Anja St.Clair JonesLead Pharmacist Digestive Diseases

Royal Sussex County Hospital Brighton

Medicines Optimisation in IBDCan we base it on evidence?

Aims and Objectives

Enable medicines optimisation in IBD

• Understand Inflammatory Bowel Disease (IBD),

• Describe drugs used in treatment of IBD • Develop strategies for medicines

optimisation

Stomach

Duodenum

Jejunum

Ileum

Caecum

Terminal ileum

Ascending colon(Right sided/ proximal)

Transverse colon

Splenic flexure

Descending colon (Left sided/distal)

Sigmoid colon

Hepatic flexure

Rectum

Anus

Epidemiology• Disease of YOUNG people (peak 10-25y, 50+y)• Up to 260’000 people affected in UK• UC: 10/100’000 per year

– prevalence 146/100’000 (NICE 2013, CG 166)– Incidence stable – Difference in ethnic groups (Ashkenazi Jews)– 50% have relapse in any year – 25% acute sever colitis during lifetime (NICE 2013)– 90% are able to FT work 1year after diagnosis

• CD: 5-10/100’00 per year– prevalence 157/100’000 (NICE 2012, CG152) – Incidence increasing– 75% able to work in year after diagnosis– 15-20% disabled by disease within 5 years (NICE 2012)– 50-80% require surgery for strictures (NICE 2012)

Anatomic distribution in Crohn’s

80% left sided only

PathogenesisTheories of inflammatory bowel disease etiology

-Toxic response to luminal contents-Specific microbial pathogen-Abnormal luminal constituents-Increased absorption of luminal macromolecules-Enhanced immunologic response to normal constituents-Autoimmune response-To epithelial cell or mucus glycoproteins-Molecular mimicry (cross-reactivity of intestinal microflora and epithelia)-To immune cells

Trigger – what? Genetic involvement

Immune dysregulation in Crohn's disease

CD or UC?

  Ulcerative colitis Crohn's disease

Site of disease Colon onlyAny part of gastrointestinal

tractSymptoms    Bleeding +++ +Diarrhea +++ ++Abdominal pain ++ +++Growth failure + +++Tenesmus +++ ±Perianal disease — +Endoscopic findings    Rectal involvement +++ +Inflammation Continuous Discontinuous  Diffuse erythema Patchy lesions

  Ulceration in inflamed mucosaDiscrete ulcers in normal

mucosaComplications    Fistulas Exceedingly uncommon Frequent  (? Crohn's)  Strictures Uncommon (? malignancy) CommonCancer risk (>10 years) Increased Increased

Fistulae in IBD

Diagnosis and investigations• History and examination• FBC, LFT, ESR or CRP• Microbiological testing (C. Diff., CMV)• Abdo imaging• Endoscopies +/- biopsies• Barium enema, small bowel studies• Colonoscopy• Assessment of disease extent

Figure 1a and 1b: endoscopic views of Crohn’s disease showing mucosal oedema, ulceration and exudates.

Crohn's Disease Activity Index

• CDAI = 2x1 + 5x2 + 7x3 + 20x4 + 30x5 + 10x6 + 6x7 + (weight factor)8 • 1. Number of liquid or very soft stools in one week • 2. Sum of seven daily abdominal pain ratings:

    (0=none, 1=mild, 2=moderate, 3=severe)• 3. Sum of seven daily ratings of general well-being:

    (0=well, 1=slightly below par, 2=poor, 3=very poor, 4=terrible) • 4. Symptoms or findings presumed related to Crohn's disease

arthritis or arthralgia iritis or uveitis erythema nodosum, pyoderma gangrenosum, apththous stomatitis anal fissure, fistula or perirectal abscess other bowel-related fistula febrile (fever) episode over 100 degrees during past week

• 5. Taking Lomotil or opiates for diarrhea • 6. Abnormal mass

    0=none; 0.4=questionable; 1=present     • 7. Hematocrit [ (Typical - Current) x 6 ]

• 8. 100 x [(standard weight-actual body weight) / standard weight]

Harvey–Bradshaw Index for Crohn's disease

• Number of liquid stools per day• Abdominal pain, sum of seven daily ratings:

(0-none, 1-mild, 2-moderate, 3-severe)

• Abdominal mass(0-none, 1-questionable, 2-definite, 3-definite & tender)

• General well being(0-very well, 1-slightly below par, 2-poor, 3-very poor, 4-terrible)

• Complications (score 1 point per item)Arthritis/arthalgiaSkin/mouth lesionsIritis/uveitisAnal fissure, fistula/perianal abscess

UC activity scores

Therapeutic aim• Remission• Avoid surgery• CRC (5x) Also:

– Smoking cessation– VTE prophylaxis (always!!)– Pain control (no NSAIDs)– Osteoporosis prophylaxis– Opportunistic infections – https://www.ecco-ibd.eu/documents/ECCOconsensusOI.pdf

Treatments

How to optimise treatment?• Correct dose• Co-prescribing• TDM• Exit strategies• Rescue strategies

Steroids• Indication: CD and UC

– Moderate to severe relapse• Maximise local effect and limit systemic effect• No role in maintenance

– 40mg OD Prednisolone reduced slowly by 5mg/week– ≤ 15mg ineffective in active disease

• Budesonide not as effective as Pred but alternative in ileo-ascending colonic disease– Less systemic effect

• Osteoporosis

Rectal steroidsOnly for patient not responding to rectal mesalazine• Hydrocortisone (Colifoam) 1 od-bd

– High plasma levels after administration

• Prednisolone NaPhos (Predsol) 1 bd– Rectal mucosa only

• Prednisolone metosulphbenzoate (Predenema 1 od)– Poorly absorbed – Increased spread (reached ascending colon in some patient)

• Prednisolone metosulphbenzoate (Predfoam 1od-bd)– Poorly absorbed– Retained in rectum and sigmoid colon

Rectal steroidsRectal steroid Peak plasma nmols/L Peak tissue ng/g

Prednisolone phosphate 20mg

365 (2hrs) 44

PredenemaPrednisolone meta-sulphbenzoate 20mg

45 (2hrs) 257

PredfoamPrednisolone meta-sulphbenzoate 20mg

320 (4hrs) 4874

ColifoamHydrocortisone Acetate 125mg

510(4hrs) Not recorded

Optimisation

• Correct dose– Start at 40mg and slow reduction

• Correct formulation– Know where the disease is located

• Prevent osteoporosis• Consider infection risk

Rectal reparations: site of action and indication

Formulation Site of action Disease extent

Suppository Rectum Proctitis

Foam Sigmoid Colon Procto-sigmoiditis

Enema Descending colon to splenic flexure and in some cases even distal part of transverse colon.

Left sided ( distal)colitis

5-ASA• Dose:• Crohn’s:

– higher doses ≥ 4g no evidence (post op only)• UC:

– Induction of remissions ≥ 4g/day– Maintenance of remission ≥ 2g/day

• Rectal preparations (PINCE) – 15% past splenic flexure:2g bd oral + 1g OD

rectal (64% remission at week 8 vs 43% oral)• Compliance at week 8

– (PODIUM: OD vs BD:71% vs 59% remission)

Drug Formulation Optimal drug release pH

Site of drug release

MesalazineAsacol MR 400mg: Enteric coated with Eudragit S

800mg: Enteric coated with layer of Eudragit S followed by Eudragit S+L

pH-dep. delayed release (>7)

 

Terminal ileum & large bowel (colon & rectum)

Ipocol Enteric coated with Eudragit S >7 Terminal ileum & colonMesren MR Enteric coated with Eudragit S >7 Terminal ileum & colonOctasa MR Enteric coated with Eudragit S >7 Terminal ileum & colonMezavant XL Film coated with methacrylate copolymers Type

A, Type BGastroresistant

coating with Lipophylic and

hydrophilic matrix(>7)

Colon

Pentasa Ethylcellulose coated microgranules to allow slow continuous release

Diffusion through semi-permeable

membrane (Enteral pH)

Duodenum to rectum

Salofalk Tablets: Enteric coated with Eudragit LGranules: Eudragit L and matrix granule structure (slow continuous release)

pH-dep. delayed release (>6) and

matrix

Terminal ileum & colon

Azo-bonded preparationsSalazopyrin (Sulfasalazine) Colazide (Balsalazide)Dipentum (Olsalazide)

5-ASA +SA Prodrug Dimer

Cleavage by intestinal bacteriaAzoreductase(>7)

Colon

Adherence and switching• 39% adherence in maintenance

Robinson; APT 2013– 61% chance of relapse vs 11% – Increased risk of CRC 31% vs 3%

• 75% risk reduction in adherers– Cost :14% admission = 49% of cost

Kane 2006, Bassi 2004, Hawthorne 2008• Switch patients had 3.5-fold risk of relapse• Endoscopic healing rate is not equivalent

Optimisation• Top and tail in sever flares• Consider switching carefully• Support Adherence

– Tailor formulation to patient– Reinforce message of CRC prevention – Consider switch of preparation carefully– Consider impact on endoscopic healing