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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)
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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)
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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)
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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.)
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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
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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
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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
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Anatomical localization of effect of aminosalicylates
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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
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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)
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Biotransformation of azathioprine
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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)
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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
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Spasmolytics/antispasmodic drugs –
smooth muscles
(of GIT, urinary tract)
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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
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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
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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
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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
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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
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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)
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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)
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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
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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
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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)
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Antibiotics for ACUTE CHOLECYSTITIS and CHOLANGITIS
Ac. cholecystitis• AMP
• Tetracycline
• Cotrimoxazole
Ac. cholangitis• AMP
• (Chloramphenikol)
• Tetracycline