IBD Tx Flashcards
What drug classes are used in IBD
5 aminosalicylic acid preparations corticosteroids immunosuppressants Anti TNF alpha Ab alpha4 integrin monoclonal Ab Antibiotics
What are the drug classes used in IBS
laxatives anti diarrheal agents prokinetic agent serotonin antagonist antiaspasmodic agents (Anticholinergics) antidepressents
UC affects what areas of GI
affects rectum and colon, mucosal and submucosal layers
superficial inflammation
complications UC
hemorrhoids, anal fissures, perirectal abscesses
toxic megacolon
colorectal carcinoma
what is toxic megacolon
segmental or total colonic distention of greater than 6 cm with acute colitis and signs of systemic toxicity
describe ulcers in CD
deep and elongated with nodular submucosal thickening
UC or CD has higher risk for fistula formation
CD
complications of CD
small bowel structures, fistulas, bleeding,nutritional deficiencies and extra-intestinal manifestations
What drugs are amiosalicylates used for IBD
sulfasalazine, olsalazine, balsalazide, various forms mesalamine
MOA aminosalicylates
uncertain. maybe modulates inflammatory medioators derived from cyclooxygenase and lipooxygenase
describe metabolism sulfasalazine, balsalazide and olsalazine
decrease absorption of parent drug in small intestine
high [ ] of active drug in terminal ileum or colon
describe the delayed or extendened release forms of msealamine
coated in special resins, pH sensitive film or ethylcellulose that release drug slowsly thorugh GI tract or only in terminal ileum and colon
what are the rectal formulations of mesalamine
rowasa and canasa
therapeutic use for aminosaliclyates
1st line for mild to moderate UC
effectiveness of aminosalicylates is determined how
by drug reaching site of active disease
suppositories useful in UC or CD rectum or distal colon
if proximal colon use axo and mesalmine formulations
adverse effects aminosalicylates
dose related: nausea, GI upset, HA, arthralgias, myalgias, bone marrow suppression, malaise
nephrotoxicity
lupus like syndrome, pancreatitis, hepatotoxicity
what are the glucocorticoids used for IBD
prednisone, budesonide, hydrocortisone
MOA glucocorticoids
inhibit production inflammatory cytokines TNFa and IL-1 and IL-8
reduce expression inflammatory cell adhesion molecules
inhibit gene transcription NO synthase, PLA2, COX-2, NFkB
therapeutic use glucocorticoids
mod- severe IBD
higher dose treat active disease
once responding, taper dose
hydrocortisone enemas used to maximize colonic tissue effects and minimize absorption
What is budesonide
potent synthetic analog of prednisolone with high affinity for glucocorticoid receptor
rapid first pass metabolism, low oral bioavailability and controlled release formulation that releases drug in distal ileum and colon
adverse effects glucocorticoids
insomnia, behavioral changes, acute peptic ulcers
fluid and electrolyte abnormalities, metabolic changes, HTN, hyperglycemia, increased susceptibility to infections, osteoporosis, myopathy, behavioral disturbances, cataracts, growth arrest
what are the purine analogs
azathioprine, 6 mercaptopurine
MOA purine analogs
inhibits purine NT synthesis
azathioprine is converted to 6 MP which coverts to active metabolites that suppress inosinic acid synthesis, B cell and T cell function, Ig production and IL-2 secretion
PK of purine analogs
delay of 17 weeks before onset therapeutic benefit from oral azathioprine of 6 MP in IBD
therapeutic use purine analogs
induction and maintenance of remission of UC and CD
for patients who need long term glucocorticoid therapy to control active disease, purine analogs, allow dose reduction or elimination of steroids in the majority,
d/t delay onset limited short time but effective long term
adverse effects purine analogs
dose related nausea vomiting bone marrow depression and hepatic toxicity
also HS: fever rash, pancreatitis, diarrhea, hepatitis
increase risk lymphoma with long term therapy
drug interactions with purine analogs
allopurinol with 6MP
allopurinol inhbits the enzyme that metabolizes 6MP to inactive compound increasing toxic effects
MOA methotrexate MTX
inhibits dihydrofolate reductase affecting lymphocyte and macrophage function
may stimulate release of adenosine, an endogenous anti-inflammatory autocoid
may also stimulate apoptosis and death of activated T lymphocytes
therapeutic use of MTX
induction and maintenance of remission in patients with CD
Efficacy in UC uncertain
adverse effects MTX
high doses may cause bone marrow depression, megaloblastic anemia, alopecia and mucositis
what should you give with MTX
folate supplementation to decrease risk of adverse effects
MOA cyclosporine
an inhibitor of calcineurin; cyclosporine is a potent inhibitor of cell-mediated immune responses
- inhibits IL2 production form T helper cells
- decreases recruitment of cytotoxic T cells and blocks other cytokines, including IL3 and 4, IFalpha and TNGa
therapeutic use cyclosporine
IV infusion used to Tx severe UC that is unresponsive to IV glucocorticoids; may save patient from colectomy, but carries significant toxicity
TNF levels in IBD
increased because key pro-inflammatory cytokine and mediator of intestinal inflammation
Available TNFa Ab agents in IBD
infliximab, adalimumab are Ab of IgG1 subclass certolizumab- recombinant Ab that contains a Fab fragment conjugated to polyethylene glycol (PEG)
what monoclonal Ab are fully humanized
adalimumab
MOA TNFa Ab
all 3 Ab, bind soluble membrane bound TNFa with high affinity, preventing the cytokine from binding its receptors
suppreses cytokine release
lyses macrophages and T cells through Cā fixation and Ab dep cytotoxicity
therapeutic use of TNFa
acute and chronic Tx of mod-severe CD in patients who have inadequate response to conventional therapies
median time to clinical response TNFa
2 weeks
adverse effects TNFa
serious infections, Ab to Ab, delayed serum sickness like reaction
hepatic failure, lupus like syndrome, demyelinating disorders, hematologic reactions and new or worsening CHF
psoriatic skin rashes- resulting after drug discontinuation, lymphoma
what serious infections can occur with TNFa
bacterial sepsis, TB, invasive fungal infections
before starting on TNFa therapy what must you check for
TB infection because TB therapy needs to be initiated first
What infecitons are more common with TNFa
URI(sinusitis, bronchitis, pneumonia) and cellulitis, risk of serious infection increases when taking concomitant glucocorticoids
describe delayed serum sickness like reaction from TNFa
1-2 weeks post antiTNFa therapy
myalgia, arthralgia, jaw tightness, fever, rash, edema
What are integrins
family of adhesion molecules on leukocytes that interact with selectins allowing leukocytes to enter vascular endothelium and into tissue
what are the available anti-integrin agents
natalizumab, humanized IgG2 monoclonal Ab
MOA natalizumab
prevent integrin binding to vascular adhesion molecules inhibiting subsequent migration into surround tissues
therapeutic use of natalizumab
subset of patients with mod- severe CD
why was natalizumab withdrawn in general.
lead to progressive multifocal leukoencephalopathy
what is natalizumab still approved for
restricted use in patients with mod-severe CD who failed other Tx
adverse effects natalizumab
acute infusion reactions and a small risk of opportunistic infections
