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Gastrointestinal Drugs 0 Patrick T. Ronaldson, Ph.D. Department of Medical Pharmacology [email protected] 0 Topics for Discussion Drugs for Acid-Peptic Disorders Eradication of Helicobacter pylori (Antibiotic/Inhibition of Acid) Proton Pump Inhibitors (Omeprazole)

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slide1
Gastrointestinal Drugs

0

Patrick T. Ronaldson, Ph.D.

Department of Medical Pharmacology

[email protected]

topics for discussion
0Topics for Discussion
  • 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)
what is gerd
0What is GERD?
  • 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.

what causes gerd
0What Causes GERD?

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 Barrett’s esophagus – can result in adenocarcinoma

barrett s esophagus
Barrett’s 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.

what is peptic ulcer disease
0What is Peptic Ulcer Disease
  • 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

peptic ulcer disease
0Peptic Ulcer Disease

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.

who gets peptic ulcers
0Who Gets Peptic Ulcers
  • 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
what causes peptic ulcer disease
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;
what causes peptic ulcer disease12
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).

pathophysiological processes involved in duodenal and gastric ulcers
Duodenal Ulcer

Gastric Ulcer

HP

NSAID

Cancer (ZE)

Other

Pathophysiological Processes Involved in Duodenal and Gastric Ulcers
helicobacter pylori
Helicobacter pylori

Spiral shaped, flagellated, Gram negative bacterium

h pylori adapted to an acidic environment
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.
role of h pylori in peptic ulcer disease
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.
role of h pylori in peptic ulcer disease20
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 (?)
prevalence of h pylori infection in the u s
Prevalence of H. pylori Infection in the U.S.

HP-

HP+

Duodenal

ulcer

Gastric

ulcer

Gastric

lymphoma

Gastric cancer

role of h pylori in peptic ulcer disease22
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)
what causes peptic ulcer disease24
0What Causes Peptic Ulcer Disease
  • Helicobacter Pylori
  • NSAIDs
  • Gastrinoma (Zollinger-Ellison Syndrome)
  • Stress ulcers
cyclooxygenase pathway
Cyclooxygenase Pathway

Arachidonic Acid

COX-1

Prostacycline

Synthase

Thromboxane

Synthase

Prostaglandin H2

Prostaglandin G2

Prostaglandin

Synthase

Prostacycline PG12

Thromboxane A2

Thromboxane B2

Prostacycline E2, F2

Prostacycline G2

RESULT = DECREASED ACID SECRETION &

INCREASED MUCUS PRODUCTION

slide28
Neuroanatomy of the GI

0

Thalamus

& Insula

Hypothalamus

& Amygdala

Olfactory

bulb

Olfactory

tract

Olfactory

epithelium

Parabrachial

nucleus

slide29
CNS Conditioned Reflexes:

1) Nucleus Tractus Solitarius (NTS);

2) Hypothalamus;

3) Dorsal Motor Nucleus of the Vagal Nerve (DMNV)

Reflexes Include:

Smell, Taste, Chewing, Swallowing & Hypoglycemia

Vagal Nucleus

0

Ach

Ach

slide30
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

acetylcholine gastrin and histamine stimulate parietal cell secretion of acid
Ach

Ach

H

G

G

G

G

G

G

G

G

G

G

H

0

Acetylcholine, Gastrin and HistamineStimulate Parietal Cell Secretion of Acid

Cholinergic

Neuron

Cholinergic

Neuron

Enterochromaffin-

like Cell

Antral G Cell

Ach

Ach

Parietal Cell

Acid

Acid

Circulation

slide32
CNS Conditioned Reflexes:

1) Nucleus Tractus Solitarius (NTS);

2) Hypothalamus;

3) Dorsal Motor Nucleus of the Vagal Nerve (DMNV)

Reflexes Include:

Smell, Taste, Chewing, Swallowing & Hypoglycemia

Vagal Nucleus

0

Ach

Parietal Cell

Histamine

H+

Ach

G-cell

Gastrin

multiple mechanisms regulate gastric acid
Multiple Mechanisms Regulate Gastric Acid
  • Neural

Acetylcholine

  • Hormonal

Gastrin

  • Paracrine

Histamine

each secretagogue binds to its own receptor and interacts with the others
Each Secretagogue Binds to its Own Receptor and Interacts with the Others

CCK2

Gastrin

Ca+2 dep. pathway

H2

Histamine

cAMP dep. pathway

H+

PP

Gastric

Lumen

M3

Ca+2 dep. pathway

Acetylcholine

strategies for protecting the gastric mucosa from acid exposure
0Strategies for Protecting the Gastric Mucosa from Acid Exposure

Mechanisms

Example

Cimetidine

Omeprazole

Prostaglandins

Muscarinic antagonists

Inhibit

secretion

H+

Prevent

contact

H+

Sucralfate

Neutralize

acid

Antacids

H+

strategies for inhibiting parietal cell acid secretion
0Strategies for Inhibiting Parietal Cell Acid Secretion

CCK2

Gastrin

Antagonists

↓ Ca+2

H2

Histamine

Antagonists

↓cAMP

H+

PP

Gastric

Lumen

M3

Muscarinic

Antagonists

↓ Ca+2

slide37
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 2

pH 6.7

slide38
Ca2+

Strategies for Inhibiting Parietal Cell Acid Secretion

CCK2

Proton pump

Inhibitors

(-)

EP3

cAMP

Protein

Kinase

  • H+

H2

PP

(+)

ATP

M3

Ca2+

h k atpase the proton pump is the final transport pathway for parietal cell hydrogen ion secretion
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.
omeprazole prilosec
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.
esomeprazole nexium
0Esomeprazole (Nexium)

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.

proton pump inhibitors ppi
0Proton Pump Inhibitors (PPI)

Well Tolerated

Hypergastrinemia

(can lead to tumor growth in the GI)

Nausea

Headaches, skin rashes

strategies for inhibiting parietal cell acid secretion43
Ca2+Strategies for Inhibiting Parietal Cell Acid Secretion

CCK2

EP3

(-)

cAMP

H+

Protein

Kinase

Histamine

Antagonist

H2

PP

K+

ATP

M3

Ca2+

histamine receptors
Histamine Receptors
  • H1 receptors
    • Smooth muscle
    • Nerves
  • H2 receptors
    • Parietal cells
histamine h 2 antagonists decrease acid output
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

histamine h 2 antagonists
Histamine H2 Antagonists
  • Cimetidine (Tagamet)
  • Ranitidine (Zantac)
  • Famotidine (Pepcid)
  • Nizatidine (Axid)
drugs for acid peptic disorders cimetidine tagamet
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.
drugs for acid peptic disorders cimetidine tagamet48
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...

drugs for acid peptic disorders cimetidine tagamet49
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.
drugs for acid peptic disorders ranitidine zantac famotidine pepcid nizatidine axid
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.
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)

Top Selling Prescription Drugs (1996)
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)

Top Selling Prescription Drugs (2000)
top selling prescription drugs 2003 billions
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

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

0

Top Selling Prescription Drugs (2003)(billions)

3. Ranitidine $0.7138. Famotidine $0.1951. Cimetidine $0.14

Generic Drug Sales (2003)

www.pharmacytimes.com

strategies for inhibiting parietal cell acid secretion54
0Strategies for Inhibiting Parietal Cell Acid Secretion

Gastrin

CCK2

Ca2+

Prostaglandin

Agonists

EP3

(-)

cAMP

H+

Protein

Kinase

H2

PP

Histamine

K+

ATP

Acetylcholine

M3

Ca2+

drugs for acid peptic disorders anticholinergics
0Drugs for Acid-Peptic Disorders - Anticholinergics
  • 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
drugs for acid peptic disorders anticholinergics56
0Drugs for Acid-Peptic Disorders - Anticholinergics
  • General muscarinic receptor antagonists

(block all types of muscarinic receptors)

    • Atropine
    • Propantheline (Pro-Banthine)
    • Dicyclomine (Bentyl)
  • Selective M1 receptor antagonists
    • Pirenzepine
    • Telenzepine
strategies for inhibiting parietal cell acid secretion57
0Strategies for Inhibiting Parietal Cell Acid Secretion

CCK2

Ca2+

Prostaglandin

Agonists

EP3

(-)

cAMP

H+

Protein

Kinase

H2

PP

K+

ATP

M3

Ca2+

drugs for acid peptic disorders prostaglandins pge 2 pgi 2
Inhibits:

Acid secretion

Gastrin release

Pepsin secretion

Stimulates:

Mucus secretion

Bicarbonate secretion

Mucosal blood flow

0

Drugs for Acid-Peptic Disorders – Prostaglandins (PGE2 & PGI2 )
  • Act at prostaglandin EP3 receptors on parietal cells & on epithelial cells

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”
drugs for acid peptic disorders prostaglandins
0Drugs for Acid-Peptic Disorders - Prostaglandins

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
drugs for acid peptic disorders antacids
0Drugs for Acid-Peptic Disorders - Antacids
  • 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

drugs for acid peptic disorders antacids61
0Drugs for Acid-Peptic Disorders - Antacids
  • Magnesium hydroxide
  • Magnesium trisilicate
  • Magnesium-aluminum mixtures
  • Calcium carbonate
  • Sodium bicarbonate
drugs for acid peptic disorders sucralfate carafate
0Drugs for Acid-Peptic Disorders – Sucralfate (Carafate)
  • Sucralfate is a basic aluminum salt of sucrose octasulfate;
  • In the presence of acid (pH < 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.
drugs for acid peptic disorders sucralfate carafate64
0Drugs for Acid-Peptic Disorders - Sucralfate (Carafate)
  • 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
role of h pylori in peptic ulcer disease65
0Role of H. pylori in Peptic Ulcer Disease
  • 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%.
role of h pylori in peptic ulcer disease66
0Role of H. pylori in Peptic Ulcer Disease
  • Combination therapy with Omeprazole and Amoxycillin
eradication of h pylori reduces the rate of duodenal ulcer relapse
Smith et al.

1988

18

80

0

Borody et al.

1988

12

-

25

100

0

Rauws & Tyt

gat

1990

12

81

0

Blum et al.

1990

6

41

0

0

Eradication of H. pylori reduces the rate of duodenal ulcer relapse

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

h pylori eradication rates with either dual triple or quad therapy 199969
0H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)

GENERIC NAME DOSING DURATION CURE RATE (%)

Dual therapies

omeprazole 500 mg TID 14 days 70-80

amoxycillin1,000 mg TID 14 days

ranitidine400 mg BID 28 days 73-84

clarithromycin 500 mg TID 14 days

lansoprazole 30 mg TID 14 days 66-77

amoxycillin1,000 mg TID 14 days

h pylori eradication rates with either dual triple or quad therapy 1999 cont
0H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont.

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

h pylori eradication rates with either dual triple or quad therapy 1999 cont71
0H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont.

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

new strains of h pylori
0New Strains of H. pylori
  • 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
drugs for acid peptic disorders
0Drugs for Acid-Peptic Disorders

Drugs

Stage I

Stage II

Stage III

Gastric &

Major

Side

GERD

GERD

GERD

Duodenal

Effects

(Chronic)

Ulcers

(sporadic)

(>

2

-

3

episode

/wk)

CYP450

Proton Pump

+

++

++

Hypergastr.

Inhibitors

Antibiotics

+

+

CYP450

H

Antagonists

+

+

+

2

Antiandrogen

Parasym.

non

-

Anticholinergics

ANS

U.S.?

diar

r

h

ea

Prostaglandins

+

NSAID

GI

Antacids

+

+?

+2

Ca

GI

Sucralfate

+

Stress

topics for discussion74
0Topics for Discussion
  • 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)
structure of the gi tract
Structure of the GI Tract

MU = Muscularis Mucosa

Consists of:

- inner circular layer

- outer longitudinal layer

functional disorders of the gi
0Functional Disorders of the GI
  • Contractions may be propulsive - i.e., proximal to distal contractions called “mass action” contractions;
  • Contractions may be non-propulsive - segmenting or mixingcontractions which increase luminal fluid to mucosal surface to promote absorptive action of the colon.
peristalsis produced by coordinated contraction and relaxation of muscle coats
0Peristalsis Produced by Coordinated Contraction and Relaxation of Muscle Coats

Myenteric plexus

(Auerbach’s)

Longitudinal muscle

*****

*****

*****

*****

Oral

*****

Bolus

Anal

*****

*****

*****

Contracted

Circular muscle

Submucous plexus

(Meissner’s)

Relaxed

colonic transit and stool frequency in healthy volunteers
0Colonic Transit and Stool Frequency in Healthy Volunteers

80

60

40

transit time (hr)

Average mean colonic

20

0

2

4

6

8

10

12

14

  • No. stools/wk
functional disorders of the gi79
0Functional Disorders of the GI
  • 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.
functional disorders of the gi80
0Functional Disorders of the GI
  • 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; Hirschsprung’s disease (agangliosis of myenteric plexus); sphincter dysfunction, etc.
prokinetic drugs are often used for
0Prokinetic Drugs are Often Used for:
  • Gastroesophageal reflux disease (GERD)
  • Gastroparesis
  • Nighttime heartburn
  • Severe refractory constipation (sometimes caused by irritable bowel syndrome (IBS))
prokinetic drugs
0Prokinetic Drugs
  • Increase neuromuscular transmission
  • Substances which enhance transit of materials through the GI tract;
slide83
Prokinetic Drugs Act on Enteric Nerves to Increase Cholinergic Stimulation

0

Muscarinic M2 (stimulated by Bethanechol)

Dopamine D2 (Blocked byMetoclopramide 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

prokinetic drugs cholinomimetics carbachol bethanechol
0Prokinetic Drugs - Cholinomimetics(Carbachol; Bethanechol)
  • 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)
prokinetic drugs metoclopramide reglan
O

CH

CH

2

3

Cl

C

NH

CH

CH

N

2

2

CH

CH

2

3

NH

OCH

2

3

0

Prokinetic Drugs – Metoclopramide (Reglan)
  • 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
prokinetic drugs domperidone motilium
0Prokinetic Drugs – Domperidone (Motilium)
  • 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

prokinetic drugs cisapride propulsid
0Prokinetic Drugs - Cisapride (Propulsid)
  • 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

prokinetic drugs additional compounds
0Prokinetic Drugs - Additional Compounds
  • Erythromycin
    • Motilin agonist
    • Antibacterial
    • Diarrhea
  • Motilin (22 amino acid active peptide)
    • Agonist for the Motilin receptor
    • Stimulates gastric emptying
laxatives
0Laxatives

Three general mechanisms of action:

  • Hydrophilic or osmotic propertiespromote retention of water in the colon - increase bulk and softness and facilitate transit;
  • Act on colonic mucosa todecrease absorption of water;
  • Increase intestinal propulsive motility, decreasing absorption of fluid secondary to decreased transit time.
laxatives91
0Laxatives

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), andbisacodyl (Dulcolax, Correctol)are popular OTC substances.
  • Active ingredient in Ex-Lax is now Senna.
laxatives92
0Laxatives

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 includemagnesium hydroxide (Milk of Magnesia),sodium phosphateandsodium sulfate;
  • Disadvantage is rapid delivery of a large pressure head to the distal colon and anal sphincter- difficult to time and control.
laxatives93
0Laxatives

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 oilis also used - difficult to contain by the anal sphincter - can be socially distressing (kind of likeOlestra).
laxatives94
0Laxatives

Bulk-forming agents:

Bran,methylcelluloseandpsyllium (Metamucil).Innocuous, inexpensive and recommended.

diarrhea is associated with excessive flow through the lumen of the bowel
0Diarrhea is Associated with Excessive Flow Through the Lumen of the Bowel

Normal

Diarrhea

Net fluid

absorption

Net fluid

accumulation

Increased propulsive

contractions

Normal mixing

and propulsive

contractions

Decreased mixing

contractions

Increased Flow

Normal Flow

the goals of antidiarrheal therapy are to correct the pathophysiology
0The Goals of Antidiarrheal Therapy are to Correct the Pathophysiology

Goals:

  • Eliminate cause;
  • Decrease fluid accumulation in lumen;
  • Decrease propulsive contractions;
  • Increase mixing contractions.
slide98
Opioids and Intestinal Motility

0

Segmenting Contractions

Normal

Flow

Normal

Reduced Contractions

Increased

Flow

{

Diarrhea

Propulsive Contractions

Increased

Flow

Segmenting Contractions

Decreased

Flow

Opioids

antidiarrheal agents opioids
0Antidiarrheal Agents - Opioids
  • 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

opioids and mucosal transport of salt and water
0Opioids and Mucosal Transport of Salt and Water

Physiological

Balance

Normal

Net Fluid

Accumulation

Diarrhea

Net Fluid

Absorption

Opioids

antidiarrheal agents loperamide imodium
0Antidiarrheal Agents - Loperamide (Imodium)

Mu opioid agonist

Very little distribution into CNS

Low addiction liability

Side Effect

Constipating

some opioid drugs act both in the cns and on enteric nerves others act only on enteric nerves
0Some Opioid Drugs Act Both in the CNS and on Enteric Nerves, Others Act Only on Enteric Nerves

Loperamide does not effectively cross the blood-brain barrier

after oral administration and exerts mainly peripheral effects

antidiarrheal agents anticholinergics
0Antidiarrheal Agents - Anticholinergics

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

antidiarrheal agents clonidine catapres
0Antidiarrheal Agents - Clonidine (Catapres)

Alpha2 agonist

Decreased release of secretagogues

Action on villus cells

increase fluid and electrolyte absorption

Side Effect

Induces hypotension

clonidine acts at alpha 2 adrenergic receptors to decrease secretion and increase absorption
0Clonidine Acts at Alpha-2 Adrenergic Receptors to Decrease Secretion and Increase Absorption

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

antidiarrheal agents bismuth subsalicylate
0Antidiarrheal Agents - Bismuth Subsalicylate

Bismuth Subsalicylate (Pepto-Bismol)

Binds bacterial toxins

Reduces formation of prostanoids

Antibacterial

bismuth subsalicylate
0Bismuth Subsalicylate

Blocks?

Bacterial

Toxins

Fluid

Accumulation

cAMP

PGs

antidiarrheal agents gel forming agents
0Antidiarrheal Agents - Gel Forming Agents

Attapulgite- natural clay

Kaolin - natural clay

Pectin- citrus pulp(Kaopectate)

ineffective

Reduce

Flow

Excessive

Fluid

Increase Viscosity

bile acid catharsis
0Bile Acid Catharsis

Cholestyramine(anion-exchange resin)

Lowers LDL cholesterol

binds Bile Acids

Reduce

Flow

Side Effects

Not well absobed

Constipation

antidiarrheal drugs act by a variety of mechanisms
0Antidiarrheal Drugs Act By a Variety of Mechanisms

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

slide112
9

0

What type of therapy is recommended for a person diagnosed with peptic ulcer disease and H. pylori positive?
  • Tagamet with Omeprazole
  • Antacid with Amoxicillin
  • Amoxicillin with Metronidazole
  • Omeprazole with Amoxicillin
  • Omeprazole
the drug misoprostol cytotek will
10

0

The drug Misoprostol (Cytotek®) will:
  • 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
propantheline works by what mechanism to reduce gastric acid
10Propantheline 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
what type of antacid may result in a laxative side effect
10What type of antacid may result in a laxative side effect?
  • Calcium based antacids
  • Sodium Bicarbonate Antacids
  • Magnesium based antacids
  • Aluminum based antacids
prokinetic drugs result in
10Prokinetic 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
slide117
10

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
slide118
10

0

Sucralfate (Carafate®) is a basic aluminum salt of sucrose octasulfate. It is used for peptic ulcers due to its ability to:
  • 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
slide119
10

Laxatives work by decreasing secretions into the lumen

  • True
  • False
slide120
10

The antidiarrheal drug that is best for “bug”-induced diarrhea is bismuth subsalicylate

  • True
  • False
an opioid such as loperamide is useful as an antidiarrheal drug since it can
10

0

An opioid such as Loperamide is useful as an antidiarrheal drug since it can:
  • 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
medpharm fall 2004 john d palmer ph d m d
GI CASE I

0

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

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

what is the most likely diagnosis
10

0

What is the most likely diagnosis?
  • NSAID induced ulcer
  • Food and Stress induced ulcer
  • H. pylori induced ulcer
  • Acute Myocardial Infarction
  • Gastric Cancer
how would you treat such a patient
10How would you Treat such a patient
  • Proton pump inhibitor
  • Antibiotic
  • H2 receptor antagonist & sucralfate
  • Proton pump inhibitor & antibiotic
  • Prostaglandins (Misoprostol)
gi case ii
0

GI – CASE II

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

what is the most likely diagnosis127
10

0

What is the most likely diagnosis?
  • NSAID induced ulcer
  • Food and Stress induced ulcer
  • H. pylori induced ulcer
  • Zollinger Ellison Syndrome
  • Gastric Cancer
slide128
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.

what is the most likely diagnosis130
10

0

What is the most likely diagnosis?
  • NSAID induced ulcer
  • Food and Stress induced ulcer
  • H. pylori induced ulcer
  • Zollinger Ellison Syndrome
  • Gastric Cancer
how would you treat such a patient131
10How would you Treat such a patient
  • Proton pump inhibitor & antacids
  • Antibiotic
  • H2 receptor antagonist & sucralfate
  • Proton pump inhibitor & antibiotic
  • Prostaglandins (Misoprostol)
slide132
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

what are the possible causes
10What 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
further laboratory evaluation what test s do you want
10Further 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
hospital course
Hospital Course
  • All Laboratory Tests Within Normal Limits
  • GI Consult
  • Did Not Meet Criteria for EGD
  • Discharged With Instructions to Discontinue Use of NSAIDs
return to er
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

hospital course137
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
what is going on differential diagnosis would include all of the following except
10What 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
post mortem
Post-mortem
  • Pathologist finds communication between third portion of duodenum and abdominal aortic aneurysm
  • Microscopic exam: no evidence of inflammation seen in duodenal wall
how does h pylori contribute to peptic ulcer disease
10

0

How does H. pylori contribute to peptic ulcer disease?
  • Increases prostaglandin synthesis
  • Decreases the mucosal barrier
  • Increases the synthesis of HCL
  • Increases pepsin production
the three major pathways regulating parietal cell acid secretion include
10

0

The three major pathways regulating parietal cell acid secretion include:
  • Vagal nerve stimulation
  • Endocrine stimulation via gastrin
  • Paracrine stimulation via histamine
  • 1 an 2
  • All of the above
cimetidine an h2 antagonist is effective at reducing acid but has several side effects except
10

0

Cimetidine, an H2 antagonist, is effective at reducing acid but has several side effects EXCEPT:
  • Inhibition of drugs metabolized by CYP450’s
  • An antiandrogen effect
  • Can result in hypergastrinemia
  • Can cause confusion and disorientation in the elderly
therapeutic strategy for peptic ulcer disease
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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