Exam 4 lecture 1 Flashcards
What is IBD? What are the two types?
IBD: Is an inflammatory condition with chronic or recurring immune response and inflammation of the GI tract.
Two types
1) Ulcerative colitis (UC): Mucosal inflammation (superficial) confined to rectum and colon. Smoking is protective.
2) Crohn’s disease (CD): Transmural (deeper and thicker) inflammation of GI tract that can affect any part from mouth to anus. You see fistulas. Smoking is a risk factor.
What signs and symptoms are consistent with IBD
Frequent bowel movements.
Include blood and mucous.
FInd out if they smoke? Gluten allergy?
Nsaids cause IBD aswell.
What is an imprtant goal of therapy for IBD
Inducing and maintaining remission , Mucosal healing associated with better long term outcomes.
Nutrition support for IBD
No specific diet shown to be beneficial
Nutritional support to address nutritional deficiencies, impaire absorption (supplement vitamin/mineral deficiencies like calcium/vit D, folate), EN/PN
Pharmacologic therapy for IBD
None of them are curative. They get patients into remission.
- ASAs (aminosalicylates)
- SUlfasazine, Mesalamine (5-ASA) - Corticosteroids
- Immunomodulators (immunosuppressives)
- Azathropine, mercaptopurine, cyclosporine, methotrexate - Biologics
- anti TNF agents (infliximab, adalimumab, certolizumab, golimumab)
- Other- Natalizumab, vedolizumab, ustekinumab, risankizumab - Tofactinib, upadactinib, ozanimod, estrasimod
Name ASA agents
Sulfasazine, Meslamine
What is sulfasazine made of? WHat happens to it in the body? What is associated with ADRs? WHat is the inactive component? active component?
Made up of sulfapyridine + 5- ASA (mesalamine)
cleaved by colonic bacteria to release sulfapyridine (absorbed and renally excreted) and 5- ASA (mainly remains in lumen, excreted in stool)
Sulfapyridine is inactive, but is associated with ADRs
5-ASA is active component
Can we administer mesalamine alone ( to prevent ADRs?) Explain
Yes we can. It is rapidly and completely absorbed in small intestine, but not colon. It is important to deliver to affected area.
How can we get Mesalamine to colon (past small instestine)
Suppository (for patients with Proctitis
Enema (for patients with left sided disease)
Is topical or oral mesalamine more effective? Can we use both together?
Topical is more effective
We can give both
ASA agents ADRs? how to avoid?
Sulfasalazine-> Sulfapyridine is associated with ADRs
- > 10% nausea, vomiting, headache, anorexia, rash
-Initiate with low dose and titrate up slowly
-<10% anemia, hepatotoxicity, thrombocytopenia
What in sulfasalazine causes ADRs? What to monitor? Drug interactions of sulfasalazines
May be associated with hypersensitivity rxns in sulfonamide allergy
MOnitor CBC and LFTs at baseline, every other week for first 3 months, monthly for second three months and perioically there after
Monitor BUN/Scr periodically
Drug i/a with antiplatelets/anticoags/NSAIDs-> increase bleeding risks
If sulfasalazine is not tolerated, what drug is used? Side effects?
Mesalamine (much better tolerated)
N/V, headaches
olsalazine has diarrhea (up to 25%)
Drug i/a of mesalamine
Antiplatelets/anticoags/NSAIDs may increase bleeding risk
Agents affecting gastric PH (PPIs, H2RAs, antacids) could influence release of drug in PH dependent dosage forms
MOA of coticosteroids? ROA? use?
Antiinflammatory (systemic or local)
Can be used parenterally (severe exacerbation, orally or rectally)
systemic corticosteroids may be used for induction of remission, but not for maintenance
tOPICAL FORMULATIONS FOR IBD
RECTAL HYDROCORTISONE (Suppositories, foam, enema)
Budesonide (can be inhaled), systemic absorption is lower than other steroids, can be used for 16 weeks
Prednisone/prednisolone
What are the two types of budesonide
Entocort- Pill
Uceris- foam
Budesonide drug i/a
CYP3A4 inhibitors (ketoconazole, grapefruit juice), may increase systemic exposure
What are IV steroids used in IBD
Methylprednisolone\Hydrocortisone
ADRs for corticosteroids
Short term- hyperglycemia, gastritis, mood changes, elevated BP
Long term- aseptic necrosis, cataracts, obesity, growth failure, HPA suppression, Osteoporosis
What supplemets should be given for patients on systemic corticosteroids
Give calcium and vitamin D while on steroids
May give bisphosphonates for patients with high risk for osteoporosis, patients using for more than 3 months or recurrent users
Monitoring for corticosteroids
BP, blood glucose baseline and every 3-6 months
Consider occasional bone mineral density scan (DEXA) in pts > 60 years old, at risk for osteoporosis, patients using for more than 3 months or recurrent users
What are immunosuppresants used in IBD
Thiopurines
1) Azathropine (AZA)
2) Mercaptopurine (MP, 6-MP)
AZA is a prodrug rapidly converted to 6-MP
What are the uses AZA and MP? WHo can use them? MOA? Can they be used in other drugs?
can be used n long term tx of UC and CD
Reserved for pts who fail tx with ASA or refractory to steroids.
Can maintain remission, but are not used in induction
They can be use din conjunction with ASA, steroids, TNF
ADRs of AZA and 6-MP? Monitoring?
Hematologic effects :(life threatening anemia) due to bone marrow suppression
GI: N/V/D, anorexia
Hepatic: Hepatotoxicity
Monitoring
Baseline- TOMT, CBC, LFTs
CBC- weekly for 1st months and every 1-2 weeks after dose change.
Use of cyclosporine in IBD? Can be used long term? WHo is itreserved for?
Can be effective in inducing remission in patients with refractory UC (not recommended for CD)
NOt used long term
Generally reserved for pts who are refractory to steroids
ADRs of cyclosporine? Monitoring?
nephrotoxicity (dose related)
Neurotoxicity
Metabolic (HTN, HLD, hyperglycemia)
other: GI upset, hirsutism, gingival hyperplasia
Monitoring
Baseline BP, BUN/SCr, LFTs, Cya tr. concentration
BP- q visit
BUN/SCr- q 2 weeks until stable, then periodically
LFTs- q 2 weeks until stable, then periodically
cyclosporine drug i/a? drugs/food that iincreases cyclosporine concentrations? Drugs that decrease cyclosporine concentrations
substrate CYP3A and p- glycoprotein
Increase cyclosporone concentration
- azole antifungal, macrolide antibiotics, calcium channel blockers, grapefruit
decrease cyclosporine
phenytoin, rifampin
Methotrexate use?
Can be used in tx and maintenance of CD (not UC)
May have steroid sparring effects, assist in inducing remission, allow steroid tapering
Methotrexate ADRs
Hematologic (bone marrow suppression) (thats why we add folic acid 1 mg/day)
GI: N/V/D, mucositis
Hepatic: Cirrhosis, hepatitis, fibrosis
Pulmonary: Pneumonitis
derm: rash, urticaria, alopecia
teratogenic drug (contraception)
CI of methotrexate? Monitoring
CI
Pregnancy
pleural effusions
chronic liver/EtH abuse
Immunodeficiency
preexisting blood dyscrasias
CrCl<40
leukopenia/thrombocytopenia
Monitoring
Baseline: Chest x ray, CBC, SCr, LFTs, pregnancy,
check CBC, Scr and LFTs q 4-8 weeks
What are some biologic TNF-a antagonist drugs
infliximab
adalimumab
golimumab
certolizumab
Which TNF-a antagonists treat CD? UC? both? are they anti TNF-a? human monoclonal or human pegylated (only know UC OR CD FOR EXAM)
infliximab (remicade) - Anti- TNF-a antibody for CD AND UC
adalimumab (humira)- anti TNF-a antibody for CD AND UC
golimumab- human monoclonal anti- TNF only used for UC
Certolizumab pegol- human pegylated anti TNF-a Fab fragemnt. Only used in CD
What are anti integrin bilogics used in CD and UC? Which drug is used inwhich?
Natalizimab- CD
Vedolizumab (UC and CD
What are some IL biologics that target CD and UC? Which ones can we use them for?
Ustekinumab- CD and UC
Risankizumab (skyrizi)- CD and UC
mirikizumab-mrkz- UC
WHat are some small molecule biologics used in IBD? Which one do they treat?
Tofactinib- UC
upadacitinib- UC, UD
Ozanimod- UC
estrasimod- UC
TNF-a inhibitors ADRs
- increased risk of infection (bacterial, viral, fungal)
- avoid if active infection
- tuberculin test (PPD), CXR, hepatitis prior to therapy
- ensure vaccinations up to date
-live vaccines contraindicated during tx and for 3 months after - Injection site rxn and infusion related rxns
- Risk of malignancy (lymphoma)
- hepatosplenic T cell lymphoma - Risk of demyelinating disease
Contraindocated in pts with history of cancer, demyelinating CNS disease, optic neuritis - May exacerbate CHF
- hepatotoxicity
Monitoring TNF inhibitors
Baseline
chest x ray, PPD, s/s infection
Maintenance (every 8-12 wks)
s/s of infection, UA, CBC, Scr, LFTs (for LFTs q 1-2 wks for first 1-2 months)
what is infliximab approved for? ROA? Induction/maintenance use?
mod-severe CD and UD.
used as induction and maintenance therapy
IV infusion
What is a common thing to worry about with all biologics
development of antibodies (they are foreign proteins that may cause immune response)
It this immune response occur the drug becomes less efficacious
These are called ADA (anti drug antibodies) or ATIs (anti treatment antibodies)
What does development of ADAs (antidrug antibodies) lead to? How common is it in infliximab? How to counteract?
ADAs lead to decreased response and potentially increased chance of infection.
Up to 10% of pts/year need to discontinue infliximab
Combining with immunosuppressives (AZA or MTX) may be of value, but will increase risk of ADRs
Can escalate dose or decrease dosing interval
What happens if Infliximab is co administered with azathioprine?
Hepatosplenic t cell lymphoma (HSTCL) risk
Infliximab could also cause infusion related rxns
monitoring of infliximab
Maintenance
s/s of infection
vitals (each dose)
Infusion rxn (each dose)
TDM (consider if tx failure)
What is adalimumab used for? Induction/maintenance? biggest difference with infliximab?
Mod- severe active CD and UC, steroid dependent
can use for pts with poor response to infliximab
induction and maintenance therapy
Biggest d/c is that it is an SQ injection not an infusion (self injection technique is needed)
What is more likely to give you ADAs infliximab or adalimumab
adalimumab is less likely than infliximab
What is golimumab approved for? Induction/maintenance?
ROA?
Are ADAs likley compared to infliximab
Mod-severe UC
induction and mainetnance
SQ inj (self injection)
ADAs possible, but less likely than infliximab
What is certolizumab pegol used for? ROA? Induction/maintenance?, ADAs?
Used for CD
SQ injection (self administration)
Induction and maintenance
develops ADAs
What type of drug is natalizumab? What IBD is it used in? Induction/maintenance? Which patients use it? Which patients can not use it? When to discontinue?
Natalizumab is an anti integrin (prevents leukocyte adhesion/migration)
Used in CD
induction and maintenance
Can use in pts who fail/do not tolerate TNF inhibitors
Not to be used in combination with immunisuppressants or TNF inhibitors
discontinue in patients with no benefits by 12 weeks and/or steroid dependent within 6 months
Why is natalizumab not commonly used
Associated with progressive multifocal leukoencephalopathy (PML) (rare CNS disorder related to JC virus)
Test for JC antibody. Even if JC virus negative, it is not impossible to get PML
What is vedolizumab used for? ADRs?
UC and CD
No PML risk (but still monitor for it)
Can see infection, HS rxn, ADAs
What are IL antagonist drugs
Ustekinumab
What is ustekinumab used for? What kind of IL antagonist is it? Induction/maintenance?
CD and UC
IL 12 and 23 antagonist
induction and maintenance
ADRs of ustekinumab
ADAs
HS rxn
Possible neurotoxicity (RPLS, PRES)
reports of rapidly developing cutaneous cell carcinomas
Monitoring Ustekinumab baseline
Baseline
Check pt for TB/ hepatitis
CXR (chest x ray), PPD, Hep B and C
Lipids, LFTs, renal function, infection, skin
Monitoring Usketinumab maintenance
Lipids and LFTs- 1-2 months after start and then periodically
renal function- periodically
infection- monitor for s/s
skin- annually
What kind of drug is Skyrizi? What is it used for? Induction/maintenance?
Selective IL 23 antagonist
CD and UC
USed for induction and maintenance
Adverse effects of skirizi
common- Headache, nasopharyngitis, arthralgia, abdominal pain, anemia, nausea
infection/latent infection (TB)
HS rxn possible
ADAs possible
Potential hepatotoxicity (increases LFTs)
increase in lipids
Monitoring skyrizi
Monitor LFTs and bilirubin at baseline and by week 12
What kind of drug is mirikizumab? What does it treat? Induction/maintenance?
IL 23 p 19 antagonist
Only used in UC
induction and maintenance (infusion and then maintenance SQ)
ADRs of mirikizumab
COmmon- headache, arthralgia, rash, inj site rxn
Infection/latent infections (TB)
Upper repsiratory tract infection
HS rxn
ADAs
Potential hepatotoxicity (increase LFTs) (monitor)
Monitoring Mirikizumab
Similar to other IL inhibitors
Baseline
CXR, PPD
HEP B, C
Lipids and LFTs (1-2 months after start)
renal func
infection (monitor for s/s)
WHat is TDM? Use?
Therapeutic drug monitoring
Potential for determining concentrations of drugs and ADAs
Why consider TDMs?
Consider if loss of treatment response (check ADA concurrently) always do both together
For TDM of biologics, what are 3 things we do at IBD treatment fauilure
Confirm inflammation (biomarkers)
Exclude infection and non compliance to treatment
Send for serum drug TLs and ADA levels
What TDM to do if detectable ADAs at subtherapeutic drug levels
This could be caused by “immune mediated PK failure “(insufficient bioavailability of drug as a result of induced immunogenicity resulting n increased drug clearence
Change to alternate drug within the same class
What TDM to do for subtherapeutic drug levels with undetectable ADAs
Could be caused by non-immune mediated PK failure (insufficient availability of drug)
Escalate dose
What to do for therapeutic drug levels with detectable ADAs? What could it be caused by?
False positive OR mechanistic failure
repeat TDM levels
If repeat results consistent, switch to out of class biologic agent
What to do for therapeutic drug levels with undetectable ADAs? What could it be caused by?
Could be caused by mechanistic failure (not effective drug), switch to out of class biol0gic
What type of drug is tofactinib? What is it approved for? Who can use it? ROA? WHen to discontinue
It is an oral janus kinase (JAK) inhibitor
Approved for UC only
Used for patients who have had an inadequate response or who are intolerant to TNF blocker
Orl drug
Dx after 16 weeks if repsponse is not adeqyate
Tofactinib should not be used in conjunction with
Immunosuppressants (AZA, CYA) or biologics
ADRs of tofactinib
COmmon- Diarrhea, elevated cholesterol, headache, herpes (shingles), rash, nasopharyngitis, URI,
rare- malignancy (lymphoma), serious infection (TB and Hep B and C) (activation of latent TB), neutropenia, HS rxn
Live vaccines CI during tx and 3 months after
blackbox warning of tofactinib
Increase mortality in RA patients 50 years and older with atleast one cV risk factor
increase in thrombosis in same population
Monitoring tofactinib
baseline- CXR, PPD, HEP B, C
maintenance
ANC (q 3 months) , CBC (q 1-2 months then q 3 months), lipids (1-2 months after start, then periodically), LFTs (1-2 months after start) , renal fun, infection, skin exam
What type of drug is upadacitinib? WHat is it approved for?
oral selective JAK inhibitor (like tofactinib)
UC and CD (different dosing)
What should upadactinib not be used in combo with? Who is it an option for?
Immunosuppressants or biologics
option for pts who fail biologics
upadactinib Blackbox? WHne to avoid? COntraindications?
Blackbox similar to tofactinib (Increase mortality in RA patients 50 years and older with atleast one cV risk factor
increase in thrombosis in same population)
ADRs increase of risk of serious infection (bacterial, viral, fungal)
Avoid if active infection present, pregnant or breast feeding
Live vaccines contraindicated immediately prior to and during therapy (ensue=re vaccines are up to date)
common ADRs of upadactinib
Common
upper respiratory tract infection, acne, increased creatine phosphokinase, elevated cholesterol, headache, herpes, shingles
rare- malignancy (lymphoma), serioud infection, increase in LFTs, anemia, neutropenia
Monitoring for ipadactinib
Same as tofacitinib
What type of drug is ozanimod? MOA? UC or CD? How is it dosed? WHne not to use it? WHat to do if patient misses dose in first 2 weeks
S1P receptor modulators
Prevents lymphocyte mobilization to inflammatory sites
Only for UC
7 day dose titration, if missed dose within 2 weeks, we reinitiate the whole thing
should not be used with non corticosteroid immunosuppressants or immunomodulators
CI of ozanimod
CVevents within last 6 months (TIA, MI< unstabe angina)
sleep apnea
MAO inhibitor
ADRs of ozanimod
increased risk of infection (PML), vaccinate with varicella prior to txm live vaccines CI
bradycardia/AV conduction delays
liver injuries (LFTs)
Drug interaction of ozanimod (exam)
Inhibition of MAO (exam)
BB and CCB
adrenergic and serotonergic drugs
Monitoring with ozanimod
CXR, PPD
HEP B, C
CBC
LFTs
Infection
BP
Spirometry
ECG
optho
What kind of drug is estrasimod? UC or CD? When not to be used?
Oral S1P receptor modulator
Approved for UC only
not used with non corticosteroid immunosuppressives or immune modulating drugs
CI of estrasimod
CV event in last 6 months
ADRs of estrasimod
Potential risk of infection (potential for PML), recommended to vaccinate against varicella prior to tx, live vaccines CI
Bradycardia/AV conduction delays
ADRs of estrasimod
Liver injuries
Moderate increase in BP
edema
RPLS/PRES
respiratory effects
monitoring of estrasimod
Same as ozanimod
