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Pharmacology of Drugs Affecting Gastrointestinal Function

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Title: Pharmacology of Drugs Affecting Gastrointestinal Function


1
Gastrointestinal Drugs
0
Patrick T. Ronaldson, Ph.D. Department of Medical
Pharmacology pronald_at_email.arizona.edu
2
Topics for Discussion
0
  • Drugs for Acid-Peptic Disorders
  • Eradication of Helicobacter pylori
    (Antibiotic/Inhibition of Acid)
  • Proton Pump Inhibitors (Omeprazole)
  • Histamine (H2) Receptor Antagonists (Cimetidine,
    Ranitidine)
  • Anticholinergics
  • Prostaglandins (Misoprostol)
  • Antacids
  • Mucoprotective Drugs (Sucralfate)
  • Drugs for Motility Disorders
  • Prokinetics (Metoclopramide)
  • Laxatives (Bran)
  • Antidiarrheals (Opioids)

3
What is GERD?
0
  • Gastroesophageal Reflux Disease (GERD)
  • GERD is when acid and pepsin from the stomach
    flows backward up into the esophagus often called
    heartburn

Approximately 10-20 of Americans experience
GERD symptoms every day. - One of the most
common medical conditions. - Source
El-Serag (2007). Clin Gastroent Hepatol. 5
17-26.
4
(No Transcript)
5
What Causes GERD?
0
  • 1) Overproduction of acid/pepsin
  • 2) Over relaxation of the Lower Esophageal
    Sphincter (LES)

Complications if not treated - severe chest
pains, bleeding or a pre-malignant change in the
lining of the esophagus called Barretts
esophagus can result in adenocarcinoma
6
Barretts Esophagus
  • Demarcated by histological changes in cells
    lining the esophagus.
  • Occurs in 10 of GERD patients.
  • Incidence is 1 in the general population.
  • Associated with adenocarcinoma of the esophagus.

Lower esophagus lined by red-coloured tissue, not
the usual white-pink colour.
Cameron. 2002. Diseases of the esophagus. 15
106-108.
7
What is Peptic Ulcer Disease
0
  • Definition of Peptic Ulcer
  • A benign lesion of gastric or duodenal mucosa
    occurring at a site where the mucosal epithelium
    is exposed to acid and pepsin

1) Excess acid production 2) Intrinsic defect
in the mucosal defense barrier
8
Peptic Ulcer Disease
0
25 million Americans suffer from peptic ulcer
disease Each year there are 500,000 to 850,000
new cases More than one million ulcer-related
hospitalizations. Average size ¼ and ½ inch in
diameter U.S. - duodenal ulcers are three times
more common than gastric ulcers.
9
A Gastric Peptic Ulcer
0
10
Who Gets Peptic Ulcers
0
  • Peptic Ulcer Disease Affects All Age Groups
  • Can occur in children, although rare
  • Duodenal ulcers tends to occur first at around
    the age 25 and continue until the age of 75
  • Gastric ulcers peak in people between the ages of
    55 and 65
  • Men Have Twice The Risk as Women Do
  • Genetic Factors
  • High levels of acid production, weakness in
    mucosal layer, abnormal nonprotective mucus
    production
  • Increase Acid Production and/or Decrease in
    Bicarbonate and PG Production
  • Caffeine, Cigarettes, Alcohol, Fruit Juices,
    Stress

11
What Causes Peptic Ulcer Disease
  • Helicobacter Pylori (H. pylori)
  • Most ulcers are the result of infection with H.
    pylori
  • Not all of those infected with H. pylori develop
    ulcers
  • H. pylori MAY result in a weakening of the
    mucosal defense systems, allowing for development
    of ulcer subsequent to acid/pepsin aggression

12
What Causes Peptic Ulcer Disease
  • NSAIDs
  • Long term use of nonsteroidal anti-inflammatory
    drugs. NSAIDs block COX enzymes and decrease
    prostaglandins (PGs).
  • Gastrinoma (Zollinger-Ellison Syndrome)
  • Tumors of the duodenum or pancreas and secrete
    abnormally high amounts of gastrin which
    stimulates gastric acid.
  • Stress ulcers
  • Result of physical trauma (i.e., burn
    patients).

13
Pathophysiological Processes Involved in Duodenal
and Gastric Ulcers
14
Helicobacter pylori
Spiral shaped, flagellated, Gram negative
bacterium
15
Barry Marshall, M.D.
16
Helicobacter pylori on gastric mucus-secreting
epithelial cells
17
H. pylori Adapted to an Acidic Environment
  • Primarily colonizes in the antrum of the stomach
  • Resides mainly within the gastric mucus
  • Has a high activity of the enzyme urease which
    enables it to colonize in the stomach.

18
Role of H. pylori in Peptic Ulcer Disease
  • Transmission
  • Thought to be spread by fecal-oral route
  • Possible ?oral-oral transmission?
  • Infection thought to occur between parents and
    young children
  • Additional Notes
  • Correlated with socioeconomic status
  • Almost universal infection in developing
    countries
  • Most of those infected are asymptomatic.

19
Percentages of Population Infected with H. pylori
www.helico.com
20
Carrier State from childhood infection (before
1945)
Low incidence of new infection in young people
Infected
Age
21
Role of H. pylori in Peptic Ulcer Disease
  • The host reaction to H. pylori determines the
    outcome of the infection
  • Gastritis
  • GERD
  • Gastric Duodenal Ulcers
  • Gastric Cancer (?)

22
Prevalence of H. pylori Infection in the U.S.
HP-
HP
Duodenal ulcer
Gastric ulcer
Gastric lymphoma
Gastric cancer
23
Role of H. pylori in Peptic Ulcer Disease
  • Diagnosis
  • The majority cases of peptic ulcer disease are
    related to H. pylori.
  • The diagnosis of H. pylori infection must be
    confirmed prior to initiation of therapy
    (histology and culture, antibody test, urease CLO
    test)

24
Cost of test 50-100
Urease CLO test (PYtest)
www.helico.com
25
What Causes Peptic Ulcer Disease
0
  • Helicobacter Pylori
  • NSAIDs
  • Gastrinoma (Zollinger-Ellison Syndrome)
  • Stress ulcers

26
Cyclooxygenase Pathway
Arachidonic Acid
COX-1
Prostacycline Synthase
Prostaglandin H2 Prostaglandin G2
Thromboxane Synthase
Prostaglandin Synthase
Prostacycline PG12
Thromboxane A2 Thromboxane B2
Prostacycline E2, F2 Prostacycline G2
RESULT DECREASED ACID SECRETION INCREASED
MUCUS PRODUCTION
27
NSAID Induced Ulcers
28
The Physiological Cellular Production of
Gastric Acid and Pepsin
29
Neuroanatomy of the GI
0
Thalamus Insula
Hypothalamus Amygdala
Olfactory bulb
Olfactory tract
Olfactory epithelium
Parabrachial nucleus
30
Vagal Nucleus
0
Ach
Ach
31
Gastric lumen
Mucus
Superficial Epithelial Cells
Found in the
Mucous Neck Cells
Body and Fundus
of the Stomach
Parietal Cells
Peptic Cells (also known as Chief Cells)
Muscularis Mucosa
32
Acetylcholine, Gastrin and Histamine Stimulate
Parietal Cell Secretion of Acid
0
Cholinergic Neuron
Cholinergic Neuron
Enterochromaffin- like Cell
Antral G Cell
Ach
Ach
Parietal Cell
Acid
Acid
Circulation
33
Vagal Nucleus
0
Ach
Parietal Cell
Histamine
H
Ach
G-cell
Gastrin
34
Multiple Mechanisms Regulate Gastric Acid
  • Neural
  • Acetylcholine
  • Hormonal
  • Gastrin
  • Paracrine
  • Histamine

35
Each Secretagogue Binds to its Own Receptor and
Interacts with the Others
CCK2
Gastrin
Ca2 dep. pathway
H2
Histamine
cAMP dep. pathway
H
PP
Gastric Lumen
M3
Ca2 dep. pathway
Acetylcholine
36
Strategies for Protecting the Gastric Mucosa
from Acid Exposure
0
Mechanisms
Example
Cimetidine Omeprazole Prostaglandins Muscarinic
antagonists
Inhibit secretion
H
Prevent contact
H
Sucralfate
Neutralize acid
Antacids
H
37
Strategies for Inhibiting Parietal Cell Acid
Secretion
0
CCK2
Gastrin Antagonists
? Ca2
H2
Histamine Antagonists
?cAMP
H
PP
Gastric Lumen
M3
Muscarinic Antagonists
? Ca2
38
Strategies for Inhibiting Parietal Cell Acid
Secretion
Apical
Basolateral
cAMP
H2
()
Histamine
()
Protein Kinase
H
PP
K
ATP
(-)
(-)
EP3
cAMP
PGI2 PGE2
Parietal Cell
EP3
Mucus
M?
HCO3-
Superficial Epithelial Cell
pH 6.7
pH 2
39
Strategies for Inhibiting Parietal Cell Acid
Secretion
CCK2
Proton pump Inhibitors
(-)
EP3
cAMP
Protein Kinase
H
H2
PP
()
ATP
M3
Ca2
40
H, K-ATPase (the proton pump) is the final
transport pathway for parietal cell hydrogen ion
secretion
  • H, K-ATPase is located in the apical membrane
    of the oxyntic cell along the secretory
    canaliculi
  • The pump requires large amounts of energy that is
    supplied by intracellular ATP
  • Inhibition of H, K-ATPase blocks both basal and
    stimulated acid secretion.

41
Omeprazole (Prilosec)
  • Prototype H, K-ATPase inhibitor A prodrug that
    needs a low pH to be active
  • Irreversible (forms a covalent bond with the
    proton pump) - long lasting inhibition of acid
    production
  • Profound reduction of gastric acid - elevates
    gastric pH significantly (20mg/day for 7days will
    decrease acid by 95)
  • Highly protein bound Metabolized by CYP2C
    CYP3A plasma half life of 1 to2 hours but long
    duration of action Should be taken just prior to
    a meal and should NOT be taken with other
    acid-suppressing agents.

42
Esomeprazole (Nexium)
0
  • Simply the S-isomer of omeprazole
  • H, K-ATPase inhibitor
  • Given orally.

Rabeprazole (Aciphex) Lansoprazole (Prevecid)
  • H, K-ATPase inhibitor
  • Given orally.

Pantoprazole (Protonix)
H, K-ATPase inhibitor An acid-stable form
and can be given by i.v.
43
Proton Pump Inhibitors (PPI)
0
  • Well Tolerated
  • Hypergastrinemia
  • (can lead to tumor growth in the GI)
  • Nausea
  • Headaches, skin rashes

44
Strategies for Inhibiting Parietal Cell Acid
Secretion
CCK2
EP3
(-)
cAMP
H
Protein Kinase
Histamine Antagonist
H2
PP
K
ATP
M3
Ca2
45
Histamine Receptors
  • H1 receptors
  • Smooth muscle
  • Nerves
  • H2 receptors
  • Parietal cells

46
Histamine H2 Antagonists Decrease Acid Output
Histamine
cAMP
H
Protein Kinase
PP
K
ATP
H2 antagonist administered orally at arrow
Histamine Antagonist
30
20
Acid Output (mEq/hr)
10
Time (hr) 1 2 3 4
5
47
Histamine H2 Antagonists
  • Cimetidine (Tagamet)
  • Ranitidine (Zantac)
  • Famotidine (Pepcid)
  • Nizatidine (Axid)

48
Drugs for Acid-Peptic Disorders - Cimetidine
(Tagamet)
  • Competitive H2 receptor Antagonist
  • Markedly inhibits basal acid secretion including
    nocturnal secretion
  • Readily absorbed after oral administration
  • Relatively brief duration of action (4-8 hr)
  • Given on a multiple dosing schedule
  • (300-400 mg, 2-4 times daily)
  • Typical therapy is for 4-8 weeks.

49
Drugs for Acid-Peptic Disorders - Cimetidine
(Tagamet)
  • Side effects include inhibition of the microsomal
    metabolism of other drugs
  • results in higher blood levels and enhancement of
    their effects
  • Interactions have been shown with
  • Diazepam Chlordiazepoxide
  • Theophylline Phenytoin
  • Warfarin Propranolol
  • Meperidine Pentobarbital
  • Lidocaine and many others...

50
Drugs for Acid-Peptic Disorders - Cimetidine
(Tagamet)
  • Additional Side effects
  • In some patients, cimetidine acts as a
    nonsteroidal antiandrogen (i.e., interferes with
    estrogen metabolism).
  • decrease in male sexual function
  • gynecomastia (swelling of the breasts and
    soreness of the nipples in males)
  • Can produce confusion and disorientation in
    elderly patients
  • Diarrhea, rash and miscellaneous other effects in
    a small number of patients.

51
Drugs for Acid-Peptic Disorders - Ranitidine
(Zantac), Famotidine (pepcid), Nizatidine (Axid)
  • Same mechanism of action as Cimetidine but a
    longer duration of action (8 to 12 hrs)
  • Can be given less frequently
  • 150 or 300 mg, 1-2 times daily
  • Less interactions at P450 than Cimetidine.

52
Top Selling Prescription Drugs (1996)
  • 1. Zantac (Ranitidine)
  • 2. Procardia (blood pressure)
  • 3. Mevacor (cholesterol)
  • 4. Vasotec (blood pressure)
  • 5. Prozac (depression)
  • 6. Cardizam (blood pressure)
  • 7. Tagamet (Cimetidine)
  • 8. Premarin (estrogen)
  • 9. Cipro (antibiotic)
  • 10. Prilosec (Omeprazole)
  • 11. Capoten (blood pressure)
  • 12. Pepcid (Famotidine)
  • 13. Naprosyn (arthritis)
  • 14. Ceclor (antibiotic)
  • 15. Xanax (anxiety)
  • 16. Seldance (antiallergic)
  • 17. Augmentin (antibiotic)
  • 18. Zovirax (antiviral/herpes)
  • 19. Zoloft (antidepressant)
  • 20. Humulin (diabetes)

53
Top Selling Prescription Drugs (2000)
  • 1. Prilosec (Omeprazole)
  • 2. Lipitor (cholesterol)
  • 3. Prevacid (Lansoprazole)
  • 4. Prozac (depression)
  • 5. Zocor (cholesterol)
  • 6. Celebrex (analgesic)
  • 7. Zoloft (depression)
  • 8. Paxil (depression)
  • 9. Claritin (antihistimine)
  • 10. Glucophage (diabetes)
  • 11. Norvasc (heart failure)
  • 12. Augmentin (antibiotic)
  • 13. Vioxx (analgesic)
  • 14. Zyprexia (antipsychotic)
  • 15. Pravachol (cholesterol)
  • 16. Premarin (estrogen)
  • 46. Pepcid (Famotidine)
  • 108. Axid (Nizatidine)
  • 134. Zantac (Ranitidine)
  • ???. Tagamet (Cimetidine)

54
Top Selling Prescription Drugs (2003) (billions)
0
  • 11. Advair Diskus (asthma) 2.2
  • 12. Plavix (anticoagulant) 2.2
  • 13. Norvasc (blood pressure) 2.1
  • 14. Effexor XR (depression) 2.1
  • 15. Aciphex (GI) 2.0
  • 16. Protonix (GI) 2.0
  • 17. Risperdal (schizophrenia) 1.9
  • 18. Pravachol (cholesterol) 1.9
  • 19. Vioxx (analgesic) 1.8
  • 20. OxyContin (analgesic) 1.7
  • 1. Lipitor (cholesterol) 6.3
  • 2. Zocor (cholesterol) 5.1
  • 3. Prevacid (GI) 4.4
  • 4. Procrit (anemia) 3.2
  • 5. Nexium (GI) 2.9
  • 6. Zyprexa (antipsychotic) 2.8
  • 7. Zoloft (depression) 2.8
  • 8. Celebrex (analgesic) 2.5
  • 9. Epogen (anemia) 2.5
  • 10. Neurontin (analgesic) 2.0

3. Ranitidine 0.71 38. Famotidine 0.19 51.
Cimetidine 0.14
Generic Drug Sales (2003)
www.pharmacytimes.com
55
Strategies for Inhibiting Parietal Cell Acid
Secretion
0
Gastrin
CCK2
Ca2
Prostaglandin Agonists
EP3
(-)
cAMP
H
Protein Kinase
H2
PP
Histamine
K
ATP
Acetylcholine
M3
Ca2
56
Drugs for Acid-Peptic Disorders - Anticholinergics
0
  • Blockade of acetylcholine at muscarinic (M3/M1)
    receptors
  • Effectively blocks acid secretion (30 to 40)
  • Limited by side-effects
  • Side-effects are typical of anticholinergics such
    as atropine
  • Dry mouth
  • Tachycardia
  • Blurred vision
  • Bowel discomfort (constipation)
  • Difficulty in urination

57
Drugs for Acid-Peptic Disorders - Anticholinergics
0
  • General muscarinic receptor antagonists
  • (block all types of muscarinic receptors)
  • Atropine
  • Propantheline (Pro-Banthine)
  • Dicyclomine (Bentyl)
  • Selective M1 receptor antagonists
  • Pirenzepine
  • Telenzepine

58
Strategies for Inhibiting Parietal Cell Acid
Secretion
0
CCK2
Ca2
Prostaglandin Agonists
EP3
(-)
cAMP
H
Protein Kinase
H2
PP
K
ATP
M3
Ca2
59
Drugs for Acid-Peptic Disorders Prostaglandins
(PGE2 PGI2 )
0
  • Act at prostaglandin EP3 receptors on parietal
    cells on epithelial cells
  • Inhibits
  • Acid secretion
  • Gastrin release
  • Pepsin secretion
  • Stimulates
  • Mucus secretion
  • Bicarbonate secretion
  • Mucosal blood flow

These compounds act by both inhibition of acid
production and by increasing defense mechanisms
  • These compounds are also effective against direct
    damage produced by alcohol, aspirin and NSAIDs,
    and are therefore termed cytoprotective

60
Drugs for Acid-Peptic Disorders - Prostaglandins
0
  • Misoprostol (Cytotec)
  • Synthetic Analog of Prostaglandin E1
  • Anti-acid secretory
  • 0.1 to 0.2 mg results in 85 to 95 acid
    reduction
  • Prevention of NSAID gastric ulcers
  • Side Effects
  • Diarrhea
  • Abortion
  • Exacerbate IBD and should not be given

61
Drugs for Acid-Peptic Disorders - Antacids
0
  • Antacids are weak bases that neutralize HCl in
    the stomach
  • They do not decrease the secretion of acid, and
    in some cases increase secretion
  • They do not suppress nocturnal acid secretion

1. Neutralize acid 2. Decrease acid load to
duodenum 3. Diminish pepsin activity
62
Drugs for Acid-Peptic Disorders - Antacids
0
  • Magnesium hydroxide
  • Magnesium trisilicate
  • Magnesium-aluminum mixtures
  • Calcium carbonate
  • Sodium bicarbonate

63
0
64
Drugs for Acid-Peptic Disorders Sucralfate
(Carafate)
0
  • Sucralfate is a basic aluminum salt of sucrose
    octasulfate
  • In the presence of acid (pH lt 3-4) some of the
    aluminum ions dissociate and the resulting
    negatively charged molecule polymerizes to form a
    viscous paste-like substance
  • This substance adheres strongly to gastric and
    duodenum mucosa and adheres even more strongly to
    partially denatured proteins such as those found
    at the base of the ulcer.

65
Drugs for Acid-Peptic Disorders - Sucralfate
(Carafate)
0
  • This compound does not decrease the concentration
    or total amount of acid in the stomach
  • Sucralfate protects the gastric and duodenal
    mucosa from acid/pepsin attack.
  • Side effects
  • The compound is not really absorbed and,
    therefore, side-effects are minimal
  • constipation
  • diarrhea
  • nausea

66
Role of H. pylori in Peptic Ulcer Disease
0
  • Treatment
  • If H. pylori detected, eradication of the
    bacteria, along with inhibition of acid.
  • Eradication of H. pylori is a cure as reinfection
    rates in Western countries is less than 1.

67
Role of H. pylori in Peptic Ulcer Disease
0
  • Combination therapy with Omeprazole and
    Amoxycillin

68
Eradication of H. pylori reduces the rate of
duodenal ulcer relapse
0
Ulcer relapse ()
Study

Year

Follow
up
H. pylori
(months)


Negative
Positive
Coghlan et al.

1987

12

76

10

Lambert et al.

1987

6

76

0

Marshall et al.

1988

12

81

12

George et al.

1990

12
-
48

0

0



69
H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999)
0
70
H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999)
0
  • GENERIC NAME DOSING DURATION CURE
    RATE ()
  • Dual therapies
  • omeprazole 500 mg TID 14 days
    70-80
  • amoxycillin 1,000 mg TID 14 days
  • ranitidine 400 mg BID 28
    days 73-84
  • clarithromycin 500 mg TID 14 days

  • lansoprazole 30 mg TID 14
    days 66-77
  • amoxycillin 1,000 mg TID 14
    days


71
H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999) Cont.
0
  • GENERIC NAME DOSING DURATION CURE
    RATE ()
  • Triple therapies

  • lansoprazole 30 mg BID
    14 days 86-92
  • amoxycillin 1,000 mg BID
    14 day
  • clarithromycin 500 mg BID
    14 days


72
H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999) Cont.
0
  • GENERIC NAME DOSING DURATION CURE
    RATE ()
  • Quad therapies
  • bismuth subsalicylate Two tablets 7 days
    85-95
  • 525 mg QID
  • metronidazole 250 mg QID 7
    days
  • tetracycline 500 mg QID 7
    days

    omeprazole 20 mg BID 7
    days
  • or
  • lansoprazole 30 mg BID 7
    days


73
New Strains of H. pylori
0
  • Recently a more virulent genetic strain of H.
    Pylori known as cytotoxin-associated gene A
    (cagA) has been found in some people with peptic
    ulcers

74
Drugs for Acid-Peptic Disorders
0
Drugs

Stage I
Stage II
Stage III
Gastric
Major
Side
GERD
GERD

GERD
Duodenal
Effects



(sporadic)
(gt
2
-
3
(Chronic)

Ulcers


episode
/wk)
CYP450


Proton Pump






Hypergastr.
Inhibitors


Antibiotics







CYP450

H
Antagonists








2
Antiandrogen
Parasym.

Anticholinergics




non
-
ANS

U.S.?

diar
r
h
ea

Prostaglandins




NSAID


GI

Antacids





?

2
Ca

GI




Sucralfate

Stress



75
Topics for Discussion
0
  • Drugs for Acid-Peptic Disorders
  • Eradication of Helicobacter pylori
    (Antibiotic/Inhibition of Acid)
  • Proton Pump Inhibitors (Omeprazole)
  • Histamine (H2) Receptor Antagonists (Cimetidine,
    Ranitidine)
  • Anticholinergics
  • Prostaglandins (Misoprostol)
  • Antacids
  • Mucoprotective Drugs (Sucralfate)
  • Drugs for Motility Disorders
  • Prokinetics (Metoclopramide)
  • Laxatives (Bran)
  • Antidiarrheals (Opioids)

76
Structure of the GI Tract
  • MU Muscularis Mucosa
  • Consists of
  • - inner circular layer
  • - outer longitudinal layer

77
Functional Disorders of the GI
0
  • Contractions may be propulsive - i.e., proximal
    to distal contractions called mass action
    contractions
  • Contractions may be non-propulsive - segmenting
    or mixing contractions which increase luminal
    fluid to mucosal surface to promote absorptive
    action of the colon.

78
Peristalsis Produced by Coordinated Contraction
and Relaxation of Muscle Coats
0
Myenteric plexus (Auerbachs)
Longitudinal muscle




Oral
Bolus

Anal



Contracted
Circular muscle
Submucous plexus (Meissners)
Relaxed
79
Colonic Transit and Stool Frequency in Healthy
Volunteers
0
80
60
40
transit time (hr)
Average mean colonic
20
0
2
4
6
8
10
12
14
No. stools/wk
80
Functional Disorders of the GI
0
  • Pharmacotherapy (prescription and
    non-prescription) amounts to 5 to 6 billion
    annually for real or perceived disorders of
    colonic motility
  • Patients seek medical care because they are not
    experiencing presumed normal pattern of bowel
    movement (one per day) or stool consistency
  • Complaints are highly subjective and personal,
    and difficult to quantify and validate.

81
Functional Disorders of the GI
0
  • Primary
  • infection, inflammation, congenital defects
    (disorders of the neuronal/muscular activity)
  • Secondary
  • metabolic disorders (hypo- or hyper-parathyroidism
    , hypercalcemia), neurologic (diabetes mellitus -
    damage to vagal and sympathetic extrinsic nerves,
    intrinsic nerves MS, heavy metal toxicity,
    carcinoma)
  • Examples of colonic dysfunction
  • IBS chronic constipation Hirschsprungs disease
    (agangliosis of myenteric plexus) sphincter
    dysfunction, etc.

82
Prokinetic Drugs are Often Used for
0
  • Gastroesophageal reflux disease (GERD)
  • Gastroparesis
  • Nighttime heartburn
  • Severe refractory constipation (sometimes caused
    by irritable bowel syndrome (IBS))

83
Prokinetic Drugs
0
  • Substances which enhance transit of materials
    through the GI tract
  • Increase neuromuscular transmission

84
Prokinetic Drugs Act on Enteric Nerves to
Increase Cholinergic Stimulation
0
Muscarinic M2 (stimulated by Bethanechol)
Dopamine D2 (Blocked by Metoclopramide and
Domperidone)
Dopaminergic Neuron
5HT4 Stimulated by Metoclopramide Cisparide
DA
()
(-)
Smooth Muscle Cell
()
()
Ach
Ach
Cholinergic Neuron
()
Motilin
Stimulated by Erythromycin
()
Motilin
Indirect effects are mediated by M2 muscarinic
receptors Metoclopramide crosses the
blood-brain barrier
85
Prokinetic Drugs - Cholinomimetics (Carbachol
Bethanechol)
0
  • Actions
  • Muscarinic receptor agonist
  • Increase force of contraction
  • Little effect on intestinal transit
  • Adverse Side-effects
  • Cardiovascular (hypotension, bradycardia)
  • Urinary Bladder (increase voiding press.,
    decrease capacity)
  • Exocrine Glands (increase secretions)
  • Eye (pupil constriction and loss of accommodation)

86
Prokinetic Drugs Metoclopramide (Reglan)
0
  • Metoclopramide is an antiemetic and improves
    gastric emptying indirectly releases
    acetylcholine
  • Actions
  • Dopamine D2 receptor antagonist
  • 5-HT4 receptor agonist
  • Ganglionic stimulant
  • Pharmacokinetics
  • Oral bioavailability
  • Crosses blood-brain barrier
  • Adverse Side-effects
  • Sedation
  • Dystonic reactions
  • Anxiety reactions
  • Gynecomastia
  • Galactorrhea

87
Prokinetic Drugs Domperidone (Motilium)
0
  • Domperidone is an antiemetic and improves gastric
    emptying Not very effective for GERD
  • Actions
  • Dopamine receptor antagonist
  • Ganglionic stimulant
  • Pharmacokinetics
  • Low oral bioavailability
  • Does not cross blood-brain barrier
  • Adverse Side-effects
  • Headaches
  • Gynecomastia
  • Galactorrhea

88
Prokinetic Drugs - Cisapride (Propulsid)
0
  • Actions
  • 5-HT4 agonist other unknown actions.
  • Adverse Side-effects
  • Serious cardiovascular problems including
    arrhythmias (i.e., ventricular tachycardia,
    ventricular fibrillation and QT prolongation
  • As of December 1999, 80 deaths
  • Janssen Pharmaceutical Inc. has stopped making
    cisapride in the US as of 2000

89
Prokinetic Drugs - Additional Compounds
0
  • Erythromycin
  • Motilin agonist
  • Antibacterial
  • Diarrhea
  • Motilin (22 amino acid active peptide)
  • Agonist for the Motilin receptor
  • Stimulates gastric emptying

90
Comparison of Gastric Prokinetic Drugs
0
91
Laxatives
0
  • Three general mechanisms of action
  • Hydrophilic or osmotic properties promote
    retention of water in the colon - increase bulk
    and softness and facilitate transit
  • Act on colonic mucosa to decrease absorption of
    water
  • Increase intestinal propulsive motility,
    decreasing absorption of fluid secondary to
    decreased transit time.

92
Laxatives
0
  • Secretory agents
  • Increase secretion of fluid in the intestine,
    probably by opening chloride channels
  • Castor oil, cascara and senna (Senokot) are
    naturally occurring substances. Phenolphthalein
    (Ex-Lax), and bisacodyl (Dulcolax, Correctol) are
    popular OTC substances.
  • Active ingredient in Ex-Lax is now Senna.

93
Laxatives
0
  • Saline Agents
  • Contain a cation (magnesium) or anion (sulfate or
    phosphate) that carries obligatory water of
    hydration and is poorly absorbed from the
    intestinal lumen
  • Retain fluid in the bowel to promote flow.
    Examples include magnesium hydroxide (Milk of
    Magnesia), sodium phosphate and sodium sulfate
  • Disadvantage is rapid delivery of a large
    pressure head to the distal colon and anal
    sphincter - difficult to time and control.

94
Laxatives
0
  • Emollients
  • Nonabsorbed lubricants which enhance flow.
  • Dioctyl sodium sulfosuccinate (Colace, Doxinate,
    Surfak) - these are anionic surfactants. They
    produce softening of the stool over a period of
    1-3 days. Details of pharmacology are uncertain.
  • Mineral oil is also used - difficult to contain
    by the anal sphincter - can be socially
    distressing (kind of like Olestra).

95
Laxatives
0
  • Bulk-forming agents
  • Bran, methylcellulose and psyllium (Metamucil).
    Innocuous, inexpensive and recommended.

96
0
97
Diarrhea is Associated with Excessive Flow
Through the Lumen of the Bowel
0
Normal
Diarrhea
Net fluid absorption
Net fluid accumulation
Increased propulsive contractions
Normal mixing and propulsive contractions
Decreased mixing contractions
Increased Flow
Normal Flow
98
The Goals of Antidiarrheal Therapy are to Correct
the Pathophysiology
0
  • Goals
  • Eliminate cause
  • Decrease fluid accumulation in lumen
  • Decrease propulsive contractions
  • Increase mixing contractions.

99
Opioids and Intestinal Motility
0
Segmenting Contractions
Normal Flow
Normal
Reduced Contractions
Increased Flow

Propulsive Contractions
Diarrhea
Increased Flow
Segmenting Contractions
Decreased Flow
Opioids
100
Antidiarrheal Agents - Opioids
0
  • Agonist at mu opioid receptors
  • Decreases fluid secretion
  • Increases fluid absorption
  • Decreases propulsive contractions
  • Increases segmenting contractions
  • Delays gastric emptying.

Adverse Side Effects - Constipation - CNS effects
101
Opioids and Mucosal Transport of Salt and Water
0
Physiological Balance
Normal
Net Fluid Accumulation
Diarrhea
Net Fluid Absorption
Opioids
102
Analgesics that can be used as Antidiarrheal
Agents
0
  • Morphine
  • Codeine

103
Antidiarrheal Agents - Loperamide (Imodium)
0
  • Mu opioid agonist
  • Very little distribution into CNS
  • Low addiction liability
  • Side Effect
  • Constipating

104
Some Opioid Drugs Act Both in the CNS and on
Enteric Nerves, Others Act Only on Enteric Nerves
0
Loperamide does not effectively cross the
blood-brain barrier after oral administration and
exerts mainly peripheral effects
105
Antidiarrheal Agents - Anticholinergics
0
  • Muscarinic antagonists
  • Decrease propulsive contractions
  • Decrease cholinergic secretions
  • Side Effects
  • Produce typical antimuscarinic side-effects
  • Dry mouth
  • Tachycardia
  • Blurred vision
  • Bowel discomfort (constipation)
  • Difficulty in urination

106
Antidiarrheal Agents - Clonidine (Catapres)
0
  • Alpha2 agonist
  • Decreased release of secretagogues
  • Action on villus cells
  • increase fluid and electrolyte absorption
  • Side Effect
  • Induces hypotension

107
Clonidine Acts at Alpha-2 Adrenergic Receptors
to Decrease Secretion and Increase Absorption
0
Mucosal Epithelium
Intestinal Lumen
()
Villus
Clonidine
a2
()
a2
Secretomotor Neuron
Ach () VIP ()
Crypt
Clonidine acts at neural a2 receptors to inhibit
release of secretory neurotransmitters and at
epithelial a2 receptors to stimulate absorption
108
Antidiarrheal Agents - Bismuth Subsalicylate
0
  • Bismuth Subsalicylate (Pepto-Bismol)
  • Binds bacterial toxins
  • Reduces formation of prostanoids
  • Antibacterial

109
Bismuth Subsalicylate
0
Blocks?
Bacterial Toxins
Fluid Accumulation
cAMP
PGs
110
Antidiarrheal Agents - Gel Forming Agents
0
  • Attapulgite - natural clay
  • Kaolin - natural clay
  • Pectin - citrus pulp (Kaopectate)
  • ineffective

Reduce Flow
Excessive Fluid
Increase Viscosity
111
Bile Acid Catharsis
0
Cholestyramine (anion-exchange resin) Lowers LDL
cholesterol
Reduce Flow
binds Bile Acids
Side Effects Not well absobed Constipation
112
Antidiarrheal Drugs Act By a Variety of Mechanisms
0
Drugs

Inhibit

Stimulate

Decrease

Enhance

Bind

propulsive

nonpropulsive

fluid

fluid

luminal

contractions

contractions

secretion

absorption

secretagogues


Opioids










a






agonists

2

Anticholinergics







Somatostatin







(Octreotide)



Bismuth




subsalicylate



Cholestyramine







Stimulated by secretagogues
113
What type of therapy is recommended for a person
diagnosed with peptic ulcer disease and H. pylori
positive?

0
  • Tagamet with Omeprazole
  • Antacid with Amoxicillin
  • Amoxicillin with Metronidazole
  • Omeprazole with Amoxicillin
  • Omeprazole

114
The drug Misoprostol (Cytotek) will

0
  • Decrease the production of acid
  • Increase the mucosal barrier
  • Is cyto-protective
  • Is often used for NSAID induced gastric ulcers
  • All of the above
  • 2 and 3 only

115
Propantheline works by what mechanism to reduce
gastric acid
  • Directly blocks the proton pump
  • Act at the nicotinic receptors to stop Ach
    interactions
  • Block Ach activity at the M3/M1 receptors on
    parietal cells
  • Act as an agonist at M3/M1 receptors to decrease
    acid production from parietal cells

116
What type of antacid may result in a laxative
side effect?
  • Calcium based antacids
  • Sodium Bicarbonate Antacids
  • Magnesium based antacids
  • Aluminum based antacids

117
Prokinetic drugs result in
  • A decrease in propulsive contractions
  • An increase in mixing contractions
  • Increase fluidity within the lumen of the GI
    tract
  • Improve antroduodenal coordination

118
Metoclopramide acts as a prokinetic by
  • Directly acting on the smooth muscle to increase
    propulsive contractions
  • By acting as an agonist at 5HT4 receptors to
    increase the release of Acetylcholine
  • By acting as an agonist at D2 receptors to
    increase the release of Acetylcholine
  • By releasing Motilin to increase propulsive
    contractions

119
Sucralfate (Carafate) is a basic aluminum salt
of sucrose octasulfate. It is used for peptic
ulcers due to its ability to

0
  • Complexes with proteins at the ulcer site
  • Decreases back diffusion of hydrogen ions
  • Binds to pepsin and bile salts
  • None of the above
  • All of the above

120
Laxatives work by decreasing secretions into the
lumen
  • True
  • False

121
The antidiarrheal drug that is best for
bug-induced diarrhea is bismuth subsalicylate
  • True
  • False

122
An opioid such as Loperamide is useful as an
antidiarrheal drug since it can

0
  • Increase segmenting contractions of the GI
  • Decrease propulsive contractions of the GI
  • Results in contents remaining in the GI longer
    for more fluid retention
  • 1 and 2 only
  • All of the above

123
MedPharm, Fall 2004 John D. Palmer, Ph.D. M.D.

GI CASE I
0
  • A 79 year old man
  • Chief Complaint Chest Pain, ten episodes of
    bright red vomiting and maroon and black
    colored stools.
  • PROBLEM LIST MEDICATIONS
  • Ischemic cardiomyopathy CHF Allopurinol
  • Myocardial infarction Furosemide
  • Gout Metolazone
  • Hiatus hernia Spironolactone
  • Erosive esophagitis Omeprazole
  • Clopidogrel
  • Warfarin
  • Aspirin
  • Carvedilol
  • Laboratory
  • Hemoglobin/Hematocrit 6.6/19.7 (normal 14/44)
  • PT/INR 26.4/5.2

124
What is the most likely diagnosis?

0
  • NSAID induced ulcer
  • Food and Stress induced ulcer
  • H. pylori induced ulcer
  • Acute Myocardial Infarction
  • Gastric Cancer

125
How would you Treat such a patient
  • Proton pump inhibitor
  • Antibiotic
  • H2 receptor antagonist sucralfate
  • Proton pump inhibitor antibiotic
  • Prostaglandins (Misoprostol)

126
GI CASE II
0
  • A 55 year old man
  • Chief Complaint Nausea, black tarry stools with
    diarrhea and vomiting of blood
  • PROBLEM LIST MEDICATIONS
  • Psoriasis with arthritis Acetaminophen
    Obesity hydrocodone
  • Sleep apnea Folic acid
  • Chronic bronchitis Methotrexate
  • History of peptic ulcer disease Salsalate
  • No Alcohol used
  • Vital signs BP 106/45 Pulse 106 Resp 20
  • Laboratory
  • PT/INR 13.8/-
  • Hemoglobin/Hematocrit 13.6/38

127
0
128
What is the most likely diagnosis?

0
  • NSAID induced ulcer
  • Food and Stress induced ulcer
  • H. pylori induced ulcer
  • Zollinger Ellison Syndrome
  • Gastric Cancer

129
GI CASE III
0
  • A 47 year old man
  • Chief Complaint worsening abdominal pain and
    generalized weakness,
  • Complains of a 3 month history of stomach
    discomfort and indigestion, little relationship
    to mealtime.
  • noted a recent black, tar-like bowel movement,
    which he attributed to eating too many black
    beans.
  • PROBLEM LIST occult blood (a small amount of
    blood not visible to the naked eye) on a stool
    test (Hemoccult),
  • his red blood cell count was lower than normal
    (anemia).
  • MEDICATIONS Antacids
  • Vital signs BP 110/55 Pulse 90 Resp 20
  • Laboratory Endoscopy exam revealed a large ulcer
    in the bottom of his stomach with some evidence
    of recent bleeding,
  • Biopsy of the stomach demonstrated bacteria,
    Helicobacter pylori.

130
0
131
What is the most likely diagnosis?

0
  • NSAID induced ulcer
  • Food and Stress induced ulcer
  • H. pylori induced ulcer
  • Zollinger Ellison Syndrome
  • Gastric Cancer

132
How would you Treat such a patient
  • Proton pump inhibitor antacids
  • Antibiotic
  • H2 receptor antagonist sucralfate
  • Proton pump inhibitor antibiotic
  • Prostaglandins (Misoprostol)

133
GI CASE IV
0
  • A 68 year old man
  • Chief Complaint Chest pain with vomiting of
    bright red blood for several days.
  • PROBLEM LIST Chronic renal insufficiency and
    Osteoarthritis.
  • MEDICATIONS Ibuprofen
  • Vital signs BP 110/55 Pulse 80 Resp 20
  • Physical Exam Tender in epigastrium
  • Laboratory Hgb/Hct 15/44 PT/aPTT-WNL
  • Gastric aspiration- negative for blood
  • Stool negative for blood

134
What are the possible causes?
  • NSAID induced ulcer
  • Bleeding into bowel from an aortic aneurysm
  • H. pylori induced ulcer
  • Cardiovascular event
  • Gastric Cancer
  • All of the above

135
Further laboratory evaluation, what test(s) do
you want?
  • Liver cell test
  • EGD
  • H. pylori induced breath test
  • EKG Cardiac enzymes
  • Abdominal X-rays
  • All of the above

136
Hospital Course
  • All Laboratory Tests Within Normal Limits
  • GI Consult
  • Did Not Meet Criteria for EGD
  • Discharged With Instructions to Discontinue Use
    of NSAIDs

137
Return to ER
  • 36 Hours later With History of vomiting bright
    red blood and copious maroon colored stools
  • Physical Exam
  • Apperance- pale and sweaty
  • VS BP 90/50 pulse 100 R 18
  • Epigastric tenderness
  • Lab Hgb/Hct 9/30

138
Hospital Course
  • Admitted to ICU
  • Stabilized with IV fluids
  • GI Consult Requested
  • GI agrees to perform EGD
  • GI starts procedure with conscious sedation using
    local anesthesia and midazolam
  • Patient expels large volume of blood from the
    mouth that can not be controlled with suction

139
What is going on? Differential diagnosis would
include all of the following EXCEPT
  • Massive bleeding peptic ulcer
  • Hemrroidal bleeding
  • Bleeding colon cancer
  • Communication between GI tract and aorta
  • Hemorrhagic gastritis

140
Post-mortem
  • Pathologist finds communication between third
    portion of duodenum and abdominal aortic aneurysm
  • Microscopic exam no evidence of inflammation
    seen in duodenal wall

141
How does H. pylori contribute to peptic ulcer
disease?

0
  • Increases prostaglandin synthesis
  • Decreases the mucosal barrier
  • Increases the synthesis of HCL
  • Increases pepsin production

142
The three major pathways regulating parietal cell
acid secretion include

0
  • Vagal nerve stimulation
  • Endocrine stimulation via gastrin
  • Paracrine stimulation via histamine
  • 1 an 2
  • All of the above

143
Cimetidine, an H2 antagonist, is effective at
reducing acid but has several side effects
EXCEPT

0
  • Inhibition of drugs metabolized by CYP450s
  • An antiandrogen effect
  • Can result in hypergastrinemia
  • Can cause confusion and disorientation in the
    elderly

144
Therapeutic Strategy for Peptic Ulcer Disease
  • Old Therapeutic Strategy
  • USED TO BE no acid, no ulcer.
  • Accomplished by reduction of acid production OR
    improvement of the integrity of the mucosal
    barrier, or both.
  • Current Therapeutic Strategy
  • Now no NSAID damage, no Zollinger Ellison
    syndrome, no H. pylori, no ulcer.
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