inflammatory bowel diseases 3/22

clinical features of ulcerative colitis

confined to the large intestine.

corticosteroids

cortisone is the first drug proven efficacious in pt with active ulcerative colitis. oral predinsone, prednisolone, budesonide, methylprednisolone, hydrocortisone. highly effective drug for ulcerative and crohn's disease.

smoking

crohn's : positively associated ulcerative colitis: negatively associated.

tacrolimus

similar action to cyclosporin

IBD Pharmacology

-symptomatic resolution of diarrhea, rectal bleeding and abdominal pain. -anti inflammtory drugs(aminosalicylates) -immunosuppressants -biologics

biologics

-umabs-

IBD environmental factors

-unknown but maybe due to mycobacterium paratuberculosis. however most experts do not regard this agent as a biologically plausible factor in the causation of inflammatory bowel diseases. -role of measles infection or vaccination: the available evidence does not support as association

alosetron

5ht3 antagonist. it treats *diarrhea predominant IBS(only). It got withdrawn due to severe constipation and ischemic colitis.

tegaserod

5ht4 agonist. it treats *constipation predominant IBS. restricted use in women

symptoms of IBD

Abdominal pain or discomfort that occurs with diarrhea. vomiting and rectal bleeding. bloating, mucus in the stools, sense that you have not completely emptied your bowels. reduced appetite and unintended weight loss.

extra intestinal manifestations of IBD

BOTH ulcerative colitis and crohn's can be complicated by extraintestinal manifestations. treatment of underlying inflammatory bowel disease can sometimes result in resolution of the extraintestinal problems (not always). the complications are obstruction, arthritis, erythema nodosum, episcleritis, hepatobiliary disease

IBD

Chronic inflammation of the intestine that results in marked dysfunction of digestive tract. the cause is not entirely known. both sexes are equally affected.

lubiprostone

Cl channel activator. it treats *constipation predominant IBS

NOD2/CARD15(caspase recruiting domain)

CARD15 gene encodes a protein NOD2 that acts as an intercellular pattern recognition receptor. CARD domains are important for activation of the proinflammatory transcription factor NF-KB

history of IBD

IBD can develop any age. many patients experience a relapsing remitting course of disease.

firs drug to treat IBD

Locally active agents. constipation for IBS , diarrhea for IBD or IBS

crohn's disease

Mutant NOD2 will inactivate the break NF-kB protein and therefore will not be able to stop the inflammation. -the immune system become biased toward the response dominated by a particular pattern of cytokine production that is termed *TH1 polarization.* **there is excessive production of interferon gamma, tumor necrosis factor alpha, and interleukin 12.(proinflammatory cytokines)

common symptoms of IBS and IBD

Pain, discomfort, urgency and bloating, alteration of bowel habits

IBS symptoms

abdominal discomfort and pain. bloating, mucous in stools, diarrhea, constipation, or alternating diarrhea and constipation. depression, anxiety or stress. it can subdivided into diarrhea dominant, constipation dominant, alternating d and C.

Methotrexate

analogue of folic acid. just like AZA and 6MP, it was developed as a treatment for leukemia. it was later observed to have significant immunomodulating effects that have been useful in several chronic inflammatory diseases, such IBD

aminosalicylates

anti-inflammatory; cornerstone of inflammatory bowel disease therapy. prototype:sulfasalazine. treat arthritis and inflammatory bowel disease

genome wide association study

approach that involves rapidly scanning markers across complete sets of DNA of man people to find genetic variations associated with a particular disease. the most important genetic loci is IBD1 locus on chromosome 16. *crohn's disease gene is NOD2= CARD15 (not ulcerative colitis)

immunosuppresants

azathioprine(prodrug) 6 mercaptopurine(active form) AZA->6MP-> TIMP

IBD

crohn's and ulcerative colitis. inflammation or ulceration, "organic" changes in the small and/or large intestines, which are not associated with IBS. intestinal inflammation. the movement of intestinal muscle is uncoordinated. instead of contracting and relaxing in waves, they contract irregularly and tend to spasm.

2 most important /prevalent types of inflammatory bowel disease

crohn's disease and ulcerative colitis.

clinical features of crohn's disease

crohn's disease: inflammation involving ALL LAYERS of the bowel wall in any part of the GI tract. it include small intestine, colon, and stomach. the distal colon is NOT involved tho.

crohn's disease symptoms

diarrhea, stomach pain, loss of appetite, fever, fatigue, rectal bleeding, parianal lesions, stunted growth in children, upper gi symptoms, extra intestinal manifestations. skin rash, juandice, etc

psyllium

fiber

IBS

functional disease with diagnosis based on a cluster of symptoms in the ABSENSE of structural abnormalities.(It is based mostly on symptoms) it is known as spastic colon*, spastic colitis, mucous colitis, nervous stomach and nervous diarrhea. it is a number 1 digestive disease in USA.

Linaclotide

guanylate cyclase C agonist. it treats constipation predominant IBS and chronic idiopathic constipation

budesonide(entocort)

important corticosteroid in managing crohn's disease. due to high 1st pass metabolism cyp450 3a, only 10-20% of orally admin dose of budesonide reaches the systemic circulation. CR capsules deliver the drug to ileum and colon. t1/2 is 4 hrs

NBD nucleotide binding domain

important for oligomerization of the protein

histopathology of ulcerative colitis

inflammation is more superficial, no fat wrapping, pseudopolyps*

histopathology of crohn's

inflammatory and the formation of a fissure. transmural spread(entire layers of the segment of the intestine), cobble stoning, fat wrapping, thickened wall

IBD

inflammatory bowel disease

IBD-genetics

inflammatory bowel diseases run in families. the relative risk IBD is increased in 1st degree relatives of an affected patient (10x). concordance for disease in monozygotic twins(50%) is higher than fraternal twins.

Cyclosporine

inhibits the cytoplasmic phosphatase calcineurin, which is essential for the T cell receptor triggered activation of the transcription factor nuclear factor of activated T cells.

IBS:

irritable bowel syndrome

CARD15

it is under regulation by inflammatory cytokines(TNF a AND ifn gamma). thus it's possible that functional defects in CARD15 prevent innate immunity from balancing resistance to microbes in the gut of CD patients, leading to uncontrolled inflammation and mucosal damage.

antidiarrheal drugs

loperamide, ; reduce bowel movement frequency and improve stool consistency in diarrhea predominant IBD or IBS.

gut microbiome

low risk patient: higher biodiversity with more protective bacteria high risk patient: lower biodiversity with more opportunistic pathogens.

antispasmodic agents

non specific antagonists of muscarinic receptors. used on as needed bases or before meals to prevent pain and fecal urgency

5 asa

poorly absorbed->induces remission in ulcerative colitis. -> inhibit COX, Cytokines, ilq, tnfa.

ulcerative colitis

predominant ctokines include il4, and il5, which are th2 polarized cytokines**.however, it is not a pure th2 polarized disease because it also have interferon gamma and tnf alpha

salfasalazine

prodrug. metabolized by gut bacteria to 5 ASA**(5 aminosalicylate), which is responsible for anti inflammtory effect in large intestine.

sulfapyidine

rapidly absorbed-> acetylated in liver->excreted in urine->no therapeutic action

NOD2

receptor for muramyl dipeptide, a component of the outer wall of gram postivek bacteria.

LRR** c terminal leucine rich repeat region

recognition site for bacterial cell wall products****

Spasmolytic drugs(anticholinergics)

reduce gut spasms and relax smooth muscle.

Bulking agents

relieve constipation in IBS. BUT it can exacerbate ab pain.

gut function hormone

serotonin plays a major role in modulating intestinal movementt and perception of pain.

polymorphism of card 15 is associated with ONLY crohn's disease (t/f)

true.(it is not associated with ulcerative colitis)