Drugs Used for

Gastrointestinal Disorders

Maria Victoria Matias-Villarica RN, MD, DPPS, FPSECP

OLFU College of Medicine
Department of Pharmacology
Drugs Used for GIT disorders

Maria Victoria Matias Villarica RN, MD, DPPS, FPSECP

OLFU College of Medicine
Department of Pharmacology
Objectives:
 To discuss the different drugs used for the
management of:
a. Peptic Ulcer Disease
b. Vomiting
c. Constipation
d. Diarrhea
e. Gallstones
f. Inflammatory Bowel Disease
g. Steatorrhea
h. IBS
3 Major pathways regulating
parietal acid secretion:
1. Neural stimulation via vagus nerve
2. Endocrine stimulation via gastrin
(antral G cells)
3. Paracrine stimulation by local release
of histamine (ECL cells)
Gastric Hyperacidity and Peptic
Ulcer Disease
- occurs if there is an imbalance between
acid secretory mechanisms (gastrin,
pepsin, H. pylori) and local mucosal
defences (mucus, HCO3, PGs)
- 2 types of PUD:

1. type 1 – impaired mucosal protective

factors (malignancy, H. pylori, NSAIDs)
2. type 2 – acid hypersecretion
(H. pylori, NSAIDs)
Gastroesophageal Reflux Disease
(GERD)
 reflux of gastric contents into the
esophagus
 due to incompetence of the LES
 delay in gastric emptying
- managed by:
 elevate the head of the bed by 6 in.
 avoid bedtime meals
 avoid direct irritants/strong stimulants,
smoking, drugs like theophylline,
chocolates, fats, alcohol
Drug regimens for GERD: 4-8 weeks
 Nonerosive GERD: Proton Pump Inhibitors:
Omeprazole 20mg OD or BID
Lansoprazole 30mg OD or BID
Rabeprazole 20mg OD or BID
Pantoprazole 40mg OD or BID
H2 Blockers:
Cimetidine 400mg BID
Ranitidine or Nizatidine 150mg BID
Famotidine 20mg BID
Cholinergic agonist: Metoclopramide 10 mg a.c and HS
 Erosive GERD: Proton Pump Inhibitors
H2 Blockers:
Cimetidine 400mg QID
Ranitidine or Nizatidine 150mg QID
Famotidine 40mg BID
Helicobacter pylori Gastritis
- A gram (-) rod that colonizes the mucus on
the luminal surface of the gastric epithelium
causing an inflammatory gastritis and is a
putative contributor to PUD, gastric
lymphoma and adenocarcinoma
- Multiple drug therapy is needed to avoid
resistance
Therapeutic mgt. x 14 days
1. triple therapy (best option):
PPI plus
Clarithromycin, 500mg BID and Ampicillin/Amoxicillin 1 g or
Metronidazole 500mg BID
after 14 days, continue PPI OD X 4-6 weeks
2. quadruple therapy (2nd line option): 10-14 days
PPI BID;
Tetracycline HCl 250-500mg 4x a day;
Bismuth subsalicylate 2tabs (262mg each) 4x a day;
Metronidazole 500mg 3x a day
3. Sequential treatment:
days 1-5 PPI BID + Amoxicillin 1 g. BID
days 6-10 PPI BID + Clarithromycin 500mg BID and
Tinidazole 500mg BID
I. Proton Pump Inhibitors
(H+K+ATPase Inhibitor)
 Irreversibly inhibit the gastric parietal cell proton pump ( H+ K+
ATPase pump)
 “pro-drug” – requires activation in an acidic environment
 Superior to H2 receptor antagonist and Misoprostol in healing
 Therapeutic indication: PUD (duodenal: 4 weeks; gastric: 6-8
weeks) , GERD (3 mos.), Z-E syndrome, NSAIDs (OD),
rebleeding from peptic ulcers (IV pantoprazole 80mg with
infusion at 8mg/h), stress-related mucosal bleeding (omeprazole
BID, then OD thru NGT)
 Acid inhibition: 24 hrs.
 Serum t ½ : 1.5 hrs.
 Full acid inhibiting potential: 3-4 days of daily
medication
 18 hrs. – required for synthesis of new proton pump
molecules
Adverse Effects:
 General: diarrhea, headache, abdominal pain
 Affects B12, Ca+, Mg, Iron salt absorption
 Respiratory and enteric infections
 Alters normal feedback inhibition that serum gastrin
levels rise (rats) and other potential problems
Proton pump inhibitors:
empty stomach x 4-8 weeks
 Omeprazole* – Losec 10/20mg
 Lansoprazole* – Prevacid 15/30mg
 Dexlansoprazole
 Rabeprazole – Pariet 10/20mg
 Pantoprazole – Pantoloc 20/40mg; oral and IV
 Esomeprazole – Nexium 20/40mg; oral and IV
II. Histamine (H2) receptor
antagonists
- competitive inhibitor of the action of histamine with
H2 receptor, inhibiting acid secretion; ↓pepsin
- capable of >50% reduction (in 10 hrs) in basal and
food stimulated secretion of acid after a single dose;
90% reduction in nocturnal secretion
- promotes healing of ulcers and prevent their
recurrence
- low side effects; great margin of safety
- decrease dose in renal and hepatic insufficiency
- serum t ½ : 1.1 – 4 hrs.
Therapeutic indications of H2
blockers:
 Peptic ulcer – OD x 6-8 weeks
 Duodenal ulcer
 Zollinger-Ellison syndrome
 GERD – before meal BID
 Others: reflux esophagitis, stress ulcers, short bowel syndrome,
hypersecretory states, preanesthetic medications
 H. pylori gastritis that cannot be eradicated: Famotidine 20mg
or Ranitidine 150mg OD HS
 Bleeding of stress-related gastritis – continuous IV infusion
 H2 Blockers:
PUD:can be administered at bedtime or twice a day
x 4-8 weeks
Maintenance: bedtime ½ dose x 1 year
 Cimetidine – interacts with cytochrome p450 (inhibitor);
gynecomastia, galactorrhea, impotence Tagamet 200/400mg
 Ranitidine – less cytochrome p450 effect; Zantac 150/300mg
 Famotidine – less effect on cytochrome p450; H2Bloc 20/40mg; 20-
50x relative potency
 Nizatidine – no effect on cytochrome p450; little 1st pass metabolism
Axid 150/300mg
 AE: <3%: LBM, HA, fatigue, myalgia, constipation
IV (cimetidine): mental status changes (confusion, hallucinations,
agitation)
crosses placenta and excreted in breastmilk
rare: bradycardia, hypotension; blood dyscrasia
 DI: ethanol – inhibits 1st pass metabolism
procainamide – competes with renal excretion
III. Muscarinic Antagonists
 Reduce basal secretion of gastric acid by 40-50%
 Inhibits secretion of mucus and HCO3
 Less effective than H2 antagonist in reducing acid
secretion but comparable as to the rate of healing of
ulcers
 Hydrophilic; crosses BBB
Muscarinic antagonist: seldom used

 Side effects: dry mouth, blurred vision

 Contraindications: narrow-angle glaucoma,
gastric retention, esophagitis, urinary retention
 Drugs: Poldine
Propantheline
Glycopyrrolate
IV. Antacids – commonly used remedies for
intermittent heartburn and dyspepsia

 Weak bases that react with gastric HCL to form a

salt and water (CO2 and water)
 After a meal: 45 mEq/h of HCL : 156mEq antacid 1
hr after a meal neutralizes acid in 2 hrs.
 ↑pH, reduces pepsin activity; (-) effect on volume of
gastric acid; promotes healing of ulcers
 Net buffering capacity – ability of a drug to neutralize
gastric acid and duration of the medication’s
residence in the stomach (factors)
 Drug combination was developed to maximize drug
effect and minimize side effect
Antacids: not recommended for the
treatment of active peptic ulcer

 Presence of food prolongs the neutralizing capacity

of antacids for about 2 hrs.
(given 1 hour after meals and at bedtime)
A. Non-absorbable antacids: Maalox, Mylanta, Gelusil
1. AlOH – slowly; constipation
2. MgOH – slowly; diarrhea
B. Absorbable antacids (relatively insoluble salts):
1. CaCO3 – milk-alkali syndrome; more slowly; TUMS
2. NaHCO3 – alkalosis; rapid; ALKA SELTZER
- CO2 produced causes distention and belching
ANTACIDS:
 ADVERSE EFFECTS
1. NaHCO3 and CaCO3:
EXCESSIVE DOSES: hypercalcemia, renal acidosis and
metabolic acidosis
2. AlOH and MgOH:
C/I: renal insufficiency
 DRUG INTERACTION:
Tetracycline, Fluoroquinolone, Itraconazole and Iron –
Antacids reduces absorption or increases gastric pH
 V. Mucosal protective Agents
A. Sucralfate – salt of sucrose + AlOH; adheres to
epithelial cells and to the base of the ulcer craters;
protects from further hydrolysis (6h); acts as a
barrier to acid and pepsin; stimulate PGs synthesis
- 1 gm. QID (1 h before meals and HS): Carafate ,
Iselpin
- reduces incidence of upper GI bleeding in critically
ill patients (NGT) and prevention of stress related
bleeding (concerns with PPI)
- AE: constipation; renal insufficiency
- DI: impair absorption of certain drugs
B. Prostaglandin Analogs (PGE2, PGI2)
 Are predominant PGs synthesized by the gastric mucosa,
inhibiting the secretion of acid and stimulate the secretion of
mucus and HCO3
 Modest acid inhibition by reducing histamine-stimulated cAMP
 3-4times a day
 Indication: NSAIDs induced gastritis
 Issue: high adverse effect profile and multiple daily dosing
 Drugs: Misoprostol (Cytotec/ Arthrotec)
 C/I: pregnancy, renal insufficiency
 AE: diarrhea, abdominal cramps, uterine contractions
C. Bismuth compounds:
Pepto-Bismol, Kaopectate

 Enhance the secretion of mucus and HCO3, inhibition

of pepsin activity; accumulation of bismuth
subcitrates in the crater of gastric ulcers (coats)
 Drugs: Bismuth subsalicylate (also for diarrhea –
effect of salicylate on PG and Cl secretion ; 30ml or 2
tabs 4x/day), subcitrate potassium (H. pylori)
 AE: darkening of tongue; blackening of stools;
rare: encephalopathy (ataxia, HA, confusion, seizure)
Agents affecting water flux and
motility
A. Laxatives – promote defecation of soft, formed stools
1.) bulk-forming – indigestible, hydrophilic colloids that absorbs
water forming a bulky, emollient gel that distends the colon
and promote peristalsis
Psyllium prep, Methylcellulose – plant fibers (bloating)
Polycarbophil – synthetic fibers
2.) surfactant laxatives -allow water and lipids to penetrate stools;
softens stools and facilitate transit because of their
hydrophilic and osmotic properties
(1-3 days)
Docusates and Glycerin suppository
Mineral oil
3.) Stimulant laxatives

 Act directly or indirectly on the colonic mucosa to

decrease net absorption of water and NaCl
 Soft, semi-fluid stools (6-8 hrs.)
 Drugs:
 Diphenylmethane derivative:
(Phenophthalein (N/A), Bisacodyl)
 Anthraquinone derivative (Senna, Cascara sagrada,
Aloe): - may cause “melanosis coli” – concern in
chronic use (lipofuschin- brown pigment in
macrophages; pigmentation of colonic wall)
 4.) osmotic laxatives and castor oil

 Increase intestinal motility by an obligate increase in fecal

fluid), causing decreased absorption of salt and water
secondary to decrease transit time
 Watery evacuation (1-3 hrs)
 Drugs: Non-absorbable sugars: NaPo4 (not used in elderly,
renal insufficiency, cardiac problems)
MgPo4, Mg citrate, milk of magnesia, lactulose,
sorbitol – cause cramps or flatus
Balanced polyethylene glycol – ingested rapidly 2-4 L over
2-4 hrs.; safe; PEG powder mixed with water or juice
(17g/8 oz) daily
4.) serotonin (5HT4) receptor agonists
 Tegaserod – enteric neurons stimulate bowel contents;
peristalsis and increase intestinal secretions
5.) opioid receptor antagonist –
methylnalterxone bromide, aluimopan (post-
op ileus)
6.) Cl-channel activator
Lubiprostone – Cl channel opening – increase
liquid secretion in the intestines and shortens
intestinal transit time
7.) Guanylyl cyclase C agonist (Linaclotide)
B. Anti-diarrheal Agents
1.) Opioids – act on mu and delta receptors, enhancing NaCl and
water absorption
Drugs: Diphenoxylate (Lomotil) 2.5mg 3-4x/day
Loperamide (Imodium, Diatabs)
2 mg 3-4x/day
2.) colloidal bismuth cmpds (subsalicylate)
3.) Octreotide – stable analog of somatostatin (physiologic effects)
in the GIT (high dose 100-250mcg SC)
therapeutic uses: GIT tumors (carcinoid, VIPoma, glucagonoma,
gastrinoma, insulinoma); AIDs related diarrhea, motility
disorders, GI bleeding
4.) kaolin and pectin
5.) bile salt resins (Cholestyramine, Colestipol or Colesevelam) –
cause bloating, flatulence, constipation and fecal impaction; 1-
3x daily before a meal
C. Anti-emetic Agents

1.) H1 receptor antagonists – specific depression of

conduction of vestibulocerebellar pathway
Drugs: Diphenhydramine (Benadryl)
Meclizine (Bonamine 12.5mg/25mg)
Hyoscine (Scopolamine) transdermal patch
2.) Phenothiazines – block dopamine/muscarinic
receptors in CTZ - radiation induced; post-op emesis
Drugs: Chlorpromazine
Perphenazine
Promethazine
Triethylperazine
Butyrophenone (Droperidol) – IM/IV
Side effects: EPS and hypotension
3.) Metoclopramide – D2 receptor antagonist
4.) 5-HT3 antagonists – used for prevention of
vomiting in chemotherapy and post-operative nausea
and vomiting ; IV 30 mins before chemo / oral 1 hr
prior to chemo
Drugs: Ondansetron – 8mg / 8mg BID or 24mg OD
Granisetron – 1mg/2mg
Dolasetron – 100mg/ 100mg
Palonosetron – 0.25mg
5.) Neurokinin Receptor antagonist – Aprepitant
125mg oral or Fosaprepitant 115mg IV 1 hr prior to
chemo then 80mg/d x 2days of oral aprepitant
5.) Marijuana – CTZ receptors are affected; disinhibition of dopamine thru
inhibition of GABA neurons at VTA
Drugs: Dronabinol, Tetrahydrocannabinol, Nabilone
6.) Corticosteroid –enhances efficacy of 5HT3receptor antagonists (8-20mg before
and 2-4days after chemotherapy)
Drugs: Dexamethasone
7.) Benzodiazepines – anticipatory nausea and vomiting;blocks D1-4;
5HT2A,2C/T3,T6
Drugs: Diazepam
8.) Antimuscarinic agents –
Drugs: Scopolamine, Benztropine
 Prokinetic agents – stimulate motilin
receptors to ↑ gastric motility

1.) Benzamidines
a. metoclopramide – dopaminergic
antagonist; enhances motility of smooth muscles
from esophagus to proximal small bowel; ↑ gastric
emptying time
- release Ach in intestinal myenteric plexus
increasing LES tone
- therapeutic use: diabetic gastroparesis, esophageal
reflux, nausea and vomiting, Ca chemotherapy
- AE: EPS, restlessness, drowsiness; 10mg
b. Cisapride – dopaminergic (D2) antagonist;
↑colonic motility; may cause diarrhea; enhances the
release of myenteric Ach; no dopaminergic activity
therapeutic use: gastric and colonic hypomotility;
GERD; gastroparetic conditions; chronic idiopathic
constipation
2.) Benzimidazole derivative
(Domperidone)
- D2 receptor antagonist
- possess both prokinetic and antikinetic property;
inhibits receptive relaxation; enhance coordinated
motility and accelerate transit time in the small
intestines
therapeutic use: gastroparesis, chronic and
debilitating nausea and gastric retention, antiemetic;
antagonize the effect of levadopa and bromcriptine
3.) Erythromycin – stimulate motilin receptors to stimulate
enteric nerves and smooth muscle agonist
4.) Cl channel activator
Lubiprostone (8mcg BID for IBS; 24 mcg for chronic
constipation); avoided in pregnancy
Linaclotide – guanylyl cyclase-C agonist; CFTR activation;
290mcg OD
5.) Tegaserod – selective serotoin type 4 partial agonist
6.) Cholinomimetic agents: betanechol , neostigmine
(Ogilvie’s syndrome)
 Pancreatic Enzyme Replacement Products
- For steatorrhea, azotorrhea, vitamin malabsorptin and weight loss
caused by cystic fibrosis, chronic pancreatitis or pancreatic resection
- Drugs: Pancrealipase - Viokace (enriched preparation – amylase,
lipase, protease) 60,000-90,000 IU (20-30,000 IU) cap with meals
and snack; swallowed, not chewed (oropharyngeal mucositis)
- Pancreatin ( low dose hog extract)
- Adverse effect: high dose formulations (removed from the market):
hyperuricosuria (high purine content) and renal stones; diarrhea and
abdominal pain
 Drugs Used for the Dissolution of
Gallstones – (<5mm and <4% Ca by weight)

1. Ursodiol *(Actigal, Ursofalk -250mg cap) –

decreases cholesterol content of bile by reducing hepatic
cholesterol secretion; stabilizes canalicular membrane of
hepatocytes; dissolves small stones; 10-20mg/kg/d for 12-24 mos
2. Methyl tert-butyl ether – infusion to bile duct
3. Monoctanoin – infusion to bile duct

Alternative treatment: Shock wave lithotripsy

Drugs in Porto-systemic Encephalopathy

Neomycin + protein restriction +

lactulose (degraded to lactic acid, acetic acid and
other organic acids that traps ammonium ions in the
intestinal tract)
Drugs to treat variceal
hemorrhage
 Somatostatin (IV 250 mcg/h) and Octreotide
(50mcg/h) – reduce portal blood flow and variceal
pressures; administered for 3-5 days
 Vasopressin (high adverse-effect profile) and
Terlipressin – cause splanchnic arterial
vasoconstriction that leads to reduced splanchnic
perfusion and lowered portal venous pressure for
acute GIT bleeding
 Beta-receptor antagonist (Nadolol and Propanolol) –
reduce portal venous pressure
Drugs used in the Treatment of
Inflammatory Bowel disease
(severity)
 Aminosalicylates: Sulfasalazine,
Olsalazine, Balsalazide, Mesalamine
 Infliximab*/ Adalimumab/Certolizumab
 Glucocorticoids
 Purine analogs: azathioprine, 6-
mercaptopurine
 Methotrexate
 Antitumor Necrosis Factor
 Aminosalicylates
(5-aminosalicylic acid)
 5-ASA – 80% does not reach the distal bowel and colon so formulations are
designed; N-acetylation
1. AZO (N=N) compound –cleaved by azoreductase enzyme (terminal ileum or
colon)
Sulfasalazine (sulfapyridine); 85%
Balsalazide (5-aminobenzoyl-B-alanine); 70%
Olsalazine (2 5-ASA molecules)
2. Mesalamine – 20-30% is absorbed in the SI
Pentasa time-released capsule in the SI)
Asacol and Apriso (coated in a pH-sensitive (6-7) resin: distal ileum and
proximal colon)
Lialda (pH-dependent resin- slow release multimatrix core: colon)
Rowasa (enema) and Canasa (suppository) – rectum and sigmoid colon
 Aminosalicylates
 Blocks PG synthesis by inhibition of cyclooxygenase
 Interfere with production of inflammatory cytokines (NF-kB (transcription
factor)
 Inhibit cellular function of natural killer cells, mucosal lymphocytes and
macrophages)
 Indications:
1. 1st line tx for mild to mod UC but unproven for Crohn’s disease (colon or
distal ileum)
2. supp./enema – UC and Crohn’s dis. in rectum (proctitis) and distal colon
(proctosigmoiditis)
 Adverse effects: sulfapyridine molecules and slow acetylators – (dose
related)nausea, GIT upset, headaches, athralgia, myalgia, BM suppression and
malaise; hypersensitivity; oligospermia; impairs folate absorption
rare: osalazine may cause secretory diarrhea
 Glucocorticoids
 Prednisone and prednisolone 40-60mg/d X 1-2 weeks; tapered; IV
 Hydrocortisone enema, foam or suppositories – avoid systemic
effects (although 15-30% absorbed systemically)
 Budesonide (cap) – analog of prednisolone; TID
1. Entocort - oral; 9mg/d; distal ileum and colon
2. Uceris - colon
 Clinical indication: moderate to severe IBD; not for maintenance
 Mechanism of action:
- inhibit the production of inflammatory cytokines (TNF-, IL-1) and
chemokines (IL-8)
- reduce inflammatory cell adhesion molecules
- inhibit gene transcription of nitric oxide synthase, phospholipaseA2,
cyclooxygenase-2 and NF-κB
Purine analogs: Azathioprine
> 6-Mercaptopurine
 Purine antimetabolites; immunosuppressive; reduces need for
steroids
 Xanthine oxidase and thiopurine methyltransferase – active
thioguanine nucleotides – 17 weeks delay of onset of
therapeutic benefit
 Induction and maintenance of remission of IBD; 3-6 mos
treatment
 Azathioprine 2-2.5mg/kg/d
 6-MP 1-1.5mg/kg/d (50mg tab –Php60)
 AE: nausea, vomiting, BM depression, hepatic toxicity, allergic
reactions; opportunistic infections; risk of lymphoma; TPMT
(thiopurine-S-methyltransferase) activity
 DI: allopurinol – increase in active 6-thioguanine nucleotides
Methotrexate
 Antimetabolite; Crohn’s disease and RA
 Oral, SC (15-25mg once a week X 8-12 weeks), IM
 Inhibits dihydrofolate reductase, an enzyme important in the
production of thymidine and purines ( inhibits cellular
proliferation) and interleukin-1
 Stimulate release of adenosine (anti-inflammatory)
 Stimulate apoptosis and death of activated lymphocytes
 Induce and maintain remission in Crohn’s disease
 Adverse effects: BM depression, megaloblastic anemia, alopecia,
mucositis; hepatic damage is common in treatment of psoriasis
 Anti-tumor necrosis factor
 Targets helper T-cell type 1 and regulatory cells (Tregs) – Crohn’s disease
(dysregulation); monoclonal Abs; IgG subclass
 Infliximab (IV 5-10mg/kg 0,2 and 6 weeks); t ½ 8-10d; 8-12 weeks; chimeric mouse Ab
 Adalimumab ( SC - 160 mg BID then 80mg after 2 weeks )
 Golimumab
 Certolizumab (SC 400mg 0,2 and 4 weeks) – humanized; lacks Fc portion
 Indication: acute and chronic treatment of mod to severe Crohn’s disease (Infliximab,
Adalimumab, Certolimumab) – 30%
mod to severe UC (Infliximab, Adalimumab, Golimumab) – 60%
 Maintenance: Infliximab 5mg/kg IV infusion every 8 weeks
Adalimumab 40mg SC every 4 weeks
Certolizumab 400mg SC every 4 weeks
 Prevent cytokine from binding to its receptors
 Fc portion promotes Ab-mediated apoptosis, complement activation and cellular
cytotoxicity of activated T lymphocytes and macrophages
Anti-tumor necrosis factor
Adverse effect:
bacterial sepsis, TB, invasive fungal infections, reactivation of hep
B, listeriosis and other opportunistic infections
development of Ab to the Ab (ATA)

serum sickness in 1%- myalgia, arthralgia, jaw tightness, fever,

rash, urticaria, edema

Hepatic reactions – acute hepatic failure, demyelinating disorders,

hematologic reactions, worsening CHF; psoriatic skin rashes

lymphoma (relative risk is uncertain)
Anti-Integrin therapy
 Integrin - Adhesion molecule
 Natalizumab – humanized IgG4 monoclonal Ab;mod
to severe Crohn’s disease; 300mg every 4 weeks IV
infusion
 Crohn’s disease that have failed other therapies
 Risk: multifocal leukoencephalopathy (JC virus-
human polymavirus); acute infusion reactions and
opportunistic infections (small risk)