Download TOPIC OUTLINE

OS 214 [B]: Digestion and Excretion
2
Lec 11: Gastrointestinal Pharmacology
October 9, 2013
Maria Concepcion C. Sison, MD, FPPS, FPCC
TOPIC OUTLINE
I.
II.
Rational Prescribing
Acid Peptic Disease
A. Peptic ulcer disease
B. Gastric acid secretion
C. Drug therapy in peptic ulcer disease
D. Antacids
E. Histamine (H2) receptor antagonists
F. Proton pump inhibitors
G. Drugs that protect the mucosa
H. Treatment of H. pylori
III. Gastrointestinal Motility
A. Drugs affecting GI motility
B. Prokinetic Agents
IV. Constipation
A.Stool Formation
B. Pathophysiology
C. Laxatives
V. Diarrhea
A. Pathophysiology
B. Treatment
VI. Vomiting
A. The Reflex Mechanism of Vomiting
B. Emetic Drugs
C. Antiemetic Drugs
VII. Irritable Bowel Syndrome
A. Pharmacologic Therapy
VIII. Inflammatory Bowel Disease
A. Pharmacologic Therapy
IX. Biliary Tree
A. Bile Acids
B. Drugs Affecting the Biliary System
Objectives:
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Enumerate the classes of drugs used for common GI symptoms and disease

Discuss the pathophysiology of the following GI diseases relevant to drug
therapy
o
Acid peptic disease
o
Vomiting
o
Diarrhea
o
Constipation
o
Irritable bowel syndrome
o
Inflammatory bowel disease
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State the targets of therapy for these common GI problems
Legends:
From the Powerpoint presentation
From the lecturer and other sources
Figure 1. Acid peptic disease. This results from an imbalance between
the aggressive and defensive factors in the GIT. Treatment should
reduce aggressive factors and stimulate formation of protective factors.
A. PEPTIC ULCER DISEASE
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Note: First two (H. pylori and NSAIDs) comprise more than 90% of the
causes of acid peptic disease.
B. GASTRIC ACID SECRETION
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Establish diagnosis
Know the problem (pathophysiology)
Address the problem (solution / therapeutic objective):
pharmacologic or non-pharmacologic
Choose drug
Monitor drug action (re-evaluate effectiveness / toxicities)
Determine endpoint of therapy and plan a program for patient
education
Gastric acid secretion is a complex continuing process which
culminates in the secretion of H+ by parietal cells
The most important mechanism of ion-gradient generation is
through the K+/H+-ATPase Pump or the Proton Pump (most hardworking pump in the body); this generates the largest known ion
gradient in vertebrates with intracellular pH of 7.3 and
intracanalicular pH of 0.8
Logical to target the proton pump itself if you want to prevent
gastric acid secretion.
o
Proton pump inhibitors are widely used because of its efficacy
and safety in decreasing gastric acid secretion
Note: Refer to figure 7 for the complete diagram of gastric acid
secretion.
C. DRUG THERAPY IN PEPTIC ULCER DISEASE
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I. RATIONAL PRESCRIBING
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The most common cause are as follows:
o
Helicobacter pylori
o
Nonsteroidal anti-inflammatory drugs (NSAIDs)
o
Alcohol and drug abuse
o
Trauma and stress
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Reduce gastric acidity
o
Antacids
o
Histamine (H2) receptor antagonists
o
Proton pump inhibitors
Promote mucosal defense (prevent ulceration)
Eradicate H. pylori infection (if present)
Example of drugs used in PUD:
o
Antacids – to neutralize the secreted acid
o
Sucralfate – coats ulcer base when theres already an ulcer
o
PPI – inhibits K+H+ATPase pump
o
H2 blockers – block histamine receptors to decrease secretion
of gastric acid
Note: We should not be satisfied with just giving the drug, we should
also educate the patient.
II. ACID PEPTIC DISEASE
Q:
All of the following drugs protect gastrointestinal tract from
ulceration, EXCEPT
a. Cimetidine
b. NSAIDs
c. Calcium carbonate
d. Omeprazole
Figure 2. Sites of action of some drugs used in Peptic Ulcer
Disease. Gastrin (G), Histamine (H2) and Muscarinic (M3) receptors are
the most important sites of action.
QUINIO, RAMOS, REYES
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Lec 11: Gastrointestinal Pharmacology
Q:
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D. ANTACIDS
A patient takes 30 mL Maalox (Aluminum magnesium hydroxide)
per orem 1 hour and 3 hours after meal (height of gastric acid
production) and bedtime for treatment of duodenal ulcer. Why does
she take this antacid so frequently?
a. It has a slow onset of action
b. It has a short duration
c. It has a prolonged half-life
d. It is highly metabolized
Used for centuries for acid peptic diseases
Neutralize gastric acid since they are weak bases
o
Weak bases + gastric acid  salt + water
Stimulates mucosal prostaglandin formation  increases mucus
production
May cause increased acid production, must be used repeatedly to
reduce acidity
156 meqs antacid given 1 hour after a meal neutralize gastric acid
for up to 2 hours
Can be used in diagnosis: if relief is felt after intake, then it is
probably a case of peptic acid disease
Highly variable acid-neutralization capacity of various formulations
Differ mainly in absorption and effects on stool consistency
If patient has abdominal pain in the ER & acute abdomen has been
ruled out, you may give antacid as it has fast onset of action of
approximately 30 minutes
PREPARATIONS
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Sodium bicarbonate (baking soda, Alka Seltzer)
o
Produces CO2 (can cause bloating and increased burping
capacity), and NaCl (may aggravate sodium retention and
cause fluid overload) by coupling with your hydrochloric acid
Calcium carbonate (Tums)
o
CO2 and CaCl2
o
Both sodium bicarbonate and calcium carbonate cause
metabolic alkalosis if reabsorbed
Magnesium hydroxide, Aluminum hydroxide: weak bases
PHARMACOKINETICS
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Onset: 5-15 minutes
Duration: 2 hours
Faster symptom relief, though short-lived, than H2 antagonist
Should be given 1 and 3 hours after meals (when gastric acid
production is at its peak)
May affect (decrease) absorption of other medications (tetracycline,
fluoroquinolones, itraconazole, iron) since it alters the pH of the
stomach; these drugs must be given at least 1-2 hours after you
give the antacid
E. HISTAMINE (H2) RECEPTOR ANTAGONISTS
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Used for fast relief of gastric discomfort, often in combination with
other therapies
Dyspepsia
Symptomatic relief in peptic ulcer, esophageal reflux
ADVERSE EFFECTS
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Antacids can affect absorption, bioavailability, or urinary excretion
of other drugs by altering gastric and urinary pH or by delaying
gastric emptying
Can cause hypokalemia
Overuse can also cause the following problems
o
Aluminum hydroxide – may cause constipation and
hypophophatemia, proximal muscle weakness,
osteodystrophy, seizures
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Aluminimum amount of feces
o
Magnesium hydroxide – may cause diarrhea, hyporelexia,
hypotension, cardiac arrest
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Mg = Must go to the bathroom
*Commonly used: salts of magnesium (Mg) with aluminium (Al) is a
good combination because they offset each other’s side effect (eg.
Maalox)
o
Calcium carbonate – hypercalcemia, increased rebound acid
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Can chelate and decrease effectiveness of other drugs
(eg. Tetracycline)
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Has the probability of being absorbed so not frequently
used
QUINIO, RAMOS, REYES
Competitively, reversibly inhibit histamine actions at all H2
receptors
o
Block histamine release from ECL cells via gastrin or vagal
stimulation
o
Diminish gastrin- or Ach-stimulated acid secretion (decreased
cAMP, attenuate protein kinase activation)
Inhibit 60-70% of total 24-hr acid secretion (vs PPI’s which
decreases as much as 90-98% of acid secretion), mostly during
meal time
Decrease both basal and food-stimulated acid secretion (linear,
dose-dependent); less on food-stimulated acid secretion
Especially effective in inhibiting nocturnal acid secretion (90%)
Recommended prescription doses maintain >50% inhibition for 10
hours
Cimetidine (prototypic drug, but lots of side effects and drug
reactions), Ranitidine, Nizatidine, Famotidine (most potent)
o
Take H2 blockers before you DINE
o
Think table for 2 to remember H2 (it’s best to eat with
someone else)
PHARMACOKINETICS
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Given orally and is well-absorbed
Peak effect: 1-3 hours
With intravenous preparations as well
Cleared by hepatic metabolism, glomerular filtration and renal
tubular secretion
Except for Nizatidine, there is decreased (50%) bioavailability due
to first-pass metabolism
Dosage: BID (twice a day) or at HS (bedtime)
Table 1. Clinical comparison of H2 blocker
Drug
Relative
>50% acid
Frequency
inhibition
(10h)
Cimetidine
1
400-800 mg
Ranitidine
4-10x
150 mg
Nizatidine
4-10x
150 mg
Famotidine
20-50x
20 mg
Acute
duodenal /
gastric
ulcer
800 mg HS
400 mg BID
300 mg HS
150 mg BID
150 mg BID
300 mg HS
20 mg BID
40 mg HS
Usual
dosage for
GERD
800 mg BID
150 mg BID
150 mg BID
20 mg BID
Note: Potency does not equate with efficacy, it just means some drugs
need to be given at a higher dose
CLINICAL USE
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CLINICAL USE
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OS 214
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Peptic ulcer disease
o
Nocturnal acid suppression
o
Healing >80-90% after 6-8 weeks (uncomplicated)
o
NSAID-induced
Gastroesophageal reflux disease
Erosive esophagitis
Non-ulcer dyspepsia (questionable benefit)
Prevention of bleeding from stress-related gastritis (especially
when patient is put on nothing per orem)
If you are going to use H2 receptor antagonist for NSAIDs-induced
peptic ulcer disease, you have to discontinue use of NSAIDs. In
using PPI’s, you can still use NSAIDs and expect healing.
ADVERSE EFFECTS
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Extremely safe drugs
<3% of patient: diarrhea, headache, fatigue, myalgias, constipation,
mental status changes (elderly, cimetidine)
Crosses palcenta, secreted in breastmilk (not administered in
pregnancy)
CIMETIDINE
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First found but least used due to adverse effects
Inhibits binding of dihydrotestosterone and metabolism of estradiol
( testosterone +  estrogen  galactorrhea in women,
gynecomastia and impotence in men; decreased sperm count,
diminished libido)
*Hardly anyone uses this drug. Fortunately, there are alternatives.
Inhibits cytochrome P450 (1A2, 2C19, 2D6)
o
2C19 is important in the metabolism of Warfarin and Coumadin.
If patient is on anticoagulants, watch out because they may
bleed.
o
Drug interaction: oral anticoagulants, tricyclic antidepressants,
lidocaine, quinidine, metoprolol, ethanol, CCBs, others
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Lec 11: Gastrointestinal Pharmacology
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o
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Fatal if it causes arrhythmia, and potent if it can causes
bleeding that can be fatal as well
Ranitidine binds 4-10x less avidly to cytochrome P450
Negligible binding with nizatidine and famotidine
CLINICAL USE
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F. PROTON PUMP INHIBITORS (PPI)
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First choice drug for acid peptic disease
Major role for the treatment of acid-peptic diseases (most effective
of them all)
Outstanding efficacy and safety (most widely-used now)
Omeprazole (first PPI – prototypic drug), lansoprazole,
pantoprazole, rabeprazole, esomeprazole
Irreversibly inhibit K+/H+ ATPase (proton pump) – a
noncompetitive inhibitor; inhibits synthesis of new pumps
Lipophilic weak bases
Inactive at neutral pH but accumulated in the acid environment of
the canaliculi of parietal cell (ie. where the action is)
Effectively inhibits meal-stimulated acid secretion during the day as
well as basal secretion overnight
Inhibits 90-98% of 24-hour acid secretion
H2 antagonists are more effective than PPIs in nocturnal acid
secretion
OS 214
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GERD
o
Most effective agents
o
Once daily dosing provides symptom relief and tissue healing
(85-90%)
o
Empiric treatment – symptom relief in 70-80%
PUD
o
More rapid symptom relief and faster ulcer healing
o
H. pylori associated ulcers
o
NSAID-associated ulcer – healing despite continued therapy;
in acute coronary syndrome, osteoarthritis, etc.
Non-ulcer dyspepsia (10-20% > placebo)
Prevention of stress gastritis
Hypersecretory conditions (gastrinoma)
SIDE EFFECTS
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Not common
Headache, diarrhea, rashes, dizziness, somnolence, mental
confusion, impotence, gynecomastia, myalgia, arthralgia have been
reported
Chronic treatment – hypergastrinemia, since body tries to
compensate
May affect (decrease) absorption of other drugs (digoxin,
ketoconazole); iron, Ca, zinc, vitamin B12 (cobalamin deficiency)
Inhibits metabolism of Coumadin, diazepam and phenytoin
(CYP2C19) but not to the same extent cimetidine would
G. DRUGS THAT PROTECT THE MUCOSA
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Sucralfate, Bismuth chelate, Carbenoxolone, Misoprostol (not freq
used anymore)
Enhance mucosal protection mechanisms specifically increase in
bicarbonate production
Provide physical barrier over the surface of the ulcer
SUCRALFATE
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Figure 3. PPI shows consistent inhibition of acid formation. Spikes
in the graph of H2 block indicate periods where Ach or gastrin released,
such as during meal times.
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PHARMACOKINETICS
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Administered as inactive prodrugs (acid-labile – if they are released
in the gastric acid, they will be immediately inactivated)
o
Is only active in the canaliculi
Formulated for delayed release as acid-resistant, enteric coated
capsules/tablets
Bioavailability decreased to 50% by food intake
Ideally given approximately 1 hour before meals
Absorbed in the small intestine  blood  diffuse readily into
acidified compartment (parietal cell canaliculus)  protonated (and
trapped, being a weak base that is ionized) and concentration
increases 1000-fold  thiophillic sulfonamide cation  covalent
(thus irreversible, with long duration of action) disulfide linkage with
H+K+ATPase
Given orally
Short half-life: 1-2 hours (serum concentration, because they are
concentrated at the target site of action)
Long duration of acid inhibition (because it is an irreversible
inhibitor): 24 hours (because it will take at least 18 hours to
synthesize new pumps); diffuses to extracellular space immediately
and is protonated, which does not allow it to cross back
Full acid-inhibiting potential is achieved after 3-4 days
o
In a fasting state, not all pumps will be immediately inhibited
since not all are active
Hepatic metabolism, negligible renal clearance
Ideal drug (from a pharmacokinetic perspective) because of short
half-life (leaves the serum readily), long duration of action
(irreversible binding) and concentrated at the target site of action,
where it is most needed
Table 2. PPIs: Pharmacokinetics
Drug
Bioavailability
Omeprazole
40-60% (20)
Esomeprazole
50-89% (20)
Lansoprazole
80-90% (20)
Rabeprazole
52% (20)
QUINIO, RAMOS, REYES
Half-life
0;5-1
1.2
1.9
0.7-2.0
Tmax
1-3.5
1.5
2.0-4.0
2.0-5.0
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Complex of aluminium hydroxide and sulphated sucrose
Coats the ulcer base and stimulates mucus, bicarbonate and
prostaglandin production (defensive factors)
In the presence of acid, sucralfate forms an insoluble amorphous
complex that binds to base of ulcers and erosions for up to 6 hours
o
Short duration, problems in compliance
Given orally, requires acid environment for activation
30% is still present in the stomach 3 hours after administration
Reduces absorption of a number of drugs including:
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Fluoroquinolone antibiotics
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Theophylline
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Tetracycline
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Digoxin
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Amitryptilline
Increases defensive factors
Clinical use
o
Gastric, duodenal and oral ulcers, GI bleed, stress ulcer
prevention, critically-ill patients
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Minimal absorption
o
Dosing: 1g QID, 1 hr before meals & HS (compliance is an
issue)
o
Side effects: constipation (Al); less commonly, dry mouth,
nausea, vomiting, headache, rashes
o
Caution to renal insufficiency (if Al is absorbed)
Note: Any drug that acts locally can alter absorption of other drugs.
Thus, if drugs for bleeding and arrhythmia are involved, take note of
possible drug interactions because these can be lethal.
BISMUTH CHELATE
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Colloidal bismuth subcitrate (Europe), bismuth subsalicylate (US)
Mucosal protecting actions (binds to ulcer base, promote mucin
and bicarbonate production)
Used in combination regiments to treat H. pylori infection in peptic
ulcer (bismuth chelate is a 2nd choice regimen in treatment of H.
pylori peptic ulcers)
Has toxic effects to bacillus (bactericidal; compared to sucralfate),
prevents its adherence to mucosa, inhibit its proteolytic enzymes
Small amount absorbed with raised amount of bismuth
Side effecs: nausea and vomiting, irreversible blackening of the
tongue and feces
Also used in diarrhea because of its anti-bacterial effect
Avoided in patients with renal insufficiency
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Lec 11: Gastrointestinal Pharmacology
MISOPROSTOL
Q: This drug is used for prevention and treatment of gastric ulcers but
has been withdrawn from the market because it has been used by many
as abortifacient (and has teratogenic effects)
a. Rioprostil
b. Carbenoxolone
c. Misoprostol (prostaglandin analogue)
d. Sucralfate
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Stable analogue of PGE1 (prostaglandins are protective)
Decreases gastric acid secretion
Augments secretion of mucus and bicarbonate
Uses: very effective prostaglandin analogue for prevention and
treatment of NSAID-related ulcers
Half-life < 30 minutes; given 3-4x daily
Side effects: diarrhea and abdominal cramps; uterine contractions
can also occur
Absolute contraindication: pregnancy (since it can cause uterine
contractions)  premature delivery or miscarriage (abortion)
Not readily available due to potential to cause miscarriage and
abortion and potential for abuse
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OS 214
5HT (Serotonin) – main NT
5HT3 receptors – extrinsic afferent nerves stimulate nausea,
vomiting, abdominal pain
5HT4 receptors – intrinsic primary afferent neurons (IPAN) enhance
release of Ach and cGRP (calcitonin gene-related peptide) 
increased GI motility
Pressure and stimuli will release substances that when coupled
with 5HT3 receptor would cause symptoms of nausea, vomiting and
abdominal pain
So you want something to activate 5HT4 and inhibit 5HT3
A. DRUGS AFFECTING GI MOTILITY
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Purgatives – accelerate passage of food through the GIT; when
you want to empty the bowel (ex. for constipation and surgery
preparation)
Agents which increase motility without causing purgation
Antidiarrheal agents – decrease GIT movement (more absorption
of fluid resulting to increase formation of stool)
Antispasmodic drugs – decrease GIT movement (relieve abdominal
pain)
o
Do not use antidiarrheals and antispasmodics when you’re not
sure. These may mask the symptoms of a greater disease
H. TREATMENT OF H. pylori
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H. pylori infection may be detected in almost 100% of patients with
duodenal lcers and 70-80% of patients with gastric ulcers
Combination therapy with three drugs is employed
o
Omeprazole, amoxicillin, metronidazole
o
Omeprazole, clarithromycin, amoxicillin
o
Tetracycline, metronidazole, bismuth chelates
Give something that will protect the mucosa or inhibit acid
production plus two antibiotics (to prevent resistance and
recurrence)
10-14 days: PPI 2x a day (for 4-6 weeks), clarithromycin 500 mg
2x/day, amoxicillin 1g 2x/day
Bismuth plus triple therapy – decreased treatment to two weeks of
quadruple therapy
B. PROKINETIC AGENTS
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DOPAMINE-RECEPTOR ANTAGONISTS
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III. GASTROINTESTINAL MOTILITY
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5HT4 receptor agonists / Serotonin receptor modulators
5HT4 = 4ward = FORWARD
Enhance coordinated GI motility and transit of material (propulsive
movement)
Enhance release of excitatory neurotransmitter without altering
physiologic motility pattern and rhythm
Dopamine-receptor antagonists
Serotonin receptor modulators
Motilin agonists
GIT is supposedly in a continuous, contractile, absorptive, and
secretory state even at rest
Control: muscle itself, Enteric nervous System, CNS, humoral
pathways
Enteric Nervous System (ENS) – autonomous collection of nerves
(myenteric/Auerbach’s plexus, submucosal/Meissner’s plexus)
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Figure 4. Propulsive peristalsis (esophagus, stomach, small
intestine) versus mixing segmentation. Contraction from oral end
results in propulsion of the bolus distally.
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Dopamine
o
Significant amount in the GIT
o
Suppression of Ach release from myenteric plexus (mediated
by D2 receptors)
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Ach is cholinergic, so suppressing it prevents motility
o
Inhibitory effects on motility
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Reduction of lower esophageal sphincter pressure
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Reduction of intragastric pressure
o
D2 receptor antagonist – prokinetic agent
Metoclopromide (e.g. plasil; also a serotonin receptor modulator)
and domperidone
o
Dopamine receptor (D2) blockade  Ach release  primary
prokinetic mechanism of action
o
 Esophageal peristaltic amplitude
o
 LES pressure – prevents GER and promote movement
towards colon
o
 Gastric emptying
GERD where LES is lax, impaired gastric emptying (postsurgical,
diabetic gastroparesis), prevention of vomiting
METOCLOPROMIDE
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DOMPERIDONE
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Figure 5. Control of GI Motility.
QUINIO, RAMOS, REYES
Serotonin receptor modulator
Other receptors involved: 5-HT4 agonist (good!), 5HT3 antagonist (vagal and central) (anti-bad =
good, addressing nausea, vomiting and pain),
muscarinic receptors sensitization
Absorbed rapidly
Excreted in the urine
Half-life 4-6 hours
Peak concentration/effects = within 1 hour
Duration 1-2 hours
Adverse effects because it crosses the blood-brain
barrier
o
Extrapyramidal
effects
(dystonias,
parkinsonian-like movements) – since it
crosses
blood-brain
barrier
causing
involuntary movements
o
Tardive dyskinesia
o
Galactorrhea
D2 receptor antagonist
Does not involve other receptors
Modest prokinetic activity at 10-20 mg 3x a day
Does NOT cross the blood-brain barrier (diference
with Metoclopromide)
Exerts effect in parts without this barrier
o
Regulation of emesis, temperature and
prolactin release (helps in post-partum
lactation)
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Lec 11: Gastrointestinal Pharmacology
OTHER SEROTONIN RECEPTOR MODULATORS
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Tegaserod
o
5HT4 agonist – stimulates motility (see Figure 5)
o
Female patients with Irritable Bowel Syndrome; mostly used
for constipation (proven clinical efficacy)
o
Removed from the market because of cardiovascular effects
Cisapride
o
Stimualte 5HT4 and Ach release in the myenteric plexus in the
UGIT
o
May directly stimulate smooth muscle
o
GER, reflux esophagitis
o
Withdrawn from the market because it prolongs QTc (which
may lead to torsades de pointes) especially with erythromycin
 arrhythmia, specifically torsades de pointes  shock
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Motilin
o
Potent contractile agent of UGIT (smooth muscles and enteric
neurons)
o
Action mimicked by macrolides (erythromycin, azithromycin,
clarithromycin, oleandomycin)
Erythromycin
o
 LES pressure
o
Stimulates gastric and small bowel contractility
o
Cholinergic facilitation at lower doses
o
Diabetic gastroparesis
o
Very hard to tolerate, but it is used as prophylaxis for
diphtheria
IV. CONSTIPATION
STOOL FORMATION
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Fluid content – principal determinant of stool volume and
consistency (70-80% SW).
Net fluid content depends on luminal input (I,S) - output (A)
o 8-9 L enter small intestine, 1.5 L crosses ileocecal valve and
enters colon, 100 mL fecal water excreted.
Normally within absorptive capacity.
o Factors which may alter processes: neurohumoral mechanisms,
pathogens, drugs, altered motility (absorption depends on transit
time).
Ex: cholera: water and fluid secretion  relative decreased
absorptive capacity
PATHOPHYSIOLOGY
Decreased motility, excessive absorption
o Constipation: hard, dehydrated stool
o Increases strain on defecation (some may tolerate it)
o Harmful for a subset of patients
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May cause dehiscence of wounds (recent episiotomy,
colostomy), hemorrhoids.
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Valsalva due to constipation can activate the vasovagal reflex
which can cause shock or death in patients with severe mitral
stenosis or any cardiovascular disease.
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Ex: Patients with mitral stenosis (cvd) are given laxatives to
soften stools because straining may cause cardiorespiratory
arrest. Their mitral valve area so small that their cardiac
output is compromised by vagal insult.
Lack of dietary fiber
Hormonal disturbances
Drugs (opioids, morphine)
Neurogenic disorders, systemic illnesses
60% with normal colonic transit.
“Decreased motility” of mass action type; “increased motility” of
nonpropulsive type.
Treatment is empirical and based on non-specific principles.
NON PHARMACOLOGIC THERAPY
 High fiber diet (green vegetables and fruits)
 Adequate fluid intake
 Regular exercise
 Use of alternative drugs
 Heeding of nature’s call
*when you feel it, go for it!
LAXATIVES
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Production of soft formed stool over 1 or more days.
Enhance intraluminal fluid retention:
o Hydrophilic
o Osmotic mechanisms.
Decrease net absorption of fluid (fluid and electrolyte transport).
Altering motility:
QUINIO, RAMOS, REYES
o Inhibit nonpropulsive action
o Stimulate propulsive contractions.
Summary of laxatives
o Luminally active agents

Bulk-formers

Osmotics

Stool softeners/lubricants
o Stimulants/Irritants (fluid secretion and motility)

Bisacodyl, senna
o Prokinetic agents

5HT4 receptor agonists

Opioid receptor antagonists
o Chloride channel activator
o Opioid receptor antagonist
LUMINALLY ACTIVE AGENTS (LAA)
MOTILIN AGONISTS

OS 214
Q: Psyllium husk, more popularly known as Metamucil, is used as what type
of laxative?
a. Lubricant
b. Stimulant
c.
Bulk-forming
d. Emollient
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LAA
BULK LAXATIVES
Stool Softeners/ Lubricants.
Polysaccharide polymers not broken down by the normal digestion
in the upper GIT.
Capacity to retain water and promote peristalsis by afferent
stimulation of the gut (increased sensation of fullness).
Onset: 12-24 hours to several days.
o Takes a while to take effect because it has to attract water.
Methycellulose, psyllium husk
Plant gums– sterculia, agar, bran, ispaghula husk
Use: chronic constipation, irritable bowel syndrome
LAA
OSMOTIC LAXATIVES
Agents which will attract water faster and that will poorly absorbed
solutes.
Saline purgatives and lactulose attract water (lactulose is mostly
used in cardiac patients).
Increased volume of fluid in the lumen through osmosis.
Large volume in the colon distension and purgation about an hour
later.
Can increase motility, causing abdominalc ramps.
Colon distention stimulates 5-HT3 abdominal cramps due to
distention.
Main salts– magnesium sulfate and magnesium hydroxide (Milk
of Magnesia; remember ‘Must go to the bathroom’).
Minimal absorption and adverse systemic effects.
Should be avoided in small children and patients with poor renal
function because Mg may accumulate and cause the following:
o Heart block
o Neuromuscular block
o CNS depression.
Q: This cathartic is used in cases of portal HPN and hepatic encephalopathy
due to its ability to decrease intestinal absorption of ammonia:
a. Magnesium citrate
b. Magnesium hydroxide
c.
Milk of magnesia
d. Lactulose
LACTULOSE
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o Semisynthetic disaccharide of fructose and galactose
– poorly absorbed
o Fermented to lactic and acetic acids – osmotics
o Takes 2-3 days to act; has side effects if given at high
doses:
 Flatulence,
cramps,
diarrhea,
electrolyte
disturbance tolerance can develop
LAA
STOOL SURFACTANT AGENTS (STOOL SOFTENERS)
Docusate sodium (Colace, Doss), glycerin, mineral oil)
Given per orem or per rectum
Soften stool material allowing water and lipid to penetrate
Mineral oil lubricates fecal material retarding water absorption from
stool
May be mixed with juices - to be more palatable
Onset: 24-48 hrs (up to 3-5 days)
Side effects: (rare) GI pain, cramping, rash
Administer with adequate fluids
Page 5 / 10
Lec 11: Gastrointestinal Pharmacology
o
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LAA
STIMULANT LAXATIVES
Bisacodyl (Dulcolax), senna, sodium picosulfate
Increases water and electrolyte secretion by the mucosa
Increases peristalsis possibly by stimulating enteric nerves
Potent, may cause watery stools and cramping
Often used for preprocedure bowel preps, postop
Potential for abuse (especially for those trying to lose weight)
Long-term use is not recommended because (cause dependence,
destruction of myenteric plexus, colonic atony and dilatation)
Side effects: abdominal discomfort, nausea, cramps
Active in stimulating enteric nerves
BISACODYL
SENNA
CHLORIDE
CHANNEL
ACTIVATOR
OPIOD
RECEPTOR
ANTAGONIST
o Usually given as suppository (especially when Pt
has mucosal bleeding in the anus because of the
constipation, or when the parent is really worried)
o Stimulates rectal mucosa
o Peristaltic action and defecation in 15-30 minutes
o Tablets: onset is 6-12 hours (bowel preparations)
o Contains derivatives of anthracene (e.g. emodin)
plus sugars = glycosides
o Bacteria hydrolyze the glycoside bond→ direct
stimulant effect on the myenteric plexus
o Used for simple constipation, postop, etc.
o Onset: 6-12 hours (up to 24)
o Chronic use: “melanosis coli” (brown pigmentation
of the bowel on colonoscopy; reversible) has no
clinical significance
o Lubiprostone
o Chronic constipation and Irritable Bowel Syndrome
with predominant constipation
o Stimulates type 2 Cl channels in the small intestine
o Increased chloride-rich secretion stimulates
intestinal motility
o Minimal systemic absorption, increased fetal loss in
guinea pigs
o Effects through µ-opioid receptors
o Inhibit peripheral µ-opioid receptors without
impacting analgesic effects in the CNS
o Methylnaltrexone: opioid-induced constipation in
palliative care
o Alvimopan: short-term use for postoperative ileus in
cases of small or large bowel resection
CLINICAL IMPLICATION OF LAXATIVES (FROM 2016)
 Instruct in diet, adequate fluid intake, activity
 Promote alternatives when appropriate to minimize laxative
dependency
 Assess for abuse or overuse, especially in the young (eating
disorders, purging) and the elderly
 Always assess bowel pattern before administering laxatives
- Hold for loose stools
 Nursing orders for bowel care common
 Choose agent according to onset of action, tolerability, patient
preference
 Nonpharmacologic treatment is preferred if possible



V. DIARRHEA
Frequent passage of liquid feces
May be caused by infectious agents, toxins, anxiety, and drugs
Consequence: discomfort and inconvenience to a medical
emergency



Increase in GIT motility
Increased secretion and decreased absorption of fluid
Loss of electrolytes and water

There are three approaches to the treatment of severe acute
diarrhea:
1. Maintenance of fluid and electrolyte balance – first priority
2. Use of anti-infective agents (for selected cases like amoebiasis,
cholera, giardia)
3. Use of non-antimicrobial anti-diarrheal agents
PATHOPHYSIOLOGY
TREATMENT
REHYDRATION
 Mainstay of therapy
ZINC SUPPLEMENTATION

Zinc is lost in large amounts during diarrhea
QUINIO, RAMOS, REYES
o
OS 214
Supplementation decreases duration and severity of diarrhea
and lowers incidence of diarrhea in the next 2-3 months
Recommended dosage
< 6 months : 10 mg once a day for 10/14 days
≥ 6 months: 20 mg once a day for 10/14 days
ANTI-MOTILITY AGENTS: OPIATES
 The most effective antidiarrheal drugs are the opioids and
derivatives of opioids.
 Selected for maximal antidiarrheal and minimal CNS effect.
 Inhibit presynaptic cholinergic nerves in the submucosal and
myenteric plexus leading to constipation
 Activation of opioid receptors in GI tract decrease motility 
increased colonic transit time and fecal water absorption
 Decrease mass colonic movements and gastrocolic reflex
 Side Effects:
o Constipation
o Dizziness
o Abdominal cramps
o Paralytic ileus
 Diphenoxylate and loperamide: meperidine analogs with very
weak analgesic effects.
 Diphenoxylate is formulated with antimuscarinic alkaloids (eg,
atropine) to reduce the likelihood of abuse
ATROPINE
o
o
o
o
o
o
o
o
o
MORPHINE
o
o
DIPHENOXYLATE
o
"Hot as a hare”- flushing
“Blind as a bat”- mydriasis, blurred vision
“Dry as a bone”- dry mouth
“Red as a beet”- flushing
“Mad as a hatter“- confusion, hallucination
OTHERS:
arrhythmia, TACHYCARDIA,
DIZZINESS, NAUSEA, photophobia, loss of
balance
Increases tone and rhythmic contractions of the
intestine; diminishes propulsive activity
Complex effect: overall effect is constipating
Does not have morphine-like activity in the CNS
in therapeutic dose
Large doses (25-fold higher) produce typical
opioid effects
The pyloric, ileocolic, and anal sphincters are
contracted and the tone of the large intestine is
markedly increased
Lomotil®
o Imodium®
o Used in Traveler’s diarrhea – enterotoxin
producing E. coli, Cyclospora cayetanensis, etc.
LOPERAMIDE
o Selective action in the GIT
o Reduces frequency of passage of feces and
duration of illness
o Anti-secretory action as well
*Muscarinic receptor antagonists – rarely used
BISMUTH SUBSALICYLATE
 Used in Traveller’s diarrhea
 Recall that this is also a protectant in H. pylori infection for peptic
ulcer diseases
 Prevent up to 65% of cases of diarrhea in areas of high risk
 Work largely by salicylate component
 Side effects: tinnitus and blackening of feces
ABSORBENTS
 Act by adsorbing microorganisms or toxins
Altering intestinal flora
Coating and protecting intestinal mucosa
 No hard evidence for action
 Used extensively
 No properly controlled trials
 Activated attapulgite, kaolin, pectin, charcoal, methylcellulose
RACECADOTRIL (HILDRASEC)
 Antisecretory agent
 Enkephalinase inhibitor
o Enkephalin
 Endogenous opioid peptide
 Inhibits intestinal secretion
 Increase endogenous enkephalin
 Decrease intracellular cAMP and secretion of water and electrolytes
 Does not promote bacterial overgrowth
 Does not affect basal absorption of water and electrolytes
 Does not alter motility or duration of intestinal transit
 Only affects the secretory part (not motility, absorption, transit, and
growth of bacteria)
Page 6 / 10
Lec 11: Gastrointestinal Pharmacology
SUMMARY: ANTIDIARRHEAL AGENTS
 Replacement and maintenance agents: ORAL REHYDRATION
SALTS
 Antimotility: LOPERAMIDE, diphenoxylate
 Adsorbents/bulk forming agents: Attapulgite, kaolin, pectin, psyllium,
carboxymethylcellulose
 Antisecretory agent: Racecadotril
 Bile-Acid binding resins, Octreotide
BUTYROPHENONES
VI. VOMITING
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Forceful evacuation of gastric contents through mouth
May be valuable – to induce vomiting in toxic ingestion
Usually unwanted – during chemotherapy
Accompanies pregnancy, motion sickness, numerous disease states
THE REFLEX MECHANISM OF VOMITING
See figure 8 in appendix
Emetic stimuli include
o
Chemicals in blood
o
Neuronal input from gastrointestinal tract, labyrinth and
CNS
Impulses from chemoreceptor trigger zone, and various CNS
centers relay to the vomiting center.
Chemical transmitters include: histamine, acetylcholine,
dopamine and 5-hydroxytryptamine, acting on H1-, muscarinic, D2and 5-HT3-receptors, respectively
EMETIC DRUGS

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
Ingestion of toxic substances
Should not be attempted when
o
Patient is not fully conscious
o
The substance is corrosive
o
High probability of aspiration (hydrocarbons)
IPECACUANHA
o
Acts locally in the stomach
o
In case of poisoning, activated charcoal can be given to
sequester toxic drug
o
Irritant due to two alkaloids
- Emetine
- Cephaeline
METOCLOPROMIDE
AND
DOMPERIDONE
METOCLOPROMIDE
(REGLAN®)
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
OS 214
o Chlorpromazine, prochlorperazine, trifluoperazine,
thiethylperazine
 Thiethylperazine is an antiemetic alone (never
used or licensed as an antipsychotic).
o Side effects: sedation, hypotension, extrapyramidal
symptoms (tardive dyskinesia, dystonia)
o Antipsychotics
o Haloperidol (Haldol®), Droperidol (Inapsine®)
o Side effects: extrapyramidal effects and hypotension;
Droperidol- prolong QTc
o Central dopaminergic blockade
o Acute chemotherapy-induced emesis
“DOLpamine receptor antagonist”
o D2 receptor antagonists that act in the CTZ
o Important gastric kinetic and antiemetic properties
o Domperidone does not penetrate BBB
o Vomiting
caused
by
radiation,
uremia,
gastrointestinal disorders, cytotoxic drugs
o
o
o
o
o
Blocks dopamine receptors elsewhere in the CNS
Recall: a prokinetic
Given orally
Plasma half-life of 4-5 hours; excreted in the urine
Side effects:
 Disorders of mov’t (fatigue, motor restlessness,
spasmodic torticollis, Occulogyric crises)
 Stimulates prolactin release
AED
ANTICHOLINERGICS – HYOSCINE (SCOPOLAMINE)
Most widely used antimuscarinic agent
Prophylaxis and treatment of motion sickness
Effective in vomiting caused by irritants in the stomach
Have little effect against substances that act directly on the CTZ
Used in post-op nausea and vomiting
AED
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H1-RECEPTOR ANTAGONISTS
Meclizine,
cinnarizine,
cyclizine,
dimenhydrinate,
promethazine, diphenhydramine
Indications same as hyoscine
Not used in chemotherapy-induced emesis
Clinical Uses:
o
Cyclizine – motion sickness
o
Cinnarazine – motion sickness, vestibular disorders (i.e.,
Meniere’s Disease)
ANTI EMETIC DRUGS (AED)
AED
AED
SEROTONIN (5HT3) ANTAGONISTS
 Selective 5-HT3-receptor antagonists
 Ondansetron (Zofran®), Granisetron (Kytril®), Tropisetron,
Dolasetron
 Primary site of action: CTZ (chemoreceptor trigger zone)
 Prevent and treat radiation therapy- and chemotherapy- induced
emesis
 Given orally
 Side-effects: headache and gastrointestinal upsets (relatively
uncommon)
o A carbazole that binds to the serotonin and
alpha-1 adrenergic and u-opioid sites
o Controls nausea without having the prokinetic
action of Metoclopromide
ONDANSETRON o Used in vomiting caused by cytotoxic anti-cancer
drugs; post-operative vomiting; radiation-induced
vomiting
(ZOFRAN)
o Metabolism: liver
o Mechanism: 5-HT3 antagonist. Powerful centralacting antiemetic
o Clinical use: Control vomiting post-operatively
and in patient s undergoing cancer chemotherapy
o Toxicity: Headache, constipation
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AED
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YOU WILL NOT VOMIT WITH ONDANSETRON, SO YOU CAN GO ON
DANCING.
AED
DOPAMINE (DA) ANTAGONISTS
PHENOTHIAZINES
o Antipsychotic agents with potent antiemetic and
sedative properties
o For severe episodes of nausea and vomiting
associated with vertigo, motion sickness, uremia,
radiation and viral gastroenteritis, migraine
o Prochlorperazine (Compazine®)
o Promethazine (Phenergan®)
QUINIO, RAMOS, REYES
CANNABINOIDS
No receptor involved
For vomiting caused by cytotoxic anti-cancer drugs
Effectiveness initially anecdotal
Since then, synthetic derivatives have been found to decrease
the vomiting caused by agents which stimulate the CTZ
Action antagonized by naloxone
Opioid receptors important in the action of these drugs
Utilizes CB1 type of cannabinoid receptor
Tetrahydrocannabinol (THC)
o
Active ingredient in marijuana
o
Dronabinol (Marinol®)
o
Nabilone (Cesamet®) (half life = 120 mins.)
 Given orally, well absorbed
Side Effects:
o
Common: Drowsiness, dizziness, dry mouth
o
Frequent: mood changes and postural hypotension
o
Hallucinations, psychotic reactions

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
STEROIDS
No receptor involved, no effect on receptors
High dose glucocorticoids may have anti-emetic action
Includes Dexamethasone, methylprednisolone
o
Dexamethasone enhances efficacy of 5-HT3 receptor
antagonists
o
8-20mg IV before chemo followed by 8 mg/d orally for 24 days
MOA not clear
o
Action may involve inhibition of prostaglandin synthesis
Neurokinin I (substance P) antagonist: vofopitant (GR-205171)
may be effective in the control of both chemotherapy-induced and
post-operative nausea and vomiting
Can be used alone or in combination with a phenothiazine or
ondansetron
Page 7 / 10
Lec 11: Gastrointestinal Pharmacology
AED
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
NEUROKININ RECEPTOR ANTAGONIST
Example is Aprepitant
o
Combined therapy with aprepitant, HT3 receptor
antagonist and dexamethasone prevents acute emesis in 8090% (vs. 70% without aprepitant)
o
Prevention of delayed emesis (70% vs. 30-50%)
Adverse effects:
o
Fatigue
o
Dizziness
o
Diarrhea
Metabolized by CYP3A4 (metabolism of drugs are impaired ->
can affect plasma levels)
SIDE EFFECTS OF ANTIEMETICS
 Drowsiness and anti-parasympathetic effects (hyoscine, nabilone >
cinnarizine)
 Dystonic reactions (thiethylperazine > metoclopramide)
 General CNS disturbances (nabilone)
 Headache, gastrointestinal tract upsets (ondansetron).
SUMMARY: ANTIEMETIC AGENTS
Anti-emetic Drugs
Example
Vomiting most effective
against
5-HT3
ANTAGONIST
Ondansetron
Cytotoxic drug emesis
D2 ANTAGONIST
Metoclopromide
Promethazine
Cytotoxic drug emesis
H1 ANTAGONIST
Cyclizine
Vestibular (motion
sickness)
MUSCARINIC
ANTAGONIST
CANNABINOID
AGONIST
NEUROKININ
ANTAGONIST
Hyoscine
(Scopolamine)
Dronabinol
Nabilone
Aprepitant
OS 214
VIII. INFLAMMATORY BOWEL DISEASE


The two major important entities are
o Crohn’s disease
- Can affect intestines from the mouth down to the anus.
- Systemic manifestation.
o Ulcerative colitis
- Affects the colon.
There is dysregulation of TH1 response and regulatory T-cells.
PHARMACOLOGIC THERAPY

1.
2.
3.
4.
5.
Treatment involves different drug classes with anti-inflammatory
action:
Aminosalicylates
Glucocorticoids
Immunomodulators/immunosuppressives
Anti-tumor necrosis therapy
Anti-integrin therapy.
PHARMACOTHERAPEUTIC GOALS
1. Control acute exacerbation
2. Maintain remission
3. Treat complications like fistula (more common in Crohn’s disease)
*Dampen generalized inflammatory response
Motion sickness
Cytotoxic drug emesis
Cytotoxic drug emesis
VII. IRRITABLE BOWEL SYNDROME



Incidence of irritable bowel syndrome is not really high.
Idiopathic chronic, relapsing disorder.
Abdominal discomfort associated with alterations in bowel habits.


Relief or abdominal pain and discomfort
Improving bowel function
PHARMACOLOGIC THERAPY
ANTISPASMODIC AGENTS
 Muscarinic receptor antagonists inhibit parasympathetic activity.
 Of value in irritable bowel syndrome and diverticular disease, mainly
for abdominal pain.
 DICYCLOVERINE (dicyclomine) – direct relaxant effect on
smooth muscle. (dec. contraction dec. spasm dec. abdominal
pain)
 Mebeverine – direct relaxant effect on GI smooth muscle.
 Side effects: light-headedness, drowsiness, nervousness,
anticholinergic effects (dry mouth, urinary retention, constipation).
SEROTONIN 5HT3 RECEPTOR ANTAGONISTS
 5HT3 receptors activate visceral afferent pain sensation 
inhibition of receptors will inhibit unpleasant sensation.
 Used to inhibit colonic motility via enteric cholinergic neurons.
 Alosetron – severe IBS and diarrhea.
o Adverse effects – constipation (1/1000-surgical), ischemic colitis
(3/1000).
SEROTONIN 5HT4 RECEPTOR AGONISTS: TEGASEROD
 IBS with predominant constipation.
 Increased number of cardiovascular deaths.
 Removed from the market.
CHLORIDE CHANNEL ACTIVATOR: LUBIPROSTONE
 For women, IBS with predominant constipation.
 Increase chloride ion secretion, thus increasing motility.
If IBS + constipation, increase bowel movement. If IBS + vomiting and
diarrhea (which are related to 5HT3 receptor), give Alosetron to inhibit
unpleasant sensation.
QUINIO, RAMOS, REYES
Figure 6. Algorithm for treatment of inflammatory bowel disease;
for milder diseases, drugs with relatively less side effects are
given. (One side effect is immunosuppression, which could make one
more prone to infection and sepsis, because the drugs modulate the
inflammatory system.)
AMINOSALICYLATES (5-ASA)
 The most popular for IBD
 Sulfasalazine, olsalazine, balsalazide – contain 5-ASA bound by an
azo (N=N) bond to an inert compound or to another 5-ASA molecule
(azo compounds), various mesalamine.
 5-ASA (released in the large intestine) – works “topically” in
areas of diseased GI mucosa, formulations have been designed to
deliver 5-ASA to various distal segments of the small bowel or the
colon since up to 80% of unformulated 5-ASA is rapidly absorbed in
the proximal small intestine.
 Mechanism is not certain.
o Modulates inflammatory mediators.
o Interfere with production of inflammatory cytokines.
o Inhibit NK cells, lymphocytes, macrophages.
o Scavenge oxygen metabolites.
 Sulfasalazine
o First Aminosalicylate made
o 5-ASA and sulfapyridine linked by azo bond.
o Induce and maintain remission in UC.
o For mild or moderately active UC.
o High incidence of adverse effects attributed to coupled
sulfapyridine molecule.
o Side effects (treats inflammation, but causes other
inflammation):
- Nausea, GI upset, headaches, myalgia, arthralgia, bone
marrow suppression; hypersensitivity results in fever and
exfoliative dermatitis, pancreatitis, pericarditis, pneumonitis,
hepatitis
- Interstitial Nephritis
- Impairs folate absorption.
 2nd generation- 5-ASA bound to 1) 5-ASA or to 2) inert material.
(The 5-ASA of these drugs are not bound to Sulfapyridine molecule
anymore  unfavorable effects decreased)
Page 8 / 10
Lec 11: Gastrointestinal Pharmacology
GLUCOCORTICOIDS
 Inhibit formation of inflammatory cytokines, reduce expression of
ICAM, and inhibit gene transcription of NO synthase, PA2, COX2,
NF-κB.
 Prednisone and prednisolone are most commonly used.
 Hydrocortisone enemas, foams, suppositories.
 Moderate to severe active inflammatory bowel disease:
o If disease in only mild, use topically.
o If severe, administer orally or IV.
 Prednisone 40-60 mg/day (~1-2 weeks, then taper)
 Not useful to maintain remission.
 Major side effects: immunosuppression and suppression of the
pituitary release of ACTH, GH, TSH and LH; stunted growth in
children.
PURINE ANALOGS
 6-mercaptopurine and azathioprine
 Antimetabolites with immunosuppressive properties causing
anti-inflammation.
 Induction and maintenance of remission of IBD.
 Allow steroid dose reduction or elimination of steroids in the majority
(long term therapy).
 Remission achieved in 50-60% of patient; maintained in 80%.
 Side effects: Nausea, vomiting, BM depression, hepatic toxicity
 6-mercaptopurine undergoes a complex biotransformation via
competing catabolic enzymes that produce inactive metabolites and
anabolic pathways that produce active thioguanine nucleotides →
side effects.
ANTI-TNF THERAPY
 TNF- key proinflammatory cytokine in IBD.
 Three monoclonal antibodies to human TNF approved in IBD.
 Bind to soluble and membrane-bound TNF preventing binding to its
receptor.
 Reverse-signalling suppressing cytokine release.
 Infliximab, Adalimumab (Fc portion)- antibody mediated apoptosis,
complement activation, cellular cytotoxicity of activated Tlymphocytes and macrophages.
 Most important adverse effect:
o Suppression of TH1 inflammatory response  infection such
as bacterial sepsis, tuberculosis, invasive fungal organisms,
reactivation of Hepatitis B and other opportunistic infections.
 Mechanism: a monoclonal antibody to TNF, proinflammatory
cytokine
 Clinical use: Crohn’s disease, rheumatoid arthritis
 Toxicity: respiratory infection (including reactivation of latent TB),
fever, hypotension
OS 214
Since cholesterol  cholesterol stones, give bile acids to inhibit
cholesterol synthesis (and decrease cholesterol stones).
DRUGS AFFECTING THE BIILIARY SYSTEM




Litholytic bile acids (for cholesterol cholelithiasis)
Dissolve non calcified cholesterol gallstones.
Chenodeoxycholic acid (CDCA)
Ursodeoxycholic acid (UDCA) / Ursodiol
o Naturally occurring bile acid.
o Reduce hepatic cholesterol secretion by negative feedback.
o Stabilizes hepatocyte canalicular membranes.
o For patients with symptomatic gallbladder disease who refuse
cholecystectomy or are poor surgical candidates.
o 10 mg/kg/d x 12-24 mos → dissolution in half of the patients
(small non-calcified stones).
o May have cytoprotective effects on hepatocytes and effects on
the immune system – cholestatic liver disease.
o Absorbed → conjugated in the liver with glycine or taurine
→ excreted in the bile.
o Extensive enterohepatic circulation.
o Serum half-life = 100 hrs = long!
o Practically free of adverse effects.
o In primary biliary cirrhosis reduces concentration of bile acids
and improves biochemical and histological features.
o Greater efficacy and less frequent side effects (hepatotoxicity)
than chenodiol.
o basically decrease the sizeof cholesterol stones so they can be
small enough to be sent out of the body system.
END OF TRANSCRIPTION
Lean: Saan nga ulit related ang 6-mercaptopurine? Baka lumabas sa
exam haha. Konting push nalang, 2017 
Nikki: Hi 2017!! Last trans for the sem, last module exam, finals, tapos
sembreak naaaaa! Finally. Enjoy the break boys and girls!
Aldric: AFTG!
INFLIXIMAB, INFLIX PAIN ON TNF
ANTI-INTEGRIN THERAPY
 Integrin: adhesion molecules in leukocytes.
o Allows movement through vessel wall into tissue.
 Used in moderate to severe Crohn’s disease – not in mild cases
because of its side effects.
 Natalizumab - humanized IgG4 against the α4 subunit.
o Leukocyte cannot go through the vessel wall and into the tissue
because of absence of integrin.
 Adverse Effect: progressive multifocal leukoencephalopathy,
acute infusion reactions, small risk of opportunistic infections.
SA NATALIZUMAB…NATALIZUD SI LEUKOCYTE, KAYA DI
NA MAKAGALAW (THROUGH THE VESSEL WALL AND
INTO THE TISSUE).
IX. THE BILIARY TREE
BILE ACIDS






Essential component of bile.
Induce bile flow.
Feedback-inhibit cholesterol synthesis.
Promote intestinal excretion of cholesterol.
Facilitate absorption of lipids and ADEK.
Undergoes enterohepatic circulations.
*NEGATIVE FEEDBACK MECHANISM
Cholesterol synthesized by hepatocyte 
(either incorporated in membranes OR secreted in bowel OR ) enters
enterohepatic circulation in the form of bile acids  the body will sense
bile acids in enterohepatic circulation  decreased cholesterol
synthesis.
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Figure 7. Gastric acid secretion. Acid in the GIT is secreted by the parietal cell. Acid secretion is stimulated by: (1) Ach from the vagus preganglioni nerve,
though the muscarinic repector (M3), (2) Histamine from the ECL (enterochromaffin-like) cell through the H2 receptor and (3) Gastrin from G cell through the
gastrin receptor, increasing gastric acid secretion. (4) Somatostatin from D cells is generally a GIT inhibitor, preventing gastrin and histamine release. The H 2
and gastrin receptors are targets of drugs inhibiting drug release, M2 receptors are not targeted because of the myriad of side effects that may result from its
inhibition. H. pylori is said to inhibit the release of somatostatin from D cells leading to increase in the secretion of gastrin, hence increased acid secretion.
Figure 8. Reflex mechanism of vomiting
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