Ulcer disease

1. Peptic Ulcer Disease, GORD
&
Nausea & Vomiting.
Constipation & Diarrhea.
BY PATRICK CHELANGAT

2. SUMMARY
• Peptic ulcer
 Duodenal & gastric ulcers
 Pathogenesis
 Clinical presentation and Management
• Gastro-oesophageal reflux disease (GORD)
• Nausea and Vomiting
 Patterns and Management
• Constipation
 Causes and Mechanism of drug induced constipation
 Treatment
 Laxative abuse syndrome
• Diarrhea
 Pathophysiologic mechanisms
 Drugs causing diarrhea
 Management

3. • Condition characterized by erosion of GI mucosa
resulting from digestive action of HCl and pepsin
• Prevalence 5-10%
• 50% of these have recurrence within 5 yrs.
• Discovery of H. pylori of great importance
diagnostically & therapeutically in PUD (Nobel
prize-Marshall & Warren)
• H. pylori cultured from stomach of ~90% DU pts &
~80% GU pts
• Eradication of H. pylori ↓ recurrence of PUD by
~75-90%
Peptic Ulcer Disease (PUD)

4. Peptic Ulcer Disease
• Ulcer development
– Lower esophagus
– Stomach
– Duodenum
– 10% of men, 4% of women
TYPES
• Acute
– Superficial erosion
– Minimal erosion
• Chronic
– Muscular wall erosion with formation of fibrous tissue
– Present continuously for many months or intermittently

5.  duodenal sites are 4 times common
compared to gastric sites
 most common in middle age with
peak 30-50 years
 Male to female ratio—4:1
 Genetic link: 3x more common in 1st
degree relatives
 more common with blood group O
 associated with increased serum
pepsinogen
 H. pylori infection common up to 95%
 smoking is twice as common
common in late middle age.
incidence increases with age.
Male to female ratio—2:1
More common with blood group A
Use of NSAIDs: associated with a
three- to four-fold increase in risk of
gastric ulcer
Less related to H. pylori than
duodenal ulcers: about 80%
10 - 20% of patients with a gastric
ulcer have a concomitant duodenal
ulcer
Duodenal Ulcer Vs. Gastric Ulcer

6. Protective factors vs. hostile factors
Pathogenesis of PUD

7. Pathogenesis of PUD
• Not fully understood, but 3 major factors identified
Factor Treatment approach
Infection with Gram-negative
H. pylori
Eradication of H. pylori
infection, e.g. triple tx
↑ gastric HCl secretion ↓ HCl secretion or neutralizing
it, e.g. H2 antagonists,
pirenzepine, antacids
Inadequate mucosal defence
against gastric HCl
Agents that protect gastric
mucosa, e.g. sucralfate

8. Symptoms of PUD
• Asymptomatic
• Epigastric pain typically worse at night and
when hungry (DU)
• Epigastric pain; worse with food (GU)
• Nausea, vomiting
• Oral flatulence, bloating, distension and
intolerance of fatty food
• Heartburn
• Pain radiating to the back

9. ALARM signs for epigastric pain
• Chronic GI bleeding
• Iron-deficiency anaemia
• Progressive unintentional weight loss
• Progressive dysphagia
• Persistent vomiting
• Epigastric mass
• Patients aged 55 years and older with
unexplained and persistent recent- onset
dyspepsia alone

10. treating PUD
• Gastric ulcers:
 5% malignant
 Endoscopic biopsy at time of initial diagnosis
recommended & repeat endoscopy after 6-8 weeks tx
 Surgical tx for nonhealing GU
• Duodenal ulcers:
 Usually not malignant
 If pt asymptomatic do not need to prove ulcer healing
 Many heal without tx
 H2-receptor antagonists, sucralfate & high dose antacids
shown to ↑ rate of healing and % of ulcers that heal.

11. treating PUD (cont)
• Complications of PUD
1) GI bleeding
2) Gastric outlet obstruction
3) Perforation
4) Penetration into pancreas
5) Intractability

12. Stomach

13. Stomach

14. Duodenum

15. Non-pharmacological
measures to treat PUD
• Diet
• Stop smoking
• Avoid aspirin/NSAIDs. Enteric coating or anti-
ulcer tx may ↓ mucosal damage from aspirin. In
pts with strong indications for NSAID tx treating
with PPI, H2-R antagonists, sulcralfate or
misoprostol may relieve symptoms.
• Avoid C2H5OH

16. Peptic Ulcer Disease
Diagnostic Studies
• Endoscopy procedure most often used
– Determines degree of ulcer healing after treatment
– Tissue specimens can be obtained to identify H. pylori
and to rule out gastric cancer
• Tests for H. pylori
– Noninvasive tests
• Serum or whole blood antibody tests
–Immunoglobin G (IgG)
• Urea breath test
– Invasive tests
• Biopsy of stomach
• Rapid urease test

17. • Barium contrast studies: Widely used
• X-ray studies: Ineffective in differentiating a
peptic ulcer from a malignant tumor
• Gastric analysis
–Identifying a possible gastrinoma
–Determining degree of gastric hyperacidity
–Evaluating results of therapy
• Lab analysis: CBC, Urinalysis, Liver
enzyme studies, Serum amylase
determination, Stool examination.
Peptic Ulcer Disease
Diagnostic Studies cont.

18. Drugs
used
to treat PUD
Antimicrobial
Agents
Amoxicillin
Bismuth
Clarithromycin
Metronidazole
Tetracycline
H2-Histamine
R Blockade
Cimetidine
Famotidine
Nizatidine
Ranitidine
Mucosal
Protective
Agents
Bismuth
Sulcralfate
Antacids
Al(OH)3
[Mg(OH)2]
CaCO3
Antimuscarinic
Agents
Pirenzepine
PPI
Lansoprazole
Omeprazole
Prostaglandins
Misoprostol

19. Helicobacter pylori:
 Gram negative, Spiral bacilli
 Spirochetes
 Do not invade cells – only mucous
 Breakdown urea - ammonia
 Break down mucosal defense
 Chronic Superficial inflammation

20. H. pylori Eradication
• Majority of PU can be healed with H2-
antagonists/PPI alone, but relapse of symptoms
occur in up to 80% pts within 1 year (8% if treated
with H. pylori eradication tx).
• Test for H. pylori before starting eradication tx.
• If H. pylori test is positive, use eradication tx.
• If H. pylori test is negative, treat with lansoprazole
30mg OD. Use for 4 wks for DU, 8 wks for GU. May
use lansoprazole 15mg OD to prevent relapse.
 Eradication of H. Pylori: Defined as negative tests
for the bacterium 4 wks or more after the end of tx.

21. Treatment Plan: H. pylori
• Triple therapy for 14 days is considered the
treatment of choice.
– PPI + clarithromycin and amoxicillin
• Omeprazole (Prilosec): 20 mg PO bid for 14 d or
Lansoprazole (Prevacid): 30 mg PO bid for 14 d or
Rabeprazole (Aciphex): 20 mg PO bid for 14 d or
Esomeprazole (Nexium): 40 mg PO qd for 14 d plus
Clarithromycin (Biaxin): 500 mg PO bid for 14 and
Amoxicillin (Amoxil): 1 g PO bid for 14 d
• Can substitute metronidazole (Flagyl) 500 mg PO bid
for 14 d if allergic to Penicillin
– In the setting of an active ulcer, continue qd PPI therapy for
additional 2 weeks.
• Goal: complete elimination of H. pylori. Once achieved
reinfection rates are low. Compliance!

22. Current recommendations for tx of H. pylori
1st line eradication tx for H.
pylori
2nd line tx
Preferred= PPI PO +
clarithromycin 500mg BD PO +
amoxicillin 1 gm BD PO for 7
days
If penicillin allergic= PPI +
clarithromycin 500mg BD PO +
metronidazole 400mg BD PO
for 7 days
E.g. of PPI: lansoprazole
30mg BD PO
PPI + bismuth 120mg QDS
PO + metronidazole 500mg
TDS PO + tetracycline 500mg
QDS PO for 7 days
Subsequent failures handled
on individual basis with advice
from gastro/micro

23. H. pylori eradication
• 1 week triple-therapy regimens eradicate H.
pylori in >90% cases. Usually no need for
continued antisecretory tx unless ulcer
complicated by bleeding/perforation.
• 2 weeks triple-therapy offer higher
eradication rates compare with 1 week but
side effects are common & poor compliance.
• 2 weeks dual-therapy with PPI &
antibacterial produce low rates of H. pylori
eradication & not recommended.

24. Peptic ulcer Treatment , UCG 2012
Management and Prevention
• Avoid spices, tobacco, alcohol, & carbonated
drinks
• Encourage regular, small, and frequent meals
• Encourage milk intake
Treat for H. pylori for one week using:
• Amoxycillin 500mg tds
• Plus metronidazole 400mg tds
• Plus omeprazole 20mg bd
• Or ranitidine 300mg od
- When using ranitidine all AB should be given for
2 weeks

25. H. pylori eradication
• Treatment failure may be due to:
- Resistance to antibacterial drugs
- Poor compliance
Drug Side effects
Bismuth n&v, unpleasant taste, darkening of tongue &
stools, caution in renal disease
Metronidazole n&v, unpleasant taste, ↓effectiveness OCP,
care with lithium/warfarin
Amoxicillin
& tetracycline
GI side effects, ↓ effectiveness OCP,
pseudomenbranous colitis
Lansoprazole ↓ effectiveness OCP

26. H2-receptor antagonists
• MOA: Competitively block binding of
histamine to H2 R, ↓ intracellular cAMP &
secretion of gastric acid. Reversible.
• Effective for acute/chronic DU & benign GU.
• Recurrence common after tx with H2-R
antagonists alone.
• Mainly renal excretion

27. H2-receptor antagonists
Drug Side effects
Cimetidine -reversible impotence, gynaecomastia & ↓
sperm count (high doses) (nonsteroidal
antiandrogen)
-mental status abnormalities-confusion,
hallucinations (elderly/renal impairment)
-leukopenia & thrombocytopenia (rare)
-cytochrome P450 inhibitor
Ranitidine,
fanotidine,
nizatidine
-Impotence, gynaecomastia & confusion less
frequently than cimetidine.
-Little interference with cytochrome P450
-Reversible drug-induced hepatitis with all H2-
antagonists

28. Proton-pump Inhibitors (PPI)
• MOA: blocks parietal cell H+/K+ ATPase
enzyme system (proton pump) ↓ secretion
of H+ ions into gastric lumen.
• Heals erosive oesophagitis more effectively
than H2-antagonists. Used in antimicrobial
regimens to eradicate H. pylori
• SE: n&v, diarrhoea, dizziness, headaches,
gynaecomastia & impotence (rare),
thrombocytopenia, rashes
• Dose: 20mg/day omeprazole in acute tx of
DU

29. Mucosal Protective Agents
1) Sulcralfate
MOA: Binds to positively charged proteins present
on damaged mucosa forming a protective coat.
Useful in “stress ulceration”
As effective as H2-R antagonists/high dose antacids
in healing of DU.
SE: Constipation, ↓absorption of cimetidine, digoxin,
phenytoin & tetracycline
2) Bismuth
MOA: Antimicrobial action. Also inhibit pepsin
activity, ↑mucus secretion & interact with proteins in
necrotic mucosal tissue to coat & protect the ulcer
crater.

30. Antacids
• MOA: Weak bases that
react with gastric acid
to form H20 + salt.
↓pepsin activity as
pepsin inactive at pH>4
• Symptom relief,
liquids>tablets
• E.g. Maalox= [Mg(OH)2]
+ Al(OH)3
Drug Side effect
[Mg(OH)2] Severe osmotic
diarrhoea (therefore
combined with
AlOH)
Al(OH)3 ↓phosphate,
↓absorption of
tetracycline,
thyroxine &
chlorpromazine,
constipation
CaCO3 ↑Ca in blood & urine
(high doses)

31. Antimuscarinic drugs
• Not usually recommended because of their antimuscarinic
effects.
• Muscarinic R stimulation ↑ GI motility & secretory activity
• Pirenzepine: Some selectivity due to affinity for & blockade
of M1-receptors in autonomic ganglia (low affinity for M2-
receptors of smooth muscle of ileum & bladder)
In stomach appears to inhibit transmission in
parasympathetic enteric ganglia.
Used as adjunct in refractory PUD & Zollinger-Ellison
syndrome.
Poorly absorbed from GIT and excreted mainly unchanged
in urine & bile.
Doesn’t cross BBB.
SE: Dry mouth, visual disturbances, agranulocytosis &
thrombocytopenia.

32. Prostaglandin analogues
• Endogenous PGs (PGE2 & I2) contribute to GI mucosa
integrity by:
-stimulation of mucus & bicarbonate secretion
-maintenance of blood flow (allows removal of luminal H-ions)
-prevention of luminal H-ions from diffusing into the mucosa
(e.g. in response to C2H5OH)
-↓ of gastric acid secretion
-helping to repair damaged epithelium
• Gastric & duodenal mucosal damage & chronic PU associated
with the use of NSAIDs may derive from interference with the
cytoprotective action of PGs.
• Misoprostol = synthetic prostaglandin E1 analogue
Prevents NSAID induced ulcers & heals chronic GU & DU
SE: Abdominal pain, n&v, diarrhoea, abortifacient (produces
uterine contractions)

33. NSAID-associated ulcers
• GI bleed & ulceration can occur with NSAIDs. If
possible withdraw NSAID if ulceration. Consider
alternative analgesia.
• If at risk of ulcer a PPI, H2-R antagonist or
misoprostol may be considered for protection
against NSAID-associated ulcers. Colic &
diarrhoea may limit use of misoprostol.
• If NSAID treatment needs to continue:
-treat ulcer with PPI & on healing of ulcer
continue with PPI.
-treat ulcer with PPI & on healing switch to
misoprostol for maintenance tx.

34. Gastro-oesophageal reflux disease (GORD)
GORD = Symptoms of “heartburn”
General advice includes AVOIDING Drug Tx
Meals at night, lying down after meals
Elevate head of bed
Heavy lifting, tight clothing, bending
Being overweight
Smoking (nicotine relaxes lower
oesophageal sphincter)
Aggravating substances (spicy foods,
C2H5OH)
Drugs which encourage reflux (e.g.
antimuscarinic, smooth muscle
relaxants, theophylline)
antacids=+/-alginic acid
Pro-kinetic agent, e.g.
metoclopramide
H2-antagonist
PPI
If severe sx when tx stopped, or
bleed from oesophagitis or stenosis
maintenance tx with PPI or surgery
may be necessary

35. Nausea & Vomiting

36. Definitions
• Nausea: Unpleasant feeling of need to
vomit accompanied by autonomic
symptoms (pallor, cold sweat,
salivation, tachycardia, diarrhoea)
• Retching: Rhythmic laboured spasmodic
movements of the diaphragm &
abdominal muscles (usually occurs with
Nausea and results in Vomiting)
• Vomiting: The forceful propulsion of
gastric contents through the mouth.

37. Why is Treating N & V so important?
• Common
• Affects up to 70% patients with advanced
Cancer
• Many conditions
• Ranked highly distressing

38. Treating Nausea and Vomiting
Relies on:
• Being able to recognise patterns of N&V
• Identifying likely cause in individual patients
• Understanding mode of action of commonly
used anti-emetics
• Prescribing most appropriate antiemetic
• Choosing most appropriate route
• Negotiating with patient to ensure compliance

39. Asking the right questions
• Nausea? Retching? Vomiting?
• When: did it start? Time(s) of day?
Constant/not?
• What: does vomit look like? Amount? Blood?
• How: did it start? How has it been treated so
far?
• Why: Exacerbating (& relieving) factors

40. Principles of treating N&V
• Treat reversible causes for N&V
• Appropriate Drug
• Appropriate Route
• Appropriate Prescription: Regularly?
• Re-evaluate every 24-48 hrs

42. Drugs to treat Nausea and
Vomiting

43. • Specific 5-HT3 antagonists: e.g. dolasetron,
granisetron, ondansetron, tropisetron.
• D2 antagonists:
– Phenothiazines, e.g. chlorpromazine,
prochlorperazine, thiethylperazine.
– Butyrophenones, e.g. droperidol, haloperidol.
• – Benzimidazoles, e.g. domperidone.

44. – Substituted benzamides (trimethobenzamide,).
• • D2/5-HT3 antagonists, e.g. metoclopramide.
• • Cannabinoids: dronabinol, nabilone.
• • Antimuscarinics: hyoscine (scopolamine).
• • Antihistamines: e.g. cinnarizine, cyclizine,
dimenhydrinate, meclozine and promethazine.
• • Corticosteroids, e.g. dexamethasone

45. 1. Metoclopramide
2. Domperidone
3. Cyclizine
4. Ondansetron
Receptor Action(s):
1. D2-Antagonist,
5HT4-Agonist: gastric
motility agent
2. D2-Antagonist gastric
motility agent, which
does NOT cross the
Blood-Brain-Barrier
3. Anti-histamine and
Anti-muscarinic
4. 5HT3-Antagonist
Main Side Effect(s):
1. Extra-pyramidal SEs,
abdo cramps, incr Prol.
2. Few SEs (?rarely GI upset;
abdo cramps, incr Prolactin)
3. Sedation, dry mouth,
slow bowel transit
4. Constipation, headache

46. Drug combinations to avoid:
• IV Metoclopramide + IV Ondansetron:
may cause serious cardiac arrhythmias
• Metoclopramide/Domperidone + Cyclizine:
Metoclopramide/Domperidone are motility
agents while Cyclizine slows down GI transit

47. Patterns of Nausea & Vomiting
1. Gastric Stasis
2. Other GI or Visceral irritation
3. Chemical or Metabolic
4. Motion Sickness
5. Raised Intra-Cranial Pressure
6. Unknown or Multiple causes

48. 1. Gastric Stasis
Symptoms:
• Epigastric fullness
• Early satiety
• Large volume vomits (?projectile)
• Hiccups
• Regurgitation (also if moving term ill pt)
• (?Minimal) Nausea quickly relieved by vomiting
Contributing factors:
• Stomach emptying problems (eg Autonomic: eg
Diabetes, Gastritis, Peptic Ulcer)
• Compression of gastric outflow (eg Tumour,
Hepatomegaly, Ascites)
• Drug Side-Effects (eg Anti-Cholinergics, Opioids)

49. Treating Gastric Stasis
Treatment
• Reduce volume of oral intake: Little & often
• Reduce Gastric secretions: PPI (eg
omeprazole)
 Pro-kinetic agents: Dopamine D2-
Antagonists:
• Metoclopramide (also 5HT4 agonist)
• Domperidone

50. 2. Other GI or Visceral irritation
Symptoms:
• Due to the GI or Visceral irritation (eg Constipation)
• Constant Nausea
• Less or variable Vomiting
Stimulation of Vagus / Gut 5HT3 receptors
Contributing factors: GI or Visceral irritation:
• Pharyngeal irritation (eg Tumour/ Sputum/ Candida)
Stretch receptors of:
• GI or GU Tract (eg Constipation, Bowel/ Ureteric
obstruction)
• Visceral capsules (eg Hepatomegaly)

51. Treating GI or Visceral N&V
Treatment
• Address cause (eg Constipation)
 Anti-Cholinergic (vs Vagus)
• Cyclizine
 5HT3-Antagonist
• Ondansetron

52. 3. Chemical or Metabolic N&V
Characteristics:
• Constant nausea
• Less or variable vomiting
Stimulation of CTZ: D2 and 5HT3 receptors
Contributing factors:
• Chemical: Drugs (many: esp Opioids, Antibiotics,
Digoxin, NSAIDs, SSRIs, Chemotherapy)
• Metabolic (eg Renal/ Liver failure, Hypercalcaemia
of Malignancy, Hyponatraemia, Sepsis)

53. Treating Chemical/ Metabolic N&V
Dopamine D2-Antagonist:
• Metoclopramide
5HT3-Antagonist
• Ondansetron

54. 4. Motion Sickness
Characteristics:
• Vomiting on movement
• Dizziness
Stimulation of Vestibular System:
H1 & AChm receptors
Contributing factors:
• Stimulation of vestibular system
• Opioids can increase vestibular sensitivity
• ?Intracerebral cause

55. Treating Motion Sickness
 Anti-Histamine and Anti-Cholinergic
Agents:
• Cyclizine

56. 5. Raised Intracranial Pressure
Characteristics:
• Symptoms worse in the morning?
• Headache
• Nausea
• Vomiting (?projectile)
Stimulation of the Vomiting Centre: H1 & AChm
receptors
Any cause of Raised ICP eg:
• Intracranial space-occupaying lesion (primary/
secondary tumours)
• Skull Metastases
• Intracranial Haemorrhage
• Meningeal infiltration

57. Treating N&V due to Raised ICP
Anti-Histamine & Anti-Cholinergic Agents:
• Cyclizine
Depends on cause:
?Steroids
?Radiotherapy

58. 6. Unknown or Multiple Causes
Non-Drug Measures:
• Address anxiety as a trigger
• Minimise smells (eg perfume, cooking, fungating
tumour)
• Try cool fizzy drinks (?more palatable than hot still
drinks)
• Acupuncture / Acupressure
• Ginger
• Hypnotherapy
Pharmacological Treatment:
Anti-Histamine & Anti-Cholinergic Agents:
• Cyclizine

59. Constipation and Diarrhea

60. Constipation
• Constipation may be defined as a reduced
frequency of defecation, i.e. less frequently
than is normal for the individual concerned,
accompanied by difficulty in passing hardened
stools.
• There may also be sensations of incomplete
defecation and that the rectum remains
loaded with faeces

61. Constipation
• OR
• Chronic constipation: Disorder characterized
by unsatisfactory defecation that results from
infrequent stools, difficult stool passage, or
both over a time period of at least 12 weeks
(Reduced frequency/increased difficulty).
• Leads to: Malaise, Anorexia, Abdominal
discomfort, Colic, Faecal overflow (‘Diarrhoea’=
overflow), Faecal incontinence, Nausea &
Vomiting, Urinary retention, Psychological
distress.

62. Causes of Constipation

63. Causes of Constipation
• Debility (Inactivity, inability to go to toilet at
right time)
• Diet (poor oral intake of fluids or food esp
fibre)
• Drugs
• Disordered Metabolism (Hypercalcaemia,
Hypokalaemia, Hypothyroidism)
• Disease (Cancer)
• Disordered Neurology (eg Spinal Cord
Compression, autonomic neuropathy)

64. Drugs causing constipation
1) NSAIDs (inhibit Pg
synthesis)
2) Opiates: Orally
administered opiates
have greater inhibitory
effect than parenterally
administered agents
3) Anticholinergics
4) Antihistamines
5) Antiparkinsonian agents
(e.g., benztropine or
trihexyphenidyl)
6) Phenothiazines
7) Tricyclic antidepressants
8) Antacids containing calcium
carbonate or aluminum
hydroxide
9) Barium sulfate
10) Calcium channel blockers
11) Clonidine
12) Diuretics (non K+-sparing)
13) Ganglionic blockers
14) Iron preparations
15) Muscle blockers (D -
tubocurarine,
succinylcholine)

65. Mechanism of drug-induced
constipation
1. Drugs with anticholinergic action (e.g.
first generation antihistaminic drugs, tricyclic
antidepressants, benztropine,
phenothiazines,..):
 GIT motility is under parasympathetic
control. Parasympathetic stimulation →
↑motility
 Drugs with anti-cholinergic effect (whether it
is their main action or a side effect)
→↓motility → constipation

66. 2. Opioids: Cause constipation by:
 Increasing the smooth muscle tone, suppressing
forward peristalsis, raising sphincter tone at the
ileo-cecal valve and anal sphincter. This delays
passage of feces through the GIT → increase in
absorption of electrolytes and water in the small
intestine and colon → constipation
 Reducing sensitivity to rectal distension.
3. Electrolyte disturbance as hypokalemia or
hypercalcemia
4. Laxative abuse (leads to atonic intestine)
Mechanism of drug-induced
constipation cont.

67. Types 1 – 2 = Constipation
Types 3 – 4 = Ideal Stools
Types 5 – 7 = Diarrhoea/urgency

68. Treating Constipation
• When: did they last have their bowel
movement? Flatus?
• What: are their stools like? Hard or Soft? Per
Rectal?
• How: often do they usually go? Ie What is
their ‘normal’ bowel habit
• Why: are they constipated? Ie Treat reversible
causes (eg ?contributing drugs)

69. Treatment of constipation
Aims and strategy
• The objectives are then to:
• • relieve any immediate distress;
• • remove any trigger factors and treat any
underlying disease;
• • promote normal bowel function by:
– re-educating the patient about correct bowel
habits, diet and exercise;
– appropriate medication if the problem
persists, i.e. faecal softeners, bulking agents,

70. Treatment of constipation
General measures:
1) Increase the amount of fiber consumed daily
fruits, vegetables, bran and cereals).
2. Increasing fluid intake.
3. Regulation of bowel habits
4. Regular exercise.
5. Treatment of the cause.
6. For drug causes of constipation, a non
constipating alternatives should be used. If no
alternatives exist, lower the dose.

71. If general measures alone are inadequate or
not applicable (e.g., because of old age),
they may be supplemented with bulk-forming
agents, osmotic laxatives or stimulant
laxatives.
• When stimulant laxatives are used, they
should be administered at the lowest
effective dosage and for the shortest period
of time to avoid abuse.
Treatment of constipation cont.

72. Definitions
Laxatives Cathartics
Drugs that help
evacuation of formed
fecal material from
the rectum:
-Bulk-forming laxatives,
-Stimulant laxatives,
-Osmotic laxatives,
-Emollient laxatives
(fecal softeners),
-Lubricants.
Drugs that help
evacuation of
unformed, usually
watery fecal material
from the entire colon.

73. Drug treatment of constipation
(Laxatives)
General indications:
1. Fecal impaction
2. Constipation associated with illness, surgery,
pregnancy or poor diet
3. Drug-induced constipation
4. Conditions where bowel strain is undesirable
5. Preparation for surgery or investigations
involving the GIT (e.g. sigmoidoscopy)

74. Bulk-forming agents (active after 12-36h)
• Drugs: Methylcellulose, Bran, Psyllium (granules, powders or
tablets)
• They increase stool bulk and water content (make stools bulky
(stimulate peristalsis) and soft (easy to pass) (similar to natural
fiber).
• Indications: First-line treatment of constipation. Conditions where
dietary intake of fibers can not be increased.
• Precautions: Adequate fluid intake to avoid intestinal obstruction.
• ADR: Abdominal distension (due to fermentation). Intestinal
obstruction when not consumed with sufficient fluid.
• Contraindications:
1. Atony of the colon
2. Intestinal obstruction
3. Fecal impaction (should be corrected before administration of
fiber)
4. Immobility

75. Stimulant (irritant) laxatives
• Given in an inactive form → hydrolyzed in the GIT into active
forms → GIT irritation → modify permeability of the mucosal
cells → ↑ fluid & electrolyte secretion in the GIT → distension
→ evacuation of soft (or liquid) bulky stools. They probably
cause direct stimulation of the enteric nerves.
• According to the site of GIT irritation are classified into:
1. Small bowel irritant (hydrolysed in the small intestine by
the action of lipases): Castor oil.
2. Large bowel irritants (hydrolyzed by colonic bacteria):
Bisacodyl, Sodium picosulfate, Senna and Cascara.
Used in the prevention of straining at stool following
surgery, MI or stroke; Painful diseases of the anus, e.g.,
fissure or hemorrhoids.

76. Osmotic laxatives- Saline laxatives
• They have cathartic action in large doses: Magnesium salts (sulfate,
hydroxide or citrate), Sodium phosphate.
• MOA:
1. Poorly absorbed → water retention (osmotic effect) →soft bulky stools
→ ↑peristalsis → relief of constipation
2. Magnesium-containing laxatives may stimulate the release of
cholecystokinin, which leads to intraluminal fluid and electrolyte
accumulation and to increased intestinal motility.
• Uses:
 Enema (causes bowel evacuation after 30 min)
 Oral forms (cause bowel evacuation after 2-5h)
Both are used for intestinal evacuation before abdominal radiological
procedures, sigmoidoscopy or surgery (cathartics).
• ADR: Flatulence, abdominal cramps, diarrhea. Intravascular volume
depletion. Electrolyte disturbances
• Contraindications: Renal insufficiency, Severe cardiac disease,
Preexisting electrolyte abnormalities, Patients on diuretic therapy.

77. • Lactulose (disaccharide of galactose & fructose that resists
intestinal disaccharidase activity)
• Sorbitol (monosaccharide)
MOA:
Lactulose → metabolized by colonic bacteria into short chain
fatty acids → osmotic effect → stimulate propulsive activity
ADR: Abdominal distention, Diarrhea
Uses:
Lactulose: (24-48h) Used for treatment of hepatic
encephalopathy (↓ blood ammonia by lowering fecal pH
→↓growth of ammonia-producing bacteria and conversion of
ammonia in the colon to ammonium ion). Constipation in the
elderly patient. Alternative for acute constipation.
 Sorbitol: Chronic constipation.
Osmotic laxatives- Non-digestible
sugars and alcohols

78. • MOA: Poorly absorbed, and retained in the lumen of the gut →
osmotic effect → increase water content of stools.
Uses:
1.Cathartic: high volume of aqueous PEG- isotonic electrolyte
solution (4 liters), used for colonic cleansing for radiological,
surgical, and endoscopic procedures. The isotonic electrolyte
solution avoids transfer of ions across the intestinal wall. The
osmotic activity of the PEG molecules retains the added water .
2.Laxative: small oral doses of PEG used for the short-term
treatment of occasional constipation in difficult cases (2 weeks or
less). This preparation does not contain electrolytes, so larger
volumes may represent a risk for ionic shifts. Onset of effect: 2-4
days.
Osmotic laxatives- Polyethylene
Glycol (PEG)- Electrolyte Solution

79. • Dosage form:
Suppository (laxative effect > 30 min.)
• Mechanism of action:
Osmotic effect in the rectum.
• Adverse effects:
Occasional rectal irritation.
• Uses:
Intermittent constipation in children.
Osmotic laxatives- Glycerin

80. Fecal softeners/emollient laxatives
1.Docusate salts (sodium or calcium) (weak laxatives)
• MOA:
1. Reduces surface tension of stools → increases penetration of fluids
into feces → soft bulky stools
2. Stimulate intestinal fluid & electrolyte secretion (by altering mucosal
permeability)
• Dosage forms:
1. Oral form (active within 1-3 d)
2. Rectal form has a rapid onset of action but contraindicated in
hemorrhoids and anal fissure.
• Uses:
1. In hospitalized patients following MI or surgery, when straining at
defecation should be avoided but activity and fluid intake may be
restricted.
2. They have little role in the management of chronic constipation,
except when the patient is fluid-restricted or incapable of increasing
his or her dietary fiber or activity.

81. 2. Mineral oil:
• MOA:
1.Indigestible and with minimal absorption. Coat stool and allow
easier passage.
2.Inhibit colonic absorption of water → increasing stool weight and
decrease stool transit time.
• Dosage forms: Oral or rectal. Laxative effect is noted after 2 or 3
days of oral use.
• Indications:
Similar to docusates: to maintain a soft stool and avoid straining
for relatively short periods of time (a few days to 2 weeks).
• ADR: May be absorbed systemically → foreign-body reaction in
lymphoid tissue. May be aspirated (in debilitated or recumbent
patients) → lipoid pneumonia. Decreases absorption of fat-soluble
vitamins (A, D, E, and K). When given orally, mineral oil may leak
from the anal sphincter.
Fecal softeners/emollient laxatives

82. New agents
Lubiprostone
• MOA: Opening of chloride channels locally in
the GI luminal epithelium, which stimulates
chloride-rich intestinal fluid secretion and
shortens GI transit time.
• Uses: Chronic idiopathic constipation in adults.
• Adverse effects: Headache. Diarrhea, and
nausea, as a result of delayed gastric emptying.

83. Laxative abuse syndrome

84. Laxative abuse syndrome
Mechanism 1. With the use of strong purgatives, the colon may be so
thoroughly evacuated that a bowel movement may not occur normally
until a few days later. This delay reinforces the need for more laxative.
Eventually the patient may require daily laxatives to maintain bowel
function.

85. Laxative abuse syndrome (cont.)
Mechanism 2.

86. DIARRHEA

87. Diarrhea
• The term "diarrhea“ may refer to increased
frequency of bowel movements, increased
stool liquidity, a sense of fecal urgency, or
fecal incontinence. OR
• Acute diarrhea is an increased volume or
frequency of bowel movement, relative to
that normal for an individual, associated with
greater fluidity of the motions.

88. Diarrhea
• Is a common symptom that can range in
severity from an acute, self-limited annoyance
to a severe, life-threatening illness.
•
• Classification:
Acute <14 d
Persistent >14 d
Chronic > 30 d

89. Diarrhea cont.
• In the normal state, approximately 10 L of fluid
enter the duodenum daily, of which all but 1.5 L are
absorbed by the small intestine.
• The colon absorbs most of the remaining fluid, with
only 100 mL lost in the stool.
• From a medical standpoint, diarrhea is defined as
a stool weight of more than 250 g/24 h.
• Causes of diarrhea are myriad:
 Infectious (viral or bacterial)
 Non infectious
• In clinical practice, it is helpful to distinguish acute
from chronic diarrhea, as the evaluation and
treatment are entirely different.

90. Pathophysiologic
mechanisms of diarrhea
Pathophysiologic mechanism Type of diarrhea
A stimulating substance (e.g. laxatives or
a bacterial toxin) changes active ion
transport in the intestine by either
decreased sodium absorption or
increased chloride secretion
Secretory diarrhea
Change in intestinal motility (e.g by
overgrowth of bacteria)
Altered intestinal motility
Increase in intestinal luminal osmolarity
due to poorly absorbed substances
Osmotic diarrhea
Increase in tissue hydrostatic pressure
due to inflammatory diseases of the GIT
Exudative diarrhea

91. • Malabsorptive, owing to a failure to absorb
nutrients, causing an osmotic diarrhoea,
• Neuromuscular, i.e. overactivity leading to a
shortened gut transit time and inadequate
water and nutrient absorption, e.g. diabetic
neuropathy, thyrotoxicosis

92. Complications
• Both chronic and severe acute diarrhoea may
• cause:
• • Dehydration, with hypovolaemia, low blood
pressure and tachycardia.
• • Hypokalaemia and low bicarbonate, giving
metabolic acidosis. However, these
abnormalities abnormalities are not usually so
great as to require active therapy, unless
diarrhoea is severe and prolonged.

93. • Small-bowel lactase depletion.
• Chronic diarrhoea may also cause anaemia,
which may be microcytic or macrocytic, with
low Hb, iron and folate levels

94. Drugs causing diarrhea
• Laxatives
• Antacids containing magnesium
• Antineoplastic drugs
• Antibiotics: Clindamycin, Tetracyclines,
Sulfonamides, Any broad-spectrum antibiotic
• Antihypertensives: Methyldopa, ACEI, Angiotensin
receptor blockers, α-adrenergic receptor blockers.
• Cholinergic drugs: Neostigmine
• Cardiac agents: Quinidine, Digoxin
• Nonsteroidal antiinflammatory drugs
• Misoprostol
• Colchicine
• Proton pump inhibitors
• H2-receptor blockers

95. Management
• Aims
• The aims of management are to:
• relieve symptoms, without prolonging the
condition;
• prevent dehydration and electrolyte
deficiencies, and to correct existing metabolic
abnormality in severe disease;
• treat any underlying disease or, if there is no
effective treatment, give symptomatic relief.

96. Treatment of diarrhea
Non-pharmacologic therapy:
 Dietary management:
1. Discontinue consumption of solid foods and dairy
products for 24 h (valuable in osmotic diarrhea)
2. For patients who are experiencing nausea and/or
vomiting, a mild, digestible, low-residue diet should be
administered for 24 hours.
3. If vomiting is present and uncontrollable with
antiemetics, nothing is taken by mouth. As bowel
movements decrease, a bland diet is begun.
 Rehydration and maintenance of water and
electrolytes

97. Treatment of dehydration
 Increase fluid intake (fruit juice – contain glucose and
potassium)
 Oral rehydration solution (ORS). The WHO formula contains
glucose, sodium, potassium, chloride and bicarbonate in an
isotonic fluid.
 Glucose concentrations between 80 – 120 mmol/L are
needed to optimize sodium absorption in the small intestine.
Glucose concentration > 160 mmol/L will cause osmotic
diarrhea.
 Sodium concentration = 75 mmol/L (higher concentrations
may cause hypernatremia)
 Dose in mild/moderate diarrhea for adults: 2L/first 24 h
followed by 200 ml per each loose stool

98. Antidiarrheal agents
Indications of antidiarrheal agents:
1. Patients with mild to moderate acute diarrhea.
2. Control chronic diarrhea caused by inflammatory
bowel syndrome (IBS) or inflammatory bowel
disease (IBD).
Contraindications:
- Patients with bloody diarrhea, fever or systemic
toxicity (risk of worsening of the underlying
condition)
Discontinued in patients whose diarrhea is
worsening despite therapy

99. Treatment of diarrhea
Pharmacologic therapy:
1. Antimotility agents
2. Adsorbents
3. Antisecretory compounds
4. Antibiotics
5. Enzymes
6. Intestinal microflora

100. Antimotility agents (opioids)
Opioids agonists: Action in the GIT (mediated by
binding to opioid receptors)
1.Increase segmentation and a decrease propulsive
movement→ ↑ intestinal transit time→ ↑ absorption
of water and electrolyte→ feces become more
solid.
2.Antisecretory
3.↑ tone of the internal anal sphincter
4.↓ response to the stimulus of a full rectum (by their
central action)
Examples: Diphenoxylate, Loperamide

101. Diphenoxylate
Opioid agonist that has no analgesic properties in standard
doses. Higher doses have central opioid actions. Used in
combination with a subtherapeutic dose of atropine (to prevent
abuse).
Adverse effects:
1. Caused by the atropine in the preparation and include
anorexia, nausea, pruritus, dizziness, and numbness of the
extremities.
2. Prolonged use of high doses may cause dependence.
Contraindications:
1. Children below 2 y (toxicity at lower doses than adults)
2. Obstructive jaundice
Drug interactions:
1. Potentiate the effects of CNS depressants
2. Co-administration with MAOI→ hypertensive crises

102. Loperamide
Opioid agonist that does not cross the BBB
and has no analgesic properties and no
potential for addiction.
Adverse effects:
- Abdominal pain and distention,
- Constipation,
- Dry mouth,
- Hypersensitivity,
- Nausea and vomiting.

103. Adsorbents
1. Kaolin and Pectin:
• Kaolin (hydrated magnesium aluminum silicate), often
combined with pectin (indigestible carbohydrate).
• MOA: Adsorb bacterial toxins and fluid
• Indications: Acute diarrhea (given after each loose
bowel movement)
• ADR: Not absorbed and has no adverse effects.
2. Bismuth subsalicylate:
• Insoluble complex of bismuth and salicylate
• Bismuth: antimicrobial
• Salicylate: antisecretory
• ADR: blackening of tongue and stools

104. Antisecretory agents-Octreotide
(somatostatin analogue)
Mechanism of the anti-diarrheal action:
1. Inhibits secretion of many GIT hormones, including gastrin,
cholecystokinin, glucagon, insulin, secretin, pancreatic
polypeptide, vasoactive intestinal peptide, and 5-HT3.
2. Reduces intestinal fluid secretion & pancreatic secretion.
3. Slows GIT motility and inhibits gallbladder contraction.
4. Induces direct contraction of vascular smooth muscle,
leading to a reduction of portal and splanchnic blood flow.
Indications in diarrhea:
1. Secretory diarrhea due to carcinoid tumor.
2. Diarrhea due to vagotomy.
3. Diarrhea caused by short bowel syndrome or AIDS.
4. In low doses to stimulate small bowel motility in patients with
small bowel bacterial overgrowth or intestinal
pseudoobstruction secondary to scleroderma.

105. Adverse effects:
1. Steatorrhea leading to fat-soluble vitamin deficiency
(due to impaired pancreatic secretion).
2. Nausea, abdominal pain, flatulence, and diarrhea due
to alterations in GIT motility.
3. Gall bladder sludge, gall stones or cholecystitis due to
inhibition of gallbladder motility.
4. Hyperglycemia.
5. Prolonged treatment may result in hypothyroidism.
6. Bradycardia.
Octreotide (somatostatin analogue)

106. Antimicrobials
Indications:
1. Patients with +ve stool culture
2. Patients presented with dysentery
3. Patients with suspected exposure to
bacterial infection → Quinolones (as
ciprofloxacin)

107. Traveler‘s Diarrhea (Acute)
• Whenever a person travels from one country to another—
particularly if the change involves a marked difference in
climate, social conditions, or sanitation standards and
facilities—diarrhea is likely to develop within 2–10 days.
• There may be up to ten or even more loose stools per
day, often accompanied by abdominal cramps, nausea,
occasionally vomiting, and rarely fever.
• The stools do not usually contain mucus or blood, and
aside from weakness, dehydration, and occasionally
acidosis, there are no systemic manifestations of
infection.
• The illness usually subsides spontaneously within 1–5
days, although 10% remain symptomatic for a week or
longer, and in 2% symptoms persist for longer than a
month.

108. • To avoid fresh foods & water sources likely to be contaminated
for travelers to developing countries, where infectious diarrheal
illnesses are endemic.
• Prophylaxis for those with inflammatory bowel disease, AIDS,
diabetes, heart disease in the elderly.
• Prophylaxis is started upon entry into the destination country
and is continued for 1 or 2 days after leaving.
• For stays of more than 3 weeks, prophylaxis is not
recommended because of the cost and increased toxicity.
• Prophylaxis:
 Bismuth subsalicylate (effective but turns tongue and stools
blue and can interfere with doxycycline absorption, which may
be needed for malaria prophylaxis).
 Antimicrobial regimens for once-daily prophylaxis also are
effective (norfloxacin 400mg, ciprofloxacin 500mg, ofloxacin
300mg, or co-trimoxazole 160/800mg OD for 5 days).
Traveler‘s Diarrhea cont.

109. • Because not all travelers will have diarrhea and because
most episodes are brief and self-limited, an alternative
approach that is currently recommended is to provide the
traveler with a 3- to 5-day supply of antimicrobials to be
taken if significant diarrhea occurs during the trip.
• Commonly used regimens: Ciprofloxacin 500mg BD,
ofloxacin 300mg BD, or norfloxacin 400mg BD.
• Co-trimoxazole 160/800mg BD can be used as an
alternative (especially in children), but resistance is common
in many areas.
• Aztreonam, a poorly absorbed monobactam with activity
against most bacterial enteropathogens, also is efficacious
when given orally in a dose of 100mg TDS.
Traveler‘s Diarrhea cont.

110. Enteric Fever
• A severe systemic illness manifested initially
by prolonged high fevers, prostration,
confusion, respiratory symptoms followed by
abdominal tenderness, diarrhea, and a rash
is due to infection with Salmonella typhi or
Salmonella paratyphi, which causes
bacteremia and multiorgan dysfunction.

111. Evaluation in acute diarrhea
• In over 90% of patients with acute diarrhea, the
illness is mild and self-limited and responds within 5
days to simple rehydration therapy or antidiarrheal
agents.
• Patients with signs of inflammatory diarrhea
manifested by any of the following require prompt
medical attention:
 high fever (> 38.5 °C),
 bloody diarrhea, abdominal pain, or diarrhea not
subsiding after 4–5 days.
 Similarly, patients with symptoms of dehydration
must be evaluated (excessive thirst, dry mouth,
decreased urination, weakness, lethargy).

112. • Physical examination: Patient's general
appearance, mental status, volume status,
presence of abdominal tenderness or peritonitis.
• Peritoneal findings in C. difficile and
enterohemorrhagic E. coli.
• Hospitalization in patients with severe
dehydration, toxicity, or marked abdominal pain.
• Stool specimens should be examined for fecal
leukocytes and bacterial cultures (rate of positive
bacterial cultures in patients with dysentery is 60–
75%).
Evaluation cont.

113. • Examination of the stool for amebiasis in patients
with dysentery who have a history of recent travel to
endemic areas or those who are homosexuals.
• In patients with a history of antibiotic exposure, a
stool sample should be sent for C. difficile toxin.
• If E. coli O157:H7 is suspected, the lab must be
alerted to do specific serotyping.
• If diarrhea that persists for more than 10 days, 3
stool examinations for ova and parasites also should
be performed.
• Rectal swabs may be sent for Chlamydia, Neisseria
gonorrhoeae, and herpes simplex virus in sexually
active patients with severe proctitis.
Evaluation cont.

114. Evaluation in chronic diarrhea
• Stool Analysis: 24 hours stool collection for weight and
quantitative fecal fat. A stool weight of more than 300 g/24h
confirms the presence of diarrhea, justifying further workup. A
weight greater than 1000–1500 g suggests a secretory
process. A fecal fat in excess of 10 g/24 h indicates a
malabsorptive process.
• Stool osmolality: An osmotic gap confirms osmotic diarrhea.
A stool osmolality less than the serum osmolality implies that
water or urine has been added to the specimen (factitious
diarrhea).
• Stool laxative screen: In cases of suspected laxative abuse,
stool magnesium, phosphate, and sulfate levels may be
measured. Phenolphthalein, senna, and cascara are indicated
by the presence of a bright-red color after alkalinization of the
stool or urine. Bisacodyl can be detected in the urine.

115. • Fecal leukocytes: Presence of leukocytes implies an
underlying inflammatory diarrhea.
• Stool for ova and parasites: Presence of Giardia and E.
histolytica is detected in routine wet mounts. Cryptosporidium
and Cyclospora are detected with modified acid-fast staining.
• Blood Tests: CBC, serum electrolytes, liver function tests,
calcium, phosphorus, albumin, TSH, total T4, beta-carotene,
and prothrombin time. Anemia occurs in malabsorption
syndromes and inflammatory conditions. Hypoalbuminemia is
present in malabsorption, protein-losing enteropathies, and
inflammatory diseases. Hyponatremia and non–anion gap
metabolic acidosis may occur in profound secretory diarrheas.
Malabsorption of fat-soluble vitamins may result in an
abnormal prothrombin time, low serum calcium, low carotene,
or abnormal serum alkaline phosphatase.
Evaluation cont.

116. VICTORY
BELONGS
TO
JESUS

117. Thank you......