INFLAMMATORY BOWEL

DISEASE.

QUESTION;
1. PATHOPHYSIOLOGY OF IBD/IBS
2. CLASSIFY THE DRUGS USED IN THE
MANAGEMENT OF IBD, DETAILING THEIR
MECHANISM OF ACTION, THERAPEUTIC EFFECTS,
CONTRAINDICATIONS AND INDICATIONS.
INTRODUCTION
 Inflammatory bowel disease is a group of chronic inflammatory conditions
affecting the GI tract.
 These conditions are considered to be idiopathic in their inception, however they
are linked to autoimmune disorders and dysfunction.
 They are immune mediated disorders, primarily arising due to immune system
anomaly.
 From the name of the condition itself, this group of inflammatory diseases
MAINLY affects areas of the bowel, this is the large and small intestines,
however other parts of the GI can be affected in one of the conditions
 IBD has primarily two subtypes, CROHN’S DISEASE and ULCERATIVE
COLITIS. These two constitute IBD at large.
INTRODUCTION
 Crohn’s disease can affect any part of the GIT but normally affects the distal
colon, the rectal area, the anal area, the sigmoid colon and can even involve areas
of the ascending colon once the disease is not properly managed.
 Area around the ileocecal valve is highly affected by CROHN’S disease
 Ulcerative colitis generally affects all parts of the colon rarely or almost seldom
affecting the small intestine.
 Inflammation in CROHN’S DISEASE not normally generalized, so SKIP
AREAS are seen, unlike in ULCERATIVE COLITIS where there is
GENERALIZED INFLAMMATION, primarily seen in the colon, hence its name.
CROHN’S DISEASE– PATHOPHYSIOLOGY

 CROHN’S DISEASE can be caused by immune/ genetic factors and

environmental factors.
 Normally commensal bacteria lining the gut are kept under close check by
physiologic mechanisms occurring at the gut.
 The GI tract epithelium regulates substances from moving from what is in the
lumen into the system through intestinal epithelium. Substances may include
drugs, bacteria etc.
 Paneth cells lining the intestines are responsible for production of antimicrobial
peptides and proteins keeping the levels of the commensal bacteria in the gut in
check, and in correct amounts. These substances are called defensins.
CROHN’S DISEASE PATHOPHYSIOLOGY

 Also goblet cells lining the intestinal cells produce mucin, a protective barrier against
what is in the lumen with intestinal cells. This barrier prevents infiltration of bacteria,
something called BACTERIAL TRANSLOCATION.
 A complex genetic component called the NOD2 gene is normally responsible for
bacterial sampling using bacterial antigens. This gene communicates to another set of
complex of genes called NFkB leading to cytokine release. These cytokines
communicate to macrophages and these cells are involved in immune surveillance in
the gut.
CROHN’S DISEASE– PATHOPHYSIOLOGY

 Macrophages can also activate T-helper cells( particularly T helper 17 cells). These
cells when stimulated release interleukin-22(IL-22). This cytokine in turn stimulates
paneth cells to make defensins, goblet cells to produce mucin, and also stimulating
autophagy.
 Autophagy is depicted in intestinal cells, incase a pathogen or bacteria invades,
lysosomes in the cells can engulf the bacteria, killing it.
 In patients with crohn’s disease, there is genetic mutation in the NOD2 gene. This
reduces activation of NFkB, reducing stimulation of macrophages and the TH17 cells
from releasing IL22, involved in stimulation of mucin release, defensin release from
paneth cells and the process of autophagy.
PATHOPHYSIOLOGY CONTINUATION…

 A reduction in defensin release and mucin allows for bacterial translocation across the
epithelial tissue and this is the first step in the pathophysiology of crohn’s disease.
This is also due to a lack of intact barrier.
 Therefore genetic/ immune factors predisposing to crohn’s disease include;a decrease
in defensin release from paneth cells, reduction in mucin release from goblet cells,
reduction in autophagy and mutation in the NOD2 gene, aggravating all the pre-
mentioned factors.
 Environmental factors include; infection from bacteria, certain antibiotics, NSAIDs,
smoking and even stress.
 Genetic and immune factors may lead to bacterial translocation, the first step in the
pathophysiology of crohn’s disease.
INFLAMMATORY PROCESSES LEADING TO MANIFESTATION OF
CROHN’S DISEASE

 On bacterial translocation, immune cascades occur leading to inflammation

These steps are as follows;
1. Macrophages engulf bacteria, in the lamina propria by phagocytosis.
2. Macrophages process the bacteria and present a piece of it on itself, using the MHC
class 2 molecules on its surface.
3. Macrophages present this bacterial antigen to a naive Tcell. Using the CD4 receptor
and T cell receptor the naïve t cell recognizes the bacteria presented.
 CONTINUATION;

4. Upon this interaction macrophages release proinflammatory cytokines; IL-1, IL-

12and TNF-alpha.
5. IL-12 acts on naïve t cells causing formation of TH-1 cells. These cells again produce
massive amounts of inflammatory cytokines such as IL-1,IL-6 and again, TNF- alpha.
6. All the mentioned cytokines lead to increased capillary permeability drawing more
cells into the area. This might lead to edema(localized) in the gut wall. Blood vessels
become leaky allowing for WBC’s and complement proteins to leak into the area. These
cytokines have chemotaxis, producing cell adhesion molecules in the luminal surface of
capillaries and using integrins, WBC’s bind. This is called margination.
7. By the process of diapedesis more immune cells such as neutrophils and macrophages
gain entry into the area.
CONTINUATION;

8. Neutrophils and macrophages can further produce reactive oxygen species upon
entry into the site of inflammation from the blood stream, to try and kill invading
bacteria. This might be beneficial but may lead to further damage and destruction
nearby tissue inadvertently, thus worsening the inflammation.
9. IL-23 production from macrophages can generate TH-17 cells from naïve T-cells.
These cells produce massive amounts of IL-17, leading to recruitment of more
neutrophils that produce more reactive oxygen species(ROS).
 Primarily three inflammatory cytokines may join the systemic circulation and
affect different organs. These are IL-6, TNF-alpha and IL-1.
LOCAL AND SYSTEMIC EFFECTS.
 SYSTEMIC EFFECTS
 LOCAL EFFECTS( GI INVOLVEMENT)

1. Malabsorption(transmural inflammation).– 1. Fever( hypothalamus)

growth retardation in children, weight loss
in adults. 2. Erythema nodosum( skin)
2. Diarrhea( bloody). 3. Arterial and venous thrombi.
3. Strictures– might lead to bowel obstruction.
4. Spondylitis( vertebral column)—
4. Abscesses. lower
5. Fistulas
5. Sacroiliitis( sacroiliac joint)
6. High risks of colorectal cancer.(constant
DNA replication due to damage and repair 6. Primary sclerosing
—proofreading mistake)
cholangitis(hepatobiliary system)
7. Pain felt on lower right abdominal quadrant
or near the navel.
ULCERATIVE COLITIS– PATHOPHYSIOLOGY

 Normally involves GENERALIZED INFLAMMATION of the colon.

 Involves the rectal area and anus, which are normally spared in crohn’s disease.
 No ‘skip lesions’ or ‘skip areas’ are notably present unlike in crohn’s disease.
Inflammation normally doesn’t spare any colonic part but affects all areas.
 Inflammation normally begins at the rectal area, hence pain normally located on
lower left abdominal quadrant.
 Genetic/immune components and environmental factors can predispose one to
ulcerative colitis.
ULCERATIVE COLITIS– PATHOPHYSIOLOGY

 Genetic/ immune components include;

1. hyperactivity of TH2 lymphocytes, producing large amounts of inflammatory
cytokines
2. hyperactivity of cytotoxic T cells causing direct damage to the gut wall
3. plasma cells releasing antibodies and perpetuating the inflammatory cycle.
 Environmental factors (potential triggers) include; antibiotics and certain infections.
ULCERATIVE COLITIS-- PATHOPHYSIOLOGY.

 Macrophages interact with naïve t cells presenting a piece f bacterial antigen. Massive
amounts of cytokines are produced by the macrophage such as IL-1, IL-6, IL-12,IL-4
and TNF-alpha.
 Unlike in CROHN’S disease IL-4 released by macrophages works on naïve t cells
converting them to TH2 cells.
 TH2 cells release IL-5 and IL-13. These cytokines lead to increased distruption of the
intestinal epithelium. This leads to more bacterial translocation.
 IL-12 can work on naïve T cells causing production of T- helper 1 cells which can
produce INF-gamma and TNF-alpha.
ULCERATIVE COLITIS—PATHOPHYSIOLOGY.

 Some naïve t cells, by mechanisms unknown and being acted upon by specific
cytokines might form large amounts of cytotoxic T cells, involved in destruction in
the intestinal epithelium and translocation of more bacteria.
 TNF-alpha, IL-6 and IL-1, just like in CD can stimulate blood vessels to increase
expression of CELL ADHESION MOLECULES(ADHESINS) bringing more
neutrophils, lymphocytes and monocytes into the area
 Also, plasma cells, activated by certain cytokines produce antibodies against the
bacteria but due to molecular mimicry neutrophils are also destroyed as well as tissue
because they present with the same antigens as the bacteria. This worsens the
inflammatory process.
LOCAL AND SYSTEMIC EFFECTS
 GI INVOLVEMENT
1. Diarrhoea– dehydration– watery  SYSTEMIC EFFECTS
diarrhea
1. Fever ( hypothalamus)– increased
2. Fulminant colitis production of PGE2.
3. Toxic megacolon– risk of 2. Spondylitis( vertebral column)
perforation– bowel dilation.
3. Sacroiliitis
4. Affects region of the whole
colon( pancolitis) 4. Primary screlosing cholangitis–
might lead to cholangiocarcinoma.
5. Strictures
6. Colorectal cancer
DRUGS USED FOR IBD

 Drugs used in IBD primarily target four goals;

1. Improve Quality of life by reducing symptoms, by achieving and maintaining
remission, and to prevent complications. This is the primary role of treatment
2. Prevention of further inflammation.
3. Prevention of infection by bacteria
4. Immunosuppressive therapy to calm down the overactive immune system.
 DRUGS USED FOR IBD( CLASSIFICATION)
DRUG CLASS EXAMPLES
ANTI- INFLAMMATORIES-- Aminosalicylates– 5-ASA(5- amino-salicylic
AMINOSALICYLATES AND acid)
GLUCORCORTICOIDS Balasalazide, olsalazine, sulfasalazine.

Glucocorticoids – prednisone, methyl

prednisolone/hydrocortisone
IMMUNO-MODULATORS– Immunosuppressive agents– azathioprine,
IMMUNOSUPPRESSIVE AGENTS AND methotrexate and cyclosporine.
ANTI-TNF THERAPY
Anti-TNF therapy– infliximab, adalimumab.
ANTIBIOTICS Metronidazole, ciprofloxacin, clarithromycin.
MESALAMINE( 5-ASA). SULFASALAZINE, OLSALAZINE,
BALSALAZIDE
 Exact mechanism of action is unknown but is thought to decrease synthesis of
prostaglandin and leukotriene, modulating the inflammatory response derived from
the cyclooxygenase and lipoxygenase pathways. Also, inhibition of synthesis of
prostaglandins and inflammatory leukotrienes, interfering with production of
inflammatory cytokines.
 Sufasalazine is a pro-drug composed of 5-ASA linked to sulfapiridine by an azo
bond. Linkage minimizes absorption of the drug in the upper GIT.
 In the colon bacteria break the azo bond and free sulfapiridine and 5ASA.
 Inflammation in cells normally stimulates NFKB to promote production of
inflammatory cytokines such as TNF-alpha and IL-1. These inflammatory cytokines
create a more inflammatory environment by attracting more and more immune cells
such as neutrophils to the area, worsening inflammation.
SULFASALAZINE

 5ASA acts locally as an anti-inflammatory molecule by inhibiting enzymes such as

COX and LIPOX, as well as NFKB. In this way sulfasalazine reduces inflammation
because of limited production of TNF-alpha and IL-1.
 Sulfapiridine is absorbed metabolized in liver and excreted in urine. Sulfapirdine
responsible for exerting systemic actions( adverse effects). These include nausea,
vomiting, blood dyscrasia, hepatitis and hypersensitivity reactions( sulfur allergies).
Also risk of low sperm count in males.
GLUCOCORTICOIDS.
GLUCOCORTICOIDS(MOA)

 Carriedby the transporter glucocorticoid binding protein which is then coupled to two
heat shock proteins called HSP70 and HSP90, located in the cell cytoplasm.
 This activates the receptor and dissociates the two proteins. Activated receptor binds
to GRE in the nucleus and activates it. It upregulates the gene for LIPOCORTIN and
decreases gene transcription for proteins leading to down regulation of COX2
ENZYME.
 LIPOCORTIN inhibits PLA2 and prevents liberation of arachidonic acid from
membrane phospholipids reducing production of prostaglandins and thromboxane A2.
IMMUNOSUPPRESANTS E.G AZATHIOPRINE

 Is a pro-drug activated by the liver into 6- mecaptopurine then further to

6- thioguanine nucleotides responsible for immunosuppressive therapy.
6TG are false nucleotide bases. This are incorporated into the DNA chain
during the S phase of the B and T cell cycle leading to apoptosis of some
of these cells.
 An additional cytotoxic effect is related to incorporation into RNA.
ANTI- TNF DRUGS

 infliximab directly bind onto the

inflammatory cytokines such as TNF-
alpha inhibiting them and reducing
tissue damage and severity of
inflammation.
 Nazatilumab is a humanized
monoclonal antibody that blocks
integrins on circulating leukocytes.
 THERAPEUTIC EFFECTS OF IBD DRUGS.

 5ASA’s– are the first line therapy of mild to moderate ulcerative colitis. These
drugs prevent relapses once remission has been achieved. They exert an anti-
inflammatory effect. Migration of inflammatory cells into the bowel wall is
prevented and mucosal secretion is reduced.
 Remission refers to the state in which the signs and symptoms of the disease are
significantly reduced or completely absent. It indicates a period of disease
quiescence or low disease activity, allowing individuals with IBD to experience a
better quality of life.
Glucocorticoids provide relief in symptoms, reduce inflammation markedly but
not effective in maintaining remission in either disease.
SIDE EFFECTS OF IBD DRUGS

 Dose related adverse effects of sulfasalazine include headache nausea and fatigue.
 Sulfasalazine has a higher incidence of side effects than other 5ASA drugs, due to the systemic absorption of the
sulfapyridine moiety. Other aminosalicylates that do not contain pyridine are better tolerated.
 Allergic reactions, due to the sulfur component, include ulcerations on lips and genitals, rash, fever, hepatitis, pneumonitis,
hemolytic anemia & bone marrow suppression. Drop in the sperm count, which is reversible on stopping the drug.
 Glucocorticoids can cause fluid retention, insomnia, osteoporosis and hypertension with prolonged use. They are
teratogenic. Also may delay onset of puberty and retard growth in children and early adolescents.
 Side effects of immunosuppressive agents may include, nausea and vomiting, liver toxicity, pancreatitis, bone marrow
suppression and skin reactions. More specific side effects include high risk of development of malignancies and other
types of cancer and high risks of lymphoma.
 Side effects of anti-TNF drugs may include skin reactions, congestive heart failure and drug induced lupus, fluid retention.
CONTRAINDICATIONS OF IBD DRUGS
Group of drug Contraindication

Aminosalicylates Allergy/ hypersensitivity, salicylate allergy,

GI obstruction,renal impairement, hepatic
impairement, individuals with peptic
ulcers.
Glucocoticoids Pregnancy, osteoporosis, uncontrolled
diabetes, glaucoma, systemic infections,
hypersensitivity.
Anti- TNF drugs Congestive cardiac failure—RAAS
dysregulation, hypersensitivity, risk of
cancer.
Immunosuppressive agents Pregnancy, breast feeding, live vaccines.
IRRITABLE BOWEL SYNDROME (IBS)

 Irritable bowel syndrome is associated with recurrent episodes of abdominal

discomfort( pain, bloating, distension, or cramps) plus diarrhea or constipation or
both. It does not cause ulcers, bowel damage but mostly discomfort.
 Often associated with chronic abdominal pain and bowel habits without structural or
inflammatory abnormalities. Its exact cause and pathophysiology is not really clearly
understood but certain factors may contribute to its pathophysiology;
 Altered gut microbiota, low grade intestinal inflammation, brain- gut axis– stress, diet
and food sensitivities such as dietary foods are some of the predisposing factors to
IBS.
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