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Gastrointestinal drugs. Weiwei HU. Phone: 0571-88208226. E-mail:[email protected] 1.Hepatic, pancreatic and biliary disorders. 2. Acid-peptic disorders. 3.Gastrointesinal motility disorders. 4. Inflammatory bowel diseases. Gastrointestinal drugs. 1. Drugs used for acid-peptic disorders

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Gastrointestinal drugs

Weiwei HU

Phone: 0571-88208226

E-mail:[email protected]


1.Hepatic, pancreatic and biliary disorders

2. Acid-peptic disorders

3.Gastrointesinal motility

disorders

4. Inflammatory bowel diseases


Gastrointestinal drugs
Gastrointestinal drugs

1. Drugs used for acid-peptic disorders

2. Modulators of gastrointestinal functions


1) Peptic ulcer disease (PUD, 消化性溃疡)

1. Acid-peptic disorders

2) Gastroesophageal reflux disease (GERD)

3) Drug-induced mucosal injury, especially by

non-steroidal anti-inflammatory drugs (NSAIDs)

4) Pathologic acid-hypersecretory conditions (e.g.

Zollinger-Ellison syndrome)

5) Acute stress ulcers



The feature of peptic ulcer disease:

High incidence, Recurrence frequently, Drug treatment is the main way

Symptoms:

Upper abdominal burning or hunger pain

Emesia (呕吐), belching (嗳气)

Ulcer complication

Ulcer bleeding (出血)

Ulcer perforation (穿孔)

Pyloristenosis (幽门狭窄)

Canceration (癌变)


2) Gastroesophageal reflux disease (GERD)

Abnormal reflux in the esophagus


3) Drug-induced mucosal injury, especially by

non-steroidal anti-inflammatory drugs (NSAIDs)


4) Pathologic acid-hypersecretory conditions (e.g.

Zollinger-Ellison syndrome)

Tumor

Gastrin

Gastic acid

Peptic ulcer



2. Gastric acid secretion and regulation

Gastric cells of mucosa

  • Surface epithelial cells (secrete mucus)

  • Mucus neck cells (secret mucus and are the source of proliferating cells);

  • Chief cells (secret pepsinogens)

  • G cells (release gastrin in the antrum);

  • Parietal cells in the gastric fundus ( secrete HCl and intrinsic factor)


2. Gastric acid secretion and regulation

(the proton pump)

Basolateral membane




2.Pathogenesis of peptic ulcers

Aggressive factors

Defensive factors

Gastric acid

Mucus

Pepsin

bicarbonate

Helicobacter pylori

Mucosa


Pathogenesis of peptic ulcers

Treatment approaches

(1)Reducing secretion of gastric acid or neutralizing the acid

(1)Increased gastric acid secretion

(2)Infection with gram-negative Helicobacter pylori

(2)Eradicating H. pylori infection

(3)Inadequate mucosal defense against gastric acid

(3)Protecting the gastric mucosa from damage


3.Drugs used for peptic ulcers

(1) Antacids: neutralizing the acid

(2) Drugs suppressing gastric acid secretion

①Muscarinic receptor antagonists

②H2 receptor antagonists

③Gastrin receptor antagonists

④H+-K+-ATPase inhibitors (proton pump inhibitors)

(3)Antimicrobial drugs (Helicobacter pylori)

(4)Mucosal protective drugs


(Weak bases)

Chemistry of antacids:

Salts of aluminum (aluminum hydroxide) ,

Salts of magnesium (carbonate, hydroxide, trisilicate) , aluminum magnesium carbonate (Al2Mg6(OH)16CO3·4H2O)

calcium(carbonate)

sodium (bicarbonate)


Antacids

×

(the proton pump)

Mechamism of action


(1) Antacids

1. Pharmacological effect

Neutralizing gastric acid, diminish gastric acidity and inactivate pepsin(胃蛋白酶)activity

The effect depends on the dose and dosing frequency.

Starting effect within 5-15 min after taking the drugs.

2. Clinical uses

Commonly used for acid-peptic disorders (peptic ulcer), gastritis, duodenitis.


3. Adverse effects

(1) Constipation and stomach cramp (salt of aluminum)

(2) Diarrhea (salt of magnesium )

Combination products such as maalox

(3) Hypercalcium which can cause renal failure (Calcium)

(4) Hypernatremia (sodium-containing antacids)

All antacids are generally regarded as safe in pregnancy.

4. Drug interactions

Avoid concurrent administration of antacids and a variety of drugs .

(1) Affect rates of dissolution and absorption, bioavailbility, and renal elimination of many drugs

(2) By binding to drugs (for example, tetracycline四环素), form insoluble complexes that are not absorbed


Adminstration and dosage

  • Take antacids after meals and at bedtime

  • Should taken continuously for a long time

  • To help avoid or reduce drug interaction, other medication should not be taken within 1-2 hours of taking an antacids


(2) Drugs affecting gastric acid secretion

② H2 receptor antagonists

Cimetidine


cimetidine

×

(Proton pump)

Mechamism of action


Cimetidine

1. Pharmacological effect

Blocking H2 receptors, decreasing H+ secretion

2. Clinical uses

1) Duodenal and gastric ulcer

2) Zollinger-Ellison syndrome,

3) Acute stress ulcers

4) Gastroesophageal reflux disease (heartburn)


Cimetidine

  • 3. Adverse effects

    (1) common side effects: constipation, diarrhea, tiredness, muscular pain, etc.

    (2) CNS effects: headache, dizziness, confusion, hallucination, etc. (elderly, long-term uses)

    (3)Endocretion effects: antiandrogen(抗雄激素), gynecomastia, galactorrhea,reduced sperm count, and male sexual dysfunction

    4. Drug interactions

    Inhibiting hepatic P450, raising plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline


5. Elimination

Urinary excretion is the principal route of elimination of cimetidine, the dose should be modified in patients with renal impairment.


Other H2 receptor antagonists

Ranitidine

4-10 times more potent than cimetidine

Minimal side effects, weakly inhibiting CYP

Famotidine

7-10 times more potent than ranitidine, but no inhibiting CYP

Nizatidine

Bioavailability is near 100%, principally eliminated by kidney


(2) Drugs affecting gastric acid secretion

③H+-K+-ATPase inhibitors

(proton pump inhibitors)

Omeprazole 奥美拉唑


Omepranzole

×

(the proton pump)


Omeprazole

  • 1. Pharmacological effects

  • (1) Inhibiting gastric acid secretion by various stimuli (histamine, gastrin, aspirin, ethanol, stress)

  • (2) Inhibiting H. pylori

  • (3) protection for gastric mucosa

  • 2. Clinical uses

  • (1) Highly effective for duodenal and gastric ulcer: relieving symptoms,promoting healing of ulcers, with antimicrobial regimens to eradicate H. pylori

  • (2) Gastro-esophageal reflux disease

  • (3) Zollinger-ellison syndrome


Omeprazole

  • 3. Adverse effects

  • (1) Side effects: nausea, headache, diarrhea, constipation and rash occur but are uncommon

  • (2) Increase of gastric carcinoid tumor: prolongated hypochlorhydria and secondary hypergastrinemia (only found by animal experiments)

  • (3) Others: gynecomastia (男性乳房发育),hypersensitivity

  • 4. Drug interactions

  • It is metabolized by hepatic P450;

  • Inhibiting hepatic P450, raising plasma concentrations of warfarin, phenytoin, diazepam, etc.



M receptor antagonists

  • Non-selective: atropine (block M3 receptor in Parietal cells, block M1 receptor in ganglion, block M receptors in ECL and G cells), seldom use now.

  • Selective: pirenzepine (block M1 receptor)


(3) Mucosal protective drugs

Effects:Protecting the gastric and duodenal mucosa from damage by acid and pepsin

Misoprostol 米索前列醇

Sucralfate 硫糖铝

Colloidal bismuth subcitrate胶体次枸橼酸铋


(3) Mucosal protective drugs

Misoprostol米索前列醇

A prostaglandin E1 analogues


(3) Mucosal protective drugs

Misoprostol米索前列醇

1. Pharmacological effects

Inhibiting gastric acid secretion

Promoting mucus and HCO3- secretion, and mucosal repair

2. Clinical uses

Only approved for the prevention of NSAIDs-induced gastric

Ulcer.

3. Adverse effects

Side effects (13%): abdominal pain, diarrhea, headache, nauseaetc.

Contraindicated in pregnancy women

(Abortifacient 堕胎 property)


(3) Mucosal protective drugs

Sucralfate

A sulfated disaccharide(二糖) complex of aluminum hydroxide


(3) Mucosal protective drugs

Sucralfate

1. Pharmacological effects

1) Binding to tissue surface and forms a protective barrier

2) Enhancing cell restitution and re-epithelization.

3) Weakly inhibiting H.Pylory growth.

4) Promote PGE2 production

5) Binding to pepsin and then reduce its activity

2. Clinical uses and Adminstration

Peptic ulcers, but with the more effective agents (proton pump inhibitors. Gastro-esophageal reflux disease. H pylori infection.

Take sucralfate 1 hour before meals

Four times a day before meals and at bedtime

3. Adverse effects

Constipation occurs in 2% due to the aluminum salt, not together with alkaline agents


(3) Mucosal protective drugs

Colloidal bismuth subcitrate (CBS 胶体次枸橼酸铋)

1. Pharmacological effects

1) Probably coats ulcers and erosions, creating a protective layer against acid and pepsin

2) Inhibit pepsin activity, stimulate prostaglandin, mucus, and bicarbonate secretion

3) Have direct antimicrobial activity against H pylori


Bismuth Compounds

2. Clinical uses

1) Peptic ulcers, chronic gastritis, duodenitis, functional dyspepsia

2) Used in multidrug regimens for the eradication of H pylori infection.

3. Adverse effects

Causes blackening of the stool, which may be confused with gastrointestinal bleeding

Bismuth toxicity resulting in encephalopathy (ataxia, headaches, confusion, seizures).


(3) Mucosal protective drugs

Smectite

  • Bind to the glycoprotein in the mucus to increase its coverage ability, enhancing cell restitution, antimicrobial activity against H pylori.

  • 2) Use for acute or chronic diarrhea and ulcer.


(4) Antimicrobial drugs

(for Helicobacter pylori)

1. Anti-ulcer drugs

H+-K+-ATPase inhibitors; bismuch ; sulralfate

Weaker, combined with antimicrobial drugs

2. Antibiotics

metronidazole (甲硝唑); amoxicillin(阿莫西林);

tetracycline(四环素); gentamicin(庆大霉素);

clarithromycin (克拉霉素)


The best treatment regimen consists of a 10–14 day regimen of "triple therapy":

Program 1

1) A proton pump inhibitor twice daily,

2) Clarithromycin 500 mg twice daily,

3) Amoxicillin 1 g twice daily.

For patients who are allergic to penicillin, metronidazole

500 mg twice daily should be substituted for amoxicillin.

Program 2

1) Bismuth subsalicylate (2 tablets; 262 mg each),

2) Tetracycline (500 mg),

3) Metronidazole (250 mg), each taken four times daily for 14 days.


For patients with resistant infections, of "quadruple therapy”

  • A proton pump inhibitor twice daily

  • 2) Bismuth subsalicylate (2 tablets; 262 mg each),

  • 3) Tetracycline (500 mg),

  • 4) Metronidazole (250 mg), each taken four times daily for 14 days.


Gastrointestinal drugs1
Gastrointestinal drugs of

1. Drugs used for acid-peptic disorders

2. Modulators of gastrointestinal functions


Abnormalities of of gastrointestinal functions

Nausea and vomiting

Constipation

Diarrhea


Modulators of of gastrointestinal functions

1. Antiemetic drugs

2. Prokinetic drugs

3. Anti-diarrheals

4. Laxatives


Antiemetic drugs of

  • There are various sources of input to the vomiting center:

  • The chemoreceptor trigger zone at the base of the fourth ventricle has numerous dopamine D2 receptors, serotonin 5-HT3 receptors, opioid receptors, acetylcholine receptors, and receptors for substance P. Stimulation of different receptors are involved in different pathways leading to emesis, in the final common pathway substance P appears involved.

  • The vestibular system, which sends information to the brain via cranial nerve VIII (vestibulocochlear nerve), plays a major role in motion sickness, and is rich in muscarinic receptors and histamine H1 receptors.

  • The Cranial nerve X (vagus nerve) is activated when the pharynx is irritated, leading to a gag reflex.

  • The Vagal and enteric nervous system inputs transmit information regarding the state of the gastrointestinal system. Irritation of the GI mucosa by chemotherapy, radiation, distention, or acute infectious gastroenteritis activates the 5-HT3 receptors of these inputs.

  • The CNS mediates vomiting that arises from psychiatric disorders and stress from higher brain centers.


Antiemetic drugs of

  • H1 antagonists: sedative effect, antiemetic effect, use for motion sickness and Meniere disease.

  • M receptor antagonists: scopolamine, use for motion sickness.

  • D receptor antagonists: chloropromazine, thiethylperazine (硫乙拉嗪).

  • 5-HT3 receptor antagonists: ondansetron, granisetron, tropisetron, et al. Use for vomiting induced by chemotherapy for cancer, but not for motion sickness.


Prokinetic drugs of

NANC

neuron

Post-ganglionic primary motor neuron

Cholinergic

neuron

GI tract smooth muscle cells


prokinetic drugs of

Metoclopramide 甲氧氯普胺

Mechanism of action

  • Block D2 receptor, to stimulate 5-HT4 receptors and enhance coordinated transmission in cholinergic nerve plexues

2) An dopaminergic neuron antagonist in the central nervous system; at higher doses, 5-HT3 antagonist activity may also contribute to the anti-emetic effect.

Clinical uses

1) Used for treatment of diabetic gastroparesis

2) Used for the prevention of nausea and vomiting associated with cancer chemotherapy or occurring post-operatively.


Metoclopramide of

Adverse effects

1) Fatigue, dizziness, faintness

2) Various extrapyramidal syndromes caused by its central

anti-dopaminergic activity.

Parkinsonism (reversible)

tardive dyskinesia (irreversible)

3) Increased serum prolactin levels (chronic uses)


prokinetic drugs of

Domperidone 多潘立酮

Mechanism of action

A peripherial dopamine antagonist, has no procholinergic

effects

Adverse effects

Has few side effects because it can not cross the BBB

Increased serum prolactin levels ( 6% of patients)

Rare cases of prolongation of QT interval.


Modulators of of gastrointestinal functions

Anti-diarrheals

Diarrhea

1) An increase in the active secretion, or an inhibition of absorption

2) Abnormally high motility


Modulators of of gastrointestinal functions

Anti-diarrheals

1. Antimotility drugs

2. Astringents

3. Absorbants


Anti-diarrheals of

Antimotility drugs:

Mechanisms: Agonists for  receptors in GI tract

(1) Opium preparation

(2)Diphenoxylate 地芬诺酯

Diphenoxylate dose not cross the blood-brain-barrier as easly as most opioids do and is relatively selective for peripheral opioid receptors. Has CNS effects at larger doses)


Anti-diarrheals of

Antimotility drugs:

(3) Loperamide 洛哌丁胺

It is two to three times potent than diphenoxylate, and its action is more rapid in onset and more prolonged.

Use for acute or chronic diarrhea but not induced by infection.

It has less CNS or cardiovascular effects .


Anti-diarrheals of

Astringents:

Mechanism:astriction

(1)Tannalbin 鞣酸蛋白

(2) Bismuch subsalicylate; bismuch

subcarbonate (铋制剂)

Absorbants:

(1) Medical charchol 药用炭(活性炭)

(2) Agysical 矽炭银


Modulators of of gastrointestinal functions

Laxatives

Constipation

An decrease in the active secretion, or an enhancement of absorption

Treatment

  • Increase the intake of fluids and dietary fiber

  • Regular exercise

2) Laxatives

3) Physical intervene


Modulators of of gastrointestinal functions

Laxatives

1. Contact laxatives (接触性、刺激性泻药)

2. Osmotic laxatives (渗透性泻药)

3. Emollient Laxatives (润滑性泻药)

4. Bulk-forming Laxatives (膨胀性、容积性泻药)


1. of Contact laxatives (接触性泻药)

Laxatives

Phenolphthalein 酚酞

( No longer used because of concerns about carcigenicity)

Bisacodyl 必沙可啶

(It is active after deacetylation, stimulating enteric nerves to cause colonic mass movements; increases fluid and NaCl secretion. )


Laxatives of

1. Contact laxatives (接触性泻药)

Anthraquinones 蒽醌类(中药成分)

promote colon movements

Cascara

(鼠李皮)

Senna

(番泻叶)

Rhubarb

(大黄)


Laxatives of

2. Osmotic laxatives (渗透性泻药)

1) Salt laxatives: magnesium sulfate 硫酸镁;

sodium sulfate 硫酸钠;

These agents contain ions that are only slowly absorbed from the intestine. These ions retain fluid in the bowel lumen and cause a large volume of fluid to enter the colon.

magnesium sulfate


Laxatives of

2. Osmotic laxatives (渗透性泻药)

2) Lactulose 乳果糖;

In the small bowel, it is resistant to hydrolysis and has an osmotic effect.

In the large intestine, lactulose is acted upon by the endogenous flora with the production of lactic acid, Lactic acid also has an osmotic effect.

It is used to reduce ammonia blood levels in the prevention and treatment of hepatic encephalopathy


3. Emollient of Laxatives (润滑性泻药)

Liquid petrolatum

( Lubricate the fecal mass, prevent excessive dehydration of the material , and may inhibit water reabsorption by coating the gut wall)


4 bulk forming laxatives
4. Bulk-forming Laxatives of (膨胀性、容积性泻药)

Celluloses: used for functional constipation


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