Docstoc

GI Pharmacology

Document Sample
GI Pharmacology Powered By Docstoc
					GI Pharmacology
    Johann Graggaber
 SpR Clinical Pharmacology
Topics

   Peptic ulcer disease/dyspepsia
   GORD
   Inflammatory bowel disease
   Irritable bowel syndrome
   Diarrhoea
   Constipation
   Pancreatitis
Dyspepsia / Peptic ulcer disease
Dyspepsia:       upper abdo pain/discomfort
                 (fullness, bloating, distension, nausea)

Peptic ulcers
   defects in mucosa extending through
   muscularis mucosae

Prevalence
   PUD 5-10% lifetime
   dyspepsia 25-40%

Aetiology (most common)
     H.pylori
     NSAIDs
Mucosa protective factors
Parietal cell and acid regulation
                                    NSAIDs
   Antiinflammatory
   Analgesic
   Antipyretic

   Chemically heterogeneous
   Reversible competitive inhibitors of COX activity (Aspirin irreversible)

   Reduce prostaglandin synthesis (COX-1)
        ↓ Mucus
        ↓ bicarbonate
        ↓ blood flow
        ↓ proliferation of cells
        ↑ gastric acid secretion
   Reduce production of superoxide radicals, induce apoptosis, inhibit expression of
    adhesion molecules, decrease NO synthase and proinflammatory cytokines, modify
    lymphocyte activity and alter cellular membrane functions
   Biliary excretion and reflux of metabolites into stomach
                     Helicobacter pylori

   Peptic ulcers
   Gastric carcinoma/lymphoma
   Mucosal atrophy

Tests
       Urea breath test (sens. and spec. ~95%)
       Endoscopic (urease, histology)
       Stool antigen (sens. and spec. ~ 95%)
       (serology)
       Omit PPI for 2 weeks prior to tests
H. pylori
               Management of dyspepsia
   Therapeutic trial of acid
    suppressing medication
                                       Gastric ulcer
   H. pylori screening
   If alarm features
       GI bleeding
       Unintentional weight loss
       Progressive dysphagia
       Odynophagia
       Persistant vomiting
       Iron deficiency anaemia
       Mass/ suspicious barium meal
   Do Endoscopy
                        Treatment
Lifestyle advice
      Diet (alcohol, caffeine…)
      Smoking
Medication
      Stop NSAIDs if possible
      H-2 receptor antagonists
      Proton pump inhibitors
      H. pylori eradication
      Antacids
      Misoprostol (NSAIDs)
                     H2 receptor antagonists

   Cimetidine, Ranitidine, Famotidine, Nizatidine

   Competitive and selective inhibition of histamine H-2 receptor
   Suppress 24 hr gastric secretion by 70%
   Less effective than PPI

   Caution:           renal failure, pregnancy, breast feeding
   Interaction:       Cimetidine binds to CYP 450 (retards oxidative drug metabolism)
                       note interactions with warfarin, phenytoin, theophylline..

   Side effects
        Well tolerated, less than 3% adverse effects
        Diarrhoea, headache, drowsy, fatigue, constipation, CNS, LFT
        Rarely pancreatitis, bradycardia, AV block, confusion (elderly, especially cimetidine)
        Rarely blood dyscrasias
                     Proton pump inhibitors
   Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole

   Prodrugs activated in acidic secretory canaliculi
   Inhibit gastric H+K+ ATPase irreversibly
   Decrease acid secretion by up to 95% for up to 48 hours

   Use: Ulcers, GORD, Zollinger-Ellison Syndrome, reflux oesophagitis
   Side effects
        Generally well tolerated
        mc Gastrointestinal, headache, headache dizziness
        Omeprazole – impotence, gynaecomastia
        May increase risk of GI infections (reduced acidity)
   Note: pH > 6 necessary for platelet aggregation
    Give high dose PPI in active GI bleed (eg Omeprazole 8mg/hr for 72 hrs)
                         H. pylori eradication

   Eradication increases ulcer healing
   Reduces recurrence
   MALT, Ca (can lead to resolution)


Triple therapy
For 7 (14) days twice daily eg

   full dose PPI +
   Amoxicillin +
   Clarithromycin/Metronidazole

Effective in 80-85%
                                  Other
Antacids
      Mg and Al hydroxides
      May chelate other drugs (avoid concomitant administration of other
       drugs)
      Side effects: diarrhoea (Mg), constipation (Al)
      Milk alkali syndrome (alkalosis, renal insufficiency, hypercalcemia)
Sucralfate
      Forms sticky polymer in acidic environment
      Inhibits hydrolysis of mucous proteins by pepsin
      1 g bd to 1g qds
      SE: constipation, aluminium absorption (avoid in severe renal impairment
       due to risk of encephalopathy)
Misoprostol

   PGE1 analogue
   Stimulates Gi pathway (↓cAMP and ↓gastric acid)
   ↑ blood flow and ↑ mucus and bicarbonate secretion

Use: prevention of NSAID induced injury
Side effects: diarrhoea, pain, cramps (30%)
               Can cause exacerbation of IBD
Contraindication: pregnancy, caution in women of childbearing age
                  can induce labour!
                Nonvariceal Upper GI Bleed

   Resuscitate (iv access, fluids, catheter, transfusion)
   Bloods (cross match, FBC, U&E, clotting)
   Drugs
        Acid suppressing drugs (stabilize clot)
        Somatostatin – reduces acid secretion and splanchnic blood flow
        Antifibrinolytic drugs – tranexamic acid reduces need for surgery
         and mortality
   +/- transfuse
   Endoscopy: cause of bleeding, haemostasis (injection, clips,
    banding...), can usually wait until next day
                                  GORD
Definition
   Abnormal reflux of gastric contents into oesophagus
   ± mucosal damage


Prevalence
   > 50% of population > once a year
   50% of patients have erosive oesophagitis


Pathophysiology
   Antireflux barrier (sphincter…)
   Acid, pepsin, trypsin, bile acids, hiatus hernia
                              Symptoms
   Heartburn
   Belching
   Asthma, cough
   Hoarseness, sore throat, globus

Alarm features
   GI bleeding
   Unintentional weight loss
   Progressive dysphagia
   Odynophagia
   Persistent vomiting
   Iron deficiency anaemia
   Mass/ suspicious barium meal
Precipitants

   Food (fatty food, alcohol, caffeine)
   Smoking
   Obesity
   Medication
        calcium antagonists, nitrates, theophyllines, NSAIDs, corticosteroids
   Pregnancy



Usually chronic relapsing course
Diagnosis

   Symptoms
   Empirical therapy

   Endoscopy
        Failure of response to therapy
        Alarm features
        Barrett’s


   24-hour pH monitoring
        pH < 4
        Limited sensitivity
                    Complications
   Oesophagitis
   Strictures, ulcers
   Barrett's
                          Barrett's



   Intestinal columnar
    metaplasia
   Malignant potential
   Needs surveillance
                              Treatment
Lifestyle advice
       Dietary habits (fat, alcohol, caffeine, timing)
       Smoking
       Weight loss
       Raising head
       But little evidence for all those


Medication
       H-2 receptor antagonists
       PPI
       Antacids
       Prokinetics
         Inflammatory Bowel Disease
Ulcerative colitis
             Diffuse mucosal inflammation limited to the colon

Crohn's disease
             patchy transmural inflammation
             May affect any part of GI tract



Features
     UC             bloody diarrhoea, colicky pain, urgency,
                     tenesmus
        CD          abdominal pain, diarrhoea, weight loss
                     intestinal obstruction
                     systemic symptoms
                       Drugs in IBD


   Aminosalicylates
   Corticosteroids
   Thiopurines
   Methotrexate
   Ciclosporin
   Infliximab
                                Aminosalicylates

   Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance)
   Mesalazine (5-ASA), eg Asacol, Pentasa
   Balsalazide (prodrug of 5-ASA)
   Olsalazine (5-ASA dimer cleaves in colon)

   Oral, rectal preparation

   Use
      Maintaining remission
      Active disease
      May reduce risk of colorectal cancer
   Adverse effects
      10-45%
      Nausea, headache, epigastric pain, diarrhoea, hypersensitivity, pancreatitis, blood
       disorders, lung disorders, myo/pericarditis
      Caution in renal impairment, pregnancy, breast feeding
                           Corticosteroids

   Antiinflammatory agents for moderate to severe relapses
   eg 40mg Prednisolone
   Inhibition of inflammatory pathways (↓IL transcription,
    suppression of arachidonic acid metabolism, lymphocyte
    apoptosis)

   Side effects
        Acne, moon face, oedema
        Sleep, mode disturbance
        Dyspepsia, glucose intolerance
        Cataracts, osteoporosis, myopathy…
                                   Thiopurines
Azathioprine, mercaptopurine

   Inhibit ribonucleotide synthesis
   Inducing T cell apoptosis by modulating cell signalling
   Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides

Use
         Active and chronic disease
         Steroid sparing
Side effects
         Leucopaenia (myelotoxic)
         Monitor for signs of infection, sore throat
         Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity
                             Methotrexate
   Inhibits dihydrofolate reductase
   Probably inhibition of cytokine and eicosanoid synthesis

Use
 Relapsing or active CD refractory or intolerant to AZA or Mercaptopurine
 Monitor FBC, LFT


Side effects
      GI
      Hepatotoxicity, pneumonitis
                                Ciclosporin
  Inhibitor of calcineurin, preventing clonal expansion of T cell subsets
Use
       Active and chronic disease
       Steroid sparing
       Bridging therapy
Side effects
       Tremor, paraesthesiae, malaise, headache, abnormal LFT
       Gingival hyperplasia, hirsutism
       Major: renal impairment, infections, neurotoxicity
Monitor
    Blood pressure, FBC, renal function
                     Infliximab
   Anti TNF-α monoclonal antibody
   Potent anti inflammatory effects

Use
 Fistulizing CD

 Severe active CD refractory/intolerant of steroids or immunosuppression

 iv infusion



Side effects
 Infusion reactions

 Sepsis

 Reactivation of Tb, increased risk of Tb
          Principles of Managment of IBD

   Assess severity

   Mild and distal
        topical steroids/aminosalicylates
   Diffuse or not responding –
        add oral steroids
   Severe
        admit, iv steroids, iv fluids, ?TPN etc
   Ulcerative colitis:
        Avoid antimotility drugs and antispasmodics as may precipitate paralytic
         ileus and megacolon
        Medical management of UC
Active left sided/extensive
       Aminosalicylate eg Mesalazine
       Prednisolone 40mg (for prompt response or if mesalazine unsuccessful) – reduce
        dose gradually
       Azathioprine for steroid dependant disease
       Topical agents (rectal symptoms)
       Ciclosporin for severe, steroid refractory colitis


Active distal UC
       Mild/Mod topical mesalazine (or steroid) + oral mesalazine
       +/- oral steroids
                                    Severe UC

   Admission for iv therapy
   Close monitoring
      Daily physical examination, regular vital signs, stool chart, CRP, AXR
      FBC, ESR, CRP, U&E, albumin, LFT every 24-48 hours
      Daily AXR if colonic dilatation (transverse >5.5cm)
   Therapy
      iv fluids and electrolytes if necessary
      sc heparin (thromboembolism prophylaxis)
      ? Nutritional support
      iv steroids
      Withdrawal of antidiarrhoeal agents (can precipitate dilatation)
      Aminosalicylates
      Topical therapy


     +/- surgical referral (colonic dilatation)
     Stool frequency (>8) and CRP (>45) on day 3 predict need for surgery
     Consider colectomy or iv ciclosporin
                    Medical Management of CD

   Assessment
        Site, pattern (inflammation, stricturing, fistulating), prior disease activity
        Confirm disease activity (CRP, ESR)
   Active intestinal disease
        Mild – aminosalicylate
        Mod/severe – oral corticosteroids (reduce gradually over 8 weeks)
        Severe – iv steroids
        Elemental/polymeric diets
        TPN (fistulating)
        Azathioprine as steroid sparing agent
        Consider surgery
   Fistulating and perianal
        Metronidazole +/- ciprofloxacin
        Azathioprine
        Infliximab
   Other sites
              Maintenance of remission of CD

   STOP SMOKING
   Mesalazine of limited benefit
   Azathioprine effective but toxicity
   Methotrexate
   Infliximab

Steroid refractory disease
 Definition
        Active disease on >20 mg prednisolone > 2 weeks
        Relapse when dose reduction
   Azathioprine (monitor FBC)
   MTX, Infliximab
                            Constipation
   Stool: 70-85% water (100ml/d)
   Normal stool frequency ≥ 3/week

Causes
        Dietary (fibre), drugs, hormonal disturbances, neurogenic disorders
        systemic illnesses, IBS
        colonic motility
        disorder of defecation or evacuation (outlet)
Management
      Diet, fluid, fibre rich diet
      Avoidance of constipating drugs

     Only then consider medication (haemorrhoids, exacerbation of angina from
       straining…)
                          Laxatives
   Bulk-forming
   Stimulant
   Faecal softeners
   Osmotic laxatives
   Bowel cleansing solutions


   Oral
   Rectal-suppositories, enemas

General Contraindications: intestinal perforation and obstruction
Bulk-forming laxatives

   Increase faecal mass which stimulates peristalsis
   Bulk/softness/hydration dependant on fibre
   Ensure adequate fluid intake (obstruction)
   Effect can be delayed by a few days

   Try dietary fibre first!
        Wheat bran, oat bran, bran buiscuits
        Pectins/hemicellulose (fruits, vegetables)

   Ispaghula (Fybogel, Isogel)
   Methylcellulose (Cevelac)
   Sterculia (Normacol)
   Contraindication:           intestinal obstruction, colonic atony, faecal impaction
   Side effects: flatulence, abdominal distension, GI obstruction, rarely
    hypersensitivity
Stimulant Laxatives

     Increase intestinal motility

  Diphenylmethane derivatives
    Sodium picosulfate, hydrolyzed by bacteria to active form, effects vary
    Bisacodyl (Dulco-lax), usually 5-10mg nocte

  Anthraquinone Laxatives
    Require activation in colon (bacteria), onset of action delayed (6-12 hours)
    Senna (Senokot), plant derivative
    Danthron (Co-danthramer) possibly carcinogenic, only use in terminally ill

  Docusate Sodium
      stimulant and softening

  Glycerol suppositories
  (Parasympathomimetics such as bethanechol, neostimin rarely used)

  Side effects: cramps, diarrhoea, hypokalaemia
Osmotic laxatives

Osmotically mediated water retention

   Nondigestible sugars and alcohols
        synthetic disaccharide, resists intestinal disacharidase
        draw water in osmotically, not absorbed
        Lactulose
        Use: elderly, opioids, hepatic encephalopathy (↓ ammonia production)

   Magnesium salts
   Phosphates (rectal, Fleet)
   Sodium citrate (rectal, Micralax Micro-enema)


   Polyethylene Glycol-Electrolyte Solutions - Macrogels
        Sequester fluid in bowel, poorly absorbed
        Movicol
Faecal softeners - Emollients

   Sodium docusate (stimulant and softening)

   Arachis oil enema for impacted faeces

   Liquid Paraffin (oral solution)
         Side effects: anal irritation, interference with
         absorption of fat soluble vitamins, granulomatous
         reactions
Bowel cleansing solutions



   Before colonic surgery, colonoscopy and radiological examinations

   eg Fleet, Klean-Prep, Picolax

   Contraindications: obstruction, GI-ulceration, perforation, CCF, toxic colitis
    or megacolon, ileus

   Side effects: nausea, bloating, cramps, vomiting
                                Diarrhoea
Definition
       Excessive fluid weight (200g/day)
Mechanism
       Increased osmotic load
       Excessive secretion (electrolytes and water)
       Exudation of protein and fluid
       Altered motility (rapid transit)
       Often combined
Management
 Rehydration, maintain fluid and electrolyte balance
 NaCl absorption linked with glucose uptake (rehydr. solutions)
 Antimicrobial therapy. May mask clinical picture, delay clearance of organism,
  increase risk of systemic invasion.
                                Antimotility drugs
Opioids
        μ (motility) and δ (secretion) receptors, absorption (both)

   Loperamide – Imodium
        40-50x more potent than morphine
        Poor CNS penetration
        Increases transit time and sphincter tone
        Antisecretory against cholera toxin and some E.coli toxin
        T½ 11 hours, dose: 4 mg followed by 2mg doses (16mg/d max)
        Overdose: paralytic ileus, CNS depression
        Caution in IBD (toxic megacolon)

   Codeine phosphate

Other
        Bismuth subsalicylate
        Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents)
                                  Diarrhoea


Clostridium difficile
        Clinical suspicion, test for toxins (stool)
        Metronidazole PO
        Vancomycin PO
            Irritable bowel syndrome
   Recurrent abdominal pain with disturbed bowel habits
   9-12% of population affected
   ? Pathophysiology

Treatment
 Dietary modification
 Psychological therapies
 Fibre – binding water (diarrhoea and constipation)
 Antispasmodics
        Anticholinergic – Hyoscyamine, methscopolamine
        Calcium channel antagonists and peripheral opioid receptor antagonists
        Mebeverine: direct effect on smooth muscle cell
   Tricyclic antidepressants
   Analgesic and neuromodulatory properties
   Loperamide, codeine
                                  Antispasmodics

   Antimuscarinics
      Reduce motility
      Quaternary amines
              eg hyoscine butylbromide (Buscopan) less lipid soluble and thus less well absorbed
               than atropine
      CI: angle-closure-glaucoma, mysthenia, paralytic ileus, pyloric stenosis and
       prostatic enlargement
      SE: constipation, transient bradycardia, reduced bronchial secretions, urinary
       urgency etc
   Other
        Direct relaxants of intestinal smooth muscle
        No serious side effects but avoid in paralytic ileus
        Alverine
        Mebeverine
        Peppermint oil (Colpermin)
                      Pancreatitis
Causes (mc)   gallstones
              alcohol

Diagnosis     symptoms (abdominal pain, N&V)
              pancreas enzymes (amylase, lipase)
              USS +/- CT abdo

              severity scores (APACHE)

Treatment     rescuscitation (fluids + oxygen)
              symptomatic control (analgesia)
              prophylactic antibiotics if significant necrosis (30%)
              ?enteral nutritition
              chronic pancreatitis: pancreatin eg Creon
                          Liver and Drugs
   First pass metabolism in some drugs

   Hepatic biotransformation
        Phase I: oxidation, reduction, hydrolysis
              Cytochrome P-450 system
              Note: enzyme induction by eg rifampicin, carbamazepine, phenobarbitone, alcohol

        Phase II: conjugation to glucoronide, sulphate, glutathion, usually resulting in
         inactive compounds
        Decrease lipid solubility and facilitate renal excretion

        Export into plasma or bile -> excretion via GI tract or kidney

   Enterohepatic circulation (digoxin, morphine, …)

   Most drugs lipophilic and thus crossing intestinal membranes
                    Drug induced hepatotoxicity


   50% of causes of acute liver failure
   Diagnosis
        History
        Anorexia, nausea, fatigue
        Jaundice
        Blood tests
        Rule out other causes (viral, alcohol…)

     Overall rare
     Importance of postmarketing surveillance to detect liver toxicity
                   Liver Injury and Its Patterns




Navarro, V. J. et al. N Engl J Med 2006;354:731-739
Key Guidelines in the Recognition and Prevention of Hepatotoxicity in Clinical Practice




                     Navarro, V. J. et al. N Engl J Med 2006;354:731-739
  Diagnosis of Drug-Related Hepatotoxicity




Navarro, V. J. et al. N Engl J Med 2006;354:731-739
Key Elements of and Caveats in Assessing Cause in the Diagnosis of Drug-Related
                                Hepatotoxicity




     Navarro, V. J. et al. N Engl J Med 2006;354:731-739
Factors Predictive of a Sustained Beneficial Response to Interferon Alfa in Patients with Chronic
                                            Hepatitis




                Hoofnagle, J. H. et al. N Engl J Med 1997;336:347-356
      References/further reading
   BNF
   Harrison‘s Principles of Internal Medicine
   Pharmacology textbooks eg.
    Goodman&Gilman‘s
   Nice Guidelines
   Guidelines of the British Society of
    Gastroenterology
   Review articles (NEJM, Lancet…)
Additional slides
Flow chart for Mx of GU
                                                                Gastric ulcer                                        Entry or final state
                                                                                                                     Action
                                                                                                                     Action and outcome

                                                                Stop NSAIDs,
                                                                   if used 1




                   Full-dose            H. pylori positive,        Test for           H. pylori             Full-dose PPI for
                    PPI for             ulcer associated          H. pylori 2         negative             1 or 2 months
                  2 months               with NSAID use

                                                                        H. pylori positive,
                                                                        ulcer not associated
                                                                        with NSAID use
             Eradication therapy 3




 H. pylori
 positive        Endoscopy and       Ulcer healed,            Low-dose treatment                  Healed
                                                                                                              Endoscopy 4
                 H. pylori test4     H. pylori                   as required 5
                                     negative
       Ulcer not healed,                                                                                             Not healed
       H. pylori negative


                                                               Periodic review 6




             Refer to specialist                                                                           Refer to specialist
                                                              Return to self care
              secondary care                                                                                secondary care
Flow chart for Mx of DU
                                                        Duodenal ulcer
                                                                                                          Entry or final state
                                                                                                          Action
                                                                                                          Action and outcome
                                                         Stop NSAIDs,
                                                            if used1



                  Full-dose            Test positive,                            Test negative
                   PPI for          ulcer associated
                                                        Test for H. pylori2
                 2 months            with NSAID use
                                                                  Test positive,
                                                                  ulcer not associated
                                                                  with NSAID use
 Response        Eradication
                  therapy3

            No response
              or relapse


                                                                                                         Full-dose
                Re-test for
                H. pylori4        Negative                                               Response
                                                                                                    PPI for 1 or 2
                                                                                                          months
                Positive                                                                                      No response



                                                            Low-dose
                 Eradication                                                                          Exclude other
                  therapy5        No response
                                                          treatment as             No response        causes of DU 7
                                  or relapse                required6
              Response                                            Response




            Return to self care                             Review8
Characteristics of Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus




 Lauer, G. M. et al. N Engl J Med 2001;345:41-52
                   The Replication Cycle of HBV




Ganem, D. et al. N Engl J Med 2004;350:1118-1129
The Natural History of HCV Infection and Its Variability from Person to Person




  Lauer, G. M. et al. N Engl J Med 2001;345:41-52
Side Effects of Treatment with Interferon Alfa and Ribavirin




          Lauer, G. M. et al. N Engl J Med 2001;345:41-52
Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection




               Suerbaum, S. et al. N Engl J Med 2002;347:1175-1186

				
DOCUMENT INFO
Shared By:
Categories:
Stats:
views:1103
posted:3/28/2008
language:English
pages:66