Gastrointestinal drugs Weiwei HU E-mail:[email protected] Phone: 0571-88208228

Gastrointestinal drugsGastrointestinal drugs

Weiwei HU

E-mail:[email protected]

Phone: 0571-88208228

1.Hepatic, pancreatic and b1.Hepatic, pancreatic and biliary disordersiliary disorders

2. Acid-peptic disorders

3.Gastrointesinal motilitydisorders

4. Inflammatory bowel diseases

Gastrointestinal drugs

1. Drugs used for 1. Drugs used for acid-peptic

disorders

2. Modulators of gastrointestinal 2. Modulators of gastrointestinal

functionsfunctions

1. Acid-peptic disorders

1) Peptic ulcer disease (PUD, 消化性溃疡 )

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

1)

The feature of peptic ulcer disease: High incidence, Recurrence frequently, Drug treatment is the main way

Symptoms:

Upper abdominal burning or hunger painEmesia ( 呕吐 ), belching ( 嗳气 )

Ulcer complicationUlcer 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

4) Pathologic acid-hypersecretory conditions (e.g.Zollinger-Ellison syndrome)

Tumor

Gastrin

Gastic acid

Peptic ulcer

2. Gastric acid secretion and regulation2. Gastric acid secretion and regulation

Gastric cells of mucosa

(1)Surface epithelial cells (secrete mucus)

(2)Mucus neck cells (secret mucus and are the s

ource of proliferating cells);

(3)Chief cells (secret pepsinogens)

(4)G cells (release gastrin in the antrum);

(5)Parietal cells in the gastric fundus ( secrete H

CI and intrinsic factor)

2. Gastric acid secretion and regulation2. Gastric acid secretion and regulation

Basolateral membane

(the proton pump)

Mucus-bicarbonate barrier

Helicobacter pylori infection

Gastric acidGastric acid

PepsinPepsin

Helicobacter pyloriHelicobacter pylori

Mucus

bicarbonate

Mucosa

2.Pathogenesis of peptic ulcers

Aggressive factors Defensive factors

Pathogenesis of peptic ulcers

Treatment approaches

(1)Increased gastric Increased gastric acid secretionacid secretion

(3)Inadequate mucosal (3)Inadequate mucosal defense against gastric defense against gastric acidacid

(2)Infection with gram-(2)Infection with gram-negative negative Helicobacter Helicobacter pyloripylori

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

(3)Protecting the gastric (3)Protecting the gastric mucosa from damagemucosa from damage

(2)Eradicating (2)Eradicating H. H. pyloripylori infection infection

(1) Antacids: (1) Antacids: neutralizing the acidneutralizing the acid

(2) Drugs suppressing gastric acid secretion(2) Drugs suppressing gastric acid secretion

①①Muscarinic receptor antagonistsMuscarinic receptor antagonists

②②HH22 receptor antagonists receptor antagonists

③③Gastrin receptor antagonistsGastrin receptor antagonists

④ ④ HH++-K-K++-ATPase inhibitors (proton pump inhi-ATPase inhibitors (proton pump inhi

bitors)bitors)

(3)Antimicrobial drugs ((3)Antimicrobial drugs (Helicobacter pyloriHelicobacter pylori))

(4)Mucosal protective drugs(4)Mucosal protective drugs

3.Drugs used for peptic ulcers

(1) (1) Antacids Antacids (Weak bases)

Chemistry of antacids:

Salts of aluminum (aluminum hydroxide) ,

Salts of magnesium (carbonate, hydroxide, trisil

icate) , aluminum magnesium carbonate (Al2Mg6(O

H)16CO3·4H2O)

calcium(carbonate)

sodium (bicarbonate)

(1) (1) Antacids Antacids

× Antacids

Mechamism of action

(the proton pump)

(1) Antacids(1) Antacids

1. 1. Pharmacological effectPharmacological effect

Neutralizing gastric acid, diminish gastric acidity and inactivaNeutralizing gastric acid, diminish gastric acidity and inactiva

te pepsinte pepsin （胃蛋白酶）（胃蛋白酶） activityactivity

2. 2. Clinical usesClinical uses

UUsed for peptic ulcer and acid-hypersecretory conditions.sed for peptic ulcer and acid-hypersecretory conditions.

3. 3. Adverse effectsAdverse effects

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

(2) Diarrhea (salt of magnesium)

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

(4) Hypernatremia (sodium-containing antacids)

4.4. Drug interactions Drug interactions

Avoid concurrent administration of antacids and a variety of Avoid concurrent administration of antacids and a variety of

drugs .drugs .

(1) Affect rates of dissolution and absorption, bioavailbility, an(1) Affect rates of dissolution and absorption, bioavailbility, an

d renal elimination of many drugsd renal elimination of many drugs

(2) By binding to drugs (for example, tetracycline(2) By binding to drugs (for example, tetracycline 四环素四环素 ), for), for

m insoluble complexes that are not absorbedm insoluble complexes that are not absorbed

Adminstration and dosage

(1) Take antacids 1 h and 3 h after meals

Seven times a day after meals and at bedtime.

(2) Should not be taken continuously for more than 3

m for ulcer

(3) To help avoid or reduce drug interaction, other

medication should not be taken within 1-2 hours of

taking an antacids

CimetidineCimetidine

NNN

CH2SCH2CH2NHCNHCH3

H

H3C

CN

(2) Drugs affecting gastric acid secretion(2) Drugs affecting gastric acid secretion

②② HH22 receptor antagonists receptor antagonists

(Proton pump)×

cimetidinecimetidine

Mechamism of action

1. 1. Pharmacological effectPharmacological effect

Blocking HBlocking H2 2 receptors, decreasing Hreceptors, decreasing H++ secretion secretion


1) Duodenal and gastric ulcer1) Duodenal and gastric ulcer

2) Zollinger-Ellison syndrome,2) Zollinger-Ellison syndrome,

3) Acute stress ulcers3) Acute stress ulcers

4) Gastroesophageal reflux disease (heartburn)4) Gastroesophageal reflux disease (heartburn)


3. 3. Adverse effectsAdverse effects (1) Common side effects: (1) Common side effects: constipation, diarrhea, tirednesconstipation, diarrhea, tirednes

s, muscular pain, s, muscular pain, etc.etc.

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

(3) Endocretion effects: (3) Endocretion effects: antiandrogenantiandrogen （抗雄激素）（抗雄激素） , gy, gynecomastia, galactorrheanecomastia, galactorrhea,, reduced sperm count, and mal reduced sperm count, and male sexual dysfunctione sexual dysfunction

4.4. Drug interactions Drug interactions Inhibiting hepatic PInhibiting hepatic P450450, , raising plasma concentrations of raising plasma concentrations of

warfarin, phenytoin, diazepam, propranolol, quinidine awarfarin, phenytoin, diazepam, propranolol, quinidine and theophyllinend theophylline


5. Elimination

Urinary excretion is the principal route of eli

mination of cimetidine, the dose should be modi

fied in patients with renal impairment.

Other HOther H22 receptor antagonists receptor antagonists

Ranitidine Ranitidine

44 ～～ 10 times more potent; Duration of action is com10 times more potent; Duration of action is comparable.parable.

Minimal side effects, weakly inhibiting CYPMinimal side effects, weakly inhibiting CYP

Famotidine Famotidine

Similar to ranitidine, but no inhibiting CYPSimilar to ranitidine, but no inhibiting CYP

NizatidineNizatidine

Bioavailability is near 100%, principally eliminated bBioavailability is near 100%, principally eliminated by kidney as primary formy kidney as primary form

Omeprazole Omeprazole 奥美拉唑奥美拉唑

N

OCH3H3C CH3

CH2

OCH3

S

O

H

N

N

(2) Drugs affecting gastric acid secretion(2) Drugs affecting gastric acid secretion

③③HH++-K-K++-ATPase inhibitors -ATPase inhibitors

(proton pump inhibitors)(proton pump inhibitors)

Omepranzole

×

(the proton pump)

1. 1. Pharmacological effectsPharmacological effects (1) Inhibiting gastric acid secretion by various stimuli (his(1) Inhibiting gastric acid secretion by various stimuli (his

tamine, gastrin, aspirin, ethanol, stress)tamine, gastrin, aspirin, ethanol, stress) (2) Inhibiting (2) Inhibiting H. pyloriH. pylori ((3) protection for gastric mucosa3) protection for gastric mucosa

2. 2. Clinical usesClinical uses (1) Highly effective for duodenal and gastric ulcer (relievi(1) Highly effective for duodenal and gastric ulcer (relievi

ng symptoms,ng symptoms, promoting healing of ulcers),promoting healing of ulcers),

reflux esophagitis, Zollinger-Ellison syndromereflux esophagitis, Zollinger-Ellison syndrome (2) Used with antimicrobial regimens to eradicate (2) Used with antimicrobial regimens to eradicate H. pyloH. pylo

ri ri

OmeprazoleOmeprazole


(1) Side effects: (1) Side effects: nausea, headache, diarrhoea, constipation annausea, headache, diarrhoea, constipation an

d rash occur but are uncommond rash occur but are uncommon

(2) Increase of gastric carcinoid tumor: (2) Increase of gastric carcinoid tumor: prolongated hypochlprolongated hypochl

orhydria and secondary hypergastrinemia orhydria and secondary hypergastrinemia (only found by ani(only found by ani

mal experiments)mal experiments)

(3) Others: (3) Others: gynecomastia gynecomastia (( 男性乳房发育男性乳房发育 )),, hypersensitivityhypersensitivity

4.4. Drug interactions Drug interactions

It is metabolized by hepatic P450; It is metabolized by hepatic P450;

Inhibiting hepatic P450, Inhibiting hepatic P450, raising plasma concentrations of waraising plasma concentrations of wa

rfarin, phenytoin, diazepam, rfarin, phenytoin, diazepam, etc.etc.

OmeprazoleOmeprazole

Others proton pump inhibitorsOthers proton pump inhibitors

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)

M receptor antagonistsM receptor antagonists

(3) Mucosal protective drugs(3) Mucosal protective drugs

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

Misoprostol Misoprostol 米索前列醇米索前列醇Sucralfate Sucralfate 硫糖铝硫糖铝Colloidal bismuth subcitrateColloidal bismuth subcitrate 胶体次枸橼胶体次枸橼酸铋酸铋

OHCH3OCH3

O O

HO


MisoprostolMisoprostol 米索前列醇米索前列醇

A prostaglandin E analogues

MisoprostolMisoprostol 米索前列醇米索前列醇

1. 1. Pharmacological effectsPharmacological effectsInhibiting gastric acid secretionInhibiting gastric acid secretion

Promoting mucus and HCOPromoting mucus and HCO33-- secretion, and mucosal repair secretion, and mucosal repair

2. 2. Clinical usesClinical usesOnly approved for the prevention of NSAIDs-induced gastricOnly approved for the prevention of NSAIDs-induced gastricUlcer.Ulcer.

3. 3. Adverse effectsAdverse effectsSide effects (13%):abdominal pain, diarrhea, nausea, headache, Side effects (13%):abdominal pain, diarrhea, nausea, headache,

etc.etc.

Contraindicated in pregnancy womenContraindicated in pregnancy women (Abortifacient (Abortifacient 堕胎堕胎 property)property)



Sucralfate

A sulfated disaccharide （二糖） complex of aluminum hydroxide

1. 1. Pharmacological effectsPharmacological effects1) Binding to mucosal surface and forms a protective barrier2) Enhancing cell restitution and re-epithelization.3) Weakly inhibiting H.Pylory growth.4) Promote PGE2 production5) Binding to pepsin and then reduce its activity

2. 2. Clinical uses and AdminstrationClinical uses and Adminstration peptic ulcers, but with the advent of more effective agents (proton pump inhibitors); reflux esophagitis; mucosa impairment. Take sucralfate 1 hour before meals Four times a day before meals and at bedtime

3. 3. Adverse effectsAdverse effectsConstipation occurs in 2% due to the aluminum salt, not together with alkaline agents


Sucralfate


Bismuth Compounds

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

Bismuth subslicylate

1. 1. Pharmacological effectsPharmacological effects1) Probably coats ulcers and erosions, creating a protective layer against acid and pepsin2) Inhibit pepsin activity, stimulate prostaglandin, mucus, and bicarbonate secretion3) Have direct antimicrobial activity against H pylori


1) Treatment of dyspepsia, peptic ulcer, chronic gastritis.

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

infection.


Causes blackening of the stool, which may be confused

with gastrointestinal bleeding

Bismuth toxicity resulting in encephalopathy

(ataxia, headaches, confusion, seizures).

Bismuth Compounds


Smectite

1) 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 (4) Antimicrobial drugs (for (for Helicobacter pyloriHelicobacter pylori))

1. 1. Anti-ulcer drugsAnti-ulcer drugs HH++-K-K++-ATPase inhibitors; bismuch ; sulralfate-ATPase inhibitors; bismuch ; sulralfate

Weaker, combined with antimicrobial drugsWeaker, combined with antimicrobial drugs

2. 2. AntibioticsAntibiotics metronidazole metronidazole (( 甲硝唑甲硝唑 )); amoxicillin ; amoxicillin (( 阿莫西林阿莫西林 ));;

tetracycline tetracycline (( 四环素四环素 )); gentamicin ; gentamicin (( 庆大霉素庆大霉素 )); ;

clarithromycin clarithromycin (( 克拉霉素克拉霉素 ))

The best treatment regimen consists of a 7–14 day regimen of "triple therapy":

1) Bismuth subsalicylate (2 tablets; 262 mg each),2) Tetracycline (500 mg), 3) Metronidazole (250 mg), each taken four times daily for 14 days.

Program 2

Program 1

1) A proton pump inhibitor twice daily, 2) Clarithromycin 500 mg twice daily, 3) Amoxicillin 1 g twice daily. Daily for 7 d.For patients who are allergic to penicillin, metronidazole 500 mg twice daily should be substituted for amoxicillin.

1) A proton pump inhibitor twice daily

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

3) Clarithromycin 500 mg twice daily,

4) Amoxicillin 1 g twice daily

for 14 days.

For patients with resistant infections, "quadruple therapy”

Gastrointestinal drugs

1. Drugs used for 1. Drugs used for acid-peptic

disorders

2. Modulators of gastrointestinal 2. Modulators of gastrointestinal

functionsfunctions

Abnormalities ofAbnormalities of gastrointestinal functionsgastrointestinal functions

Nausea and vomiting ConstipationDiarrhea

Modulators ofModulators of gastrointestinal functionsgastrointestinal functions

1. Antiemetic drugs1. Antiemetic drugs

2. Prokinetic drugs 2. Prokinetic drugs

3. Anti-diarrheals3. Anti-diarrheals

4. Laxatives4. Laxatives

Antiemetic drugsAntiemetic drugs

There are various sources of input to the vomiting center:1. 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.

2. 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.

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

4. 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.

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

Antiemetic drugsAntiemetic drugs

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

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

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

4. 5-HT3 receptor antagonists: ondansetron （昂丹司琼） , granisetron （格拉司琼） , tropisetron （托烷司琼） , et al. Use for vomiting induced by chemotherapy for cancer, but not for motion sickness.

GI tract smooth muscle cellsGI tract smooth muscle cells

NANCneuron

Cholinergic neuron

Post-ganglionic primary motor neuron

Prokinetic drugsProkinetic drugs

prokinetic drugsprokinetic drugs

Metoclopramide Metoclopramide 甲氧氯普胺甲氧氯普胺Mechanism of action

1) 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 usesClinical 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.

Adverse effectsAdverse 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)

MetoclopramideMetoclopramide

Domperidone Domperidone 多潘立酮多潘立酮

prokinetic drugsprokinetic drugs

Mechanism of action A peripherial dopamine antagonist, has no procholinergic

Effects

Clinical usesClinical uses 1) Used for treatment of diabetic gastroparesis 2) Used for the prevention of nausea and vomiting induced by

dyspepsia, chemotherapy, gastroesophageal reflux diseasegastroesophageal reflux disease .

Adverse effectsAdverse effects

Has few side effects because it can not cross the BBBHas few side effects because it can not cross the BBBIncreased serum prolactin levels (6% of patients)Rare cases of prolongation of QT interval.

Anti-diarrhealsAnti-diarrheals


Diarrhea

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

2) Abnormally high motility


1. Antimotility drugsAntimotility drugs

2. AstringentsAstringents

3. AbsorbantsAbsorbants


Antimotility drugs: Antimotility drugs:

Mechanisms: Mechanisms: Agonists for Agonists for receptors in GI tr receptors in GI tr

actact

(1) Opium preparation (1) Opium preparation 阿片制剂阿片制剂 (2)(2) Diphenoxylate Diphenoxylate 地芬诺酯地芬诺酯Diphenoxylate Diphenoxylate dose not cross the blood-brain-barrierdose not cross the blood-brain-barrier as easly as as easly as

most opioids do and is relatively selective for peripheral opioid remost opioids do and is relatively selective for peripheral opioid re

ceptors. Has CNS effects at larger doses)ceptors. Has CNS effects at larger doses)


(3) Loperamide (3) Loperamide 洛哌丁胺洛哌丁胺


Antimotility drugs:Antimotility drugs:

It is two to three times potent than diphenoIt is two to three times potent than dipheno

xylate, and its action is more rapid in onset xylate, and its action is more rapid in onset

and more prolonged. and more prolonged.

Use for acute or chronic diarrhea but not iUse for acute or chronic diarrhea but not i

nduced by infection.nduced by infection.

It has less CNS or cardiovascular effectsIt has less CNS or cardiovascular effects .

Astringents:Astringents:

Mechanism:Mechanism: astrictionastriction

(1)(1) Tannalbin Tannalbin 鞣酸蛋白鞣酸蛋白

(2) Bismuch subsalicylate; bismuch(2) Bismuch subsalicylate; bismuch

subcarbonate (subcarbonate ( 铋制剂铋制剂 ))

AbsorbantsAbsorbants ：： (1) Medical charchol (1) Medical charchol 药用炭（活性炭）药用炭（活性炭） (2) Agysical (2) Agysical 矽炭银矽炭银



Constipation

LaxativesLaxatives

Treatment

1) Increase the intake of fluids and dietary fiber Regular exercise

2) Laxatives

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


2. Laxatives that work osmotically2. Laxatives that work osmotically

3. Laxatives that decrease absorption3. Laxatives that decrease absorption

LaxativesLaxatives

1. Laxatives that increase secretion1. Laxatives that increase secretion

LaxativesLaxatives

Phenolphthalein Phenolphthalein 酚酞酚酞 ( No longer used because of concerns about carcigenicity)( No longer used because of concerns about carcigenicity)

Bisacodyl Bisacodyl 必沙可啶必沙可啶 (It is active after deacetylation, stimulating enteric nerves to cause colo(It is active after deacetylation, stimulating enteric nerves to cause colo

nic mass movements; increases fluid and NaCl secretion. )nic mass movements; increases fluid and NaCl secretion. )


LaxativesLaxatives


Anthraquinones Anthraquinones 蒽醌类（中药成分）蒽醌类（中药成分）

promote colon movementspromote colon movements

Cascara（鼠李皮）

Rhubarb （大黄）

Senna （番泻叶）


1) Salt laxatives: magnesium sulfate 1) Salt laxatives: magnesium sulfate 硫酸镁硫酸镁 ;;

sodium sulfate sodium sulfate 硫酸钠；硫酸钠；

LaxativesLaxatives

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 sulfatemagnesium sulfate


2) Lactulose 2) Lactulose 乳果糖乳果糖 ;;

LaxativesLaxatives

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. Laxatives that decrease absorption3. Laxatives that decrease absorption

Liquid petrolatum

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

Documents

Gastrointestinal drugs Weiwei HU E-mail:[email protected] Phone: 0571-88208228