IBD pharmacology/therapeutics Flashcards
drugs to induce remission for UC
5-ASA
corticosteroids
anti-TNF
anti-Integrin
drugs to induce remission for CD
croticosteoids anti-TNF anti-Integrin anti-IL 12/23 methotrexate
5-ASA drugs
mesalamine
sulfasalazine
olsalazine
balsalazide
mesalamine must reach where to be effective
the colon
-delayed release formulation is better at this
mesalamine rectal formulations can be used when
inflammation is very distal
-left sided colitis
sulfazalazine acts where in GI
colon
olsalazine acts where in GI
colon
5-ASA drugs mechanism of action
anti-inflammatory by inhibiting the action of nuclear factor kappa B, and decreased cytokines
additional action mesalamine has in its action
PPAR gamma agonist - reduce inflammation as well
what makes nuclear factor kappa B a good target in IBD
it is overactive in these diseases
PPAR gamma action
binds to NFkB, preventing it from initiating transcription and thus immune responses
PPAR gamma is expressed where
in colonic epithelial cells
NSAIDs and PPARgamma
NSAIDs activate at high antiinflammatory doses
mesalamine and COX enzymes
very weak inhibitor
mesalamine efficacy
improvement in 60-80% of patients w/ UC
mesalamine adverse effects
n/v
abdominal pain
headache
rarely interstitial nephritis
best mesalamine regimin
uses both topical and oral
corticosteroids MoA
- decreased expression of cytokines
- increased anti-inflammatory IL-10
- inhibition of NFkB
long term use adverse effects of corticosteroids
- immune suppression
- osteoporosis
- hypertension
- insulin resistance/hyperglycemia
steroid that avoids some of the long term adverse effects
budensonide (Entocort)
antiTNF monoclonals MoA
- bind up TNF alpha
- activate reverse signaling that results in death of TNF alpha expressing cells
adverse effects of TNF monoclonals
- injection reaction
- risk of serious infection
- increased risk of lymphomas
vedolizumab MoA
binds to alpha4beta7 integrin on surface of T cells, which prevents binding MadCAM-1 and thus prevents T cell trafficking to the site of inflammation
vedolizumab adverse effects
- hypersensitivity
- increased infection risk
- hepatotoxicity
- arthralgias
- cancer risk is unclear
Ustekinumab MoA
binds IL-12 and IL-23 which prevents them from activating Th1 and Th17 cells respectively
ustekinumab use
alternate for CD only
ustekinumab side effects
- injection site reactions
- serious infection risk
- n/v
- URTIs
- unknown cancer risk
thiopurine drugs
azathioprine
mercaptopurine
thiopurine MoA
- inhibit nucleic acid synthesis
- induce apoptosis in CD4 T lymphocytes
immunomodulator drugs
thiopurines
thiopurine use in therapy
- CD and UC maintenance only, not induction of remission
- use with anti-TNF and vedolizumab to reduce immunogenicity
how long does it take for thiopurines to be effective
3-6 months
thiopurine adverse effects
- myelosuppression w/ leukopenia
- susceptibility to infections
- pancreatitis
- hepatotoxicity, nephrotoxicity
- risk of lymphoma
TPMT
thiopurine methyltransferase
why test for TPMT activity
genetic polymorphisms exist that can make patients rapid or very slow metabolizers of thiopurines, increasing toxicity or reducing efficacy
methotrexate in IBD
alternative for induction or maintenance in mod-severe CD
methotrexate adverse effects
- n/v
- myelosuppression (dihydrofolate reductase inh.)
- increased risk of infection
- hepatotoxicity
- pregnancy category X
what do you need to take with methotrexate
folic acid to reduce typical toxicities
methotrexate anti-inflammatory effects due to
increase in synthesis and release of adenosine
how does adenosine reduce inflammation
- reduces release of TNFalpha, IL-12
- decrease production of IL-2
- decrease T cell proliferation
- decrease vascular permeability
- increases risk of antiinflammatory IL-10
treatment goals of CD
- stop progression
- prevent complications
- heal mucosa
initial steps in CD before starting drug treatment
- identify and treat any infections (C.diff, CMV)
- stop NSAIDs
- stop smoking
low risk CD ractors
- age at diagnosis >30
- limited anatomic involvement
- no perianal and/or rectal disease
- superficial ulcers
- no prior surgical resection
- no stricturing and/or penetrating behavior
high risk CD factors
- age at diagnosis <30
- extensive anatomic involvement
- perianal and/or rectal disease present
- deep ulcers
- prior surgical resection
- stricturing and/or penetrating behavior
initial CD drug treatment options of low risk patient with ileum and/or proximal colon inflammed
- budesonide 9 mg qd w/wo AZA
- tapering course of prednisone w/wo AZA
initial CD drug treatment of low risk patient with diffuse or left colon inflammed
tapering course of prednisone w/wo AZA
initial CD drug treatment options of moderately severe CD patients
- anti-TNF + thiopurine preferred
- anti-TNF monotherapy
- anti-TNF + methotrexate if thiopurine not tolerated
how long does it take to induce remission of CD
2-4 weeks
treatment options for low risk CD patients in remission
- stop therapy and observe
- budesonide 6mg qd
- immunosuppressive therapy
treatment options for high risk CD patients in remission
- if anti-TNF used for induction keep using +/- thiopruine
- if steroid used for induction use immunomodulator or anti-TNF
UC treatment goals
- induce and maintain remission
- stop rectal bleeding
- stop diarrhea
- prevent disability, colectomy and colorectal cancer
initial steps in treatment of UC before starting drugs
- identify and treat infections (C.diff, CMV)
- stop NSAIDs
- stop smoking
low risk factors for colectomy
- limited anatomic extent of UC
- mild endoscopic disease
high risk factors for colectomy
- extensive colitis
- deep ulcers
- age <40
- high CRP and ESR
- Hx hospitalization
- C.diff or CMV infection
- requires steroid
UC low risk treatment for induction
- oral 5ASA and/or
- rectal 5ASA and/or
- oral budesonide or prednisone and/or
- rectal steroids
UC low risk treatment for maintenance
- oral 5ASA and or/ rectal 5ASA
- taper steroid over 60 days
UC high risk treatment options for induction
- short course of steroids w/ thiopurine
- anti-TNF +/- thiopurine
- vedolizumab +/- immunomodulator
UC high risk treatment for maintenance
- if steroids were used continue thiopurine, or switch to anti-TNF or vedolizumab
- if using anti-TNF or vedolizumab for induction continue using w/wo thiopurine
5ASA indication
-induction and maintenance of low risk UC
5ASA efficacy
- topical are better than oral
- combo is best option though
5ASA suppository reach
10 cm, rectum
5ASA enema reach
as far as splenic flexure
treatment for low risk left sided UC
rectal 5ASA +/- oral 5ASA
treatment for low risk extensive UC
both rectal and oral 5ASA
5ASA onset of action
2-4 weeks
supplement sulfasalazine use with what
folic acid
sulfasalazine adverse effects
n/v
dyspepsia
bone marrow suppression
folate deficiency
monitoring for 5ASAs
CBC
SCr
why is budesonide preferred over prednisone
less systemic ADRs
corticosteroid foam reach
sigmoid colon
supplement corticosteroid use with what
calcium and vit D
thiopurine monitoring
- need TPMT screen before initiating
- CBC every 1-2 weeks initially, then every 3 months
- hepatic panel
methotrexate dosing
25 mg SC or IM
methotrexate monitoring
baseline chest x-ray
CBC
hepatic panel
anti-TNF drugs
infliximab
adalimumab
certolizumab
golimumab
anti-TNF drugs are SC injections except
infliximab, IV
anti-TNF drug indication
mod-high risk CD and UC
both induction and maintenance
when to consider anti-TNF monotherapy
high risk of ADRs
- greater than 65
- male and younger than 35 years
- history of cancer
screening to do before using anti-TNF
hepatitis B
latent TB
monitoring for anti-TNF drugs
CBC
hepatic panel
trough concentrations
anti-TNF antibodies
if loss of response to anti-TNF, subtherapeutic level, and not Ab what do we do
increase dose
maybe add immunomodulator
if loss of response to anti-TNF drug, subtherapeutic leve, and high Ab what do we do
switch to another anti-TNF
if loss of response to anti-TNF drug and we have therapeutic level what do we do
switch to vedolizumab +/- immunomodulator
ustekinumab monitoring
TB screen prior to initiation
which surgery is considered curative for UC
proctocolectomy
surgery effectiveness in CD
high rate of recurrence after surgery, so not great
health maintenance for IBD
- colonoscopy every 1-2 years if UC or CD are extensive
- skin cancer screening
- osteoporosis screen if on steroids
- depression and anxiety
vaccinations to do if using immunosuppressants
- PCV12 and PPSV23
- Hep B and Varicella before initiation
drugs for IBS-C
lubiprostone
linaclotide
lubiprostone MoA
stimulates Cl channels in small intestine
lubiprostone use
only females 18 or older
linaclotide MoA
increases cGMP and chloride secretion
drugs for IBS-D
alosetron
eluxadoline
rifaximin
linaclotide counseling
take on empty stomach
alosetron MoA
selective serotonin antagonist
alosetron use
only for females
has a black box warning so use only when absolutely necessary
eluxadoline MoA
mixed opioid agonist
rifaximin MoA
antibiotic and anti-inflammatory effects
