Celecoxib, etoricoxib: selective COX-2 inhibitors (p.o.) (valdecoxib for parenteral use: ac. postoperat. pain )

Celecoxibe (Celebrex)

• Pharm. Form and dosage

cps. 100/200 mg: once/twice daily

• Indications

- osteoarthritis

- rheumatoid arthritis

- pain in dysmenorrhea

• Contraindications

- CAD, heart failure NYHA III or IV,

not controlled hypertension

Etoricoxibe (Arcoxia)

• Pharm. Form and dosage

Tbl. 30/60/90/120 mg: once daily

• Indications

- osteoarthritis

- rheumatoid arthritis

- ac. gout attack

• Contraindications

- CAD, heart failure NYHA III or IV,

not controlled hypertension

Magdalena Šustková, Petr Potměšil

Selected topics in gastroenterology

Non-specific inflammatory bowel diseasesno clearly discernible 1 aetiological cause of disease

2 most important of these diseases affecting the large bowel:

• Ulcerative colitis = idiopathic proctocolitisconfined to the large bowel (few centimetres of the terminal ileum may be affected by ileitis)

• Crohn's disease = ileitis terminalismicroscopically affects the whole of the gastrointestinal tract (very often ileitis or ileocolitis or manifestation in the large bowel)

chronic diseases: try to treat the acute symptoms then maintaining remission and avoiding complications

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.)

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

Aminosalicylates• the main anti-inflammatory drugs used to treat

ulcerative colitis

• sometimes remission or at least maintaining disease with these drugs alone

• usually used in combination

• anti-inflammatory action in all these drugs - produced by5-aminosalicylic acid (5-ASA) = Mesalazine

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

MESALAZINE– absorbed in jejunum – specific drug formes for effect in large

bowel

– Local effect: COX inhibition, inhibition of lipooxygenase …? free radicals inactivation ?

– p.o. 1-4g daily (2-3x daily 250-500mg); clysma, supp (ASACOL, PENTASA, SALOFALK)

– acute problems therapy – maintenance therapy (1/2D) months, years; (success within 4 weeks)

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

Aminosalicylates• Pro-drugs of mesalazine (5-ASA):• Sulfasalazine (SALZOPYRIN, SULFASALAZIN)– 75% non-absorbable, in the large bowel bacterial degradation 5-ASA (+

sulfapyridine)– 500mg 2-4x daily till 1g 3-4x daily; maintenance d. 500mg 4xdaily

– More ADVE 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• supp., enema/clysma, foam – when problem localised near rectum,

mostly individually produced/ magistraliter (for example methyprednisolon inj. as enema)

• systemic hydrocortison, prednison (60mg – go down to 20mg/day), prednisolon

• New synthetic derivates – local use – non-absorbable, less adverse effects,

• budesonide /3 x daily, BUDENOFALK cps, controlled release, rectal foam, ENTOCORT

cps, enema/, faster metabolized, fewer side effects

Immunosuppressive drugsmostly azathioprin (1-3mg/kg/day, go down), 6-merkaptopurine (1 mg/kg/day) - reduce NK-cells of immune system – in longer-lasting highly active inflammation (higher D of corticosteroids) – haematogenesis control!

•methotrexate (folic acid antagonist) – in non tolerated (i.m. - than p.o. 10-15mg weekly)

•in severe colitis – corticosterid-resistant – short-time combination with ciclosporine A (1-7mg/kg/day – after 6-8 weeks effect), recidives

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)

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

• Chloramfenikol

• Tetracycline