Exam 4 Flashcards
What is the epidemiology and pathophysiology of inflammatory bowel disease (IBD)? (ulcerative colitis and Crohn’s disease)
IBD: Conditions where due to an immune response, the mucosa in the GI tract is inflamed (chronic or recurring). It’s a combo of immunologic, infectious, genetic, and environmental factors. These diseases are more common in Western countries.
Ulcerative Colitis (UC): Confined to the rectum and colon. It may be irregular & more superficial than CD. UC is slightly more common than CD. It effects slightly more men than women & peak incidence is in the third decade.
- Involves Th2 cytokine activity, like IL-13 and IL-5
- Smoking may be protective
- Toxic megacolon is a severe and potentially fatal complication; Involves vasculitits and thrombosis & potential perforation.
- UC -> colorectal cancer risk increased 5x; colonoscopy recommended
Crohn’s Disease (CD): transmural inflammation of the GI tract that can affect any part of the GI tract from the mouth to the anus (cobblestone appearance). It effects slightly more women than men & peak incidence is in the second decade.
- Involves Th1 cytokine activity, like IFNγ and IL-12
- Smoking associated with increased frequency and severity of CD
- fistulas are common. Carcinoma risk is increased, but not to the extent of UC.
- Nutritional deficiencies are common
What are the drug related causes of IBD?
NSAIDs: may trigger disease occurrence or lead to flares
- avoid NSAIDs in patients with IBD
Antibiotics: potential association, but the causal relationship is unclear
What is the clinical presentation and diagnosis of UC and CD?
UC - highly variable. intermittent periods of illness and remission
- abdominal cramping, frequent BMs +/- blood +/- mucous, weight loss, paradoxical constipation, fever/tachycardia
- extraintestinal: blurred vision/ocular signs, arthritis, dermatologic manifestations
- fecal calprotectin (FC) test correlates w/ degree of inflammation
- Diagnosis: made on clinical suspicion and confirmed by endoscopy and biopsy
CD - highly variable. periods of remission and exacerbation
- diarrhea, abdominal pain, hematochezia (rectal bleeding), fistula, malaise, similar to above
- Diagnosis: clinical evaluation + endoscopic (upper and lower), laboratory, and radiologic testing
What are the extra-intestinal manifestations of IBD?
Hepatobiliary - common
- hepatic: fatty liver diseaes, autoimmune hepatitis, cirrhosis
- biliary: primary sclerosing cholangitis (PSC), cholangiocarcinoma, cholelithiasis
Ocular -
- iritis, uveitis, conjuncitivitis, episcleritis
bone and joint -
- arthritis: asymmetrical, migratory, parallels disease activity
- increased risk for metabolic bone disease and osteoporosis due to nutrient deficiencies (calcium & vit D), inflammation, hypogonadism, use of corticosteroids
hematologic -
- anemia due to iron deficiency, blood loss, chronic disease
coagulation -
- increased risk of VTE (risk is increased during flares)
dermatologic and mucocutaneous -
- skin & mucosal lesions
What is the non-pharm therapy for IBD?
Nutritional Support - no specific diet has shown benefit, but need to address nutritional deficiencies
- EN if needed, PN if absolutely necessary
- supplement vitamin/mineral deficiencies (calcium/vitamin D, folate, etc.)
- potentially probiotic therapy
Surgery - resect areas of inflammation
- mainly in UC (colectomy), since CD can be throughout the entire GI tract
What are the treatment goals for IBD?
highly individualized
- resolve acute inflammation/treatment of disease flare
- resolve and/or prevent complications
- maintain remission (steroid free)
- alleviate extraintestinal manifestations
- avoid need for surgical palliation/cure (but do if needed)
- maintain QOL
Sulfasalazine vs. Mesalamine/mesalamine derivatives - MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy for IBD
Sulfasalazine - made up of sulfapyridine (inactive) and 5-ASA (active - AKA mesalamine).
- sulfapyridine is associated with ADRs, so this isn’t preferred
- MOA of 5-ASA is local and includes anti-inflammatory effects and scavenges free radials
- ADRs: N/V, headaches, anorexia, rash, anemia, hepatotoxicity, thrombocytopenia, hypersensitivity reactions
- monitor: CBC & LFTs at baseline & more frequently during the beginning of therapy, monitor BUN/SCr periodically
- drug interactions: antiplatelet/anticoagulants/NSAIDs (due to bleeding risk)
Mesalamine/derivatives - when administered alone, it’s rapidly/completely absorbed in the small intestine, but not the colon. This is why the formulation is really important (generally topical is more effective than oral).
- Topical (enemas) - use for left sided disease
- Suppository - use for proctitis
- oral - use delayed/controlled release formulations depending on the location of disease; these may be pH dependent, so be mindful of PPIs & stuff like that
- ADRs: MUCH better tolerated than sulfasalazine; N/V, headache, less anemia, hepatitis, UC exacerbation
- drug interactions: antiplatelet/anticoagulants/NSAIDs (due to bleeding risk), agents affecting pH (due to different dosage forms)
What are the MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy for the local and systemic corticosteroids?
MOA - anti-inflammatory
- ROA: PO, parenteral, or rectal/topical
- Used for induction of remission, but NOT maintenance
- ADRs: short term - hyperglycemia, gastritis, mood changes, elevated BP; long term - aseptic necrosis, cataracts, obesity, growth failure, HPA suppression, osteoporosis
- monitoring: BP & blood glucose at baseline & q3mo; consider DEXA in pts > 60 due to osteoporosis risk
*give with calcium and vitamin D
Options:
- Rectal hydrocortisone: systemic absorption possible
- Budesonide: minimal systemic exposure due to first pass metabolism; drug interactions: CYP3A inhibitors may increase systemic exposure
- Systemic corticosteroids (PO prednisone, IV methylpred): taper down when d/c due to adrenal suppression; NOT maintenance
What are the differences in MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy for the immunomodulators (azathioprine, mercaptopurine, cyclosporine, and methotrexate)?
AZA & MP/6-MP: can be effective in long term treatment of UC and CD (good for pts who fail 5-ASA and/or refractory to steroids); Can maintain remission, but not as good for induction.
*AZA is prodrug of 6-MP
- ADRs: N/V/D, anorexia, stomatitis, bone marrow suppression, hepatotoxicity, fever, rash, arthralgia, pancreatitis
- Monitoring: TPMT (metabolizes 6-MP), CBCs & LFTs at baseline & periodically
Cyclosporine: effective for inducing remission in patients with refractory UC, not an option for long-term use
- ROA: IV infusion
- ADRs: nephrotoxicity, neurotoxicity, HTN/HLD/hyperglycemia, GI upset, gingival hyperplasia, hirsutism
- Monitoring: BP, BUN/SCr, LFTs at baseline & periodically
- Drug interactions: CYP3A and P-gp
Methotrexate (MTX): used in CD, but not very common
- ROA: SC/IM
- ADRs: bone marrow suppression, N/V/D, stomatitis, mucositis, cirrhosis/hepatitis/fibrosis, hypersensitivity pneumonitis, rash/urticaria/alopecia, teratogenic
- Contraindications: pregancy, pleural effusions, chronic liver disease/EtOH, immunodeficiency, blood/cell abnormalities, CrCl <40mL/min
- Monitoring: CXR at baseline, CBC, SCr, LFTs at baseline & maintenance
What are the differences in MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy for the anti-TNF-α agents (infliximab, adalimumab, certolizumab, and golimumab)?
anti TNF-α antibodies:
- ADRs: increased risk of serious infections, injection site reactions/infusion related reactions, risk of malignancy, hepatosplenic T-cell lymphoma (HSTCL) risk, demyelinating disease, may exacerbate CHF, hepatotoxicity
- Monitoring: CXR, PPD, s/sx of infection, UC, CBC, SCr, electrolytes, LFTs, Hep B/C at baseline & maintenance; check for inflammatory markers (ex. CRP, fecal calprotectin, etc.) maintenance
infliximab - CD & UC; induction & maintenance
- ROA: IV infusion
- antibody development (ADA) is possible
- combining with immunosuppressives (like azathioprine) may help, but it also increases risks of ADRs
- Monitoring: vitals and infusion reactions with each dose, consider TDM
adalimumab - CD & UC; induction and maintenance, use if poor response to infliximab
- ROA: SQ injection
- ADA possible, but less likely than infliximab
- TDM is possible
golimumab - UC only
- ROA: SQ injection
- ADA possible, but less likely than infliximab
- TDM is possible
certolizumab - CD only; induction and maintenance; more of a second line
- ROA: SQ injection
- ADA possible
- TDM possible
What are the differences in MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy for the leukocyte adhesion/migration inhibitors (natalizumab and vedolizumab)?
natalizumab - anti-α-subunit of integrin’s (prevents leukocyte adhesion/migration; CD only; induction and maintenance
- ROA: IV infusion q4weeks
- Do NOT use in combo with immunosuppressants or TNF-α inhibitors due to adverse effects
- ADRs: progressive multifocal leukoencephalopathy (PML), rest similar to other biologics
- Monitor closely for JC antibodies/virus
vedolizumab - anti-α4β7 integrin antibody (expressed on some T-lymphocytes); UC & CD; Induction and maintenance
- ROA: IV infusion
- ADRs: similar to other biologics, PML is not observed, but be cautious, since the MOA of vedolizumab is similar to natalizumab
- TDM possible
What are the differences in MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy between ustekinumab, risankizumab-rzaa, and mirikizumab?
ustekinumab - IL-12 and IL-23 antagonist; CD and UC; Induction and maintenance
- induction is IV, maintenance is SQ
- ADAs
- TDM possible
- ADRs: similar to other biologics, cutaneous cell carcinoma, neurotoxicity, possible CV events
- Montoring: cutaneous cell carcinoma (esp if pt >60yo, prolonged immunosuppressant therapy, and/or hx of phototherapy), other monitoring is similar to other biologics, but check skin annually
risankizumab - IL-23 antagonist; CD; induction and maintenance
- induction is IV, maintenance is SQ
- ADRs: headache, nasopharyngitis, abdominal pain, anemia, nausea, arthralgia, potential hepatotoxicity, inc. in lipids
- Monitoring: same as other biologics
mirikizumab - IL-23 p19 antagonist; UC; induction and maintenance
- Induction is IV, maintenance is SQ
- ADRs: similar to risankizumab, but no nausea, anemia, or nasopharyngitis
- Monitoring: same as other biologics
What are the differences in MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy between tofacitinib and upadacitinib?
tofacitinib - oral JAK inhbitor (inhibits immuno signaling); UC only; use if inadequate response to or are intolerant to TNF blockers; more of 2nd line due to BB warning
- D/c after 16 weeks if response is not adequate
- do NOT use with immunosuppressants or biologics
- eliminated through hepatic metabolism/renal excretion (so avoid in severe hepatic impairment)
- Drug interactions: CYP3A, CYP2C19
- ADRs: diarrhea, elevated cholesterol, headache, Shingles, increased creatine phosphokinase, nasopharyngitis, rash, URI; more rare: malignancy, serious infection, neutropenia, hypersensitivity; BB Warning!! Increased mortality in RA patients 50 years and older with at least 1 CV risk factor (thrombosis)
- Monitoring: Same as ustekinumab, but also do ANC
upadacitinib - oral JAK 1 inhibitor; UC and CD; use if inadequate response to or are intolerant to TNF blockers
- do NOT use with immunosuppressants or biologics
- eliminated through hepatic metabolism/renal excretion (so avoid in severe hepatic impairment or ESRD
- Drug interactions: CYP3A
- ADRs same as tofacitinib including BB warning!!, also potentially teratogenic
- Monitoring: same as tofacitinib
What are the MOA, ROA, adverse effects/drug interactions, monitoring parameters, and place in therapy for ozanimod?
ozanimod - oral S1P receptor modulator (prevents lymphocyte mobilization to inflammatory sites); UC only
- If a dose is missed in the first 2 weeks of treatment, reinitiate titration regimen
- do NOT use with non-corticosteroid immunosuppressants or immune-modulating drugs
- metabolized by ALDH/ADH and CYP3A4, so not recommended in hepatic impairment
- Contraindicated: CV issue in the last 6 months, cardiac conduction abnormalities, severe untreated sleep apnea, taking an MAO inhibitor (since the active metabolite of ozanimod is an MAO-B inhibitor)
- ADRs: potential risk of PML, bradycardia/AV conduction delays, liver injury/elevated transaminases, inc. in systolic BP, respiratory effects, macular edema, neurotoxicity
- Drug interactions: (mostly have to do with MAO-B) adrenergic/serotonergic drugs, beta blocker+CCB, foods high in tyramine, MAO inhibitors, strong CYP2C8 inhibitors/inducers
- Monitoring: same as biologics, but also do spirometry if needed and do ECG & optho exams
When do you use the antimicrobials (metronidazole and ciprofloxacin) for IBD and what are the some ADRs?
ciprofloxacin, metronidazole, rifamycin antibiotics - can be used as adjunct therapy for CD with fistulas or abscesses.
ADRs: agent specific, resistance, C. diff
How do you select drug therapy, monitoring, and have rationale for patient’s with UC?
Mild-moderate active UC: 4-6 stools/day, minimal systemic symptoms -> use oral and/or topical ASAs
- if extensive: oral 5-ASA
- left-sided disease -> topical mesalamine enema
- proctitis -> mesalamine suppository
*if unresponsive to standard dose 5-ASA, increase the dose + rectal mesalamine
- alternatives include CR budesonide, PO corticosteroids, or topical corticosteroids (distal disease)
combo oral and topical mesalamine can be more effective
Moderate-severe active UC: 4-6 stools/day, +/- blood in stool, some systemic symptoms
- 5-ASA for moderate, NOT severe
- systemic corticosteroids (PO prednisone); can use oral budesonide if moderate
- consider adding TNF-α inhibitors (infliximab, adalimumab, golimumab) if pts unresponsive to ASA/other therapy, if they are steroid dependent, or if they fail steroids
- combine TNF-antagonists, vedolizumab, or ustekinumab with thiopurines or MTX instead of monotherapy to decrease risk of ADAs
- do not use thiopurine monotherapy for induction, only an option for maintenance (but biologic is better anyway)
*when remission is achieved, stop the 5-ASA
Severe-fulminant UC: 6-10 BMs/day w/ blood present & systemic symptoms
- inpatient treatment
- parenteral corticosteroids (methylpred or hydrocortisone) for 3-7 days, then transition to PO
- If pt unresponsive to IV steroids, consider TNF-α inhibitors or IV cyclosporine
Maintenance of remission: likely use whatever got them into remission, but don’t use corticosteroids
How do you select drug therapy, monitoring, and have rationale for patient’s with CD?
mild-moderate active CD: ambulatory, minimal systemic symptoms
- sulfasalazine, but this has marginal efficacy
- small bowel disease/distal/right-sided: CR budesonide
- perianal disease/fistulizing/unresponsive: metronidazole
moderate-severe active CD: failed treatment for mild-mod, systemic symptoms
- systemic corticosteroids (PO prednisone), hospitalized pts may receive IV corticosteroids
- early biologic therapy may be beneficial
- options: prednisone + infliximab, adalimumab, certolizumab, vedolizumab +/- MTX, azathioprine/MP
- taper prednisone when possible
- ustekimumab last line option trying everything & combo therapy
severe-fulminant CD: persistant toxicity despite corticosteroid or biologic treatment, severe symptoms
- inpatient treatment, supportive care
- parenteral corticosteroids, then transition to PO
- consider infliximab prior to surgery as “last option”
fistulizing disease:
- infliximab recommended, but adalimumab, ustekinumab, or vedolizumab may be used
- antibiotics alone are NOT recommended. Do combo biologic + antibiotic therapy
maintenance of remission: lots of options, pretty much just use what worked to get into remission
- AZA/6MP are effective, especially in steroid-induced or infliximab-induced remission; MTX also an option
- TNF-α antagonists are options: infliximab or adalimumab in combo with AZA or 6-MP is good
What is the impact of the SDOHs on the management of UC and CD?
- Lower socioecomonic status may be associated with worse outcomes in IBD
How can you use knowledge of detectable/undetectable ADAs and therapeutic/subtherapeutic drug levels to alter treatment?
For IBD patients in treatment failure:
1. confirm inflammation
2. exclude infection & non-compliance to treatment
3. Send for drug TLs and ADA levels
- If sub-therapeutic drug levels & detectable ADAs: immune mediated pharmacokinetic failure, meaning there in low bioavailability of the drug due to ADA, which caused increased drug clearance -> change to an alternate drug within the same class +/0 immunomodulator
- If sub-therapeutic drug levels & undetectable ADAs: non-immune mediated pharamcokinetic failure, meaning theres not enough drug -> increase dose
- If therapeutic drug levels & detectable ADAs: false positive OR mechanistic failure -> repeat TDM levels, if same result, switch to a biologic agent in a different class
- If therapeutic drug levels & undetecable ADAs: mechanistic failure -> switch to a biologic agent in a different class
What are the normal hematologic lab values for Hgb (hemoglobin) and MCV (mean corpuscular volume)
Hgb: represents oxygen carrying capacity
Males - 13.5-18 g/dL
Female - 12-16 g/dL
MCV: represents average volumes of RBCs (size of RBCs)
80-100mm^3
- <80 is microcytic (seen with iron deficiency, sickle cell, thalaseemia)
- 80-100 is normocytic (seen with anemia of chronic disease, blood loss, hemolysis)
- >100 is macrocytic (seen with folic acid and/or B12 deficiency)
What are the signs and symptoms of anemia?
- shortness of breath (exertional dyspnea)
- angina
- tachycardia
- fatigue
- pallor (being pale)
*can also be asymptomatic
What are the causes of anemia?
Decreased RBC production
- Chronic diseases (CKD, cancer, CHF)
- Nutritional deficiencies: lose the building blocks needed to make RBCs (iron, folic acid, vitamin B12)
Increased RBC destruction
- drugs
- sickle cell anemia/thalassemia
Increased RBC loss
- acute blood loss
- chronic NSAIDs/ASA
What are the goals of treatment for anemia?
- Increase Hgb
- Relieve symptoms (decrease fatigue)
- Reduce morbidity (HF, cognitive impairment)
- Improve quality of life
- Reduce mortality
- MORE than just normalizing lab values
What lab changes do we commonly see with iron deficiency anemia? (hgb, MCV, RDW, ferritin, TIBC/transferrin, serum iron, TSAT)
Hgb decreased
MCV decreased
RDW increased/normal
Ferritin decreased (normal is 15-200, iron deficiency is likely <45ng/mL); note that ferritin is elevated in a stress state, which may hide a deficiency
TIBC/transferrin increased
serum iron normal/decreased
TSAT decreased (normal is 20-50%); this represents the amount of iron that is ready for erythropoiesis
What are the causes of iron deficiency anemia? (4) What are the s/sx? (3)
- Blood loss (menstruation, blood donation)
- Decreased absorption (maximal absorption in the duodenum, like with celiac disease or gastric bypass)
- Vegetarian diet (dietary iron comes from heme in meat or non-heme in plants/dairy, but non-heme iron is not well absorbed)
- Increased consumption (pregnancy)
*drugs are unlikely to be the cause of iron deficiency anemia
Signs & Symptoms:
- Spoon-shaped nails (koilonychias)
- Inflamed tongue (glossitis)
- Pica (craving for a substance with no nutritional value, like ice or dirt)
How do you treat iron deficiency anemia? what is the dosing and some counseling points for PO? When is IV indicated & what are the side effects?
address the underlying cause
PO iron is preferred
- Dosing: 65mg elemental iron QOD; 120-200mg elemental iron per day (split to BID or TID)
QOD dosing is preferred due to hepcidin that prevents further absorption of iron when given daily
- Counseling: there is increased absorption when taken on an empty stomach, but can take with food or split doses if it causes stomach upset; absorption increased by ascorbic acid; causes constipation (increase fluids, activity, and fiber); causes dark stools
IV iron ($$): if ESRD, HF, failed PO iron, or malabsorption
- Side effects: hypotension during infusion, skin tatooing (rare)
What lab changes do we see with Vitamin B12 deficiency anemia? (Hgb, MCV, RDW, iron labs, serum B12, homocysteine/methylmalonic)
Hgb decreases
MCV increases
RDW increases
ferritin/TIBC/transferrin/serum iron/TSAT normal
Serum B12 decreased (<200pg/mL)
homocysteine/methylmalonic acid increased
What are the causes of Vit B12 deficiency anemia? (4) What are the consequences of B12 deficiency? (1)
- Diet (vegan/vegetarian, alcoholism)
*we cannot make Vit B12, we must absorb it in the diet - Intrinstic factor leading to pernicious anemia
- Decreased absoprtion (Crohn’s)
- Medications (PPIs, metformin)
Consequences:
- Neurologic (weakness, numbness, cognitive dysfunction)
