflammatin site NSAID COX-2 selective inhibitr Prduces PGs fr: GI mucsal integrity Platelet aggregatin Renal functin Prduces PGs fr: Pain and inflammatin Mitsis and grwth Bne frmatin Regulatin f female reprductin Other Clinical Manifestatins Patients with gastric and dudenal ulcers present similarly and cannt be differentiated n the basis f clinical findings Typical presentatin f dudenal (peptic) ulcer Epigastric pain described as gnawing, aching r like a hunger pain Rhythmic pain Usually ccurs when stmach is empty Regularly relieved by fd, milk r antacids but returns hurs after eating May awaken the patient frm sleep between 1:00 and 3:00 AM Typical presentatin f gastric ulcer Epigastric pain as described abve Rhythmic pain Least r absent during fasting but ccurs shrtly after eating and remains until the stmach empties either naturally r by vmiting Bth dudenal and gastric ulcer pain is episdic (symptms ccur at intervals f weeks r mnths fllwed by a perid f n ccurrence) Other symptms include nausea, vmiting, belching, blating and anrexia Differentiating between H. pylri and NSAID-induced ulcer Ulcers assciated with H. pylri ccur mre ften in the dudenum, are ften superficial and assciated with less severe GI bleeding Ulcers assciated with NSAIDs ccur mre ften in the stmach, are ften deep, assciated with mre severe GI bleeding and smetimes asymptmatic

5 Diagnsis Tests fr detectin f H. pylri TEST DESCRIPTION ADVANTAGES DISADVANTAGES Quantitative detectin f antibdies t HP in serum Antibdy detectin (lab based) Antibdy detectin (in ffice) Urea breath test Histlgy Qualitative detectin f IgG antibdies t HP in whle bld r fingerstick HP urease breaks dwn ingested labeled C-urea; patient exhales labeled CO 2 Micrbilgic examinatin (Warthin Starry stain) Endscpy nt required; inexpensive; mst accurate antibdy detectin test; nt affected by antibitics, bismuth and PPIs Quick (within 15 minutes); simple t use; inexpensive; nt affected by antibitics, bismuth and PPIs Endscpy nt required; less expensive; nnendscpic methd t cnfirm eradicatin; avids bipsy sampling errrs Gld standard High specificity and sensitivity Culture Culture f bipsy Used t test fr antibitic resistance High specificity Bipsy (rapid) urease Urease f HP generates ammnia, which causes a clr change Test f chice at endscpy High specificity and sensitivity Easily perfrmed; rapid results (usually within 24 hurs) Lwer specificity than endscpy r urea breath tests; nt pssible t determine whether active r cured infectin May yield indeterminate r invalid results Cannt use fr early fllw-up testing Ptential fr false (-) results after antibitics, bismuth and PPIs Results nt immediate (2 days) Requires endscpy; patient discmfrt; expensive Patchy distributin f HP can cause false (-) results Requires endscpy; patient discmfrt; expensive Patchy distributin f HP can cause false (-) results; results nt immediate Requires endscpy; patient discmfrt; expensive Antibitics, bismuth and PPIs can cause false (-) results Test Selectin Labratry-based antibdy detectin tests are the initial screening tests f chice because they are quick, inexpensive and less invasive than endscpic bipsy tests Urea breath test when there is cncern regarding a psitive antibdy test When endscpy is indicated, the diagnsis shuld be established using the bipsy urease test The urea breath test is the preferred nninvasive methd t verify H. pylri eradicatin Delay at least 4 weeks after the cmpletin f H. pylri eradicatin treatment Delay ne week after discntinuatin f a prtn pump inhibitr Eradicatin defined as the absence f the rganism at least 4 weeks after cessatin f antibitic therapy Patients t test fr H. pylri Active ulcer, past histry f ulcer, ulcer-related cmplicatins r gastric MALT lymphma Endscpy Gld standard fr diagnsing peptic ulcers Endscpy preferred in the fllwing: Patients with alarm symptms Patients wh fail H. pylri eradicatin therapy Patients wh fail a trial f empiric antisecretry therapy

6 Treatment Gals f therapy T relieve pain and heal the ulcer T prevent ulcer recurrence and ulcer-related cmplicatins T eradicate H. pylri (if applicable) Nnpharmaclgic therapy Helicbacter pylri-assciated ulcers Eradicatin regimen shuld be individualized based n efficacy, tlerability, druginteractin ptential, antibitic resistance, cst and cmpliance Regimens f chice Prtn pump inhibitr-based three-drug regimen Bismuth-based fur drug regimens REGIMEN DOSE/FREQUENCY DURATION EFFICACY ADVERSE EFFECTS COMPLIANCE 500mg p bid s Gd-excellent Lw-medium Likely 1g p bid s bid s Clarithrmycin Amxicillin PPI Clarithrmycin Metrnidazle PPI Amxicillin Metrnidazle PPI BSS Metrnidazle Tetracycline H 2 RA r PPI BSS Metrnidazle Clarithrmycin H 2 RA r PPI BSS Metrnidazle Amxicillin H 2 RA r PPI 500mg p bid 500mg p bid bid 1g p bid 500mg p bid bid 500mg p qid 250mg p qid 500mg p qid Cnventinal ulcer-healing dse 500mg p qid 250 p qid 500mg p bid Cnventinal ulcer healing dse 500mg p qid 250mg p qid 500mg p qid Cnventinal ulcer healing dse s s s s s s H 2 RA 4-6 weeks PPI 2-4 weeks H 2 RA 4-6 weeks PPI 2-4 weeks H 2 RA 4-6 weeks PPI 2-4 weeks Gd-excellent Medium Likely Gd Medium Likely Gd-excellent Medium-high Unlikely Gd-excellent Medium-high Unlikely Fair-gd Medium-high Unlikely Key pints (in general) D nt substitute ampicillin fr amxicillin, dxycycline fr tetracycline r azithrmycin fr clarithrmycin D nt substitute an H 2 RA fr a PPI in the 3-drug regimens If a secnd H. pylri treatment curse is required, a different antibitic regimen shuld be selected

7 Acquired resistance t metrnidazle (10-60%) and clarithrmycin (5-10%) is a significant prblem Patients shuld be instructed t take all medicatins (except PPIs) with meals and at bedtime (if necessary). PPIs shuld be taken minutes befre meals Cnfirmatin f H. pylri eradicatin nly necessary in patients with recurrent symptms, a histry f ulcer cmplicatins, gastric MALT lymphma r gastric cancer Key pints (regarding specific agents) Bismuth subsalicylate Pssible ulcer-healing mechanisms include a lcal gastrprtective effect, stimulatin f endgenus prstaglandins and suppressin f H. pylri Clarithrmycin Metrnidazle Amxicillin Tetracycline Cnventinal treatment f active dudenal and gastric ulcers H 2 RAs, sucralfate r antacids alleviate ulcer symptms and heal apprximately 70%, 80% r 90% f dudenal ulcers at 4, 6 r 8 weeks respectively H 2 RAs Treat dudenal ulcers fr 8 weeks and gastric ulcers fr 12 weeks PPIs prvide cmparable dudenal ulcer healing rates ver a shrter treatment Treat dudenal ulcers fr 4 weeks and gastric ulcers fr 8 weeks H 2 RAs Cimetidine Famtidine Nizatidine Ranitidine PPIs Omeprazle Lansprazle Rabeprazle Pantprazle Esmeprazle Drug Dudenal r Gastric Ulcer Healing Maintenance Therapy 300mg p qid, 400mg p bid, 800mg p hs 20mg p bid, 40mg p hs 150mg p bid, 300mg p hs 150mg p bid, 300mg p hs 20-40mg p qd 15-30mg p qd 20mg p qd 40mg p qd 20-40mg p qd mg p hs 20-40mg p hs mg p hs mg p hs 20-40mg p qd 15-30mg p qd 20mg p qd 40mg p qd 20-40mg p qd Mucsal defense Sucralfate 1g p qid r 2g p bid 1g p qid r 1-2g p bid

8 Treatment f refractry ulcers Cnsidered refractry when when symptms, ulcers r bth persist beynd 8 weeks (DU) r 12 weeks (GU) despite cnventinal treatment r when several curses f H. pylri eradicatin fail Endscpy indicated t cnfirm nn-healing ulcer, t exclude malignancy and t assess H. pylri status If H. pylri psitive, attempt anther eradicatin regimen Higher-dse PPI Maintenance therapy Maintenance therapy Largely bslete since H. pylri eradicatin is curative May be indicated fr patients wh have frequent ulcer recurrences, a histry f ulcerrelated bleeding, a healed refractry ulcer, failed H. pylri eradicatin therapy r wh are at high risk fr an ulcer/upper GI cmplicatins and require cntinuus treatment with an NSAID H 2 RAs, PPIs r sucralfate effective Lwer dsages usually effective fr dudenal ulcers Full ulcer healing dses usually required fr gastric ulcers NSAID-induced ulcers Discntinue NSAID Standard H 2 RA, PPI r sucralfate regimens (see abve table) Large ulcers require higher PPI dsages r prlnged treatment Test fr H. pylri If cntinuatin f NSAID required, cnsider the fllwing: Decrease NSAID dse Use acetaminphen r nnacetylated salicyclates (salsalate) Use relatively selective COX-2 inhibitrs (nabumetne, etdlac, melxicam) Use highly selective COX-2 inhibitrs (celecxib, rfecxib, valdecxib) MUST USE PPIs as ptent acid suppressin is required t accelerate ulcer healing Preventin f NSAID-induced ulcers Use prphylactic ctherapy with either a PPI r misprstl if the patient is at risk f develping an NSAID-induced ulcer r ulcer-related cmplicatin Misprstl 200ug p tid-qid GI adverse effects, including diarrhea, abdminal cramping, nausea and flatulence, limit usefulness Take with r after meals and at bedtime t minimize diarrhea Avid magnesium-cntaining antacids Utertrpic and prduces uterine cntractins that may endanger pregnancy (Use f cntraceptin measures must be cnfirmed and a negative serum pregnancy test dcumented within 2 weeks f initiating treatment) Fixed cmbinatin f misprstl and diclfenac available Standard dse PPIs (see table) Use selective COX-2 inhibitrs Celecxib, rfecxib, valdecxib The safety f COX-2 inhibitrs is significantly reduced in patients taking lw-dse aspirin fr MI/strke prphylaxis Sme patients (histry f GI cmplicatins, >65 years ld, dyspepsia) may still require a PPI, even after changing t a COX-2 inhibitr

9 Zllinger-Ellisn syndrme Use high dse PPIs Initiate meprazle at 60mg p qd Average meprazle dse f 60-80mg/day required 40-80mg/day esmeprazle r rabeprazle 30-90mg/day lansprazle mg/day pantprazle Titrate PPI dse t achieve a basal acid utput f <10 meq/hur Cmplicatins Upper GI bleeding (~15%) Caused by the ersin f an ulcer int an artery Perfratin (~7%) Ulcer pens freely int the peritneal cavity Obstructin (~2%) Scarring r edema f the dudenal bulb r pylric channel which leads t gastric retentin