Esophageal Disorders

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1 Gastric Acid related Disease 위산억제치료관련 가톨릭대학교내과학교실 소화기분과 정우철

3 The Normal Human Stomach Contain approximately 1 billion parietal cells secrete H + ions & proteolytic enzymes H + ions initiate digestion sustain a sterile intragastric milieu : prevent enteric colonization may play an etiologic role in producing dyspepsia & esophageal / gastroduodenal mucosal injury

4 The Generation of H + Ions 3 pathways Neurocrine Vagal postganglionic neuron Paracrine Enterochromaffine -like cell (ECL) Endocrine Antral G cells Acetylcholine Histamine Gastrin Parietal cell muscarinic M3 receptor Parietal cell H 2 -specific receptor Parietal cell gastrin receptor Acid secretion

5 Parietal Cell H +,K + -Adenosine Triphosphatase - The final step of acid secretion -

Inhibition of Acid Secretion: PPI Oral administration PPI Absorbed by intestine PPI Blood circulation Stomach (Parietal cells) Protonation in the acidic

6 Inhibition of Acid Secretion: PPI Oral administration PPI Absorbed by intestine PPI Blood circulation Stomach (Parietal cells) Protonation in the acidic space of canalicular lumen Conversion to a sulphenamid Reacts with SH-group of cysteines of H +,K + -ATPase Irreversible nhibition of the H +,K + -ATPase

Helpful Factors on the Use of PPIs PPIs are prodrugs that require activation to their active moiety (thiophilic sulfenamide) Food ingestion stimulates gastric parietal cell ATPase

7 Helpful Factors on the Use of PPIs PPIs are prodrugs that require activation to their active moiety (thiophilic sulfenamide) Food ingestion stimulates gastric parietal cell ATPase molecules to secrete acid, allowing PPIs to inhibit acid secretion when they are taken before meals. First dose should be taken before breakfast Limitation in administration of H2RA simultaneously

8 Optimal Dosing on the Use of PPIs Genetic variation in hepatic PPI metabolism Inter-individual variation in oral PPI bioavailability may necessitate higher PPI doses Selective inhibition of only actively-secreting ATPase molecules by PPIs optimal dose timing

9 Pharmacokinetics of PPI s PPI (dose, mg) T max (h) Bioavailability (%) Protein binding (%) T 1/2 (h) Hepatic metabolism Omeprazole (20) Lansoprazole (30) Pantoprazole (20) Rabeprazole (20) Esomeprazole (20) 2 35~ ~1 Yes 1.7 > Yes Yes Yes 1~2 64~ Yes T max = time to reach peak plasma concentration T 1/2 = elimination half-life

10 46 세의남자환자가가슴쓰림과구토를주소로 내원하였다. 상부위장관내시경을실시하였습니다.

12 이러한환자의처치에서가장적절하지못한방법은? 1 금식을시킨다. 2 H2 수용체길항제를투여한다. 3 지속적으로위배출이되지않는경우에는수술적치료를한다. 4 비위관을삽입하여위내가스와수분의제거를통한감압을시도한다. 5 강력한위산억제를위하여프로톤펌프억제제를구강으로복용시킨다.

13 Recurrent Duodenal Ulcer with Bulb Deformity Passage Disturbance (food remnant, reflux esophagitis) 일반적으로프로톤펌프억제제는위산에취약하고 intestinal drug 이므로위배출에문제가있는환자에게는구강복용의처방을하지않고주사치료를실시한다. 단, 특별한제형- 구강붕해정등. 기타약제가소개가되면서최근에프로톤펌프억제제의이러한단점이개선되어가고있다.

14 New PPI Formulations Lansoprazole orally disintegrating tablet (ODT) LFDT (Multiple unit granule) - 높아진약효의안정성 ( 분할투여가능 ) Easy to swallow and can be taken orally with or without water. Alternative to intravenous PPIs for patients with nasogastric or gastric tubes in ICU or long-term care settings. Baldi F, et al. Gastroenterology 2005; 128(suppl 2):A523 A524.

New PPI Formulations Multiple unit pellet system (MUPS) Extremely small enteric-coated granules (pellets) of the omeprazole formulation inside an outer shell.

15 New PPI Formulations Multiple unit pellet system (MUPS) Extremely small enteric-coated granules (pellets) of the omeprazole formulation inside an outer shell. FDA-approved immediate-release omeprazole formulation Immediate release preparation of omeprazole/sodium bicarbonate that does not require an enteric coating. Sodium bicarbonate as a buffer to protect omeprazole from gastric acid degradation.

16 Unmet Needs of PPI Current PPIs Delayed release formulation Unmet Needs Must be taken 30 minutes before meal 25% of proton pumps regenerate daily Full inhibition only after repeated dose The short dwell-time (T½ < 2 hr) in the blood CYP2C19 polymorphism Insufficient ph>4 holding time Fails to treat nocturnal acid control efficiently Individual variability

17 Refractory / Recurrent Peptic Ulcer Disease (PUD)

Assessment 1. Gastric hypersecretion (ZES, Gastrinoma,.) 2. Severe local scarring that retards healing, and comorbid disease. 3. Continued use of NSAIDs 4.

18 Assessment 1. Gastric hypersecretion (ZES, Gastrinoma,.) 2. Severe local scarring that retards healing, and comorbid disease. 3. Continued use of NSAIDs 4. Pathology that mimics ulcer disease, such as carcinoma. 5. Poor patient compliance or true resistance to secretory inhibition. intravenous PPI s switch to a new PPI. 2C19 polymorphism 6. Failed H. pylori detection or eradication

19 Initial EGD

20 3 개월후

22 58 세의남자환자가 6 개월이상위궤양소견이낫지 않고, 조직검사에서는특이한소견을보이지않을때 가장적절한처치는?

24 1 H2 수용체길항제를추가로취침전에투여한다. 2 내시경적으로악성이의심되어수술적제거를실시한다. 3 조직검사가양성이므로지속적인위산억제제를투여한다. 4 점막하박리술을이용하여병변을완전히제거하도록한다. 5 위산억제의실패로생각하고프로톤펌프억제제의용량을 2배로증량한다.

25 Early Gastric Cancer 내시경소견에서재생상피의불규칙함, mucosal island, 주름의단절이관찰되고있어전형적인조기위암의소견입니다. 조직검사가음성이라도적극적인대처가필요할것으로보이며 repeated biopsy, endoscopic resection을통한진단적부분절제혹은진단과치료를동시에할수있는위절제술이필요할것으로보입니다.

26 10 개월후

29 Assessment 1. Gastric hypersecretion (ZES, Gastrinoma,.) 2. Severe local scarring that retards healing, and comorbid disease. 3. Continued use of NSAIDs 4. Pathology that mimics ulcer disease, such as carcinoma. 5. Poor patient compliance or true resistance to secretory inhibition. intravenous PPI s switch to a new PPI. 2C19 polymorphism 6. Failed H. pylori detection or eradication

30 Clinical Use of PPIs : Peptic Ulcer Intragastric ph > 3.0 block activation of pepsin 따라서 intragastric ph를 high ph로유지하는것이 pepsin 형성을최소화할수있다. Duration of intragastric ph (> 3.0) closely related to ulcer healing rate and recovery time. Burget D, et al. Gastroenterology 1990;99:

31 Clinical Use of PPIs : Peptic Ulcer In duodenal ulcer ph 3.0, 20 hours for 4 weeks ; healing rate (above 90%) Intragastric 2 이하일경우 anti-secretory therapy failure 의가능성이높음.

Effect of acid and pepsin on blood coagulation and platelet aggregation.

32 Clinical Use of PPIs : PU Bleeding Intragastric ph (> 5.4) 지혈을위한응고계효소의활성화 Green F, et al. Effect of acid and pepsin on blood coagulation and platelet aggregation. Gastroenterology 1978;74: Intravenous PPI promising effect : rapid action onset accurate use of swallowing difficulty

33 Effect of Intravenous Omeprazole on Recurrent Bleeding After Endoscopic Therapy of Bleeding Peptic Ulcers Lau JY, et al. N Engl J Med 2000;343: After endoscopic treatment of bleeding peptic ulcers, a high-dose infusion of omeprazole reduced the rate of recurrent bleeding, decreased the need for endoscopic retreatment blood transfusions shortened the length of hospitalization.

34 Intravenous Vs. High-Dose Oral PPI Therapy after endoscopic hemostasis of high-risk lesions in patients with ANVUGIB Murthy S, et al. Dig Dis Sci 2007;52: Oral PPIs are probably equivalent to IV PPIs for preventing re-bleeding in ANVUGIB patients.

35 Intragastric ph with Oral vs Intravenous bolus plus Infusion PPI therapy in patients with bleeding ulcers Laine L, et al. Gastroenterology 2008;134:

36 Results Frequent oral PPI therapy achieves 24-hour ph control that appears to be similar to intravenous bolus plus constant infusion PPI therapy. The major pharmacodynamic benefit of the intravenous regimen was a more rapid elevation in intragastric ph.

37 Switch to a new PPI CYP2C19 genetic polymorphism 2C19 PPI 3A4 Extensive Metabolizer Poor Metabolizer Homozygous EM Heterozygous EM Poor Metabolizer Losec Lanston Pantoloc Pariet Esomezol Ilaprazole

38 77 세의여자환자가평소속쓰림을느끼다가흑색변과 함께현훈을주소로내원하였다.

39 Hematemesis Forrest IIa Endoscopic therapy PPI intravenous for 2 days

40 Hematemesis (x2) Forrest Ib Endoscopic therapy

41 지속적인내시경치료와프로톤펌프억제제주사치료에도불구하고 3 차례의재출혈이발생하였다. 가장적절한처치는? 1 복강경접근을통한수술적치료를실시한다. 2 H2 수용체길항제를추가로취침전에투여한다. 3 가스티린의길항제역할을하는소마토스타틴주사를정주한다. 4 내시경치료로조직접합제인 Histoacryl 같은것을혈관에직접주입한다. 5 프로톤펌프억제제를 non-enzymatic degradation 하는다른제제로바꾼다.

42 Refractory Duodenal Ulcer - Failure of antisectory therapy R/O 2C19 extensive metabolizer 위산억제치료의실패로보이며수술적치료를실시할수도있으나환자가고령이고혈압이흔들리는출혈상황에서복강경접근은불가능합니다. 가스트린이나조직접합제의사용은이론적이고실제적이지는않습니다. 현재로는 2C19 extensive metabolizer 를고려하여프로톤펌프억제제를 switch 하는것도좋은방법일수있습니다.

43 Helicobacter pylori

44 Intragastric ph (> 5.0) Clinical Use of PPIs : H. pylori Eradication 1. an antibacterial action against H. pylori 2. become more sensitive to antibiotics when PPI s allow the microorganism to reach the growth phase by increasing intragastric ph. 3. increase antibiotic stability and efficacy 4. by reducing gastric emptying and mucus viscosity, they increase the gastric residence time and mucus penetration of antibiotics.

45 PPI failure? : Switch to other PPI? Frequency of CYP 2C19 polymorphism Hom EMs : 70% of Caucasians, but only for 30 40% of Asians. Lww YC, Wu MS, et al. J Gastroenterol Hepatol 2007 Tseng PH, Wu MS, et al. J Clin Gastroenterol 2009

49 Refractory / Recurrent GERD

50 Clinical Use of PPIs : GERD To treat GERD, ph>4 holding time should be over 18 hrs Duration (hours) Threshold ph Burget DW et al. Gastroenterology. 1990;99:

51 Modified :Tytgat GN, et al. Aliment Pharmacol Ther. 2008;27:

52 Study on Medication : impedance ph Normal Acid reflux Re-evaluate PPI Failure Functional Heartburn? Pandolfino & Vela. Gastrointest Endosc 2009 Apr;69(4):917-30

53 What Makes Pts with GERD Dissatisfied With Tx? Patient-physician communication Patient s expectation Extra-esophageal symptom Co-morbidity

54 Patient-physician communication Patient s expectation globus sense cough

55 Patient-physician communication 잘안낫는다니까만성.. > < ;; 유지, 관리잘해!

56 Special Consideration Nocturnal Acid Breakthrough (NAB) Motility Disorder of Esophagus Eosinophilic esophagitis Other combined problems with IBS with psychological problem drug-drug interaction

57 NAB (nocturnal acid breakthrough) Definition the presence of intragastric ph < 4 during the overnight period for at least 60 continuous minutes in patients taking prolonged and high dose of PPI Overnight acid recovery regardless of PPI dose. unknown patho-physiology frequent in H. pylori negative patient

58 NAB (nocturnal acid breakthrough)

59 NAB (nocturnal acid breakthrough) Not synonymous with night time heartburn. Not PPI failure (circadian rhythm) Associated ineffective esophageal motility in the body and decreased lower esophageal sphincter pressure. : problematic in complicated esophagus An intermittent dosing fashion of H2RA might be optimal approach.

60 36 세여자환자가인근병원에서역류성식도염진단을받고 4 주간치료제를복용하였습니다. 증상이호전되는양상이다가다시나빠지는과정이고특히야간에속쓰림을심하게느꼈다고합니다. 내시경검사에서는특이한소견이없었습니다. 약을복용하게하고 24 시간보행성식도산도검사를실시하였습니다. (on therapy)

61 Time 24:00 06:00 16:00 02:00 PPI

62 처치로서가장적절하지못한방법은? 1 H2 수용체길항제를취침전에추가투여한다. 2 야식을금하게하는등의생활습관을교육시킨다. 3 프로톤펌프억제제의실패로간주하고수술적교정을하도록한다. 4 프로톤펌프억제제의용량을두배로증량하여추가로저녁식전에투여를한다 5 prokinetics 를추가함으로써하부식도괄약근압을올리고위배출능을개선시킨다.

63 GERD Nocturnal heartburn, not refractory 식도산도검사에서프로톤펌프억제제에대한반응은확실하며 Diary 를보면야식을하는것이보입니다. 우선환자의생활습관개선이필요할것으로보이며, 아침식전요법으로부족한것으로보여저녁식전의추가요법도좋은방법이라고생각합니다. 다만, NAB 와감별은어려운상황이라 H2RA 사용도조심스럽게고려할수있으나 4주간의치료를치료실패로간주하고수술적요법을실시하는데는아직 evidence 가부족한상황입니다.

64 Eosinophilic esophagitis (E.E.) Allergic esophagus infiltrative eosinophilia 15 intraepithelial eosinophilis/hpf Signs/symptoms: Dysphagia, Food impaction, Abdominal/chest pain, Vomiting, Regurgitation Clinical characteristics Male predominance (70%-80% of cases) Family or personal history of allergy/atopy Asthma, rhinitis, eczema, food allergy

65 Eosinophilic esophagitis (E.E.) Linear furrowing, vertical lines & white specks Endoscopic findings are not pathognomic.

66 IBS prevalence in GERD and non-gerd group Nastaskin I et al., 2006

67 Prevalence of GERD in IBS Author(year) IBS(n) GERD prevalence(%) Talley et al.(2003) Hungin et al.(2003) Stanghellini et al.(2002) Kennedy et al.(1998) Jones et al.(1992) Weighted average 30.3

68 H2 Receptor Antagonist - competitive antagonists of histamine at the parietal cell H2 receptor-

69 H2RA Are H2 receptor anatgonists still needed? Cimetidine, Raniditine, Famotidine, Nizatidine, Roxatidine Uncomplicated peptic ulcer disease GERD after PPI (step down treatment) Functional dyspepsia Nocturnal Acid Breakthrough (NAB) ICU patients mechanical vantilation Coronary heart disease 환자에서 clopidogrel 사용시 Young child, infant acute erosive lesion

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<B0E6C8F1B4EBB3BBB0FAC0D3BBF3B0ADC1C E687770> 개원의와함께하는임상강좌 2011 역류성식도질환제대로이해하기 Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea Jae-Young Jang, M.D., PhD. 개원의와함께하는임상강좌 2011 109 최신치료