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CBL PHC561 GROUP B2 A 32-year-old man presents for the evaluation of…
CBL PHC561 GROUP B2
A 32-year-old man presents for the evaluation of abdominal pain and diarrhea. He had a progressively worsening cramping pain for approximately three weeks. He also had watery diarrhea and from time to time has noted blood in his stool. He has lost approximately 2.3 kg. He has tried over-the-counter antidiarrheal medications without relief. He is not on any regular medication and has no significant medical history. Upon examination, he has a distended abdomen and hyperactive bowel sounds. It is diffusely tender with no palpable masses. Rectal examination is excruciating and reveals heme-positive watery stool. Blood count shows iron deficiency anaemia and an erythrocyte sedimentation rate that is markedly elevated. A flexible sigmoidoscopy reveals changes consistent with ulcerative colitis. He was prescribed corticosteroids with long-term sulfasalazine treatment.
Explain the aetiology of inflammatory bowel disease.
Genetic factors
It is more common in people who have family members with the disease. It occurs from father-son, father-daughter, mother-son, mother-daughter, and sibling-sibling.
The frequency of IBD in first-degree family members may be as high as 40%.
Environmental factors
Smoking
Smoking is an independent risk factor for recurrence in CD as it increases the disease severity and influences disease activity after surgery. However, Ulcerative Colitis is less common in smokers.
Diet
nutritional deficiencies in IBD particularly zinc in CD associate to immunologic dysfunction
Zinc important as it play important role in tissue regeneration, wound repair and immune response.
Stress
stress induced alterations in gastrointestinal inflammation due to changes in hypothalamic -pituitary adrenal (HPA) axis & alterations in bacterial-mucosal interactions
pharmacological factors
Drug Induced IBD
Oral contraceptive
The pro-inflammatory effects of estrogen promote B cells, and anti-apoptotic effect on immune cells hence increase risk of IBD
Antibiotics
Antibiotics alter the gut microbiota which then contribute to IBD
GIT Microflora
The disruption in the git microflora balance due to alteration of fermentation products such as carbohydrates and vitamins. Imbalance of Th17 propagation of disease.
T helper cell 17 (Th17) secrete proinflammatory mediators that cause progression of disease cause inflammation
Sulfasalazine cannot be used by those who are allergic to which class of drugs? Discuss.
Symptoms of Allergy
skin rash or hives, itchy eyes or skin, breathing problems and face swelling.
Serious skin effects :
Sulfonamide hypersensitivity syndrome : rash,fever & organs problem ( a week/two weeks after administration).
Drug eruption : red,swollen round patches that form after 30 minutes to 8 hours after taking the drug.
Stevens-Johnson syndrome (life threatening disease that cause skin to blister and peel off.)
Drug- drug Interaction
Sulfasalazine + warfarin = Combination increases the blood thinning effects of warfarin thus, results in abnormal bleeding.
Sulfasalazine + Methenamine = Methanamine can cause acidic urine. Sulfasalazine is crystalized in acidic urine. Thus, the combination leads to the crystallization of Sulfasalazine.
Sulfasalazine + divalproex, valproic acid, methotrexate, pyrimethamine, triamterene, or trimetrexate = Combination reduces concentration of folic acid resulting in anemia.
Sulfasalazine + cyclosporine = Combination increases the metabolism of cyclosporine by liver thus, reduces the effectiveness of cyclosporine.
Sulfonamide Allergy
Sulfasalazine is one of the drug classes of sulfonamides which are poorly tolerated in people with hypersensitivity towards sulfonamides drugs.
Example of other drugs that may cause sulfonamides allergy are : Sulfamethoxazole / trimethoprim,Sulfamethoxazole / trimethoprim,Sulfacetamide and Sulfadiazine silver (Silvadene).
Alternative drugs for sulfonamide allergy
Mesalamine
Balsalazide disodium
Discuss the non-pharmacological therapies useful for this patient.
• Drink plenty of liquids
Patient with ulcer colitis experienced diarrhea. Drinking water to keep hydrate. Water is most preferable while alcohol and beverages that contain caffeine stimulate intestines cause diarrhea worsen.
• Exercise
Stress do not cause the ulcer colitis but it can cause the symptoms worse. Exercise reduce stress and normalize bowel function.
• Diet -Consumption of diets rich in vegetables, fruit, and soluble fiber may be beneficial in IBD.
• High-fiber foods- Increase the number of bowel movements, the amount of gas, and abdominal cramping. Example: dried beans, whole grains, berries and peas,
• Dairy products: in some people dairy products can trigger symptoms of ulcer colitis. The symptoms can be minimized by eliminating dairy products consumption. Patient with lactose intolerant, the body cannot digest the milk sugar known as lactose should avoid taking dairy product.
cognitive behavioral therapy-Mental health issues with IBD. It is a problem-solving approach to reduce stress and risk of depression in patient with IBD
Discuss other general health maintenance issues and therapies should be considered for patients with UC.
Issues
Osteoporosis
Osteoporosis has increasingly been recognized as a significant medical problem in patients with IBD. The patients have markedly reduced bone mineral densities (BMD). As BMD decreases, the risk of associated fractures increases.
Some patients with IBD have a normal BMD but still incur fragile and fractures
Glucocorticoid used is the most common variable associated with decrease BMD in IBD patient. The greatest bone loss occurs in the first six months of the initial course of corticosteroids. Therefore, the greatest interventions in patients with IBD is to minimize the use of glucocorticoids.
Cancer / dysplasia surveillance
Cervical dysplasia was once one of the most common causes of cancer death for women
Women with UC, often requiring immunosuppressive therapy have been shown to have a higher prevalence of abnormal pap smear
Annual screening for cervical dysplasia should be assessed every two to three years. For patients with immunosuppressant should perform the screening twice in the first year.
Patient with UC are six times more likely to get some form of colorectal cancer. The main reason for this is inflammation
Chronic inflammation raises the chances of colorectal cancer in three ways
Patients with UC may not know they have colorectal cancer because signs of the cancer can be similar to their UC symptoms
Vaccination
Patients with UC usually are given with immunosuppressive therapy and anti-TNF medication. These patients
should not be given live virus vaccine, as they are often contraindicated in this patient population given the risk of disseminated infection
Patients on immunosuppressive therapy have a diminished immune response to vaccinations. The level of immune response typically correlates with the degree of immunosuppression. For instance, a patient on biologic agents may have a greater diminished response to a vaccination compared with a patient taking a thiopurine
The best time to be vaccinated is during the early diagnosed and not on any form of immunosuppression
Therapies
Immunomodulator-
such as azathioprine, mercaptopurine and methotrexate
Second line options for patients with UC. Thiopurines require careful management because of their limited therapeutic index
A measurement of thiopurine methyltransferase (TPMT) phenotype is recommended for each patient prior to initiating therapy. This is helpful to identify both patients with low TPMT (<4), who may have significant bone marrow suppression in the first eight weeks of therapy, and those with high TPMT (>25), who are less likely to respond to thiopurine therapy.
Biologics-
such as infliximab, adalimumab, vedolizumab, golimumab, ustekinumab
Infliximab is currently the only approved biologic for ulcerative colitis
Aminosalicylates (5-ASA)-
such as sulfasalazine and mesalazine
Describe how ulcerative colitis differs from Crohn's disease in terms of histopathophysiology.
Pathophysiology
Ulcerative colitis
Abnormal or inappropriate immune response towards stimulus within the colon
due to the defects in genes integral to the roles to preserve the colonic epithelial barrier
the disruption of the colon epithelial barrier resulting from the depletion and depletion of tight junction
Allow dendritic cells to capture normal flora as antigen
Activating the host immune system via T cells
Crohn's disease
Inflammation and abscesses
tiny focal aphthoid ulcers
deep, longitudinal transverse ulcers with edema mucosa
results in the appearance of the cobblestone in the bowel
Transmural inflammation
edema
bowel wall and mesentery thickening
image comparing the pathophysiology of Crohn's disease and Ulcerative colitis
Histopathology
Ulcerative Colitis
Lack of fissuring ulcers
Dysplasia (low or high grade) may be present, especially in patients with longstanding disease
Lack of granulomas
Neutrophilic inflammation with cryptitis, crypt abscess or ulceration
Inflammatory expansion of the lamina propria with basal lymphoplasmacytosis
Crypt architectural distortion including crypt atrophy, irregular spacing and size of crypts, crypt shortening and crypt branching
Activity is usually graded
Mild: activity involving < 50% of the mucosa
Moderate: activity involving > 50% of the mucosa; crypt abscesses usually seen at this grade
Inactive: absence of neutrophils
Severe: presence of surface ulceration or erosion
Crohn's disease
Initially focal neutrophils in epithelium and overlying lymphoid aggregates and plasmacytosis, then cryptitis, crypt abscesses but usually no neutrophils in lamina propri
Mucosa and submucosa are also edematous
Goblet cells present
Often reduplication of muscularis mucosa in diseased segments, fibrosis and thickened bowel wall
Transmural inflammation with lymphoid aggregates throughout bowel wall; sarcoid-like, noncaseating, poorly formed granulomas in all tissue layers
Superficial or deep ulceration with adjacent granulation tissue extending into deep submucosa or below
Pathogenesis
Ulcerative Colitis
Complex frameworks comprise of the environmental and host proposed for the pathogenesis of the Ulcerative Colitis due to the unknown specific cause of the disease
Environmental Factors
Smoking cesaation is believed to lead the onset of the UC
Pollution
Westernisation
Changes in eating behavior or diet
use of antibiotic
hygiene
Host factors
Genetics
UC-specific genes implicate epithelial dysfunction
67% susceptible loci Associated with Crohn's Disease
Outwith the HLA region, the ADCY7 gene has the strongest association with UC
Older age
For the patient suffering from appendicitis, it will protect the colon from the development of ulcerative colitis
Microbiota
depletion of protective (Ruminococcaceae and Lachnospiraceae) and enrichment of inflammatory (Enterobacteriaceae
and Fusobacteriaceae) microbes
Epithelial barrier
innate “at risk” barrier-specific genetic phenotype where exposure to additional injurious stimuli, such as non-steroidal
anti-inflammatories and dietary components such as emulsifiers, may be the second trigger that precipitates colitis
Crohn's Disease
The altered microbiota of the intestine is presented to the dendritic cell which is the antigen presenting cell (presents this antigen to the T cell)
The T cell further differentiates into TH-1 cell, TH-2 cell and TH-17 cell
TH-1 secretes IFN-gamma which leads to macrophages activation, it secretes tumor necrosis factor which will injure further the epithelium
The epithelium is being injured which will lead to an increase of the bacterial influx into the lamina propria, and material influx will further increase the antigen presentation, the T cell activation, and the cytokine production
This is a self amplifying cycle which will lead to destruction of the epithelium and resultant ulceration of the lining epithelium
TH-17 cell secretes IL-17 which recruits mainly neutrophils which will lead to many enzymes production and free radicals (injure the epithelium)
Pathogenesis mainly involves:
Epithelial defects
This barrier dysfunction cosegregates with NOD2 polymorphism.
Tight junction defects lead to defective physical barriers toward bacteria, enabling them to penetrate the lamina propria, which then induce the inflammatory response
Genetic
Disease-associated NOD2 variants are less effective at recognizing and combating luminal microbes, which cause the microbes to be able to enter lamina propria and trigger inflammatory reactions.
Disease-related ATG16L1 and IRGM variants cause defective autophagy towards intracellular bacteria, which lead to prolonged inflammation.
Microbiota
Alteration of the composition of gut microbiota can cause distinct immune response, suggesting dysbiosis can modulate the immune response in the gut.
Mucosal immune response
Defective immune regulation - uncontrolled inflammation
Derangement of mucosal immune activation
Discuss the mechanism of action of the drugs used in IBD and its associated adverse effects.
Purine analog (Azathioprine)
MOA: AZA converts to its active metabolites , 6-mercaptopurine and 6-thioguanine. It then inhibits purine synthesis. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of immune cells, thus causing immunosuppression.
ADVERSE EFFECT: dose related toxicity - nausea, vomiting, bone marrow depression, hepatic toxicity
Cyclosporine
MOA: Binds to cyclophilins with further inhibition of the calcium-calcineurin pathway and the resulting blockage of the nuclear activated T cell factor (NFAT) translocation to the nucleus, thus avoiding cellular activation. Consequently, there is reduction in the transcription of genes related to cytokine production such as IL-2, IL-4, and IFN-γ
ADVERSE EFFECT: hypertension, headache, Nephrotoxicity
Corticosteroids
MOA: works by binding to the glucocorticoid receptor mediates changes in gene expression. After activation, glucocorticosteroid translocate to the nucleus, inhibiting the transcription factor leading to suppression of pro-inflammatory mediators.
ADVERSE EFFECT: salt retention, weight gain, behavioural changes, large doses may cause peptic ulcer, fat redistribution and osteoporosis.
:
Prednisone, Prednisolone, Budesonide
Aminosalicylates (eg. sulfasalaizne, balsalazide, olsalazine, besalamine)
MOA: works by inhibiting cyclooxygenase and lipoxygenase enzymes in arachidonic acid metabolism, thereby preventing formation of proinflammatory prostaglandins and leukotrienes. Prostaglandins mainly function in the control of pain and inflammation. By blocking the synthesis of prostaglandins ,it will minimize inflammation in IBD patients.
ADVERSE EFFECT: headache, nausea, abdominal pain and cramping, loss of appetite, vomiting, rash, or fever
Anti tumor necrosis factor therapy
(Eg. Infliximab, adalimumab, golimumab)
MOA: Binds to TNF alpha (an inflammatory cytokine), suppress the interaction of TNF alpha with its receptor on the surface of the gut, thus reducing the inflammation
ADVERSE EFFECT: infection, a variety of psoriatic skin rashes, sinituitis, bronchitis, increase risk of lymphoma
Methotrexate
(at low dose -25 mg or less once a week, intramuscularly)
MOA: It inhibits dihydrofolate reductase (an enzyme for production of thymidine and purine), thus, no DNA and RNA synthesis in cell cycle occurs, leads to the suppression dividing cell such as immune cell, so produce immunosuppressive effect and reduces inflammation
ADVERSE EFFECT: bone marrow depression, nausea, alopecia ,mucositis
List the symptoms of UC.
Abdominal symptoms :
Abdominal/stomach pain
Stomach cramping
Stomach bloating
feeling gassy/passing gas
Stool symptoms :
diarrhea/loose stools,
The patient experinced watery diarrhea because, when the intestine is inflamed, it absorbs much less sodium and water. It also may leak more fluids. Hence, result in loose, watery stool.
Bloody in stools
In the trigger, it mention that the blood is mixed with the patient's stool and the rectal examination reveals heme-positive watery stool
Bright red blood in the stool typically indicates that there is bleeding in the rectum or colon. Rectal bleeding can also be caused by hemorrhoids. Hemorrhoids are swollen veins in the lower rectum or around the anus. Since the trigger mentions that “He has had watery diarrhoea and, from time to time”, so the episodes of diarrhea can increase irritation and swelling of hemorrhoids, which can then cause a burning, painful sensation.
Sudden/need for bowel movement
Incomplete evacuation
Frequent bowel movement
Examination of the patient abdomen reveals he had hyperactive bowel sounds and this indicates that increase in intestinal activity
Mucus in stool
Incontinence/leaking
Bowel movement tenesmus
Other symptoms :
Vomiting
Dizziness/lightheaded
flu symptoms
Give the currently available drug therapies for UC
Mild to moderate UC
Aminosalicylates
E.g: Sulfalazine, Mesalazine, Olsalazine
First-line treatment
as oral or enema or suppository (depends on the location affected)
Corticosteroids
Orally
E.g: Prednisolone, Budesonide (od)
If patient not responding to first-line treatment
Thiopurines
E.g: Azathioprine, Mercaptopurine
For patient who not respond to oral corticosteroid
TNF- inhibitor
E.g: Infliximab, Adalimumab, Golimumab
Severe UC
Corticosteroids
E.g: Methylprednisolone or Hydrocortisone
Via intravenous (IV)
Ciclosporin
Via intravenous (IV)
If no improvement after 3-5 days of IV corticosteroids
TNF- inhibitor
E.g: Infliximab
Combine with Azathioprine (synergistic effect)
Surgical intervention
Describe the short- and long-term pharmacotherapeutic goals for this patient.
Short term goal - induction of remission (to terminate the acute, symptomatic attack)
Sulfasalazine
Sulfasalazine is too big to be absorbed in the small intestine. Bacteria in the colon cleaves the azo bond and liberates active compound 5-aminosalicylic acid.
A prodrug which consists of the 5-aminosalicylic acid (mesalamine or mesalazine) and sulfapyridine linked by an azo bond.
5-aminosalicylates derivatives that help to reduce inflammation thus allows damaged tissue to heal & can be used as a short-term management for flare-ups
Oral dosage form for adults (enteric coated tablets) - 500 to 1000mg every 6 to 8 hours everyday. Not more than 4000mg per day
The sulfa moeity can causes numerous adverse effects: decreased appetite, headache, nausea, vomiting, stomach upset, hypersensitivity and interfere with folate absorption
Serious adverse reactions include hemolytic anemia and hepatitis (rarely). It also could decreases sperm count in male when taking this medication.
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Usually prescribed with folic acid to cover reduced folate absorption
Can be given alone or combined with corticosteroids
Corticosteroid
Corticosteroids suppress your immune system, which can help control conditions in which your immune system mistakenly attacks its own tissues
Systemic corticosteroids for induction of remission
Budesonide may be effective in maintaining remission for 8 weeks but has not yet proved effective for long-term maintenance.
Hydrocortisone and prednisolone are effective in left-sided UC. Provide quick relief for patients with bleeding.
Hydrocortisone, 100 mg administered intravenously every eight hours.
Prednisone, 40 to 60 mg per day.
Induction therapy before ‘withdrawing’ to maintenance treatment
Long term goal - for maintenance therapy
Sulfasalazine
use in maintenance therapy to remain remission. if stop, relapse of disease could happen
the patient need to take this medication for the full time of treatment and do not miss any doses even he feel better after a few days
This medication may cause skin to be more sensitive to sunlight thus the patient needs to be advised to stay out of direct sunlight, wear protective clothing & sunglasses and apply a sun block product
Always inform the doctor if any unusual side effects or severe adverse reaction so that the doctor can change the dose or prescribe other drugs
Corticosteroid not appropriate for maintenance therapy
Side effects
Insomnia
Hypertension
Stomach upset
Hyperglyemia
Hyperactivity
Alternative treatments
Thiopurines ( Azathioprine or 6- Mercaptopurine)
Medicines that reduce the activity of the immune system.
Azathioprine and its metabolite 6-mercaptopurine inhibit T-cell function and may induce T-cell apoptosis
Effective for long-term and may diminish corticosteroid requirements and maintain remission for years.
Give a list of drugs that is used as antidiarrheal agents and describe their mechanisms of action and adverse effect.
Based on the trigger, the patients experienced diarrhea and one of his symptoms for IDB . Thus antidiarrheal agents suggested are as listed:
Diphenoxylate/ atrpopine
Antimotility agent: slowing down movement of the bowels.
Opiate receptor agonist
MoA
It bind to the opioid receptor and stimulates mu receptors in the gastrointestinal tract, causing peristalsis to slow and sphincters to tighten. Diphenoxylate has a direct effect on the bowel's circular smooth muscle, which could lead to gastrointestinal segmentation and a longer transit time
Antimuscarinic agent
Adverse effects: Nausea, vomiting, loss of appetite, headache, restlessness, tiredness, confusion, changes in mood,
stomach discomfort
Bismuth subsalicylate
It balances the movement of fluids in intestines
Antidiarrheal effects
MoA of BSS is rather complex.
Anti-inflammatory activity inhibits cyclooxygenase enzyme and reduce formation of prostaglandin
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The inhibition of intestinal secretions.
The stimulation of reabsorption of fluids, sodium, and chloride. This helps decrease fluid loss.
Anti-inflammatory agent
Decrease inflammation and controlled the growth of bacteria and virus in gut that cause diarrhea
Adverse effects: symptoms of dehydration, such as unusual decreased urination, unusual dry mouth/thirst, fast heartbeat, or dizziness/lightheadedness
Loperamide
Antimotility agent: slowing down gut movement bypassing the content/ food consumed at a lower speed. Increase the time of food in the gut thus allow reabsorption of water
MoA
Loperamide produce direct effect on the muscles of intestinal wall thus inhibiting peristaltic activity.
It is a non-selective calcium channel blocker and bind to opioid mu- receptor
Moa: Loperamide binds to the opiate receptor in the gut wall. Consequently, it inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis, and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter, thereby reducing incontinence and urgency.
Adverse effects: severe hepatic impairment, drowsiness, urinary retention
Antibacterial agents / Antibiotic
Can be used only to treat diarrhea once confirmed the bacterial causes
Examples, antibiotics for C. difficile infection
Cephalosporins
Clindamycin
Fluoroquinolones
Penicillins
Oral Rehydration solution
1st line treatment of diarrhea.
Rehydrating agent
MoA: SGLT-1 transporter proteins are found in the jejunum. When ORS with a 2:1 ratio of Na+ to glucose is consumed, SGLT-1 actively transports both across the epithelial wall. As a result of the osmotic imbalance, water is instantly drawn into the vascular system. Fluid and electrolytes are restored rapidly, avoiding the majority of the GI tract.
Adverse effects: severe stomach/abdominal pain, blood in the stool/vomit, a fever, or signs of dehydration (such as dizziness, decreased urination, severe thirst, very dry mouth, seizures)
Antisecretory medicines
New treatments develop for rehydration treatment
Can be used for children who are older than 3 months of age and adults
Examples
Synthetic opiates: Morphine, Codeine
Somatostatin and Its Analogues, Octreotide
Discuss the mechanism of action of sulfasalazine.
The exact mechanism is currently not clear and still under investigations.
Sulfasalazine is a prodrug that linking 5-aminosalicyclic acid (mesalamine) and sulfapyridine (SP) through an azo bond (N=N).
In the colon, bacteria will cleave the azo bond via azoreductase enzyme and produce SP and the active compound 5-aminosalicylic acid (5-ASA). --> high 5-ASA in terminal ileum or colon
5-ASA :
It is believed that 5-ASA regulates inflammatory mediators in both cyclooxygenase and lipoxygenase pathways.
Ability to disrupt the production of inflammatory cytokines
It inhibits nuclear factor-κB (NF-κB) --> important transcription factor for proinflammatory cytokines
inhibits the functions of natural killer cells, mucosal lymphocytes, and macrophages
poorly absorbed
The MOA may be due to the anti-inflammatory and/or immunomodulatory properties shown from animal and invitro models
For UC, the main therapeutic activity may reside in the 5-ASA moiety.
Sulfapyridine
Gives no therapeutic action in UC
Rapidly absorbed in colon
The indications for Sulfasalazine include Rheumatoid Arthritis and UC.
considered curative in cases of UC
The maintenance treatments is a long-term treatment
Due to
avoid
Inflammation damages the genetic material in colon cells. This can create mutations in those cells that could be cancer.
It raises the levels of certain molecules that can help cancerous tumors grow
It makes viral and bacterial infections more likely. Those can interfere with your body’s immune system and encourage cancer cells to grow and multiply.
