DRUGS FOR

GASTROINTESTI
NAL TRACT
DISEASES
BANDOLA, Angelica
BONGAT, Michelle Ann
FRANCISCO, Zyrelle
GARRIDO, John Paul
NACION, Allea Joyce

GASTROINTESTINAL
TRACT
A group
of organs
working
together

Convert
food ->
energy

Digest
food and
process
waste
http://www.mayoclinic.org/gastrointestinal-tract/img-20007468

GASTROINTESTINAL
DRUGS

This chapter describes

drugs used to treat:
1) Peptic ulcers and
Gastroesophageal Reux
Disease (GERD)
2) Chemotherapy-induced
emesis
3) Diarrhea
4) Constipation
5) Inammatory bowel disease

PHASESOFGASTRICSECRETION

Phase
Cephalic
(stimulate)

Gastric
(stimulate)

Stimuli

Pathway

Sight,smell,tasteor 1)Vagus
thoughtoffood
(M3receptors)
2)Histamine(H2rece
ptor)
3)Gastrin
Foodinthestomach 1)Stretch:localree
x
(M3 receptors)
2)Chemicalsubstanc
esinfood (gastrin)
3)IncreasepH:Inhibi
tionof
somatostatin(GHIH)
release

ANATOMY OF STOMACH

PHYSIOLOGY OF THE
STOMACH
WHAT DO MECHANICAL
I
DO WHEN
YOU EAT?

DIGESTION

CHEMICAL

www.docsity.com

STOMACH SECRETES
Hydrochloric acid (HCl)
digestive acid secreted by parietal cells in the stomach

Mucus
protects the stomach lining from both HCl and digestive
enzymes

Intrinsic factor
a glycoprotein that facilitates gastric absorption of vitamin B12

Bicarbonate
a base that is a natural mechanism to prevent hyperacidity

STOMACH SECRETES
(cont)
Pepsinogen
an enzymatic precursor to pepsin, an
enzyme that digests dietary proteins
Prostaglandins
serve a variety of anti-inflammatory and
protective functions
http://philschatz.com/anatomy-book/contents/m46517.html

DRUGS FOR GASTROINTESTINAL

DISORDERS
Gastroesophageal reflux
disease (GERD)
Peptic Ulcer
Inflammatory Bowel
Disease

STATISTICSGERD

6
%

of adult
population
experience
GERD

20
%

http://www.healthline.com/health/gerd/statistics#2

Will experience
weekly
symptoms
within 12
months.

MEDICAL COST OF GERD

64.4M
Prescriptions were written for
GERD in the United States on an
annual basis

$2 billion
Are lost productivity each week of the
year because of the symptoms of
GERD.
http://www.healthline.com/health/gerd/statistics#2

MEDICAL COST OF
GERD

http://www.healthline.com/health/gerd/facts-statistics-infographic#4

62%

>
of all
hospitalizations
for GERD in
2005.

Women are more likely to be hospitalized for GERD

symptoms than men.
http://www.healthline.com/health/gerd/statistics#2

PEPTIC
COMMON
ULCER

10-15%
OF THE POPULATION

Ulcer rates are declining for young

men and increasing for older
individuals
http://www.myvmc.com/diseases/peptic-ulcer-disease-pud/

WHATISPEPTICULCER
(PUD)?
isanulcerof
anareaof
thegastrointestinal
tract
exposedtothe
acidand
pepsinsecretion
Gastritisprecursor
toPUDanditisclinic
allydifficulttodiffere

WHATISPEPTICULCER (PUD)?

Stomach
(Gastriculcer)

Duodenum
(Duodenalulcer
)

Esophagus
(Esophagealulc
er)

Meckel'sDiverticu
lum
(Meckel'sDivertic
ulumulcer)

DUODENALVSGASTRICULCERS

DUODENAL

GASTRIC

Age:2575years
Gnawingorburninguppe
r
abdomenpainrelievedb
y
foodbutreappears1
3hrs
aftermeals
Worsepainwhenstomac
h empty
Bleeding
occurswith
deep
erosionHematemesis-Melena

Age:5565years
Relievedbyfoodbutpain
may
persistevenaftereating
Anorexia,weightloss,vom
iting
Infrequentorabsentremis
sions
Small%becomecancerou
s
Severeulcersmayerodet
hrough stomachwall

WHYULCERATIONOCCUR
S?
High[H+]intheGastriclum
en
Stomach:anumberofmech
anisms
Mucussecretion:slowsiondiffusi
on
Prostaglandins:I2 andE2
(alcohol,aspirin,andotherdrug
s)
Bicarbonateions
HighBloodFlow(nitricoxide)
Because
of imbalance

MAIN CAUSES OF PEPTIC ULCER

DISEASE
Infection with gram-negative
Helicobacter pylori
Use of nonsteroidal anti-inammatory
drugs (NSAIDs), ethanol & tobacco
Stress and increased hydrochloric
acid (HCl) secretion
Inadequate mucosal defense against
gastric acid
Imbalance

IMBALANCEPRIMARILYBETWEEN
AGGRESSIVEFACTORSANDDEFENSIVEFACT
ORS
Aggressi
Defensiv
ve
e factors
factors

bile
Acid
pepsi
n

HCO3
mucu
s

H. Pylori
Gram()rodwithagella
mostcommoncauseof
PUD
Transmissionroutefecal
oral
Secretesureaseconvert
ureato ammonia
Producesalkalineenviron
ment
enablingsurvivalinstoma
ch
Almostallduodenaland2/
3
gastriculcerptsinfected

Barry J Marshall & J. Robin Warren

discovered of H. pylori & its role in
peptic ulcer

DIFFERENTIATINGBETWEENH.PYLORI
ANDNSAIDINDUCEDULCER

UlcersassociatedwithH.pylor
i
Moreoftenin duodenum
Oftensuperficial
LesssevereGIbleeding

Ulcersassociatedwith NSAIDs
Moreofteninstomach
Oftendeep moresevereGI bleeding
Sometimes asymptomatic

TREATMENT APPROACHES
Eradicating the H. pylori
infection
Reducing secretion of gastric
acid with the use of PPIs or
H2-receptor antagonists
Providing agents that protect
the gastric mucosa from
damage, such as misoprostol
and sucralfate

GASTROESOPHAGEALREFLUXDIS
EASE
(GERD)
CommonandGIm
otilitydisorder
Acidcontentsreuxb
ack intoesophagus
Intenseburning,som
etimesbelching

Commonlyassocia
ted
withobesity

AcidityofGastricc
ontentsmost
commonfactor

Canleadtoesoph
agitis,
esophagealulcers,

and strictures
Barrettsesophagus
Improveswithlife

style
management

ANTIMICROBIAL AGENTS
For patients with peptic ulcer disease
(duodenal or gastric ulcers) who are
infected with H. pylori
H. pylori is diagnosed via:
a. endoscopic biopsy of the gastric
mucosa
b. various noninvasive methods - serology
and urea breath tests

ANTIMICROBIAL AGENTS
Eradication of H. pylori
rapid healing of
active ulcers and low recurrence rates
Successful eradication of H. pylori (80% to 90%) is
possible with various combinations of antimicrobial
drugs.
Triple therapy therapy of choice
PPI combined with amoxicillin (metronidazole may be
used in penicillin-allergic patients) + clarithromycin
Quadruple therapy considered in areas with high
resistance to clarithromycin; results in a 90% or greater
eradication rate
PPI + bismuth subsalicylate + metronidazole +
tetracycline

Treatment with a Single

Antimicrobial Drug

Much less effective

Results in antimicrobial
resistance
Not recommended

Substitution of
antibiotics
Do not substitute
ampicillin for amoxicillin
or doxycycline for
tetracycline

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION

Acetylcholin
e
Gastric acid
secretion is
stimulated
by:

Histamine

Gastrin

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION

Receptormediated
binding of
acetylcholine,
histamine, or
gastrin

Activation of
protein
kinases

Stimulates the
H+/K+adenosine
triphosphatas
e (ATPase)
proton pump

Secrete
hydrogen ions
in exchange
for K+ into
the lumen of
the stomach

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION
Competitively
blocking the
binding of
histamine to H2
receptors
these agents
reduce the
secretion of
gastric acid
Potently inhibit
(greater than
90%) basal, foodstimulated, and
nocturnal
secretion of
gastric acid

Cimetidine
Ranitidine
Famotidine
Nizatidine

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION

Histamine H2receptor
antagonists

Act selectively on H2
receptors in the stomach
Have no effect on H1
receptors
Competitive antagonists
of histamine and are
fully reversible.

H2-RECEPTOR
H2-RECEPTOR ANTAGONISTS
ANTAGONISTS AND
AND
REGULATION
REGULATION OF
OF GASTRIC
GASTRIC ACID
ACID
SECRETION
SECRETION

Cimetidine
First histamine H2receptor antagonist
Its utility is limited
by its adverse
effect profile and
drug drug

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION

Cimetidine ,Ranitidine,
Famotidine & Nizatidine
Use of these agents has decreased with
the advent of PPIs
Effective in promoting the healing of
duodenal and gastric ulcers
Recurrence is common if H. pylori is
present and the patient is treated with
these agents alone

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION
Patients with
NSAID-induced
ulcers
Should be treated with PPIs
(because these agents heal and
prevent future ulcers more
effectively than H2 antagonists
Given as an intravenous infusion
to prevent and manage acute
stress ulcers associated with
high-risk patients in intensive
care units (tolerance may occur)

Effective for the treatment of

heartburn (GERD)
Low doses of H2 antagonists
OTC
Act by stopping acid secretion
May not relieve symptoms for at least 45
minutes
Antacids quickly and efficiently
neutralize stomach acid; action is only
temporary
PPIs now used preferentially in the
treatment of GERD, especially for

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION
After oral
administration
distribute widely
throughout the body
(including into breast
milk and across the
placenta)

Excreted mainly in
urine

Cimetidine, ranitidine, and

famotidine -intravenous
formulations
t in patients with
renal dysfunctio dosage
adjustments are needed

H2-RECEPTOR ANTAGONISTS AND

REGULATION OF GASTRIC ACID
SECRETION

ADVERSE EFFECTS
H2 antagonists well
tolerated
Reduce the efficacy of
drugs that require an
acidic environment for
absorption, such as

CNS
EFFECTS

Occur primarily in
elderly patients and
after intravenous
administration

Confusion &
altered
mentation

Cimetidi
ne
Endocrine effects
acts as a
nonsteroidal
antiandrogen
(Cimetidine)

Gynecomas
tia

Galactorrhe
as

Endocrine effects
acts as a
nonsteroidal
antiandrogen
(Cimetidine)
Interfere with
Inhibits
several
cytochrome
P450
isoenzymes

the
metabolism
of many other
drugs, such
as warfarin,
phenytoin,
and
Clopidogrel

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Dexlansopr
azole
Esomeprazo
le
Lansoprazol
e
Omeprazole
Pantoprazol
e
Rabeprazol
e

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Bind to the H+/K+- ATPase enzyme
system
(proton pump)
Suppress the secretion of hydrogen
ions into the gastric lumen
Membrane-bound proton pump
nal step in the secretion of gastric
acid
Require active pumps to be effective

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Prodrugs with an acid-resistant enteric
coating protect them from premature
degradation by gastric acid
Coating is removed in the alkaline
duodenum prodrug, a weak base, is
absorbed transported to the parietal
cell converted to the active drug
forms a stable covalent bond with the
H+/K+-ATPase enzyme
It takes about 18 hours for the enzyme to
be resynthesized, and acid secretion is
inhibited during this time.

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Standard doses inhibit
both
basal
and
stimulated gastric acid
secretion by more than
90%
Omeprazole + sodium
bicarbonate
Faster absorption
OTC & Rx

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Omeprazole,
Esomeprazole
and
Lansoprazole

OTC
Shortterm
treatment

THERAPEUTIC USES
Superior to the H2
antagonists in
suppressing acid
production
and healing ulcers
Prophylaxis
Preferred
drugs for
stress
ulcer
treatmen
t

and for the

treatment:
GERD
Erosive
esophagitis
Active
duodenal
ulcer
Pathologic
hypersecre
tory

Zollinger- Ellison
Syndrome
Gastrin-producing tumor causes
hypersecretion of HCl

PPIS: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

OD - partially
effective for
GERD symptoms
Reduce the risk of
bleeding from
ulcers caused by
aspirin and other
NSAIDs
Used for prevention
or treatment of
NSAID-induced
ulcers

BID / PPI (morning) + H2

Antagonist (night) improve symptom
control
If an H2-receptor
antagonist is needed should be taken well
after the PPI. H2
antagonists reduce
the activity of the
used
withpump
proton

antimicrobial regimens
to eradicate H. pylori

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Pharmacokinetics
Effective orally
Maximum effect - should be
taken 30 to 60 minutes
before breakfast or the
largest meal of the day

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Dexlansopraz
ole
Has a dual
delayed release
formulation - can
be taken without
regard to food

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Esomeprazole, lansoprazole, and
pantoprazole also avail in. intravenous
formulations
Plasma half-life of these agents - only
a few hours; long duration of action
(due to covalent bonding with the
H+/K+ATPase enzyme)
Metabolites - excreted in urine and
feces

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Adverse effects
Generally well tolerated
Omeprazole
and
Esomeprazole - decrease the
effectiveness of clopidogrel
(inhibit CYP2C19 and prevent
the conversion of clopidogrel
to its active metabolite)
concomitant use of PPIs +
clopidogrel
not
recommended because of a
possible increased risk of
cardiovascular events

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Increase the risk of fractures duration of use is 1 year or greater
Prolonged acid suppression with
PPIs (and H2 antagonists) low
vitamin B12
because acid is required for its absorption
in a complex with intrinsic factor

Elevated gastric pH - impair the

absorption of calcium carbonate
Calcium citrate
effective option for calcium
supplementation in patients on acid
suppressive therapy (absorption of the
citrate salt is not affected by gastric pH)

PPIs: INHIBITORS OF THE H+/K+ATPASE PROTON PUMP

Diarrhea & Clostridium
difcile colitis
Patients must be
counseled to
discontinue PPI
therapy and
contact their
physician if they
have diarrhea for
several days.

Hypomagnesi
a

incidence
of pneumonia

PROSTAGLANDINS

Prostaglandi
nE
Produced by the
gastric mucosa
Inhibits secretion
of acid
Stimulates
secretion of mucus
and bicarbonate

PROSTAGLANDINS

Deficiency of
prostaglandins involved in the
pathogenesis of peptic
ulcers

PROSTAGLANDINS
Misoprostol
analog of prostaglandin E1
approved for the prevention of NSAIDinduced gastric ulcers
Prophylactic use of misoprostol
should be considered in patients who
are taking NSAIDs and are at moderate
to high risk of NSAID-induced ulcers,
such as elderly patients and those with
previous ulcers
C/I: pregnancy ( stimulate uterine
contractions and cause miscarriage)
Adverse Effects
Dose-related diarrhea and nausea most common

ANTACIDS
Weak bases that react with
gastric acid to form water and
a salt to diminish gastric
acidity

Pepsin (a proteolytic enzyme)

is inactive at a pH greater
than 4, antacids also reduce
pepsin activity

Efcacy of an antacid depends on its capacity to

neutralize gastric HCl and on
whether the stomach is full or
empty (food delays stomach
emptying allowing more time
for the antacid to react)

Commonly used antacids are

combinations of salts of
Aluminum and Aluminum
Magnesium
hydroxide

Magnesium hydroxide

Calcium carbonate - reacts

with HCl to form CO2 and CaCl2
Sodium bicarbonate - Systemic
absorption can produce
transient metabolic alkalosis;
not recommended for long-

ANTACIDS
THERAPEUTIC
USES

Symptomati
c relief of
peptic ulcer
disease and
GERD

Promote
healing of
duodenal
ulcers

Calcium carbonate
preparations - used
as calcium
supplements for the
treatment
Aluminum of
osteoporosis
hydroxide + Mg
hydroxide - aid in

ANTACIDS
ADVERSE EFFECTS

Aluminum
hydroxide

Magnesium
hydroxide

ANTACIDS
Preparations that
combine these agents
aid in normalizing
bowel function.
Adverse effects may
occur in patients with
renal impairment

MUCOSAL PROTECTIVE AGENTS

Cytoprotective
compounds
These agents have
several actions that
enhance mucosal
protection mechanisms
Preventing mucosal
injury, reducing
inammation, and healing
existing ulcers

MUCOSAL PROTECTIVE AGENTS

Sucralfate
Aluminum hydroxide + sulfated
sucrose binds to positively
charged groups in proteins of both
normal and necrotic mucosa
By forming complex gels with
epithelial cells, sucralfate creates a
physical barrier that protects the
ulcer from pepsin and acid, allowing
the ulcer to heal.
Effective for the treatment of
duodenal ulcers and prevention of

MUCOSAL PROTECTIVE AGENTS

Should not be
administered
with

Well tolerated, but it

can interfere with
the absorption of
other drugs by
binding to them

PPIs
H2
antagonists
Antacid Does not prevent

NSAID-induced
ulcers, and it does
not heal gastric
ulcers

MUCOSAL PROTECTIVE AGENTS

Bismuth subsalicylate
Component of quadruple
therapy to heal peptic
ulcers
Has antimicrobial actions
Inhibits the activity of
pepsin
Increases secretion of
mucus

LIFESTYLE CHANGES TO EASE

SYMPTOMS..

QUESTION #1
Patient Allea Nacion went to your drug

store andwantstotakeaH2
EXPLANATION?

antagonistbefore
AllH2
antagonistexceptfamotidine
shetakesalcoholtoavoidgastric
ANSWER?
inhibitgastricfirstpass
irritation.
WhichH2 metabolismof
antagonistwillyouask

hertotake? ethanoland

WHY?

increaseitsbioavailability.

A. Ranitidine
B. Famotidine

C. Roxatidine
D. Tiznidine

ANSWER?

QUESTION
#2
EXPLANATION:

Antacidsneutralizethealreadysec
Zyrelle Francisco, a patient comes to your
pharmacy
of heart burn. What
retedcomplaining
acidinthestomach.
drug can relieve her pain?
Allotherdrugsact by
stoppingacidsecretionandso
A. Antacids
maynot B.
relieve
symptomsat
Anti-inflammatory
leastfor45min.
C. Analgesic

WHY?

D. Antibacterial

Question #3
EXPLAINATION:
H2 antagonists cross
A pregnant
placenta
andlady
are(first
alsotrimester) comes to
you with
ulcer
disease. Which drug
secreted
inpeptic
breast
milk.
is
not
teratogenic?
Safety of Proton pump
inhibitors not established
Sucralfate
C. Famotidine
in A.
pregnancy.
B. Ranitidine
Misoprostol
causes D. Misoprostol
abortion.

Sucralfate
ANSWER?

DRUGS USED TO TREAT

INFLAMMATORY
BOWEL DISEASE

Chrons
disease

Ulcerative
colitis

http://www.celgene.com/ulcerative-colitis-and-crohns-sing-different-tunes/

STATISTICS CROHNS
DISEASE

S
T
E
G
WHO
S
N
H
O
CR
?
E
S
A
E
DIS

http://www.healthline.com/health/crohns-disease/facts-statistics-infographic#6

MEDICAL COST OF
CROHNS DISEASE

http://www.healthline.com/health/crohns-disease/facts-statistics-infographic#6

STATISTICS OF
ULCERATIVE COLITIS

0.5 to
24.5
COMMONLY
cases per 100,000 people.

250,000
DOCTORS VISITS/YEAR

Northern Europe
North America

30,000
HOSPITALIZATIONS/ YEAR

http://www.myvmc.com/diseases/ulcerative-colitis-inflammatory-bowel-disease/

Therapeutic
Pyramid
T
Disease
severity
Severe

h
e
r
a
Surgery
p
Natalizumab
y
Cyclosporine

Responsiven
ess
Refractory

TNF antagonist
Intravenous
corticosteroid

Moderate

Mild

TNF antagonist
Oral corticosteroids
Methotrexate
Azathioprine/6-Mercaptopurine
Budesonide (ileitis)
Topical corticosteroids (proctitis)
Antibiotics
5- Aminosalicylates

Responsive

Drugs used in IBM

They are chosen on the basis of disease severity,
responsiveness, and drug toxicity:
Aminosalicylates
Glucocorticoids
Purine Analogs; Azathioprine and 6-Mercatopurine
Methotrexate
Anti-Tumor Necrosis Factor Therapy
Anti-Itegrin Theraphy

Aminosalicylates
5-aminosalicylic acid (5-ASA) active
component
Aka Mesalamine

Its mechanism of action is not entirely

understood, but is thought to involve:

Reduced cytokine formation

Reduced free radical formation
Inhibited prostaglandin production
Inhibited leucocyte chemotaxis

5-aminosalicylic acid (5-ASA)

Aminosalicylates
Clinically approved drugs:
Sulfazalazine

Oral use
Mesalazine

Available as

Enteric-coated tablets (for ileal Crohns disease)

Slow release tablets (for proximal bowel Crohns)
Enemas, suppositories (for distal colonic disease)
Used when sulfasalazine can not be tolerated
Olsalazine
Balsalazide

prodrug of 5-ASA

Location of Oral Mesalamine

Release
Stomach

Jejunum

Ileum

Colon
Sulfasalazine
Colazal
(balsalazide)
Dipentum
(olsalazine)
Asacol (mesalamine)
delayed-release tablets

Lialda (mesalamine)
Mesalamine delayed release tab
Pentasa (mesalamine) controlled-release capsules

Aminosalicylates
Clinical Uses:
The mainstay tx mild to moderately
active ulcerative colitis and Crohn's
disease (induction).

For px with distal colonic disease

suppository or enema is appropriate.

Maintenance treatment with a 5-ASA

effective for sustaining remission in
UC but is of questionable value in CD.

Aminosalicylates
Adverse Effects:
Dose-related (10-45%)
headache, nausea, epigastric pain, diarrhea

Idiosyncratic (rare)
acute pancreatitis; hepatitis; peripheral
neuropathy
blood disorders
skin reactions lupus like syndrome; StevensJohnson syndrome; alopecia

Aminosalicylates
Contraindications /Cautions

5-ASA
- Salicylate hypersensitivity

Sulfapyridine + 5-ASA = Sulfasalazine(cleaved in

colon by colonic bacteria)
- G6PD deficiency (haemolysis)
- Slow acetylator status ( risk of hepatic and
blood disorders)

Glucocorticoids
DRUGS:
ineffectiv
Prednisone and Prednisolone
e
oral/ enema

maintaining
remission
enemas, foam, or suppositories

inducing
remission

Hydrocortisone

Budesonide

efficaciou
s

(poorly absorbed used for iliocaecal CD/ UC)

Glucocorticoids
are the most commonly used oral
Prednisone and
glucocorticoids.
Prednisolone
intermediate duration of action OD.
used to maximize colonic tissue effects and
minimize systemic absorptio
via topical treatment of active inammatory
Hydrocortisone
bowel disease in the rectum and sigmoid
colon.
potent synthetic analog of prednisolone
subject to rapid first-pass hepatic metabolism low
oral bioavailability.
(Entocort) controlled-release oral formulation that
releases the drug in the distal ileum and colon..

Budesonide

Glucocorticoids
Clinical Uses:
used

in the tx of patients w/
moderate to severe active
inammatory bowel disease.

Active

disease initial oral

dosage of 4060 mg/d of
prednisone or prednisolone

Glucocorticoids
Clinical Uses:
For

the tx of IBD involving the rectum

or sigmoid colon rectal
glucocorticoids are preferred because
of their lower systemic absorption.

Oral

controlled-release budesonide (9
mg/d) is the tx of mild to moderate
Crohns disease involving the ileum
and proximal colon

Glucocorticoids

Adverse
Effects:

PURINE ANALOGS:

Azathioprine/6-Mercaptopurine (6MP)
Azathioprine & 6-MP
The most extensively used
immunosuppressive agents.
Onset of benefit several weeks up to six
months.
Dose-related BM suppression is uniformly
observed
Azathioprine
MOA: inhibit ribonucleotide synthesis; induce T cell
apoptosis by modulating cell (Rac1) signalling

AZA/6-MP Metabolism
6-TG
6-TU
XO
AZA

6-MP
TPMT
6-MMP

Circulation

nucleotides

DNA
RNA

HPRT
6-TImP

TPMT
6-MMP
ribonucleotides

Intracellula

Purine
synthesis

Azathioprine/6-MP
Indications:
Steroid
Active

sparing agents

disease CD/UC

Maintenance
General

of remission CD/UC

treatment x 3-4years

Azathioprine/6-MP in IBD
Efficacy/Issues

Intolerance/Risks

Effective in 50
70% of patients
with IBD
30% failure due to
intolerance (15%) or
no response (15%)
Metabolism issues
TPMT

Bone marrow
suppression
Pancreatitis
Hepatotoxicity
Nausea
Myalgias
Other Risks
Lymphoma 4 fold
Infection

Azathioprine/6-MP
Adverse effects:
Flu-like

symptoms (20%)
- occur at 2-3 weeks; cease on
withdrawal
Hepatotoxicity; pancreatitis (<5%)
Leucopenia (3%) myelotoxicity
- determined by TPMT activity
- weekly FBC x 8 weeks
- 3 monthly thereafter
- warn patients reg: sore throat/fever

Azathioprine/6-MP
Drug Interactions:
Allopurinol
reduces xanthine oxide catabolism of the
purine analogs

active 6-thioguanine nucleotides

severe leukopenia

METHOTREXATE
A folic acid derivative that interfere with folic
acid metabolism (folic acid antagonist)
A cytotoxic agent with multiple characteristics
and maybe describe as an antimetabolite.
Beneficial in a number of chronic inammatory diseases
including Crohns disease and rheumatoid arthritis, and in
cancer

Given PO, SC, or IM

At high doses
used for
chemotherap
y : inhibit
cellular
proliferation
At low
doses used
in the
treatment
of
inammator
y bowel
diseases
(12-25

Mechanism of action
Folate

Folate
Dihydrofolat
e reductase

Methotrexate

Active
transpor
Productio
t
n of
Methotrexatethymine
and
purines

Tetrahydrofola
Dihydrofolat
te
e (FH2)
Dihydrofolate
(FH4)
reductase

Cytotoxicity

Clinical Uses
Used to induce and maintain
remission in patients with Crohns
disease

For remmision: Patients are treated

with 15-25 mg of methotrexate once
a week by subcutaneous injection

If after 8-12 weeks the result is

satisfactory the dose is reduced to
15mg/wk

Adverse Effects
Liver toxicity
Megaloblastic anemia
Alopecia

Mucositis

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Anti tumor Necrosis Factor

Therapy
Tumor Necrosis Factor (TNF)

Produced by innate immune system, the adaptive

immune system and non immune cells

One of the key proinammatory cytokines in

inammatory bowel disease

Mechanism of action
MACROPHAGE

Help
er T
cell
type
1

-Tumor
Necrosis Factor
(TNF-)

CYTOTOXIC
METABOLITES

Anti tumor Necrosis Factor Therapy

Two biologically active forms:

1.Soluble TNF
2. Membrane-bound TNF

Three monoclonal antibodies to

human TNF:
1. INFLIXIMAB
Reduce signs and symptoms of moderate to severe Crohns disease
in which there are passageways when the inammation
penetrates beyond the wall of small intestines.
2. ADALIMUMAB
A TNF blocker, which works by blocking the protein that causes the
inammation in the body.
Useful in treatment of moderate to severe inammatory
diseases such as Crohns disease.
3. CERTOZULIMAB
Composed of the antibody binding fragment (Fab) of humanized
monoclonal antibody against TNF conjugated to polyethylene
glycol; unlike other agents, it does not contain the constant
fragment of immunoglobulin (Fc)

Anti TNF antibodies used in

inflammatory bowel disease
Inliximab

Adalimumab

Certolizumab

Class

Monoclonal
antibody

Monoclonal
antibody

Monoclonal
antibody

% human

75%

100%

95%

Structure

IgG1

IgG1

Fab fragment
attached to PEG
(Lacks Fc
portion)

Route of
administration

Intravenous

Subcutaneous

Subcutaneous

Half-life

8-10 days

10-20 days

14 days

Induction dose

5 mg/kg at 0, 2
and 6 weeks

160 mg, 80 mg
and 40 mg at 0,
2, and 4 weeks

400 mg at 0, 2,
and 4 weeks

Maintenance
dose

5 mg/kg every
8 weeks

40 mg every 2
weeks

400 mg every 4
weeks

Clinical uses
Acute and chronic treatment of
moderate to severe Crohns disease
Infliximab approved acute and chronic
treatment of moderate to severe
ulcerative colitis
After induction of 5-10 mg/wk at 0, 2,
and 6 weeks, 70% of patients have a
clinical response and 1/3 achieved a
clinical remission

Adverse Effects

Infection (due to suppression of the helper

T cell type 1 (TH1) inammatory response)
includes: Bacterial sepsis, tuberculosis, invasive
fungal organism, reactivation of Hepatitis B,
listeriosis and other opportunistic infections.

Reactivation of tuberculosis
Upper respiratory infection (sinusitis,
bronchitis and pneumonia)
T-cell lymphoma

Adverse Effects cont.

Antibodies to the
antibody (ATA)

Clinical response
Development of
acute infusion
reaction

develops in patients
given episodic anti-TNF
therapy than regular
scheduled injections

Prevalence of ATA
INFLIXIMAB

CERTOLIZUMAB

ADALIMUMAB

14%
48%
38%

GO
BACK

Anti-Integrin therapy

Integrin
Family of proteins that function
Consists of heterodimers that contains
mechanically
two subunits: alpha & beta

attach the cell cytoskeleton to the

extracellular matrix (ECM),
sense whether adhesion has occurred.

Natalizumab
Useful in induction and
clinical response to
- 4
subuni
remission in patients having
t
Inammatory Bowel
Diseases

Vs.

NATALIZUMAB

Approved dosage is 300 mg every

4 weeks by intravenous infusion
patients should
not be on other
BLOCKS
immune suppressant agent

Adverse effects
Progressive multifocal
leukoencephalopathy (due to
reactivation human polyomavirus JC
virus)

Acute infusion reactions

Small risk of opportunistic

infections
Go back to table of contents

References:
Amdbook.org.(2012).Integrins are transmembrane
protein.retrieved from:
http://www.amdbook.org/content/figure-3-alpha-and-beta-su
bunits-integrins-are-transmembrane-proteins
retrieved: October 8, 2016.
Encyclopedia.com(2012).Methotrexate.retrieved from:http
://www.encyclopedia.com/medicine/drugs/pharmacology/
methotrexate retrieved: October 8,2016.
Katzung, et. al(2009). Basic and Clinical Pharmacology. 11 th
ed. McGraw-Hill Companies. USA.pg 1100-1115
Munson, et. al. (2014).Pharmacology, indication and
adverse effects of TNF-inhibitors.retrieved from:
http://www.munsonhealthcare.org/Taxonomy/RelatedDoc
uments.aspx?id=0&sid=1&ContentTypeId=3&ContentID=403
21
retrieved October 8, 2016.