Gastrointestinal System and Drugs

Suzette B. Sagun, MD, RPh

2 11/25/15
Two Major Parts
1. Alimentary Canal
 Mouth
 Pharynx
 Esophagus
 Stomach
 small intestine
 large intestine
2. Accessory Organs
 Liver
 biliary duct system
 Pancreas

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 Alimentary Canal
 Digests food (breaks down into smaller fragments)
 Absorbs food

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 Alimentary Canal
 Digests food (breaks down into smaller fragments)
 Absorbs food

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Salivary Secretion
 Source:
 Parotid (most serous)
 Submandibular
 Submaxillary
 Sublingual (most mucinous)

 Function:
 Alpha-amylase (ptyalin) begins starch digestion
 Bicarbonate neutralizes oral bacterial acids, maintains
dental health
 Mucins (glycoproteins) lubricate food

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Alimentary Canal
 Pharynx
 Passageway for food
 subdivided into: nasopharynx, oropharynx,
laryngopharynx

 Esophagus
 Runs from the pharynx through the diaphragm to the
stomach

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Esophagus to Large Intestine
 Mucosa—innermost layer,
moist membrane

 Submucosa—found
beneath the mucosa;
connective tissue

 Muscularis externa—
contains inner circular and
outer longitudinal layer of
smooth muscle

 Serosa—outermost layer

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Stomach
 temporary storage of food
 breaks down food into chyme
 moves gastric content into the small intestine
 gastrin, hydrochloric acid, pepsinogen, mucus

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Stomach

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Small Intestine
 3 parts: duodenum,
jejunum, ileum

 Duodenum—25 cm (10
inches long)
 Jejunum—2.5 m (8 feet)
 Ileum—3.6 m (12 feet)

 longest
 Major digestive organ
 Almost all absorption
occurs in the small
intestine

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Small Intestine
 For absorption
 Microvilli
 Villi (finger-like
projections)
 Circular folds

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Large Intestine
 Parts:
 Cecum
 Appendix
 Colon
 Rectum
 Anal canal

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Large Intestine
 Dry out the indigestible
food residue by absorbing
water

 eliminates digestive
wastes as feces

 No villi

 Numerous goblet cells

(mucus production)

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Accessory Organs of Digestion
 LIVER
 Location: RUQ
 Largest gland of the body
 Many metabolic and
regulatory roles
 synthesizes plasma proteins,
nonessential a.a., & vit. A
 stores Vit. K, D, B12 & iron
 removes ammonia from body
fluids converting it to urea
for excretion in urine
 Secretes bile

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Accessory Organs of Digestion
 Gall bladder
 stores & concentrates bile
produced by the liver
 releases bile to the duodenum
 Gallstones

 BILE
 greenish liquid
 composed of water,
cholesterol, bile salts, and
phospholipids
 emulsification of fats
 promotes intestinal absorption
of fatty acids, cholesterol, and
other lipids
 aids in the excretion of
bilirubin from the liver

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Accessory Organs of Digestion
 PANCREAS
 Soft, pink, triangular
gland that extends across
the abdomen from the
spleen to the duodenum

 Retroperitoneal (lies
posterior to the parietal
peritoneum)

 Both endocrine and

exocrine

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Pancreatic enzymes
 Alpha-amylase—starch
digestion, secreted in active
form

 Lipase, phospholipase A,
colipase—fat digestion

 Protease (trypsin,
chymotrypsin, elastase,
carboxypeptidase)—protein
digestion, secreted as
proenzymes

 Trypsinogen to trypsin
(enterokinase)

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GI Secretory Products
Product Source Action Regulation Notes
1.Intrinsic Factor Parietal cells Vitamin B12 Autoimmune
(stomach) binding protein destruction of
(required for B12 parietal
uptake in the cells→chronic
terminal ileum) gastritis and
pernicious anemia

2. Gastric acid Parietal cells ↓Stomach pH ↑ by Histamine,

(stomach) Ach, gastrin
↓by somatostatin,
GIP, prostaglandin,
secretin

3. Pepsin Chief cells Protein digestion ↑Vagal Inactive

(stomach) stimulation pepsinogen→pepsi
n by H+
4. HCO3- Mucosal cells Neutralizes acid ↑By secretin
Stomach Prevents
Duodenum autodigestion
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GI hormones
Hormone Source Action Regulation Notes
1. Gastrin G cells (Stomach) ↑Gastric H+ ↑Stomach ↑↑ZES
secretion distention, amino
↑Growth of gastric acids, peptides, Phe and Trp are
mucosa vagal stimulation potent stimulators
↑Gastric motility
↑By stomach pH
<1.5
2. Cholecystokinin I cells ↑Pancreatic ↓By secretin and
(CCK) Duodenum secretion stomach pH < 1.5
Jejunum ↑Gallbladder
contraction ↑Fatty acids and
↓Gastric emptying stomach acids

3. Secretin S cells of ↑Pancreatic ↑By acid, fatty ↑HCO3

duodenum and HCO3, acids in lumen of neutralizes gastric
jejunum ↓Gastric acid duodenum acid in duodenum,
secretion allowing
pancreatic
enzymes to
function

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GI Hormones
Hormone Source Action Regulation Notes
4. D cells ↓Gastric acid ↑By acid Inhibitory
Somatostatin (Pancreatic and hormone
islets and GI pepsinogen ↓By vagal
mucosa) secretion stimulation

↓Pancreatic
and small
intestine fluid
secretion

↓Gallbladder
contraction

↓Insulin and
glucagon
release

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Factors Affecting GET

↑GET ↓GET
 Stress  Mild exercise
 Long Exercise  Cold food
 Food  Lying on right side
 Lying on left side  Gastrectomy
 Antimotility drugs  Motility enhancers

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GIT Innervation
 Parasympathetic stimulation
 increases gut & sphincter tone
 increase smooth muscle contraction & motor secretory
activities

 Sympathetic stimulation
 reduces peristalsis & inhibits GI activity

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Enteric Nerve Plexi
 Myenteric (Auerbach’s)
 Coordinates Motility along the gut wall
 Contains cell bodies of some parasympathetic terminal
effector neurons
 Located between inner (circular) and outer (longitudinal)
layers of smooth muscle in the GI tract wall.

 Submucosal (Meissner’s)
 Regulates local Secretions, blood flow, and absorption.
 Contains cell bodies of some parasympathetic terminal
effector neurons.
 Locates between mucosa and inner layer of smooth muscle
in the GI tract wall

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Regulation of Gastric Acid Secretion

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Regulation of Gastric Acid Secretion
 Gastric acid secretion by parietal cells of the gastric
mucosa is controlled
 Acetylcholine
 Histamine
 PGE2 and I2
 gastrin

 The receptor mediated binding of acetylcholine, histamine

or gastrin results in the activation of H+/K+ ATPase
proton pump that secretes HCl into the lumen of the
stomach.

 In contrast, receptor binding of prostaglandins E2 and I2

diminishes gastric acid production.

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Regulation of Gastric Acid Secretion
 Histamine binding causes activation of adenylyl
cyclase, whereas binding of of prostaglandin E2 and
I2 inhibits the enzyme.

 Acetylcholine and gastrin act by inducing an increase

in intracellular calcium levels.

 PGE2 and PGF2a—stimulates secretion of protective

mucus and bicarbonate in the stomach and intestine.
PGI2—inhibits gastric acid secretion

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 Common GI Disorder and their
Pharmacologic Treatment

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Peptic Ulcer Disease
Duodenal Ulcer Gastric Ulcer
Location of pain Midepigastric area Diffuse
May radiate below the
costal margin into the
back or right shoulder
Onset Midnight to 2AM Rarely produce nocturnal
pain
Relation to food Relieved by food Aggravated by food
Patient habitus Gains weight Loses weight

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 DUODENAL ULCER—pain ―Decreases‖ with meals
 Almost 100% have H.pylori infection
 Due to gastric secretion and ↓mucosal protection

 GASTRIC ULCER—pain ―Greater‖ with meals

 H.pylori infection in 70% of cases
 Due to ↓mucosal protection against gastric acid

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Peptic ulcer
 Occurs most frequently in the first portion of the
duodenum, the stomach, or the lower end of the
esophagus, all of which are exposed to acid and
pepsin

 Not a precursor to malignancy

 Occurs with increased frequency in Blood type O,

suggesting that genetic factors may play a role

 Often complicated by hemorrhage and melena

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Peptic Ulcer Disease
Aggressive Defensive
 HCl  Bicarbonate
 Pepsin  Mucus
 H.pylori  PG

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Peptic Ulcer Disease
 Is sometimes associated with:
1. Intake of aspirin or other NSAIDs
2. The incidence of peptic ulcer is two-fold greater in
smokers.
3. Zollinger-Ellison Syndrome
 Caused by gastric hypersecretion due to gastrin-secreting islet
cell tumor of the pancreas
 Recurrent peptic ulcer or peptic ulcer in aberrant sites (ex.
jejunum)
4. MEN I (Wermer syndrome)
 Autosomal dominant disorder characterized by pituitary,
thyroid, parathyroid, adrenal corticol, and pancreatic islet cell
adenomas or hyperplasia associated with hypergastrinemia and
peptic ulcer

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Gastroesophageal Reflux Disease (GERD)
 retrograde movement of gastric contents from the
stomach into the esophagus
 heartburn, chest pain, belching, regurgitation,etc.

 Barrett’s esophagus
 Glandular metaplasia—replacement of the nonkeratinized
squamous epithelium with intestinal or columnar
epithelium in the distal esophagus
 Due to chronic acid reflux
 Risk factor for esophageal CA (squamous cell)

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Barrett’s esophagus

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Drugs used to Peptic Ulcer Disease
1. Antimicrobial agents
2. Proton-pump inhibitors
3. H2-receptor blocker
4. Mucosal protectives
5. Antacids
6. Antimuscarinic agents
7. Prostaglandins

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Antimicrobials
 Helps heal ulcers and decrease recurrence
 Two or more antibiotics in combination with other
drugs such PPIs
 Duration: 2 weeks
 PPIs for 6 more weeks

 Amoxicillin, Clarithromycin, Metronidazole, Tetracycline

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Proton Pump Inhibitors
 MOA:
 Binds to the H+/K+-ATPase enzyme system (proton
pump) suppressing secretion of gastric acid

 more potent and rapidly effective than H2-blockers

 enteric coated preparations
 highly protein-bound and metabolized extensively in
the liver
 administer in the morning before eating

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Proton Pump Inhibitors

 Omeprazole
 Lansoprazole (Prevacid)
 prevention & healing of NSAID-induced GU
 Rabeprazole (Aciphex)
 Pantoprazole (Protonix)
 IV preparation used for Zollinger-Ellison syndrome
 Esomeprazole (Nexium), (Naproxen/Esomeprazole:
Vimovo)
 Nexium IV

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Proton Pump Inhibitors

Omeprazole & Lansoprazole

 Approved for use in infants & children for the short-
term treatment of GERD & corrosive esophagitis
 S/E:
 Headache
 n&v
 abdominal pain
 diarrhea and flatulence

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H 2-Receptor Blockers
 MOA: Inhibits the action of histamine at parietal
cell receptor sites, reducing the volume of
hydrogen ion concentration & gastric acid
secretion
 used to treat GERD, duodenal ulcer, & erosive
esophagitis

 Cimetidine – Oral, IV
 1st H2 blocker approved, 50% reduction in gastric
secretion

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H 2-Receptor Blockers
 Ranitidine – Oral, IV, IM
 more potent, 70% reduction in gastric acid secretion
 Ranitidine Bismuth Citrate + Clarithromycin: H. pylori
eradication

 Famotidine – Oral, IV
 most potent, 94% reduction

 Nizatidine – Oral
 newest H2-receptor blocker

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H 2-Receptor Blockers

 S/E: headache & dizziness

 Ranitidine
 hepatotoxicity, bradycardia

 Cimetidine
 Hepatotoxicity
 Bradycardia
 Agranulocytosis
 aplastic anemia
 weak androgenic effect (male gynecomastaia & impotence)

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H 2-Receptor Blockers
Drug Interaction
 Cimetidine – enzyme INHIBITOR
 Phenytoin, theophylline, phenobarbital, lidocaine, warfarin,
diazepam, propranolol.
 reduce clearance of propranolol & lidocaine
 inhibits excretion of procainamide
 absorption is impaired by antacid (Ranitidine)

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Mucosal Protective
 Sucralfate
 Bismuth compounds

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Mucosal Protective
Sucralfate
 nonadsorbable disaccharide containing sucrose &
Aluminum
 equally effective as H2 -blockers
 MOA:
 adheres to the base of the ulcer crater forming a protective
barrier
 Admin:
 1g , 4x a day ( 1 hr before meals & at bedtime)
 S/E: constipation
 DI: antacids

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Mucosal Protective
Bismuth compounds
 MOA:
 Prevents adhesion of H. pylori to mucosa
 suppresses its growth
 inhibits release of proteolytic enzymes
 highly effective when combined with PPIs and/or AB

 Preparations:
 Bismuth subsalicylate, Colloidal Bismuth subcitrate

 S/E:
 dark stools and tongue

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Antacids
MOA:
 neutralize gastric acid, inhibit pepsin activity &
strengthen mucosal barrier
 equally effective as H2 blockers
 heal peptic ulcers and control ulcer pain
 Admin: 1 hour and 3 hrs after meals and at
bedtime

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Antacids
Al(OH)3 Mg(OH)2
 adsorbs pepsin and  keeps pH sufficiently
removes it from solution
high to keep pepsin
at pH>3
adsorbed to it
 delays GET(constipation)
by relaxing small muscles  lessens relaxant
of the stomach effect(diarrhea)
 stimulate mucus secretion CaCO3
 hypophosphatemia  can cause rebound
acidosis that is prolonged
and prominent

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Antacids
 S/E:
 Aluminum – constipation
 Magnesium – diarrhea
 Calcium carbonate – constipation, acid rebound, milk-
alkali syndrome
 Sodium bicarbonate – alkalosis, C/I in patients with HTN,
CHF, severe renal disease

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Antacids
 D/I:
 Antacids bind to tetracycline & fluoroquinolones inhibiting their
absorption
CHELATION
 Antacids may destroy enteric-coating of drugs leading to premature
dissolution in the stomach

 impair absorption of Cimetidine and Ranitidine (give 1 hr apart),

Digoxin, INH, Anticholinergics, Iron products and Phenothiazine

 Alter urinary pH

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Antimuscarinics
 MOA: delays or prolongs gastric emptying
 Belladonna leaf, Atropine, Propantheline
 used with antacids
 has no use in ulcer healing
 Most effective when taken at night and in large doses.

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Muscarinic Receptors

Receptor Location Response

M1 Vagus nerve Stimulation, acid

secretion
M2 Heart Nerve Bradycardia

M3 Glands ↑ secretion

Endothelium vasodilation

Smooth muscles Stimulation or

contraction
Antimuscarinics
Muscarinic receptors Muscrinic Receptor
Blocker
 Inc.GI motility
 Inc.GI secretion  Dec.GI motility
 Dec.GI secretion

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Antimuscarinics
PIRENZEPINE, PROPANTHELINE

MOA: Block M1 receptors on ECL cells (↓histamine secretion) and M3

receptors on the parietal cells ( ↓H+ secretion)

Clinical Use: Peptic Ulcer

Toxicity: Tachycardia, dry mouth, difficulty focusing eyes

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Prostaglandin
 MOA:Suppress gastric acid secretion and guards the
mucosa form NSAID-induced ulcers

Misoprostol - a prostaglandin analogue with antisecretory &

mucosal protective activity by increasing bicarbonate and
mucus secretions
 indicated for NSAID-induced gastric ulcers

 S/E: diarrhea and abdominal pain

 C/I: pregnant, women with child-bearing potential

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Constipation

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Constipation
 Definition:
 Decrease in the frequency of fecal elimination and is
characterized by the passage of hard, dry, and sometimes
painful stools.

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Constipation

 S/Sx:
 abdominal bloating, headaches, sense of
rectal fullness
 Causes:
 Insufficient dietary fiber
 Inadequate fluid intake
 Poor bowel habits
 lack of exercise

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Constipation
 CAUSES:
 Medications (anticholinergic, antacids, narcotics)
 Antidepressants
 anti-HPN
 Antihistamines
 Phenothiazines
 antispasmodics
 Organic problems
 intestinal obstruction
 IBS
 Tumor
 hypothyroidism
 Pregnancy
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Constipation: Treatment
Nonpharmacologic
 increase fluid and fiber intake
 exercise regularly
 bowel training to increase regularity

Pharmacologic
 Laxatives
 stimulate defecation
 should not be taken if nausea, vomiting, or abdominal pain is
present

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Bulk-forming Laxatives
MOA: natural or synthetic polysaccharide that adsorb water
to soften stool and increase bulk, which stimulates
peristalsis

 slow onset of action (12-24 hrs, 72 hrs) thus preventive

 take with 8 oz of water

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Bulk-forming laxatives
 Natural bulk-forming laxatives
 Psyllium (Metamucil, Fiberall, Konsyl-D, Perdium Fiber
Granules)
 Malt soup extract (Maltsupex)

 Synthetic bulk-forming laxatives

 Methylcellulose
 Polycarbophil (Ca Polycarbophil impair Tetracycline absorption)

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Saline and Osmotic Laxatives

 MOA: creates an osmotic gradient pulling water into the

small and large intestines

 stimulates the activity of cholecystokinin-

pancreozymin, which increases the secretion of fluids
into the GI tract

 onset of oral : 3-6 hrs ; rectal – 5-30 minutes

 Take with water

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Laxatives

 Saline laxatives – sodium & magnesium salts

 should not be used in patients with HPN, CHF, &
renal impairment
 Examples
 Magnesium citrate
 Magnesium hydroxide
 Magnesium sulfate
 Sodium phosphate

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Laxatives
 Osmotic laxatives

 Glycerin (Fleet Babylax) – rectal burning

 Sodium stearate

 Lactulose (Chronulac, Enulose) – decrease blood

ammonia levels in hepatic encephalopathy
 flatulence & cramping
 Taken with fruit juice, milk or water

 Sorbitol- nonabsorbable sugar

 Polyethylene glycol (Miralax)

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 Stimulant Laxatives

MOA: stimulate intestinal motility and increase secretion

of fluid into the bowel
 onset of action of oral: 6-10 hrs; rectal: 30-60 minutes
 chronic use can lead to cathartic colon(should not be used for
more than 1 week)
 S/E: abdominal cramping, electrolyte and fluid deficiencies,
malabsorption and hypokalemia

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Stimulant Laxatives
 Anthraquinone glycosides
 Sennosides – most potent
 Cascara sagrada
 Casanthranol – mild stimulant laxative
 Aloe

 Bisacodyl (Dulcolax, Doxidan, Correctol)

 enteric-coated

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Stimulant Laxatives
 Castor oil (e.g. Purge)
 onset: 2-6 hrs; works in the small intestine which may produce
strong cathartic effects
 C/I in pregnant women

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Emollient Laxatives
MOA: act as surfactants by allowing absorption of
water into stool
 slow onset of action: 24-72 hrs
 MI and rectal surgery
 should not be used with mineral oil because it facilitates
systemic absorption of mineral oil leading to hepatotoxicity
 Examples:
 Docusate sodium (Colace)
 Docusate calcium (Surfak)
 Docusate potassium (Kasof)

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Diarrhea
 Diarrhea

 Abnormal increase in the frequency and looseness of

stools
 happens when some factors impair the ability of the
intestines to absorb water from the stool
 Causes:
1. Infection – virus, bacteria, protozoa
2. Diet-induced ( high fiber, fatty or spicy food, large
amounts caffeine, milk intolerance)
3. Drug-induced
 Treatment
Antidiarrheal may prevent an attack or relieve existing
symptoms

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Classification of Diarrhea
I. By Mechanism
II. By Etiology
III. By Duration

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Classification by Mechanism
1. Osmotic Diarrhea
 Large meals
 Sorbitol and glycerin
 Disaccharidase deficiency
 Lactulose
 Mg containing prep’ns
2. Secretory
 Bacteria
 Virus
 protozoa
3. Motility disorders
 IBS, diabetic neuropathy
 Drugs
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Classification by Duration
 Acute
 Self-limiting
 Less than 2 weeks

 Chronic
 Longer than 2 weeks

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Non-pharmacological approach
 Food
-BRAT diet - not advised anymore
 Banana
 Rice
 Applesauce
 Toast

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 Fluids
 ORS (NaCl, KCl, Na bicar, Glucose, Water)
 Fluids to be avoided:
 Hypertonic fruit juice
 apple juice
 powdered drink mixes
 gelatin water
 carbonated and caffeine-containing beverages
 Gatorade diluted in Water (1:1) provide necessary
combination of glucose, Na and K

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 DIARRHEA
1.Antimotility/Antiperistaltic
 MOA: stimulate mu opioid receptor slowing motility of the small and
large intestines
 Loperamide (Imodium), Diphenoxylate/atropine
 S/E: abdominal pain, distension, dizziness, drowsiness, dry mouth
 C/I: acute bacterial diarrhea

2. Adsorbent
MOA: adsorb toxins, bacteria, gases & fluids
 Kaolin
 Bismuth subsalicylate

3. Anti-infectives

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Other GI disorders

Pseudomembranous colitis
 inflammation of the colon resulting from the use of
antibiotics
 Clostridium difficile
 mild to bloody diarrhea, abdominal pain, fever
 Metronidazole or Vancomycin

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Inflammatory Bowel Disorders
Crohn’s Disease Ulcerative colitis
Possible etiology Post-infectious Autoimmune
Location Any portion of the GIT, Continuous lesions.
usually the terminal Always rectal
ileum and colon involvement
―skip lesions‖
Rectal sparing
Complications Strictures, fistula, Severe stenosis
perianal disease, Toxic megacolon
malabsorption, Colorectal CA
nutritional depletion
Extraintestinal Migratory polyarthritis Pyoderma gangrenosum
manifestations Erythema nodosum 1° sclerosing cholangitis
Ankylosing spondylitis
Uveitis
Immunologic disorders

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Sulfasalazine
 MOA: a combination if sulfapyridine (antibacterial)
and mesalamine (anti-inflammatory). Activated by
colonic bacteria

 Clinical uses: Ulcerative colitis, Crohn’s disease

 Toxicity: malaise, nausea, sulfonamide toxicity,

reversible oligospermia

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Infliximab
 MOA: a monoclonal antibody to TNF-α, a pro-
inflammatory cytokine

 Clinical uses: Crohn’s disease, rheumatoid arthritis

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Emesis
 Complex process
 Mediated by:
 D2 receptors (CTZ)
 5HT3 receptors (CTZ and GIT)
 Labyrinthine vestibular systems( cholinergic, histamine)
 Pain receptors ( GU tract)

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Drugs for nausea and vomiting
 5HT3 receptors—ondansetron (commonly used in
cancer chemotherapy), granisetron

 Dopamine antagonists: Prochlorperazine,

Metoclopramide (also used in Ca chemotherapy, also
prokinetic in GERD)

 H1 antagonits: diphenhydramine, meclizine,

prometahzine

 Cannabinoids: dronabinol
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Thank you!