Selected topics in gastroenterology: sources for IBD

A/ Literature in english:

1/ M.A. Simmons - Pharmacology an illustrated review 2012: 273-2772/ P. Rang, M. Dale - Pharmacology 2007: 395-396

B/ Literature in czech:1/ H. Lullmann, Kl. Mohr – Bar. atlas farmakologie(2/ Příprava na zk. z vnitřního lékařství – skripta studentů)

Non-specific inflammatory bowel disease2 types affecting mainly colon with genetic predisposition:

1/ Crohn's disease (ileitis terminalis)chronic segment. inflamm. that affects all layers of the intestinal wall, localization is very often in terminal ileum + colon, but manifestation can be anywhere in the GIT

aetiology + pathogenesis: asocc. with HLA-DR1, smoking, shorter breastfeeding

2/ Ulcerative colitis = idiopathic proctocolitisrecurrent inflamm. disease of colon and rectum

pathogenesis: thought to be autoimm.: assoc. with HLA-DR2, Ig-A nephritis, autoimm. hepatitis among others

goal of therapy: reduce inflamm. response by drugs such as steroids and sulfasalazine + biolog. therapy (anti TNF-alpha, more modern)

Colitis ulcerosa and morbus Crohn – therapeutic options

• Antiinflammatory drugs

1/ mesalazin (Pentasa), active ingredient from sulfasalazine

2/ glucocorticoids antininflammatory and

immunosuppressive action

• Immunosuppressive drugs1/ azathioprin (Imuran tbl.+inj.)2/ methotrexate (Trexane, Metoject)

• Probiotics

• Biological therapy

1/ inhibitors of TNF – alpha

a) Infliximab (Remicade), chimeric monocl. antib.

b) Adalimumab (Humira), hum. monoclon. antib.

c) Not etanercept (Enbrel) !!

2/ inhibition of leucocyte migration natalizumab (Tysabri): anti-integrine eff.

• Supplementation- Vit. B12 inj. (contraind. in cancer)

Non-specific inflammatory bowel disease

A) Regimen approach• Specific diet

effective, also avoiding oranges, grain legumes etc. can help

B) Influencing of pathophysiological processes• Bowel antiinflammatory drugs: aminosalicylates • Biological therapy, immunosuppressive drugs• Corticosteroids:• Hydrocortisone: rect. supposit.: local effects• Prednison: perorally 30-60mg daily if more severe

C) Complications• Antimicrobial drugs if infection (perianal festering compl.)

Aminosalicylates

1/ Mesalazine2/ prodrugs Balsalazide, Olsalazine, Sulfasalazine

metabolized to Mesalazine • the main anti-inflammatory drugs used to treat ulcerative

colitis

• sometimes remission or at least maintaining disease with these drugs alone, can be used in combination

anti-inflammatory action in all these drugs - produced by5-aminosalicylic acid (5-ASA) = Mesalazine: inhibition of prostaglandine and

leukotriene synthesis

• 5-ASA is produced from the pro-drugs in the intestine

SULFASALAZINE and MESALAZINEacute attacks of Crohn´s dis. and ulc. colitis treated with sulfasalzine and

mesalazine, crohn disease may also involve use of steroids

antiinflamm. effects: COX inhibition, inhibition of lipooxygenase, free radicals inactivation

p.o. 1-4g daily (2-3x daily 250-500mg); clysma, supp. (PENTASA)– after therapy for acute problems maintenance therapy (1/2 dose) for

months/ years (success achieved within weeks)

Adv. Eff.: less with mesalazine than after sulfasalazine – nephrotoxicity, interactions (↑toxicity p.o. antidiabetics, methotrexate); if used together with corticosteroids, risk of GIT bleeding is increased

Aminosalicylates, continued

• Sulfasalazine– 75% non-absorbable, in the large bowel bacterial degradation 5-ASA (+

sulfapyridine)– 500mg 2-4x daily till 1g 3-4x daily; maintenance dose is 500mg 4 x daily– sulfasalazine has more ADVERSE effects than mesalazine: headache, dyspeptic

disorders, allergy, reduced sperm count and damage of red / white blood cells haemolytic anemia, hepatotoxicity etc. (patients on high dose of sulfasalazine require folic supplementation to maintain normal blood cell count)

• Olsalazine and balsalazide (not registered in CZ)

AE: better tolerated, diarrhea – increased GITsecretion

Anatomical localization of effect of aminosalicylates

Corticosteroids / Glucocorticoids• local use: supp., enema/clysma, foam – when problem localised near rectum

• systemic use: prednison or prednisolon, budesonide, hydrocortison

effective in both ulcerative colitis and Crohn dis. in inducing a remission in acute persistent disease, systematically used until control of inflamm. is achieved then tapered down and discontinued

budesonide (for ex.: BUDENOFALK cps with controlled release, rectal foam, ENTOCORT cps, enema)

• faster metabolized, fewer side effects

Immunosuppressants (antimetabolites, Cyclosporine-A)

•Azathioprin, 6-merkaptopurine - false substrate for purine biosynthesis and reduction of NK-cells in immune system – in patients with severe disease (longer-lasting highly active inflammation)

•Methotrexate (folic acid antagonist) – inhibits dihydrofolate reductase which reduces purine and pyrimidine synthesis in lymphocytes (i.m. - than p.o. 10-15 mg weekly) and inhibits cell growth in rapidly proliferating tissues like bone marrow = control of blood counts

•Cyclosporine A in severe colitis – corticosterid-resistant – short-term treatment with Cyclosporine A that reduces IL-2 synthesis in T-helper lymphocytes (effect after 6-8 weeks)

Biotransformation of azathioprine

Indications for operation

Morbus Crohn• Perforation, peritonitis

• Ileus

• Massive bleeding

• Pronounced stenosis

• Fistula, abscess

• Failure of conservative therapy

Colitis ulcerosa• Perforation, peritonitis• Proven precancerosis• Toxic megacolon• Pronounced stenosis• Long severe disease course

(surgery as prevention of

carcinoma development)

Treatment of festering complications with ATB• Festering (putrefactive) complications:1) active colitis ulcerosa2) Crohn´s disease

• Ciprofloxacin: broad-spectrum chinoline ATB that blocks DNA gyrasis /CIFLOXINAL,CIPHIN, CIPLOX/

• Metronidazole: well passing to CNS, bones etc., anaerobic pathogens + against - aerobic /EFLORAN, ENTIZOL, METROZOL/

• Clarithromycin: broad-spectrum macrolide /KLACID, FROMILID/

• Rifaximine

• Co-trimoxazole

Spasmolytics/antispasmodic drugs –

smooth muscles

(of GIT, urinary tract)

SPASMOLYTICS: neurotropic

parasympatholytics - atropine-like eff. – quarternary nitrogen structure - hydrophilic – (N-butyl scopolamine)

N-butyl scopolamine, otilonii bromidum, fenpiverinium, oxyphenonium

Use: used for smooth muscels contraction, especially in tubular organs of the GIT - to prevent spasms of the stomach, gall or urinary bladder, GIT dyskinesis

In combinations with analgetic drugs

Spasmolytics: musculotropic

musculotropic – direct effect in the muscle

-papaverine-like

papaverine, drotaverine, alverine, mebeverine, pitofenone

Use: prevent spasms of the stomach, intestine or urinary bladder, GIT dyskinesis.

Combinations with analgetic drugs

Spasmoanalgesics• A) Combinations of analgesics + spasmolytics

– Pitofenone + fenpiverine + metamizol = ALGIFEN, ANALGIN, SPASMOPAN

• B) Analgetic drugs with spasmolytic effects – metamizol /NOVALGIN/, pethidin /DOLSIN/

USE: symptomatic painful spasms of GIT or urinary tract (bladder, kidney colics), spastic migraine, dysmenorrhea, instrumental checkup

Probiotics, prebiotics

• Prebiotics nonabsorbable oligosacharides supporting normal intestinal microflora (e.g. bifidobacteria) – mannan, inulin, lactulosis

• Probiotics – alive bacteriaLactobac. delbruecki, Acidophilus casei, Enteroc. faecium other bifidobacteria

– competition with pathogenes– production of substances that inhibit pathogenes (lactic acid, peroxide)– intestine immunity support

Prevention – carcinomas, allergy, traveler´s diarrhea

Deflatulents

• Meteorism – daily production of 1-2 l of gas; disturbancies – increassed production, limited absorption in inflammation, venostasis….

• Treatment - reduction of surface tension activity of liquides in the GIT tube

• Deflatulents:

– Simeticon – activated dimeticon (silicon oil dispersion) – non-absorbable

– bowel eubiotics - prebiotics and probiotics

Bowel eubiotics

• A) probiotics: alive non-pathogenic bacteria or candida)

• B) prebiotics: oligofructans – support growth of physiological microflora

• C) symbiotics: mixture of alive nonpathogenic bacteria or candida and growth substrates)

Bowel eubiotics

• Escherichia coli – well sensitive on ATB

• Lactobacillus acidophilus

• Lactobacilli acidophili metabolits (concentrate of metabolic products, no alive bacteria)

• Saccharomyces boulardii siccatus (alive probiotic candida supports natural microflora)

Other possible indications of drugs that are used for therapy of colitis ulcerosa/ m. Crohn

• Antiinflammatory drugs

1) mesalazin (Pentasa), active ingredient from sulfasalazine

only indicationfor colitis ulcerosa + m. Crohn

2) glucocorticoids antiinflammatory + immunosuppressive

astma – inhal. systems, if severe p.o. dermatology - eczema

rheumatology, ophthalmology

• Immunosuppressive drugs

1) azathioprin - transplantation, severe RA, SLE - autoimmune hemolytic anemia - polyarteritis nodosa - autoimmune chronic act. hepatitis

2) methotrexate: cytostat. + immunosuppr.

a) oncology ac. lymfobl. leucaemia, osteosarcomab) rheumatology severe active rheumat. + psoriat. artritis

Other indications of biological drugs used for therapy of colitis ulcerosa/ m. CrohnA/ inhibitors of TNF - alpha

1/ Infliximab: contraindicated in pregnancy + breastfeeding,

severe infection (sepsis, TBC), heart failure, hypersensitivity- rheumatoid artritis

- psoriatic artritis and psoriasis, ancylosing spondylitis

2/ Adalimumab: contraindicated in pregnancy + breastfeeding,

severe infection (sepsis, TBC), heart failure, hypersensitivity - rheumatoid artritis, polyarticular juvenile idiopathic artritis

- psoriatic artritis and psoriasis, ancylosing spondylitis

B/ inhib. of leucocyte migration: natalizumab - multiple sclerosis

Intestine infection, diarrhea: possible ther. options• Cloroxine (ENDIARON)

• bacteriostatic, g+, g-, against Candidas (in dysmicrobia following ATB use)• No resistance• No absorption – local effect, low toxicity, usually well tolerated • + oxyphenone – spasmolytic; + further combinations with peripheral „opioids“ (loperamide,

difenoxylate)• Possible risk of neurotoxicity in longterm therapy, appl. for max. 7-10 days

• Rifaximine (NORMIX)

nonabsorbable ATB – inhib. of RNA-synthesis; children from 2 years, bactericidal eff., g+, g-, risk of resistance

• Nifuroxazide (ERCEFURYL)

nonabsorbable, bacteriostatic chemotherapeutic for ac. infection diarrhea

• Co-trimoxazol = sulfamethoxazol+trimethoprim: from 6 yrs (BISEPTOL)

Antibiotics for ACUTE CHOLECYSTITIS and CHOLANGITIS

Ac. cholecystitis• AMP

• Tetracycline

• Cotrimoxazole

Ac. cholangitis• AMP

• (Chloramphenikol)

• Tetracycline