Farmakologi & Toksikologi I:

Obat-Obat Gastrointestinal
(GIT)

Ari Y
RUBI Farmakologi
Sekolah Tinggi Farmasi Bandung
2016
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Outline
Anatomi dan Fisiologi Saluran Pencernaan
Gastroesophageal Reflux Disease (GERD)
Ulcer : peptic, duodenal
Irritable Bowel Syndrome (IBS)
Mual dan Muntah

Diare dan Konstipasi

Daftar Pustaka

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 Sistem
Gastrointestinal

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 Gangguan Gastrointestinal

Gastroesophageal Reflux Disease (GERD)

Ulcer : Peptic, Duodenal
Irritable Bowel Syndrome (IBS)
Mual dan Muntah
Diare dan Konstipasi

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Anatomi dan Fisiologi
(Saluran Pencernaan)

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Anatomi Lambung

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Lapisan Lambung

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Kelenjar pada Lambung

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Gastric Mucosal Barrier

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Parietal Cell: Sekresi HCL
H+

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Chief Cell: Sintesis dan Aktivasi Pepsin

HCl
+HCl

Pepsin
Pepsin

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 Serotonin (5-Hydroxytryptamine)
Sebagai Key neurotransmitter di dalam intestinal

Melimpah di dalam usus.

Sebagian besar ditampung pada granula sel enterochromaffin.

Dilepas dengan adanya stimulus.

Serotonin menstimulasi syaraf di usus untuk inisiasi sekresi dan

motilitas propulsif.

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Serotonin di dalam usus

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Disfungsi Serotonin dalam Usus

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 Gastroesophageal
Reflux Disease (GERD)

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 Gastroesophageal Reflux Disease (GERD)

- Perpindahan balik isi lambung menuju esofagus.

- Gejala khas : rasa panas terbakar.
- Beberapa gejala lain: nyeri dada, susah untuk menelan makanan.
- Reflux yang mencapai tenggorokan batuk.
- Komplikasi meliputi :erosi esofageal, erosi esofageal, dan penyempitan esofagus (esophageal
stricture).

- Pada beberapa pasien (~10%), lapisan normal esofageal/epithelium digantikan dengan

lapisan epitelium abnormal - (Barrett's) epithelium. Kondisi ini berkaitan dengan munculnya
kanker esofagus.

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Gastroesophageal Reflux Disease (GERD)

Endoscope of Barretts Esophagus

(can become malignant - needs monitoring)

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 Gejala GERD
Heartburn/pirosis (sensasi panas yang menjalar sampai leher)
Hipersalivasi
Regurgitasi
Disfagia
Odinofagia (sakit waktu menelan)
Sendawa
Rasa asam dalam mulut

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Contributing Factors
Decrease LES pressure Directly irritate the gastric
Chocolate mucosa
Alcohol Tomato-based products
Coffee
Fatty meals
Spicy foods
Coffee, cola, tea
Citrus juices
Garlic
Meds: NSAIDS, aspirin, iron, KCl,
Onions alendronate
Smoking Stimulate acid secretions
Soda
Beer
Smoking
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Contributing Factors
Drugs that decrease LES pressure
Alpha-adrenergic agonists
Anti-cholinergic agents (e.g. TCAs, antihistamines)
Beta-adrenergic agonists
Calcium channel antagonists (nifedipine most reduction)
Diazepam
Dopamine
Meperidine
Nitrates/Other vasodilators
Estrogens/progesterones (including oral contraceptives)
Prostaglandins
Theophylline

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Peptic Ulcer

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Peptic Ulcer

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Ari Y - Patofisiologi GIT
Terapi Farmakologi GERD dan Peptic Ucer

Antasida
H2 Receptor Blockers (Antagonis H2)
Mucosal Protective Agents
Proton Pump Inhibitors (PPI)
Anti-kholinergik
Analog Prostaglandin, dan
Anti-microbial Agents

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 Antasida
Antasida sistemik: Sodium Bicarbonate
Antasida non-sistemik:
Aluminum Hydroxide + Magnesium Hydroxide Combinations (Maalox and
Mylanta)
Dikontraindikasikan pada pasien dengan gangguan fungsi ginjal
Magnesium dapat menyebabkan diare
Mekanisme kerja: Penetralan asam lambung

Calcium Carbonate (Tums)

Calcium dapat menyebabkan konstipasi

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 Histamine H2 Receptor Blockers

Mekanisme Kerja: Menghambat sekresi asam lambung melalui inhibisi

kompetitif reseptor H2.
Indikasi: Pencegahan & terapi terhadap peptic ulcer, esophagitis, GI bleeding,
stress ulcers, dan Zollinger-Ellison Syndrome.

Memberikan efek terhadap obat lain melalui interaksi terhadap CYP450

(khususnya cimetidine).
Efek samping yang rendah (kecuali cimetidine menghambat metabolisme
estrogen).
Contoh : Cimetidine, Famotidine, Nizatidine

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 Proton Pump Inhibitors (PPIs)
Mekanisme Kerja: Inhibitor kuat sekresi asam lambung melalui inhibisi irreversible
pompa proton, mencegah pumping atau pelepasan asam lambung (aksi 24 jam).
Indikasi: PUD, Gastritis, GERD, & Zollinger-Ellison syndrome.
Kerja cepat dibandingkan dengan H2 receptor blockers.
Menurunkan sekresi asam sampai 95% selama 48 jam.
4-8 minggu treatment.

Omeprazole Lansoprazole

Rebeprazole

Esomeprazole
Pantoprazole
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Analog Prostaglandin
Misoprostol

Menurunkan pelepasan asam lambung yang berlebihan.

Dapat digunakan untuk kerusakan lambung yang diseabkan

NSAIDs.

Efek samping: termasuk diare, nyeri, dan kram (30%)

Do not give to women of childbearing years unless a reliable

method of birth control can be DOCUMENTED
Can cause birth defects, and premature birth

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Antikolinergik
Pirenzepine

Mekanisme kerja: Antagonis reseptor Muscarinic M1-

acetylcholine

Blokade sekresi asam lambung.

Efektif seperti halnya H2 bloker.

Jarang digunakan (sebagai adjunct therapy).

Efek samping anticholinergik (anoreksia, pandangan kabur,

konstipasi, mulut kering, sedasi).

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Summary of Acid Reduction therapeutics

Antacids

H+ Cl-

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 Mucosal Protective Agents
Sucralfate (carafate)
Can be used to prevent & treat PUD
It requires an acid Ph to activate
It requires an acid Ph to activate
Forms sticky polymer in acidic environment and adheres to the ulcer site,
forming a barrier
May bind with other drugs and interfere with absorption
Give approximately 2 hours before or after other drugs
Take on an empty stomach before meals

Chelated Bismuth
Protects the ulcer crater and allows healing
Some activity against H. pylori
Should not be used repeatedly or for more than 2 months at a
time
Can cause black stools, constipation

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Helicobacter pylori

H. pylori are bacteria able to attach to the epithelial cells of the stomach
and duodenum which stops them from being washed out of the stomach.
Once attached, the bacteria start to cause damage to the cells by secreting
degradative enzymes, toxins and initiating a self-destructive immune
response.
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www.science.org.au/ nobel/2005/images/invasion.jpg
 Anti-H.pylori Therapy
>85% PUD caused by H. pylori
Antibiotic Ulcer Therapy - Used in Combinations
Bismuth - Disrupts bacterial cell wall
Clarithromycin - Inhibits protein systhesis
Amoxicillin - Disrupts cell wall
Tetracycline - Inhibits protein synthesis
Metronidazone - Used often due to bacterial resistance to
amoxicillin and tetracycline, or due to intolerance

Triple Therapy - 7 day treatment - Effective 80-85%

Proton pump inhibitor + amoxicillin/tetracycline + metronidazone/clarithomycin

Quadruple Therapy - 3 day treatment, as efficacious as triple therapy

- Add Bismuth to triple therapy
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Inflammatory Bowel
Disease (IBD)

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 Inflammatory Bowel Disease
Ulcerative colitis
Diffuse mucosal inflammation limited to the
colon
Bloody diarrhea, colicky pain,
urgency,tenesmus

Crohns Disease
Patchy transmural inflammation
May affect any part of GI tract
Abdominal pain, diarrhea, weight loss,
intestinal obstruction

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Inflammatory Bowel Disease
Treatment = Resolve acute episodes and prolong remission

Therapeutics:
Aminosalicylates - for mild symptoms
Corticosteroids - for moderate symptoms
Thiopurines - for active and chronic symptoms
Methotrexate - for active and chronic symptoms
Cyclosporin - for active and chronic symptoms refractory to
corticorsteroids- (significant side effects)
Infliximab - antibody infusion

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Aminosalicylates
Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance)
Mesalazine (5-ASA), eg Asacol, Pentasa
Balsalazide (prodrug of 5-ASA)
Olsalazine (5-ASA dimer cleaves in colon)

Oral, rectal preparation

Use
Maintaining remission
Active disease
May reduce risk of colorectal cancer
Adverse effects
10-45%
Nausea, headache, epigastric pain, diarrhoea, hypersensitivity, pancreatitis,
blood disorders, lung disorders, myo/pericarditis
Caution in renal impairment, pregnancy, breast feeding

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Corticosteroids
Anti-inflammatory agents for moderate to severe relapses

eg 40mg Prednisolone

Inhibition of inflammatory pathways (IL transcription,

suppression of arachidonic acid metabolism, lymphocyte
apoptosis)

Side effects
Acne, moon face

Sleep, mode disturbance

Dyspepsia, glucose intolerance

Cataracts, osteoporosis, myopathy

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Thiopurines
Azathioprine, mercaptopurine

Inhibit ribonucleotide synthesis

Inducing T cell apoptosis by modulating cell signalling
Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides

Use
Active and chronic disease
Steroid sparing
Side effects
Leucopaenia (myelotoxic)
Monitor for signs of infection, sore throat
Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity

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 Methotrexate
Inhibits dihydrofolate reductase
Probably inhibition of cytokine and eicosanoid synthesis

Use
Relapsing or active CD refractory or intolerant to AZA or thiopurine

Side effects
GI
Hepatotoxicity, pneumonitis

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 Cyclosporin
Inhibitor of calcineurin, preventing clonal expansion of T cell subsets

Use
Active and chronic disease
Steroid sparing
Bridging therapy

Side effects
Tremor, paraesthesiae, malaise, headache, abnormal LFT
Gingival hyperplasia, hirsutism
Major: renal impairment, infections, neurotoxicity

Monitor
Blood pressure, FBC, renal function

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Infliximab
Anti TNF- monoclonal antibody
Potent anti inflammatory effects

Use
Fistulizing CD
Severe active CD refractory/intolerant of steroids or
immunosuppression
iv infusion

Side effects
Infusion reactions
Sepsis
Reactivation of Tb, increased risk of Tb

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Constipation

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Constipation
Usually effectively treated with dietary modification.
Only if this fails should laxatives be used.
The #1 cause of constipation in laxative abuse!

Therapy:
1. Bulking agents
2. Osmotic laxatives
3. Stimulant drugs
4. Stool softners

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Laxatives

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 Bulk Laxatives
-Increase in bowel content volume triggers stretch receptors in the intestinal wall
-Causes reflex contraction (peristalsis) that propels the bowel content forward

Psyllium
Bran
Methylcellulose

Insoluble and non-absorbable

Non digestible

Must be taken with lots of water!

(or it will make constipation worse)

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 Saline and Osmotic Laxatives
-Effective in 1-3 hours
-Used to purge intestine (e.g. surgery, poisoning)
-Fluid is drawn into the bowel by osmotic force, increasing volume and triggering peristalsis

Nondigestible sugars and alcohols

Lactulose (broken down by bacteria to acetic and lactic acid,
which causes the osmotic effect)

Salts
Milk of Magnesia (Mg(OH)2)
Epsom Salt (MgSO4)
Glaubers Salt (Na2SO4)
Sodium Phosphates (used as enema)
Sodium Citrate (used as enema)

Polyethylene glycol

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 Stool Softners - Emollients

Docusate sodium (surfactant and stimulant)

Liquid Paraffin (oral solution)
Glycerin suppositories

Docusate
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Irratant/Stimulant Laxatives-Cathartics
-Increases intestinal motility
-Irritate the GI mucosa and pull water into the lumen
-Indicated for severe constipation where more rapid effect is required (6-8 hours)

Castor Oil - From the Castor Bean

Senna - Plant derivative
Bisacodyl

Lubiprostone -PGE1 derivative that stimulates chloride channels,

producing chloride rich secretions

Bisacodyl Senna Lubiprostone

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 Laxative Abuse
Most common cause of constipation!
Longer interval needed to refill colon is misinterpreted as constipation
=> repeated use

Enteral loss of water and salts causes release of aldosterone

=> stimulates reabsorption in intestine, but increases renal excretion of K+
=> double loss of K+ causes hypokalemia, which in turn reduces peristalsis.
=>This is then often misinterpreted as constipation
=> repeated laxative use

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Diare

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 Diare
Penyebab :
Toxin
Mikroorganisme (shigella, salmonella, E.coli, campylobacter, clostridium difficile)
Colitis yang berkaitan dengan antibiotika

Indikasi Pengobatan :
>2-3 hari
Diare pada dewasa dan anak-anak
Penyakit inflamasi kronis
Bilamana penyebab spesifik sudah ditentukan

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 Anti-Diarrheal Agents
Anti-motility Agents
Mengurangi peristalsis dengan stimulasi reseptor opioid di usus.
Memberikan waktu agar air dapat diabsorpsi oleh usus.
Morphine
Codeine
Diphenoxylate
Loperamide
40-50x lebih poten dari morphine
Penetrasi CNS jelek
Meningkatkan transit time dan sphincter tone.
T 11 jam
Overdose: paralytic ileus, CNS depression
Perhatian pada IBD (toxic megacolon)

Kontraindikasi :
Bahan toksis
Mikroorganisme (salmonella, E.coli) Loperamide
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 Clostridium Difficile
Penyebab sebagian besar diare dan pada pasien yang terpapar antibiotik (~20%).
Tahapan infeksi
Mempengaruhi flora normal
Kolonisasi C. difficile
Pertumbuhan dan produksi toksin
Infeksi dapat membentuk colitis & toxic megacolon

Terapi Farmakologi
Tidak melanjutkan penggunaan antibotik.
Metronidazole (dikontraindikasikan pada pasien dengan gangguan liver dan ginjal).
Vancomycin (dikontraindikasikan pada pasien dengan gangguan ginjal).

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Emesis

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Emesis

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 Emesis
(seeing something repulsive)
(motion sickness)

(Ingesting a toxin) Ari Y Farmakologi GIT 66

 Sirup Ipecac
Dibuat dari akar tanaman ipecac.
Menginduksi emesis.
Efek samping : diare, nyeri lambung
Sesuai digunakan bilamana :
Tidak ada kontraindikasi pada penggunaan ipecac
Ada resiko substansial dari toksisitas pada korban.
Tidak ada alternatif terapi yang tersedia/aktif untuk absorpsi GIT (e.g.,
activated charcoal)

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 Antagonis Reseptor
Muskarinik
Contoh obat : Scopolamine
Kontraindikasi
Efek Samping :
Penyakit ginjal dan liver
Mulut kering
Pembesaran prostat
Pusing
Kesulitan urinasi/permasalahan
Resah/gelisah kandung kemih

Midriasis Penyakit jantung

Delirium (pada dosis tinggi) Glaukoma
Reaksi alergi

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 Antagonis Reseptor Histamine H1/Dopamine D2
Contoh Obat : Golongan Phenothiazines
Promethazine (Phenergan)
Prochlorperazine (Compazine)
Efek Samping :
Kontraindikasi :
Pandangan kabur
Alergi terhadap fenotiazin
Mulut kering
Glaukoma
Pusing
Penyakit liver
Resah/Gelisah
Permasalahan prostat/kandung kemih
Kejang
Efek Extrapyramidal - Tardive dyskinesia
(pemberian jangka panjang)

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 Antagonis Reseptor Serotonin 5-HT3
Contoh Obat : Ondansetron, Granisetron
Sangat baik diberikan untuk mual/muntah yang diinduksi kemoterapi.

Efek samping :
Sakit kepala
Konstipasi

Efek samping (yang jarang) :

Rasa gatal
Kebutaan sementara

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 Cancer Chemotherapy Drugs

Dopamine agonists

Chemoreceptor
Trigger Zone
(CTZ)

Ondansetron Scopolamine
H1 Antihistamines
Phenothiazines

All

Target Terapi Antiemetik

Ondansetron

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Any Questions ???

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Daftar Pustaka
Lullman et al. Color Atlas of Pharmacology. Thieme. 2000
Stefan Silbernagl & Florian Lang. Color Atlas of Pathophysiology. Thieme.
2000.
Stephen J. Mc Phee & William F. Ganong. Pathophysiology of Diseases.
McGraw- Hills Access Medicine. 2006.

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Terima Kasih

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