IBD Part 2.1 - therapeutic options Flashcards
Nancy is a 32 year old woman with Crohn’s Disease
primarily of the ileum and ascending colon for which Nancy is taking Pentasa. Nancy’s symptoms were controlled while on Pentasa for about 2 years (after diagnosis, no other exacerbations during that time).
About two weeks ago Nancy started experiencing:
• diarrhea – 6 – 8 loose stools per day
• severe abdominal pain
• fatigue, weight loss
What are the treatment options to help Nancy?
Therapeutic Options for IBD:
Anti-inflammatory Therapies: § aminosalicylates • 5-aminosalicylic acid (5-ASA) • sulfasalazineaminosalicylates § corticosteroids
Immunosuppressants:
§ azathioprine, 6-mercaptopurine
§ methotrexate
§ cyclosporine
Antibiotics:
§ metronidazole
§ ciprofloxacin
Biologics: TNF-µ antagonists § infliximab § adalimumab § certolizumab § golimumab
Alpha-integrin therapies
§ vedolizumab
Interleukin antagonist
§ ustekinumab
Targeted immunosuppressant:
JAK inhibitor
§ tofacitinib
Aminosalicylates
Efficacy/role in IBD
• Effectiveness depends on high concentration
• Clinical response in 3-4 weeks
Role:
• Induction therapy (induction of remission)
• Mild to moderate active ulcerative colitis (UC), crohn’s
disease (CD) – unclear how effective they are for CD
Maintenance of remission:
• Role in maintenance for UC
• Role in CD controversial
Aminosalicylates: Formulations
Azo compounds:
• Azo-bond conjugates (azo bonds are cleaved by bacteria in the colon):
- Sulfasalazine – consists of 5-aminosalicylate (5-ASA) linked to sulfapyridine by a diazo-bond
- Olsalazine - 2 molecules of 5-ASA linked by diazo-bond
Aminosalicylates: Formulations
Mesalamine compounds:
§ PH dependent 5-ASA products with varied Eudragit (USP) coatings:
• delayed release: Asacol ®
• enteric coated: Salofalk ®
§ Time release 5-ASA products
• ethylcellulose coated microgranules allowing for sustained release - Pentasa ®
§ Delayed + extended release – Multi Matrix System technology - Mezavant
Considerations in choosing products:
§ Match disease location with site of drug release
§ Rectal products may be first choice for distal disease (for example suppository or
enema)
see slide 8 & slide 9
Aminosalicylates: Adverse effects
Sulfasalazine:
§ adverse effects primarily due to sulfapyridine moiety
§ slow acetylators of sulfapyridine have greater adverse effects then fast acetylators
dose related (up to 45%):
- nausea, GI upset, diarrhea, anorexia, malaise
- arthralgia, reticulocytosis,
non-dose related (rare):
- hypersensitivity: rash, fever,
- pericarditis, hep atitis, pneumonitis, pancreatitis
- hemolytic anemia
- oligospermia (reverses after sulfa. discontinuation)
Note: sulfasalazine decreases folate levels – patients may need supplementation with folic acid.
Aminosalicylates: Adverse effects
Other 5-ASA products:
§ Patients intolerant of sulfasalazine will often tolerate 5-ASA (also consider if sulfa allergy)
§ Adverse effects: GI (nausea, abdominal pain, dyspepsia), headache, flu like, rash, diarrhea
§ Most common adverse effect with olsalazine is diarrhea (12-28% of patients). Minimize by slowly increasing dose and taking with food.
§ Cross sensitivity with ASA allergy
Corticosteroids
Route of administration (see table: Corticosteroids):
Induction therapy: moderate to severe active UC/CD
Maintenance of remission: no role in maintaining remission for UC/CD
Oral: Consider oral prednisone in moderate to severe disease.
IV: active severe disease when patient has failed oral prednisone
and/or has been hospitalized (note: there may decreased
absorption of oral prednisone in acute flare-up).
• when satisfactory response switch to oral prednisone.
note: patients that require steroids on an ongoing basis (ie have flare-up of disease when the steroid is tapered) are considered steroid-dependent .
Corticosteroids: Formulations
see slide 13
Corticosteroids: Adverse Effects
short term:
- fluid and electrolyte disturbances, hyperglycemia,
increased susceptibility to infections, psychosis, gastric upset.
long term:
- HPA axis suppression, osteoporosis, cataracts, muscle wasting, Cushing s syndrome (buffalo hump, moon face, etc), depression, PUD, impaired wound healing
Corticosteroids
Tapering for oral prednisone:
- 7 – 14 days to see response
* begin tapering when feasible (ie 5 mg qweekly or 5 mg q1- 2 days if would like faster taper)
Corticosteroids
Oral budesonide
Oral budesonide (Entocort™, generics) • Formulated in a controlled ileal release preparation (CIR) - deposits budesonide predominantly in the ileum and ascending colon. • Induction therapy: mild to moderate active CD
Oral budesonide multi-matrix formulation (MMX) (Cortiment™)
• Tablet core is enteric coated, delays disintegration, upon disintegration core matrix releases budosenide time-dependent manner (throughout the colon).
• Induction therapy: for mild to moderate ulcerative colitis
Budesonide has less systemic side effects as extensive first pass metabolism and
decreased systemic levels.
Immunosuppressants: Thiopurines
name, onset
role
Azathioprine (AZA) and 6-mercaptopurine (6-MP)
• Note that these drugs have a slow onset of effect - 3 - 6 months
Dose: UC 50 – 100 mg daily, CD 150 mg daily (maintenance dose same as induction dose
Induction therapy: moderate to severe active UC/CD (but ineffective on own!)
Maintenance of remission: role in maintaining remission for UC/CD
Maintain remission
In combo with other agents like biologics
Azathioprine is a prodrug , 6-MP gets broken into metabolites
Immunosuppressants: Thiopurines
Adverse effects:
dose-related?
non-dose related?
§ dose-related:
• GI (nausea, diarrhea),
• Decrease WBC (leukopenia)
• Hepatic toxicity
§ non-dose related: • Hypersensitivity reaction (fever, rash, arthralgias) • Pancreatitis (3%) • Hepatitis
Monitor:
CBC/WBC – baseline and one month
Liver Function Tests
Immunosuppressants: Thiopurines
Adverse effects:
Note: Pregnancy “Category D” under old FDA Classification, however many clinicians will continue (weigh risk over benefit)
§ AZA/6-MP metabolized by Thioprine S-methyltransferase (TPMT)
• Patients (0.1% of population) with low level of activity have increased risk of bone marrow suppression. TPMT testing could be considered prior to initiation.
§ Risk of malignancy
• Lymphoma (lymphoproliferative disorders)
• nonmelanoma skin cancers – reduce UV exposure (sunscreen, sun protection)
Greater risk to benefit before,
Now there is data saying it is safe in pregnancy
Greater risk in fetus
