Aminosalicylate preparations

1
Medical management of ulcerative colitis

• Aminosalicylate preparations
• Preparation Delivery Dose
• Azo-bond Colon 3 6 g/d active
• Sulfasalazine 2 4 g/d maintn
• Olsalazine
• Balsalazide
• Delayed Release 5-ASA Ileum to colon 2.4 4.8
  g/d
• Sustained Release 5-ASA Stomach to colon 2 4
  g/d
• Topical Therapy Rectum 1 4 g/d

Niraj Jani et al. Gastro Clin North America 2002,
Katz S. J Clin Gastro 2002, Farrell RJ et al
Lancet 2002, Chinyu Su et al, Gastro Clin North
America 2002, Kernbluth A et al. Am J Gastro 1997
2
Medical management of ulcerative colitis

• 5-ASA in mild-moderate ulcerative colitis

Niraj Jani et al. Gastro Clin North America 2002,
Katz S. J Clin Gastro 2002, Farrell RJ et al
Lancet 2002, Chinyu Su et al, Gastro Clin North
America 2002
3
Medical management of ulcerative colitis

• Recommendations for managing mild moderate
  distal ulcerative colitis achieving remission
• Oral mesalamine 2 4.8 g / d
• Oral sulfasalazine 4 6 g / d
• Topical mesalamine suppositories 500 mg BID
• Topical mesalamine enemas 1 4 g / d
• Evidence based efficacy of agents
• 5-ASA Topical is superior to oral
• Topical 5-ASA is superior to topical steroids
• Combination of topical oral 5ASA gtgt to either
  alone
• Dose Response curve

American College of Gastroenterology Guidelines
4
Medical management of ulcerative colitis

• Recommendations for managing mild moderate
  distal ulcerative colitis achieving remission
• Oral 5-ASA 1.5 4.0 g/d ? 4.8 g/d
• Oral sulfasalazine 2 4 g /d
• 5-ASA enema 2 4 g / every 3rd night
• Combination (oral 1.6 g/d, topical 4g/ tiw)

American College of Gastroenterology Guidelines
5
Adverse effects of salicylates
Medical management of ulcerative colitis

• Sulfasalazine
• Dose dependent
• Anorexia, nausea, dyspepsia, headache, folate
  malabsorption, sperm abnormalities
• Idiosyncratic
• Hypersensitivity reaction, bone marrow ?,
  hepatitis, pancreatitis,pneumonitis
  eosinophilia, colitis

• 5-ASA
• Headache, dyspepsia
• Hypersensitivity colitis, nephrotoxicity,
  myocarditis, pneomonitis, hepatitis, pancreatitis

Niraj Jani et al. Gastro Clin North America 2002,
Katz S. J Clin Gastro 2002,
6
Medical management of ulcerative colitis

• Corticosteroids in ulcerative colitis
• Effective for inducing remission in
  moderate-to-severe disease
• Dose dependant response
• Not recommended for maintaining remission

Niraj Jani et al. Gastro Clin North America 2002,
Katz S. J Clin Gastro 2002, Farrell RJ et al
Lancet 2002,
7
Corticosteroids in ulcerative colitis
severity and response
Medical management of ulcerative colitis
Niraj Jani et al. Gastroenterol Clin North
America 2002
8
Medical management of ulcerative colitis

• Corticosteroids in moderately severe UC
• Response 84
• Failure of response 16
• Responders outcome after 1 year
• In remission off steroids 48
• Steroid dependent 22
• Required surgery 29

Faubon W. et al Gastroenterology 2001121
255-60
9
Medical management of ulcerative colitis

• Corticosteroid toxicity
• Adrenal suppression
• Osteoporosis
• Hypertension ( x 4 of controls)
• Glucose intolerance ( x 4 of controls)
• Infections ( relative risk 1.6)
• Cushingoid
• Psychiatric effects
• Posterior subcapsular cataract (9)
• Cutaneous effects

10
Medical management of ulcerative colitis
Aims of locally acting GCS therapy in IBD Induce
remission of mild to moderate active
disease Prolong remission Minimise the frequency
of adverse events Improve quality of life
11
Medical management of ulcerative colitis
Budesonide The Molecule
12
Medical management of ulcerative colitis

• Immunomodulators
• Azathioprine / 6-MP
• Role
• Inducing remission ( with steroids)
• Maintaining remission
• Steroid sparing effect
• Delayed onset of action
• Requires close monitoring

Niraj Jani et al. Gastro Clin North America 2002,
Katz S. J Clin Gastro 2002, Farrell RJ et al
Lancet 2002, Chinyu Su et al, Gastro Clin North
America 2002,
13
Immunomodulators
Medical management of ulcerative colitis
Achieving remission
Maintaining remission
Remission at 1 year
Steroid Dependant UC
Kornbluth A et al. American J Gastroenterol,
1997, Farrell RJ et al. Lancet 2002
14
Medical management of ulcerative colitis

• Adverse effects of immunomodulators
• AZA / 6 MP are metabolized
• Metabolites 6TG 6MMP
• Crucial enzyme Thiopurine methyl transferase
  (TPMT)
• Homozygous 89
• Heterozygous 11
• Absent enzyme 0.3
• Adverse effects bone marrow ?, hepatitis,
  pancreatitis

Niraj Jani et al. Gastro Clin North America 2002,
Katz S. J Clin Gastro 2002, Farrell RJ et al
Lancet 2002, Chinyu Su et al, Gastro Clin North
America 2002
15
Medical management of ulcerative colitis

• Management in fulminant colitis
• Intravenous fluids
• Electrolytes
• Nil orally
• Local ileus, toxic mega-colon, perforation ?
• Bowel decompression
• If distended and paralytic
• Transfusions blood, albumin
• Antibiotics
• Corticosteroids I.V.

16
Medical management of ulcerative colitis

• Cyclosporine A in fulminant colitis
• n 14
• Daily dose 4 mg/Kg
• Response at 8 days 64
• Remission at 1 year 78

DHaens G et al. Gastroenterology 2001 1323-9
17
Cyclosporine A in fulminant colitis
Medical management of ulcerative colitis
18
Medical management of ulcerative colitis

• Mechanism of action
• Corticosteroids
• ? release of inflammatory mediators
• ? vascular permeability
• ? infiltration of inflammatory cells
• ? proliferation of B and T cells
• Cyclosporine A
• ? Cytotoxic T cells

19
Medical management of ulcerative colitis

• Cyclosporine side effects
• GM seizures
• Pneumocystis carinii infection
• Hypertension
• Electrolyte abnormalities
• Clostridium difficile
• Neurologic toxicity
• Nephrotoxicity

20
Medical management of ulcerative colitis

• Managing severe ulcerative colitis
• Hospitalization
• IV Corticosteroids
• If no improvement within 7 days
• IV Cyclosporine (4 mg/Kg/d)
• Adding AZA / 6-MP enhances long term remission

American College of Gastroenterology
Recommendation 2002
Niraj Jani et al. Gastro Clin North America 2002,
Katz S. J Clin Gastro 2002, Farrell RJ et al
Lancet 2002, Chinyu Su et al, Gastro Clin North
America 2002
21
Medical management of ulcerative colitis

• Emerging therapies
• Nicotine
• Antibiotics
• ciprofloxacin, rifaximin, metronidazole
• Probiotics
• Fish oil
• Short chain fatty acids
• Heparin therapy
• Infliximab

22
Medical management of ulcerative colitis

• The SGPGI experience
• Total patients 400
• Limited colitis 50
• Proctitis 10
• L sided colitis 40
• Pan colitis 50
• Immune modulators 30 ( 23 of 125 )

23
Medical management of ulcerative colitis

• Current medical therapy for ulcerative colitis
• Agent Induction therapy Maintenance
• Mild- Moderate Severe
• 5-ASA
• Oral -
• Topical -
• Steroids
• Oral -
• Topical ? -
• I.V -
• AZA / 6 MP
• Cyclosporine - -