Transcript 2/ methotrexate

Selected topics in gastroenterology: sources for IBD
A/ Literature in english:
1/ M.A. Simmons - Pharmacology an illustrated review
2012: 273-277
2/ 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 disease
2 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 proctocolitis
recurrent 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
• Biological therapy
1/ mesalazin (Pentasa), active
ingredient from sulfasalazine
2/ glucocorticoids
antininflammatory and
immunosuppressive action
1/ inhibitors of TNF – alpha
• Immunosuppressive drugs
2/ inhibition of leucocyte migration
1/ azathioprin (Imuran tbl.+inj.)
2/ methotrexate (Trexane, Metoject)
• Probiotics
a) Infliximab (Remicade), chimeric monocl. antib.
b) Adalimumab (Humira), hum. monoclon. antib.
c) Not etanercept (Enbrel) !!
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/ Mesalazine
2/ 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 by
5-aminosalicylic acid (5-ASA) = Mesalazine: inhibition of prostaglandine and
leukotriene synthesis
• 5-ASA is produced from the pro-drugs in the intestine
SULFASALAZINE and MESALAZINE
acute 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
Colitis ulcerosa
Perforation, peritonitis
Ileus
Massive bleeding
Pronounced stenosis
Fistula, abscess
Failure of conservative
therapy
•
•
•
•
•
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 ulcerosa
2) 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 bacteria
Lactobac. 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 indication
for colitis ulcerosa + m. Crohn
• Immunosuppressive drugs
1) azathioprin
- transplantation, severe RA, SLE
- autoimmune hemolytic anemia
- polyarteritis nodosa
- autoimmune chronic act. hepatitis
2) methotrexate: cytostat. + immunosuppr.
2) glucocorticoids
antiinflammatory + immunosuppressive a) oncology
astma – inhal. systems, if severe p.o.
ac. lymfobl. leucaemia, osteosarcoma
dermatology - eczema
b) rheumatology
rheumatology, ophthalmology
severe active rheumat. + psoriat. artritis
Other indications of biological drugs used for
therapy of colitis ulcerosa/ m. Crohn
A/ 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
Ac. cholangitis
• AMP
• Tetracycline
• Cotrimoxazole
• AMP
• (Chloramphenikol)
• Tetracycline