ANISYAH ACHMAD, S.Si., Apt., Sp.

FRS Departement of Clinical Pharmacy, Major of Pharmacy, FKIK- UNSOED

ORGAN SISTEM PENCERNAAN Meliputi : 1. Mulut + Kelenjar Saliva 2. Pharynx 3. Esophagus 4. Lambung 5. Usus Halus (Duodenum,jejunum,ileum) 6. Colon Sigmoid Rectum Anus 7. Pancreas (Fungsi Eksokrin) 8. Hepar 9. Kandung Empedu

Hormon pencernaan
1. H.Gastrin : ~ disekresi di antrum (sel G) ~ rangs sekresi : - bila ada makanan masuk lambung ( t.u daging) - asetilkolin, parasimpatis, vagus - regangan dinding lambung

Effek Gastrin
Merangsang 1. Peningkatan gerak lambung 2. Pengosongan lambung 3. Relaksasi sfingter ileosekal 4. Gerak mass 5. Sekresi getah lambung 6. Sekresi getah pankreas

Hormon Sekretin
~ sekresi di duodenum (sel S) ~ rangs sekresi : bila isi duodenum asam ~ effek : - menghambat pengosongan lambung - menghambat gerak usus - merangs sekresi elektrolit pankreas - merangs sekresi getah empedu

LAMBUNG
Fungsi : 1. Tempat menyimpan makanan 2. Tempat mencampur makanan dg getah lambung chyme 3. Tempat mengosongkan makanan 4. Mencegah masuknya sebagian kuman 5. Tempat absorbsi alkohol + obat-obatan

Getah lambung
1,5 2 liter / hari ( pH 1,5 3,4 ) - mengandung: 1. Elektrolit : H+, Cl, K+, Na+ 2. Mucus : sel mucus - melindungi mukosa (penderita gastritis : Tx antasida) 3. Lipase dan Amilase : sedikit sekali
-

4. Enzim Pepsin di sekresi : sel utama (Chief Cell) Pepsinogen pepsin HCL ( pH : 1,5 3,5)
Protein (terutama daging) pepsin polipeptida

5. Rennin

- Hanya pada masa bayi - menggumpalkan susu

Casein susu Rennin + Ca para casein pepsin

6. Faktor intrinsik - disekresi oleh sel parietal - membantu absorbsi vit B12

7. Histamin - reseptor H2 merangs sekresi HCl (gastritis : obat H2 Bloker - cimetidine) 8. HCL - disekresi : sel parietal Ion H+ dipompa ke lumen canaliculi (pompa proton) Terapi gastritis : obat gol Proton Pump Inhibitor (PPI)

Faktor perangsang sekresi lambung : Asetilkolin / parasimpatis / vagus Hormon Gastrin Asam amino, alcohol, nikotin, kafein Stress emosi

Fase Sekresi - Fase cephalic - Fase gastric - Fase intestinal

GIT DISEASE

Gastroesophageal reflux
Reflux of gastric contents into the esophagus Heartburn, substernal pain, burning sensation Predisposing factors: alcohol, smoking, pregnancy May lead to: esophagitis, strictures, Barrett esophagus

Barrett esophagus
Normal epithelium: squamous type Barrett: becomes columnar with many Goblet cells Precursor for adenocarcinoma of the esophagus

Barrett esophagus

Barrett esophagus

Cancer of the esophagus

Most frequent type: squamous cell carcinoma Dysphagia, weight loss, anorexia Upper and middle thirds of the esophagus Adenocarcinoma type : lower third of the esophagus

Cancer of the esophagus

Congenital pyloric stenosis

Hypertrophy of the circular muscle layer of the pylorus Projectile vomiting in 1st 2 weeks of life Palpable mass

Gastritis
Acute gastritis Causes: NSAIDS smoking alcholic drinks burns : Curlings ulcer Cushings ulcer Chronic gastritis Chronic inflammation, atrophy of the mucosa Helicobacter pylori gastritis: most common form Increases risk of gastric cancer

Acute Gastritis

Peptic ulcers
Common locations: lesser curvature antrum prepyloric areas Causes: H.pylori infection bile-induced gastritis Not a precursor lesion of carcinoma of the stomach

Benign Gastric Ulcers

Cancer of the Stomach

Common: more than 50 years old, men, Blood group A Predisposing factors: H. pylori infection Nitrosamines excessive salt intake low fresh fruits, vegetables diet achlorhydia chronic gastritis

Cancer of the stomach

Most common type: adenocarcinoma Rare in the fundus Aggressive spread to adjacent organs Virchow node: large supraclavicular node Krukenberg tumors: bilateral, enlarged ovaries, signet ring cells Two types: 1. intestinal type: fungating mass; ulcer with irregular necrotic base and firm, raised margins 2. infiltrating or diffuse type: linitis plastica

Cancer of the stomach

DRUG USED

 ANTACIDS SUCRALFATE H2 RECEPTOR ANTAGONIST PROTON PUMP INHIBITOR

1. Antacids 2. H2 RA 3. Proton Pump Inhibitor 4. Sucralfat 5. Antimicrobials (Triple combination) 5

ANTACIDS

Commonly used in antacid products Katzung, B.G., 2006. Basic and Clinical Pharmacology, 10thEd. New York: McGraw-Hill.

SUCRALFAT

PHARMACODYNAMICS/KINETICS

Onset of action: Paste formation and ulcer adhesion: 1-2 hours Duration : Up to 6 hours Absorption : Oral: <5% Distribution : Acts locally at ulcer sites; unbound in GI tract to aluminum and sucrose octasulfate Metabolism : None Excretion : Urine (small amounts as unchanged compounds)
Katzung, B.G., 2006. Basic and Clinical Pharmacology, 10thEd. New York: McGraw-Hill. Lacy, C.F., Armstrong, L., Goldman, M., Lance, L., 2006. Drug Information Handbook, 14th Edition, USA: Lexi-Comps.

SUCRALFAT
It works on pH less than 4 due to paste like formation

Neal, M.J., 2005. Medical Pharmacology At a Glance, Fifth Edition, Oxford: Blackwell Publishing Comp.

 digoxin fluoroquinolone antibacterials tetracycline ketoconazole levothyroxine Phenytoin quinidine Theophylline Warfarin

INTERACTIONS
Antacid H2RA PPI

should be an interval of 2 hours before giving sucralfate

The recommended interval is 1 hour after sucralfate

(Anderson, 2007. Handbook clinical Drug Data)

Precautions For [Al(OH)3) and Sucralfate]

In patients with renal failure, aluminum may accumulate to toxic levels

the signs of aluminum toxicity : seizures, muscle weakness, bone pain, and severe aluminium encephalopathy have been reported in patients with end-stage renal disease requiring dialysis

monitored for potential signs of aluminum toxicity

Hemstreet, 2001. Use of sucralfate in renal failure. The Annals of Pharmacotherapy: Vol. 35, No. 3, pp. 360-364);( Martindale, 2007); (Anderson, 2007. Handbook clinical Drug Data)

H2 RECEPTOR ANTAGONIST

Cimetidine interferes with several Important hepatic cytochrome P450 pathway. Ranitidine binds 4-10 times less to Cytochrome P450
Katzung, B.G., 2006. Basic and Clinical Pharmacology, 10thEd. New York: McGraw-Hill.

effect

Katzung, B.G., 2006. Basic and Clinical Pharmacology, 10thEd. New York: McGraw-Hill.

COMPARISON OF H2 RECEPTOR ANTAGONIST AGENT

CHARACTERISTIC OoA DoA Bioavailability Protein binding Half-life Excretion RENAL IMPAIRMENT ClCr > 50 ml/min po CIMETIDINE 1 hour 4-5 hours 60 20% 206% 1.90.4hr urine iv po 8-12 hours 5525% 15% 20.4hr urine iv po RANITIDINE FAMOTIDINE 1 hour 10-12 hours 414% 16% 30.5hr urine iv NIZATIDINE 30 minutes 8-12 hours 955% 75% in renal failure 305% 1.40.2hr Urine po iv

300 mg 6 h 400 mg 6 h 800 mg12 h 300 mg 8-12 h 300 mg 12 h

300 mg 6h 300 mg 8-12 h 300 mg 12 h

300 mg 12 h 150 mg 24 h 150 mg 24 h

50 mg 12 h 50 mg 12-24 h 50 mg 24 h

20 mg 12 h 40 mg 12 h 20 mg 24 h 20 mg 48 h

20 mg

300 mg 24 h 150 mg 24 h 150 mg 48 h

ClCr : 10-50 ClCr < 10 Hepatic impairment

20 mg 24 h 20 mg 48 h

No dosage adjustment is needed but monitor

PRECAUTION
In renal impairment, H2RA agents need dose adjustment
Cimetidin should be avoided to use, because it is highly bound to cytochrome P450

ADMINISTRATION

H2RA
injection should be given over 30 minutes or slow injection over 5 minutes
Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous injection should be given over 30 minutes

proton pump inhibitor PROTON PUMP INHIBITOR

and feces

Use of proton pump inhibitors and risk of osteoporosis related fractures

retrospective, matched cohort study

Use of proton pump inhibitors for 7 or more years is associated

with a significantly increased risk of an osteoporosis-related fracture. There is an increased risk of hip fracture after 5 or more years exposure.

Targownik, E., Lix, L.M., Metge, C.J., Prior H.J., Leung, S., Leslie, W.D. 2008. Use of proton pump inhibitors and risk of osteoporosis related Fractures. CAMJ. 179 (4); 319-26.

Characteristic OoA DoA Bioavailability Protein binding Half-life Excretion

Renal impairment

Omeprazole

Lansoprazole

Pantoprazole

Rabeprazole

Esomeprazole

1hr 72hr 30-40% 95% 0,5-1hr

Urine(77%); feces

1hr >1day 80-85% 98% 1hr

Urine (33%) Feces (67%)

1,75 hr >1 day 77% 97% 2hr

Urine (71%); feces(18%)

1,75 hr 24 hours 52% 94,8-97,5% 1-2hr

Urine (90%); feces

1,5hr 64% 97% 1-1,5 hr

Urine (80%); feces (20%)

No dosage adjustment is needed (no significant changes) No dosage Adjustmet is needed Severe decreased dose (prolonged t) No dosage Adjustmet is needed No dosage Adjustmet is needed No dosage adjustment is needed
For patients with severe liver impairment (Child Pugh class C), do not exceed a dose of 20 mg.

Hepatic impairment

Factors that affect absorption

Pharmacokinetic

Food
Non linear

Antacids food
linear

none
linear

Food not studied

linear

Food
Non linear

PPI used 30-60 minutes before meals.

Profile of Pharmacokinetics (linear and non-linear)

ADMINISTRATION PPI iv
Omeprazol infusion diluted on100 ml in NaCl 0,9% or dextrose 5% in water administered 20-30 minute due to thrombophlebitis and abcess

po
- 30 minutes before meal. - the tablet should not be chewed due to enteric coated formulation
(AHFS Drug Information, 2007)

ACID PEPTIC DRUG USE

PRECAUTION FOR PPI

IN RENAL IMPAIRMENT Increase the risk of osteoporosis (due to the risk of osteodystrophy renal on patient with CKD) Monitor the worsening of renal failure because PPI is drug induced of tubulo-interstitial nephritis (3%)

(Torpey N, nephrology dialysis transplantation (2004). P: 14441-1446)

No 1..

Indication and possible etiology Dyspepsia - Peptic Ulcer - Gastroparesis(in DM) - Endoscopy, chronic Helicobacter pylori GERD

Use for Upper abdominal or eoigastric symptom

Drug and Dose -H2 reseptor Antagonis placebo (ranitidine, famotidine) -cicapride, metochlopramide, as prokinetic - PPI for Helicobacter pylori -Antacids are the mainstay for rapid relief of occasional heartburn. (Maalox, Mylanta) -H2 reseptor antagonis 2 x 1, or promotility agent. -PPI 1 x before breakfast -H2 reseptor antagonis no benefit in stopping acute bleeding or reducing the incidence of rebleeding. (not recommended). -PPI high dose of omeprazole, lansoprazole, 2 x1 for 5 days have been shown reduce the risk of rebleeding in patient with peptic ulcer

2.

-Mild Intermitten symptom -Moderate symtoms -Severe or refractory symtomps

3.

GI Bleeleding/upper GI bleding - Peptic ulcer - Portal HT, oesephageal varices - Erosive gastritis

-Bleeding (stabilization of Blood Pressure, heart rate, splanchnic blood flow - Acute drug therapy : octreotide continous IV infusion. Vasopressin ( splanchnic blood flow & portal Blood pressure)

4.

Erosive gastritis

Prophylaxis Therapy

5.

Spesific type of gastritis -acid antisecretary -Peptic ulcer, cause of: -mucosal defence -NSAID -H. Pylori -acid hypersecretory (zolinger Ellison)

-Sucralfat or H2 Antagonist reseptor (ranitidine,famotidin, infusion over 24 h), check pH after 4 h of infusion. -PPI in ICU should not be use due to unpredictable oral absorption -PPI -H2 antagonis reseptor. -sucralfat -Bismuth Prostaglandin analog -Antacid -H pylori eradication (t.antibiotic)

Current Medical, Diagnosis & Treatment, by Lawrence M. Tierney,Jr, Stephen J McPhee, Maxine A

DRUG OF CHOICE IN RENAL AND HEPATIC FAILURE PATIENT

PPI Pantoprazole AND Lanzoprazole - linier pharmacokinetic no dose adjustment - less interaction with others drugs less binding with CYP450 - Bioavailability greater than others - T1/2 pharmacodynamic (<49,5 hr) >>

DRUG OF CHOICE ON LOSS CONSCIOUSNESS PATIENT

PPI & H2RA (except Cimetidin) due to the less adverse effect on CNS