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Gastro-Intestinal Drugs

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Gastro-Intestinal Drugs Powered By Docstoc
					 abdominal  discomfort (pain, bloating,
  distention, or cramps)
 alterations in bowel habits (diarrhea,
  constipation, or both).
 predominant   diarrhea, antidiarrheal agents,
  especially loperamide
 predominant constipation, fiber supplements
 For chronic abdominal pain, low doses of
  tricyclic antidepressants (eg, amitriptyline or
  desipramine)
 The anticholinergic properties -
  gastrointestinal motility and secretion,
  reducing stool frequency and liquidity.
 dicyclomine   and hyoscyamine
 exhibit significant additional anticholinergic
  effects including-
 dry mouth
 visual disturbances
 urinary retention
 constipation.
 inhibit sensation, including nausea, bloating,
  and pain.
 reduces the central response to visceral
  afferent stimulation.
 inhibits colonic motility, especially in the left
  colon, increasing total colonic transit time.
 Alosetron  is a 5-HT3 antagonist that has been
  for the treatment of patients with severe IBS
  with diarrhea
 Four other 5-HT3 antagonists (ondansetron,
  granisetron, dolasetron, and palonosetron)
 Alosetron  -for the treatment of women with
  severe IBS ("diarrhea-predominant IBS").
 Its efficacy in men has not been established.
 it reduces IBS-related lower abdominal pain,
  cramps, urgency, and diarrhea.
 gastrointestinal   toxicity
 Constipation
 Episodes  of ischemic colitis
Drug Interactions:
being metabolized by a number of CYP
  enzymes, alosetron does not have clinically
  significant interactions with other drugs.
 Chloride Channel Activator
 Serotonin 5-HT4-Receptor Agonists
 Inflammatory   bowel disease (IBD) comprises
  two distinct disorders:
 ulcerative colitis and
 Crohn's disease.
 5-aminosalicylic acid (5-ASA) have been
  used in the treatment of inflammatory bowel
  diseases
 formulations have been designed to deliver
  5-ASA include sulfasalazine, olsalazine,
  balsalazide, and various forms of
  mesalamine.
 sulfasalazine,   5-ASA is bound to
  sulfapyridine;
 balsalazide, 5-ASA is bound to 4-
  aminobenzoyl--alanine; and
 olsalazine, two 5-ASA molecules are bound
  together.
 In the terminal ileum and colon, resident
  bacteria cleave the azo bond by
  azoreductase enzyme, releasing active 5-
  ASA.
 Pentasa is a
 mesalamine
 formulation that
 contains timed-
 release
 microgranules that
 release 5-ASA
 Asacol has 5-ASA
 coated in a pH-
 sensitive resin that
 dissolves at pH 7
 Lialda also uses a pH-dependent resin that
  encases a multimatrix core.
 5-ASA delivered in high concentrations to
  rectum and sigmoid colon by means of
  enema formulations (Rowasa) or
  suppositories (Canasa).
 5-ASA  drugs are considered to be the first-
  line agents for ulcerative colitis.
 efficacy in Crohn's disease is unproven
Nausea           GI Upset        Headache         Bone Marrow
                                                  Suppression




         Arthralgia



                       malaise              Myalgia
 slow acetylators of sulfapyridine
 Hypersensitivity to sulfapyridine - fever,
  exfoliative dermatitis, pancreatitis,
  pneumonitis, hemolytic anemia, pericarditis,
  or hepatitis.
 Oligospermia-reverses
 Sulfasalazine impairs folate absorption
 renal tubular damage in patients receiving
  high doses of aminosalicylates.
 nephritis are reported with high doses of
  mesalamine formulations
 prednisone  and prednisolone are the most
  commonly used oral glucocorticoids.
 Hydrocortisone enemas, foam, or
  suppositories are used - via topical treatment
  of active inflammatory bowel disease in the
  rectum and sigmoid colon.
 Budesonide    rapid first-pass hepatic
  metabolism resulting in low oral
  bioavailability.
 inhibit production of inflammatory cytokines
  (TNF-, IL-1) and chemokines (IL-8);
 inhibit gene transcription of nitric oxide
  synthase, phospholipase A2, cyclooxygenase-
  2, and NF-B.
 Glucocorticoids are commonly used in the
  active inflammatory bowel disease.
 rectally administered glucocorticoids are
  preferred
 Oral controlled-release budesonide (used in
  the treatment of Crohn's disease
 azathioprine is rapidly converted by a
  nonenzymatic process to 6-MP.
 6-Mercaptopurine undergoes
  biotransformation via competing enzymes
  that produce inactive metabolites and active
  thioguanine nucleotides.
 Azathioprine and 6-MP -in the induction and
  maintenance of remission of ulcerative colitis
  and Crohn's disease.
 long-term glucocorticoid therapy to control
  active disease
 purine analogs allow dose reduction or
  elimination of steroids
 nausea, vomiting, bone marrow depression
  and hepatic toxicity
 Severe leukopenia may predispose to
  opportunistic infections
 Hypersensitivity reactions to azathioprine
  or 6-MP occur in patients.
 include fever, rash, pancreatitis, diarrhea,
  and hepatitis.
 Allopurinol markedly reduces xanthine oxide
  catabolism of the purine analogs,
 increasing active 6-thioguanine nucleotides
  that may lead to severe leukopenia.
 Methotrexate   antimetabolite that has
  beneficial effects in Crohn's disease and
  rheumatoid arthritis
 Methotrexate may be given orally, S.C, or I.M
 inhibitionof dihydrofolate reductase
 interfere with inflammatory actions of
  interleukin-1.
 stimulate increased release of adenosine also
  stimulate apoptosis and death of activated T
  lymphocytes.
 bone  marrow depression,
 megaloblastic anemia,
 Alopecia
 At the doses used in the treatment of
  inflammatory bowel disease, these events
  are uncommon
 two biologically active forms: soluble TNF
  and membrane-bound TNF.
 The biologic activity is mediated by binding
  to TNF receptors (TNFR) that are present on
  some cells (especially TH1 cells, innate
  immune cells, and fibroblasts).
      Binding of TNF to TNFR
                 
             activates NF-B
                 
transcription, growth, and expansion.
Biologic actions:
release of proinflammatory cytokines
                 
1.T-cell activation and proliferation
2. fibroblast collagen production
3. up-regulation of endothelial adhesion
molecules
 infliximab, adalimumab, and certolizumab
 Infliximab and adalimumab are antibodies of
  the IgG1 subclass.
 Certolizumab is a recombinant antibody
 Infliximab is administered as an I.V infusion.
 Adalimumab and certolizumab are
  administered by S.C injection.
 Allthree agents bind to TNF with high affinity,
 suppresses cytokine release.
 When infliximab or adalimumab bind to
  membrane-bound TNF
    - promotes antibody-mediated apoptosis
    - complement activation, and
    - cellular cytotoxicity of activated T
lymphocytes and macrophages.
 Infliximab   also is approved for ulcerative
  colitis.
 Effective in patients with moderate to severe
  Crohn's disease
 including patients been dependent on
  glucocorticoids or not responded to 6-MP or
  methotrexate.
 infection -bacterial sepsis, tuberculosis,
  invasive fungal organisms, reactivation of
  hepatitis B, listeriosis, and other
  opportunistic infections.
 upper respiratory infections (sinusitis,
  bronchitis, and pneumonia)
 Antibodies to the antibody (ATA) may develop
  with all three agents.
 Infliximab -include fever, headache,
  dizziness, urticaria, or mild cardiopulmonary
  symptoms that include chest pain, dyspnea.
 Severe acute reactions include significant
  hypotension, shortness of breath, muscle
  spasms, and chest discomfort
A  delayed serum sickness-like reaction
  consist of
- myalgia, arthralgia, jaw tightness, fever,
  rash, urticaria, and edema
 Integrins are a family of adhesion molecules
  on the surface of leukocytes
 adhesion molecules on the surface of the
  vascular endothelium known as selectins
 humanized   IgG4 monoclonal antibody
  targeted against the alpha 4 subunit, which
  thereby blocks several integrins on
  circulating inflammatory cells
 shown efficacy in moderate to severe Crohn's
  disease
 Drawback:
-progressive multifocal leukoencephalopathy
  due to reactivation of a human polyomavirus
 Exocrine  pancreatic insufficiency is caused
  by cystic fibrosis, chronic pancreatitis, or
  pancreatic resection.
 These Supplements are the mainstay of
  treatment for pancreatic enzyme
  insufficiency.
 pancreatin  and pancrelipase
 Pancreatin -low concentrations of lipase and
  proteolytic enzymes
 pancrelipase is a preparation
   -pancrelipase has 12 times the lipolytic
activity and
-4 times the proteolytic activity of pancreatin.
 inactivated by gastric acids
 non–enteric-coated - given concomitantly
  with acid suppression therapy (PPI or H2
  antagonist)
 Encapsulated formulations contain acid-
  resistant microspheres (Creon) or
  microtablets (Pancrease, Ultrase)
 Capsules should be swallowed, not chewed, -
  cause oropharyngeal mucositis
 Excessive doses -diarrhea and abdominal
  pain.
 The high purine content -hyperuricosuria
  and renal stones.
 colonic strictures were reported been
  removed from the market.
 Ursodiol makes up the circulating bile salt
  pool in humans
 After oral administration-conjugated in the
  liver
 extensive enterohepatic recirculation.
 undergoes dehydroxylation by colonic
  bacteria to lithocholic acid, a substance with
  hepatic toxicity.
Ursodiol decreases cholesterol content by
  -reducing hepatic cholesterol secretion.
-stabilize hepatocyte canalicular membranes
    -a reduction in the concentration of other
endogenous bile acids or
    - inhibition of immune-mediated hepatocyte
destruction.
 Ursodiolis used for dissolution of small
  cholesterol gallstones -with gallbladder
  disease
 prevention of gallstones in obese patients
  undergoing rapid weight loss therapy.
 Ursodiol is free of serious adverse effects.
 diarrhea is uncommon.
 Unlike predecessor, chenodeoxycholate,
  ursodiol has not been associated with
  hepatotoxicity.
 Portal hypertension is caused by increased
  blood flow within the portal venous system
 increased resistance to portal flow within the
  liver.
 Ascites
  hepatic encephalopathy
 development of portosystemic collateral
  especially gastric or esophageal varices.
 Varices can rupture, leading to massive upper
  gastrointestinal bleeding.
 Somatostatin & Octreotide
 Vasopressin & Terlipressin
 Beta-Receptor–Blocking Drugs
 Vasopressin  (antidiuretic hormone) it is also
  a potent arterial vasoconstrictor.
 administered I.V by continuous infusion,
 causes splanchnic arterial vasoconstriction -
  reduced splanchnic perfusion and lowered
  portal venous pressure
 Systemic   and peripheral vasoconstriction can
  lead to
 Hypertension
 myocardial ischemia or infarction
 mesenteric infarction
These effects may be reduced by
coadministration of nitroglycerin (by reducing
portohepatic vascular resistance) and
-reduce the coronary and peripheral vascular
vasospasm caused by vasopressin
 Nausea
 abdominal   cramps and
 diarrhea
 theantidiuretic effects of vasopressin
 promote retention of free water, which can
 lead to hyponatremia, fluid retention, and
 pulmonary edema
A   vasopressin analog that has similar efficacy
  to vasopressin
 fewer adverse effects
 it has never been approved for use in the
  USA.
 reduce  portal venous pressure via a decrease
  in portal venous inflow.
 This decrease is due to a decrease in cardiac
  output (1 blockade) and
 splanchnic vasoconstriction (2 blockade)
  caused by the unopposed effect of systemic
  catecholamines on receptors.
 nonselective  blockers such as propranolol
  and nadolol are more effective than selective
  1 blockers
 Nonselective blockers significantly reduce
  the rate of recurrent bleeding

				
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