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GI Pharmacology
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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
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

Gastric ulcer

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:
Interaction:

renal failure, pregnancy, breast feeding
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



Features
 UC


CD

patchy transmural inflammation
May affect any part of GI tract

bloody diarrhoea, colicky pain, urgency,
tenesmus
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




Diffuse or not responding –




add oral steroids

Severe




topical steroids/aminosalicylates

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





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






Site, pattern (inflammation, stricturing, fistulating), prior disease activity
Confirm disease activity (CRP, ESR)

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




Loperamide – Imodium










μ (motility) and δ (secretion) receptors, absorption (both)

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



Diagnosis of Drug-Related Hepatotoxicity



Key Elements of and Caveats in Assessing Cause in the Diagnosis of Drug-Related
Hepatotoxicity



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 used1

Full-dose
PPI for
2 months

H. pylori positive,
ulcer associated
with NSAID use

Test for
H. pylori 2

Full-dose PPI for
1 or 2 months

H. pylori
negative

H. pylori positive,
ulcer not associated
with NSAID use

Eradication therapy3

H. pylori
positive

Endoscopy and
H. pylori test4

Ulcer healed,
H. pylori
negative

Low-dose treatment
as required5

Healed

Ulcer not healed,
H. pylori negative

Endoscopy4
Not healed

Periodic review6

Refer to specialist
secondary care

Return to self care


Refer to specialist
secondary care

Flow chart for Mx of DU
Duodenal ulcer
Entry or final state
Action
Action and outcome
Stop NSAIDs,
if used1

Full-dose
PPI for
2 months

Test positive,
ulcer associated
with NSAID use

Test for H. pylori2

Test negative

Test positive,
ulcer not associated
with NSAID use
Response

Eradication
therapy3
No response
or relapse

Re-test for
H. pylori4

Response

Negative

Positive

Eradication
therapy5
Response

Return to self care

Full-dose
PPI for 1 or 2
months
No response

No response
or relapse

Low-dose
treatment as
required6

No response

Response

Review8


Exclude other
causes of DU 7

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



Side Effects of Treatment with Interferon Alfa and Ribavirin



Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection

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


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