IBD Flashcards
What is comprised in IBD
UC: mucosal inflammatory condition confined to rectum and colon
Crohn’s: transmural inflammation of GI tract, mouth to anus
What causes IBD
Combo of infectious, genetic, environmental, and immunologic
Pharm Tx for IBD involves
anti-inflammatories
1. Aminosalicylates (Sulfasalazine, Mesalamine)
2. Corticosteroids (prednisone, budesonide)
(Also Tx with abx, immunosuppressives, biologics, and anti-integrins)
What are Sx of UC
rectal bleeding abd ttp Continuous distribution rectal involvement crypt abscesses
What are Sx of Crohn’s
Fever, malaise rectal bleeding abd pain abd mass fistulas aphthous ulcers discontinuous distribution ileal involvement strictures transmural granulomas linear clefts cobblestoning
Drugs that are less effective but with fewer ADE
Budesonide
Topical steroids
Antibiotics
5-aminosalicylates
Agents that are most effective but with a lot of ADE
Natalizumab
Cyclosporine
TNF antagonists
IV corticosteroids
What happens to aminosalicylates in the body
Sulfasalazine: converted to mesalamine in the colon
Asacol: Release is delayed until terminal ileum and cecum, then released as a bolus in right colon
What constitutes mild (low risk) Crohn’s
No/Mild Sx Nl/mils elevation of CRP Diagnosed 30+ Limited distribution No prior resections No strictures
How do you treat mild, low risk crohn’s
Budesonide to induce remission
What are the Aminosalicylates (5-ASA)
Azo compounds: Sulfasalazine, Olsalazine, Balsalazide
Mesalamine
What is the significance of Azo compounds
The structure reduces absorption from small intestine
In the terminal ileum and colon, bacteria cleave the azo bond and release active 5-ASA
What are the formulations of Mesalamine
Pentasa: timed release microgranules throughout small intestine
Asacol/Apriso: Coating dissolves at pH 6-7; distal ileum and proximal colon
Lialda: Dissolves in pH of colon. Slow release throughout colon
Rowasa: enema
Canasa: Suppository
What is the site of action of the IBD drugs
Jejunum: Pentasa
Ileum: Asacol, Lialda
Proximal colon: Sulfasalazine, Balsalazide
Rectum: Rowasa, Canasa
What is the PK of IBD drugs
Absorption of 5-ASA from colon is very low
Absorbed 5-ASA undergoes N-Acetylation in the gut and liver and is converted to a metabolite that is not anti-inflammatory
That metabolite is excreted by kidneys
What is the MOA of 5-ASA
Modulates inflammatory mediators derived from COX and LOX pathways
Interferes with production of inflammatory cytokines (NF-Kb)
Inhibit cell fxn of NK cells, lymphocytes, macrophages
Scavenge reactive oxygen metabolites
How does 5-ASA work in UC and Crohn’s
UC: Induce and maintain remission
Crohn’s: efficacy unproven, used mainly for mild-mod involving colon or distal ileum
What is first lint Tx for mild-mod UC
5-ASA!!!
Efficacy of 5-ASA depends on
achieving high drug concentration at site of active disease
- Rowasa and Canasa good for dz confined to rectum or distal colon
- azo compounds and mesalamine for dz in proximal colon
- pentasa, asacol, lialda for dz involving small bowel
What are ADE of Sulfasalazine
nausea vomiting HA rash hepatotoxicity, nephritis -monitor folate, CBC, LFT, SrCr, BUN *Has more ADE than others bc it is a fast acetylator
What are ADE of Olsalazine
secretory diarrhea
-monitor oligospermia (reverses on drug d/c)
What are ADE of Mesalamine
N/V
Headache
High dose: Interstitial nephritis
How do glucocorticoids work in IBD
Inhibit inflammatory cytokines (TNF, IL1) and chemokines (IL8)
Reduce expression of inflammatory cell adhesion
Inhibit gene transcription of NO synthase, phospholipase A2, COX2, and NF-Kb
What is the MC steroid used in IBD
Prednisone and prednisolone
Oral, QD
What are other steroids used in IBD
Hydrocortisone: maximize colon effects, minimize systemic absorption. Topical Tx in rectum and sigmoid
Budesonide: prednisolone synthetic analog. rapid first pass hepatic metabolism (low oral bioavailability) (entocort, uceris- PO forms in US)
What is Entocort
Controlled release budesonide released thru distal ileum and colon
PO
What are steroids used for
mod-severe active IBD- a flare! NOT to maintain remission (need 5-ASA or biologics for that)
Higher doses are NOT more effective, just more ADE
After response (1-2 weeks), slowly taper
If very ill, can give IV
If involving rectum or sigmoid colon, rectally administered preferred
ADE of corticosteroids are
hyperglycemia dyslipidemia osteoporosis HTN acne edema infection myopathy psychosis -Monitor BP, fasting lipids, glucose, vit. D, bone density
What are the pruine analogs
Azathioprine (more bioavailable!)- converted to 6-MP
6-Mercaptopurine
-They are anti-metabolites with immunosuppressive properties
What ahppens to 6-MP in the body
Biotransformed via competing catabolic enzymes; Xanthine oxidase, Thiopurine methyltransferase
What should you not give Xanthine oxidase with
Allopurinol (XO inhibitor)- so you get double XO inhibition
Increases active 6-thioguanine nucleotides= severe leukopenia
What is the PK of purine analogs
Half life <2 hours
Takes 17 weeks before therapeutic benefit or oral purine analogs
What are clinical uses of purine analogs
Induce and maintain remission of UC and Crohn’s after 3-6 months of Tx
Allow reduction and elimination of steroids in most pts
What are ADE of purine analogs
N/V
bone marrow depression (anemia, low plt, wbc)
hepatic toxicity (monitor CBC, LFT)
hypersensitivity to azathioprine (fever, rash, pancreatitis, diarrhea, hepatitis
Increased risk of lymphoma
Can purine analogs be used in pregnancy
CAN cross placenta but many women used during pregnancy and teratogenicity is small
How can Abx influence the course of IBD
Decrease bacteria and fungi in gut/lumen
Alter composition of mictobiota
Decrease bacterial tissue invasion and Tc microabscess
Decrease bacterial translocation and systemic dissemination
How does Methotrexate work
Inhibit dihydrofolate reductase enzyme (needed to make thymidine and purines)
Can interfere with inflammatory actions of IL
Can stimulate increased release of adenosine, and apoptosis/death of active T lymphocytes
What disorders does methotrexate treat
Crohn’s
RA
Cancer
-oral (50% bioavailable), subQ, IM (appx 100% bioavailable)
Clinically, methotrexate is used to
induce and maintain remission in crohn’s (1x wk subQ)- if effective after 8-12 weeks, can reduce dose
ADE of high dose methotrexate are
bone marrow depression
megaloblastic anemia
alopecia
mucositis
-reduce the dose! and reduce risk of ADE with FOLATE*
-permanent peripheral neuropathy if used for prolonged periods
Other ADE of methotrexate are
if w/ psoriasis: hepatic damage
hepatic accumulation and toxicity if w/ renal insufficiency
How do anti-TNF agents work in IBD
Dysregulate helper T cella type 1 (Th1) response and regulatory T cells
Wha are the biologic actions of TNF
release proinflammtory cytokines from macrophages
Activate and proliferate T cells
Up regulate adhesion molecules (leukocyte migration)
Stimulate hepatic acute phase reactants
What anti-TNF (TNF MAB’s) are approved for use in Crohn’s
Infliximab Adalimumab Certolizumab Natalizumab Vedolizumab (golimumab, Inflixi, adalim, and Vedo in UC)
How do anti-TNF work
Bind soluble and membrane bound TNF
prevent cytokine from binding to receptors
Cause reverse signaling that suppresses cytokine release
-Inflix/Adalim/Golim: Fc portion promotes Ab mediated apoptosis. Also complement activation, and cytotoxicity to T lymphocytes and macrophages
Certo: No Fc portion= no apoptosis
What are the clinical uses of anti-TNF
Acute and chornic mod-severe Crohn’s not responsive to Tx
1/3 of pts eventually lose response (may be 2/2 development of Abs to TNF Ab (Abs to the Abs; ATA)
What are ADE of anti-TNF
*Infection! 2/2 supprssion of T helper cells (Th1)- sepsis, TB, invasive fungal, reactivation of Hep B or latent TB
-Increased risk if also on steroids
Less serious: URI (sinusitis, bronchitis, PNA), cellulitis
*Delayed serum sickness-like Rxn: myalgia, arthralgia, jaw tightness, fever, rash, urticaria, edema
+ANA and anti-ds DNA
Lupus like syndrome (goes away w/ drug d/c)
Hepatic reactions, demyelinating d/o, hematologic d/o, new or worse CHF, psoriatic skin rash, lymphoma
What does concomitant use of anti-TNF and immunomodulators do
increase risk of lymphoma
What makes the likelihood of developing antibodies to antibodies while using anti-TNF
Using immunomodulators like 6-MP or methotrexate
What are Integrins
Adhesion molecules on the surface of leukocytes
interact with selectins, adhesion molecules on vascular endothelium
Allow leukocytes to adhere to vascular endothelium and move thru vessels into tissue
What is Natalizumab
Anti-integrin; IgG4 MAB that blocks integrins and prevents migration into surrounding tissues
What is Natalizumab used for
Mod-severe crohn’s who fail Tx
CArefully restricted program
ADE of Natalizumab are
Acute infusion reaction
Opportunistic infections
-Monitor brain MRI, mental status, PMI
What is Vedolizumab
Similar to natalizumab but:
Selectively blocks the gut (NOT brain)
Prevents JC virus (more selective)
Can be used in crohn’s ad UC
