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Gastrointestinal Drugs

FAKULTAS KEDOKTERAN UNISMA

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 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 Barretts esophagus can result in adenocarcinoma

What 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


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 and inch in diameter U.S. - duodenal ulcers are three times more common than gastric ulcers.

A Gastric Peptic Ulcer

Who 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


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 Disease


NSAIDs Long term use of nonsteroidal antiinflammatory 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
HP NSAID Cancer (ZE)

Gastric Ulcer

Other

Helicobacter pylori

Spiral shaped, flagellated, Gram negative bacterium

Helicobacter pylori on gastric mucussecreting epithelial cells

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 Transmission:

in Peptic Ulcer Disease

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 Disease


The host reaction to H. pylori determines the outcome of the infection: Gastritis GERD Gastric & Duodenal Ulcers Gastric Cancer (?)

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)

Urease CLO test (PYtest)

Cost of test $50-$100


www.helico.com

Vagal Nucleus

CNS Conditioned Reflexes:


1) Nucleus Tractus Solitarius (NTS);
2) Hypothalamus; Ach 3) Dorsal Motor Nucleus of the Vagal Nerve (DMNV)

Ach

Reflexes Include: Smell, Taste, Chewing, Swallowing & Hypoglycemia

Gastric lumen Mucus Superficial Epithelial Cells

Found in the Body and Fundus of the Stomach

Mucous Neck Cells

Parietal Cells

Peptic Cells (also known as Chief Cell Muscularis Mucosa

Acetylcholine, Gastrin and Histamine Stimulate Parietal Cell Secretion of Acid


Cholinergic EnterochromaffinNeuron like Cell
Ac h

Cholinergic Neuron

Antral G Cell
G
G G G G G

Ac h

H H

Ac h

Ac h

Parietal Cell

Acid
G

Circulation

Vagal Nucleus

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

Parietal Cell

Ach

Ach

H+ G-cell

Histamine

Gastrin

Multiple Mechanisms Regulate Gastric Acid


Neural Acetylcholine Hormonal Gastrin Paracrine Histamine

Each Secretagogue Binds to its Own Receptor and Interacts with the Others
CCK2

Gastrin
H2 Histamine
cAMP dep. pathway PP

H+
Gastric Lumen

M Acetylcholine
3

Strategies for Protecting the Gastric Mucosa from Acid Exposure


Mechanisms
H+ Example

Cimetidine Inhibit Omeprazole secretion Prostaglandins Muscarinic antagonists Prevent contact Neutralize acid Sucralfate Antacids

H+
H+

Strategies for Inhibiting Parietal Cell Acid Secretion


Gastrin Antagonists
CCK2

H2
Histamine Antagonists M
cAMP PP

H+ Gastric Lumen

Muscarinic Antagonists

Strategies for Inhibiting Parietal Cell Acid Secretion


Basolateral
H cAMP

Apical

Histamine

(+)

(+) Protein Kinase (-)


Parietal Cell
PP

ATP EP3

K+

H+

(-)
cAMP

PGI2 PGE2
EP3

Mucus
M?

Superficial Epithelial Cell

HCO3pH 6.7 pH 2

Strategies for Inhibiting Parietal Cell Acid Secretion


CCK2

Ca2+ (-)
cAMP
2

Proton pump Inhibitors

EP3

(+)
ATP M3

Protein Kinase

PP

H+

Ca2+

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)
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 acidsuppressing agents.

Strategies for Inhibiting Parietal Cell Acid Secretion


CCK2

Ca2+ (-)
cAMP

EP3

Histamine Antagonist

Protein Kinase

PP K+

H+

ATP

M3

Ca2+

Histamine Receptors
H1 receptors
Smooth muscle Nerves

H2 receptors
Parietal cells

Histamine H2 Antagonists Decrease Acid Output


cAMP

Histamine

Protein Kinase

K+

PP

H+

ATP

Acid Output (mEq/hr)

Histamine Antagonist

H2 antagonist administered orally at arrow 30 20 10 2 3 4 5

Time (hr) 1

Histamine H2 Antagonists
Cimetidine (Tagamet) Ranitidine (Zantac)

Famotidine (Pepcid)
Nizatidine (Axid)

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.

Esomeprazole (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.

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.

Strategies for Inhibiting Parietal Cell Acid Secretion


CCK2

Gastrin Prostaglandin Agonists Histamine

Ca2+ (-)
cAMP

EP3

Protein Kinase

PP K+

H+

ATP

Acetylcholine

M3

Ca2+

Drugs 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 - Anticholinergics


General muscarinic receptor antagonists
(block all types of muscarinic receptors) Atropine Propantheline (Pro-Banthine) Dicyclomine (Bentyl)

Selective M1 receptor antagonists


Pirenzepine Telenzepine

Drugs for Acid-Peptic Disorders Prostaglandins (PGE2 & PGI2 )

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

Drugs 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


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 Antacids


Magnesium hydroxide
Magnesium trisilicate

Magnesium-aluminum

mixtures

Calcium carbonate
Sodium bicarbonate

Drugs 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 (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

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)
GENERIC NAME Dual therapies omeprazole amoxycillin ranitidine clarithromycin lansoprazole amoxycillin 500 mg TID 14 days 1,000 mg TID 14 days 400 mg BID 500 mg TID 30 mg TID 1,000 mg TID 28 days 14 days 14 days 14 days 70-80 73-84 66-77 DOSING DURATION CURE RATE (%)

Gastrointestinal Pharmacology Acid production: 2.5 L per day Isotonic HCl solution pH < 1 Produced by parietal cells Mucus production: Produced by mucus-secreting cells Also produce bicarbonate, which becomes trapped in the mucus layer => pH gradient across the mucus layer (can become destroyed by alcohol)

Antacids: Weak bases: Aluminum hydroxide Cause constipation Magnesium hydroxide Cause diarrhea => often combined Usally taken 5-7 times per day

Gastrointestinal Pharmacology Antacids: Histamine stimulates acid production by parietal cells Mast cells produce a steady basal level of histamine, which increases in response to gastrin or acetylcholine Parietal cells express histamine H2 receptors => H2 receptor blockers: Cimetidine (Tagamet) First H2-blocker available Inhibits P450 => Drug interaction Ranitidine (Zantac) Does not inhibit P450 => fewer side effects Nizatidine (Axid) Famotidine (Pepcid)

Gastrointestinal Pharmacology Antacids:


Proton pump inhibitors:
Irreversibly inhibit the H+/K+ - ATPase in gastric parietal cells Drugs are inactive at neutral pH, but since they are weak bases, are activated in the acidic stomach milieu => restricted activity Acid production abliterated for 24-48 hours

Omeprazole (Prilosec) Lansoprazole (Prevacid) Esomeprazole (Nexium) Rabeprazole

Gastrointestinal Pharmacology Gastroesophageal reflux disease (GERD): Backflow of stomach acid into the esophagus Esophagus is not equipped to handle stomach acid => scaring Usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone (MI often mistaken for GERD !) More severe symptoms: difficulty swallowing, chest pain Reflux into the throat can cause sore throat Complications include esophageal erosions, esophageal ulcer and narrowing of the esophagus (esophageal stricture) In some patients, the normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus. Primary treatment option are proton pump inhibitors

Mucosal protective agents: Misoprostol Prostaglandin E1 analog (PG stimulate mucus and bicarbonate production) Used when treatment with NSAIDs inhibits endogenous PG synthesis Sucralfate Complex of aluminum hydroxide and sulfated sucrose Forms complex gels with mucus => mucus stabilized => diffusion of H+ impaired Not absorbed => essentially free of side effects Must be taken every 6 hours

Peptic Ulcer Disease Imbalance between defenses and aggressive factors Defensive factors: Prevent the stomach and duodenum from self-digestion Mucus: continually secreted, protective effect Bicarbonate: secreted from endothelial cells Blood flow: good blood flow maintains mucosal integrity Prostaglandins: stimulate secretion of bicarbonate and mucus, promote blood flow, suppress secretion of gastric acid Aggressive factors: Helicobacter pylori: gram negative bacteria, can live in stomach and duodenum, may breakdown mucus layer => inflammatory response to presence of the bacteria also produces urease forms CO2 and ammonia which are toxic to mucosa Gastric Acid: needs to be present for ulcer to form => activates pepsin and injures mucosa Decreased blood flow: causes decrease in mucus production and bicarbonate synthesis, promote gastric acid secretion NSAIDS: inhibit the production of prostaglandins Smoking: nicotine stimulates gastric acid production

Peptic Ulcer Disease (~25 mill. Americans will have an ulcer in their life) Most common cause (> 85%): Helicobacter pylorii (not stress or hot sauce!) Treatment options: Antibiotics Antisecretory agents Mucosal protectants Antisecretory agents that enhance mucosal defenses Antacids

Antibiotic ulcer therapy: Combinations must be used: Bismuth (PeptoBismol) disrupts cell wall of H. pylori Clarithromycin inhibits protein synthesis Amoxicillin disrupts cell wall Tetracyclin inhibits protein synthesis Metronidazole used often due to bacterial resistance to amoxicillin and tetracyclin, or due to intolerance by the patient Standard treatment regimen for peptic ulcer: Omeprazole + amoxicillin + metronidazole

Antiemetic drugs: Vomiting: Infection, pregnancy, motion sickness, adverse drug effects, Triggered by the vomiting center or chemoreceptor trigger zone (CTZ) in the medulla (CTZ is on the blood side of the blood-brain barrier). Treatment options: H1 antagonists: Meclizine, promethazine, dimenhydramine Muscarinic receptor antagonists: Scopolamine (motion sickness) Benzodiazepines: Lorazepam (during chemotherapy) D2 antagonists: have also peripheral prokinetic effects => increase motility of the GI tract => increases the rate of gastric emptying. Caution in patients with Parkinsons disease! Metoclopramide Domperidone Cannabinoids: Marihuana ? Synthetic cannabinoids: during chemotherapy Nabilone Dronabinol

Laxatives: Laxative production of a soft formed stool over a period of 1 or more days Catharsis prompt, fluid evacuation of the bowel, more intense Indications for laxative use: Pain associated with bowel movements To decrease amount of strain under certain conditions Evacuate bowel prior to procedures or examinations Remove poisons To relieve constipation caused by pregnancy or drugs Contraindications: Inflammatory bowel diseases Acute surgical abdomen Chronic use and abuse

Laxatives: Stimulate peristalsis Soften bowel contect Classification: Bulk laxatives Non-absorbable carbohydrates Osmotically active laxatives Irritant laxatives = purgatives Small bowel irritants Large bowel irritants Lubricant laxatives Paraffin Glycerol

Laxatives: Bulk laxatives:Increas e in bowel content volume triggers stretch receptors in the intestinal wall => causes reflex contraction (peristalsis) that propels the bowel content forward Carbohydrate-based laxatives Insoluble and non-absorbable Non digestable; take several days for effect Expand upon taking up water in the bowel Must be taken with lots of water Vegetable fibers (e.g. Psyllium, lineseed) Bran (husks = milling waste product) Osmotically active laxatives Partially soluble, but not absorbable Saline-based (mostly sulfates) Effect in 1-3 hrs => used to purge intestine (e.g. surgery, poisoning) MgSO4 (= Epsom salt) Na2SO4 (= Glaubers salt)

Laxatives: Irritant laxatives: Cause irriatation of the enteric mucose => more water is secreted than absorbed => softer bowel content and increased peristaltic due to increase volume Small bowel irritants Ricinoleic acid (Castor oil) Active ingredient of Ricinus communis The oil (triglyceride) is inactive Ricinoleic acid released from oil through lipase activity Ricin: Lectin from the beans of R.communis Potent toxin: inhibits protein synthesis Potential bioterrorism agent (LD ~100g) In 1978, ricin was used to assassinate Georgi Markov, a Bulgarian journalist who spoke out against the Bulgarian government. He was stabbed with the point of an umbrella while waiting at a bus stop near Waterloo Station in London. They found a perforated metallic pellet embedded in his leg that had presumably contain rich toxin

Laxatives: Irritant laxatives: Large bowel irritants Anthraquinones Active ingredient of Senna sp. (Folia and fructus sennae), Rhamnus frangulae (cortex frangulae) and Rheum sp. (rhizoma rhei): contain inactive glycosides => active anthraquinones released in colon take 6-10 hours to act
Laxatives: Irritant laxatives: Large bowel irritants Diphenolmethanes Derivatives of phenolphtalein Bisacodyl Oral administration: effect in 6-8 hrs Rectal administration: effect in 1 hr Often used to prepare for intestinal surgery Sodium picosulfate

Laxative abuse: Most common cause of constipation! Longer interval needed to refill colon is misinterpreted as constipation => repeated use Enteral loss of water and salts causes release of aldosterone => stimulates reabsorption in intestine, but increases renal excretion of K+ => double loss of K+ causes hypokalemia, which in turn reduces peristalsis. This is then often misinterpreted as constipation => repeated use

Antidiarrheal drugs: treat only symptoms! Diarrhea is usually caused by infection (Salmonella, shigella, campylobacter, clostridium, E. coli), toxins, anxiety, drugs In healthy adults mostly discomfort and inconvenience In children (particularly mal-nourished) a principal cause of death due to excessive loss of water and minerals. Antimotility agents: Muscarinic receptor antagonists (not useful due to side effects) and opiates: Morphine Codeine Diphenoxylate All have CNS effects - NOT useful for diarrhea treatment Loperamide Selective action on the GI tract Does not produce CNS effects First choice antidiarrheal opoid Combined with Dimethicone (Silicon-based gas-absorbent)

Prokinetic Drugs Act on Enteric Nerves to Increase Muscarinic M2 (stimulated by Bethanechol ) Cholinergic Stimulation
Dopaminergic Neuron 5HT4 Stimulated by Metoclopramide (+) Cisparide Cholinergic Neuron

Dopamine D2 (Blocked by Metoclopramide and Domperido

Smooth Muscle Cell

Ach

(+)

(+)

Motilin
(+)

Stimulated by Erythromycin

Motilin

Indirect effects are mediated by M2 muscarinic receptor Metoclopramide crosses the blood-brain barrier

Ach

(-) (+)

Prokinetic 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 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)


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


Erythromycin

Motilin agonist Antibacterial Diarrhea


Motilin (22 amino acid active peptide)

Agonist for the Motilin receptor Stimulates gastric emptying