Drugs Used in GI Disorders

Drug classification; important or main drugs Important drugs kinetics and dynamics Important SE & precaution Clinical used

Kutcharin Phunikhom, MD Department of Pharmacology, Faculty of Medicine, KKU

Objectives

Drugs used in PU /GU/ DU(include GERD)

Antidiarrheal drugs Laxative drugs Drugs used in emesis

Topic outline

Peptic Ulcer Disease (PUD)

Acute/chronic of gastric /duodenal ulcer Erosion of GI tract mucosa Etiologies : -high stress(trauma,burn patients) -drugs/irritants:NSAIDs -H. pylori -smoking -caffeine

In general

Enterochromaffin-like cell, parietal cell, epithelial cell Acetylcholine, histamine, gastrin, prostaglandin Vagus nerve, post ganglionic fiber H2-receptor, gastrin receptor, muscarinic receptor, prostaglandin receptor Adenylate cyclase, proteinkinase, H+/K+ ATPase HCl, mucus, HCO3-

Review: physiology of gastric secretion

HCI secretion by parietal cell

Stimulated acid secretion 1.cephalic phase: smell,taste stimulates the vagus n. 2.gastric phase: -peptides,aa.stimulate the G cell -stomach distension leads to gastrin release 3.intestinal phase: aa.induce acid secretion

M

M

M

PG

PG

G G

H2 H H

G Blood

Vagus N

Postgang. fiber

PG

+

+

+

+ +

H+ pump H

K

-

Ca

Ca

cAMP

Mucus HCO3

Gastric Lumen

Parietal cell

Epithelial cell

ECL

Short diagram on gastric acid control

-Lifestyle changes

-Medications -Surgery

Treatment of PU/GU/DU

Classification of drugs used in PU / GU/DU

Acid inhibition Acid neutralization Protection of mucosa Eradication of Helicobacter pylori Other

(I) Acid Inhibition

1) H2-receptor antagonist

Cimetidine, ranitidine, nizatidine, famotidine roxatidine, lafutidine 80-90 % acid reduction Rapidly absorbed with 1st-pass effect Excreted mainly in urine Adverse effect: relapse, gynecomastia (long term use) DI: CYP450 inhibition (warfarin, diazepam, digoxin,

propranolol, phenytoin, phenobarbital, etc)

M

M

M

PG

PG

G G

H2 H H

G Blood

Vagus N

Postgang. fiber

PG

+

+

+

+ +

H+ pump H

K

-

Ca

Ca

cAMP

Mucus HCO3

Gastric Lumen

Parietal cell

Epithelial cell

ECL

Short diagram on gastric acid control

2) Proton pump inhibitor Omeprazole, lanzoprazole, rabeprazole, pantoprazole Rapidly absorbed, active at acidic pH (enteric coated

capsule) Form irreversible, inactive complex with H+/K+

ATPase 95% plasma protein binding Low adverse effect DI: CYP450 inhibition

M

M

M

PG

PG

G G

H2 H H

G Blood

Vagus N

Postgang. fiber

PG

+

+

+

+ +

H+ pump H

K

-

Ca

Ca

cAMP

Mucus HCO3

Gastric Lumen

Parietal cell

Epithelial cell

ECL

Short diagram on gastric acid control

3) M-receptor antagonist

Pirenzepine, dicyclomine, telenzepine Low effect on acid reduction Adverse effect: general M-receptor effects

(atropine-like effects) Low use now

M

M

M

PG

PG

G G

H2 H H

G Blood

Vagus N

Postgang. fiber

PG

+

+

+

+ +

H+ pump H

K

-

Ca

Ca

cAMP

Mucus HCO3

Gastric Lumen

Parietal cell

Epithelial cell

ECL

Short diagram on gastric acid control

(II) Acid Neutralization

Antacid = anti + acid = alkaline agent Needs no / low absorbed (action mainly in lumen) Also protect mucosa (surface covering) Al-salts, Al(OH)3 - not absorbed, slow onset,

constipation, phosphate deficiency Mg-salts, Mg(OH)2 - low absorbed, rapid onset, diarrhea, Ca-salts, CaCO3 - varied absorption, rapid onset,

hypercalcemia NaHCO3 - readily absorbed, CO2, systemic alkalosis

(III) Protection of mucosa

Sucralfate

Sucrose octasulfate + poly Al(OH)3 Active at acidic pH, polymerization (gel) Increase secretion of mucus, HCO3-, PG Protein denature at ulcer site Increase healing effect Prevent absorption of other drugs Low SE

Carbenoxolone Glycyrrhizic acid

derivative Increase secretion &

viscosity of mucus Inhibit pepsin activity SE: steroidal SE (Na-

water retention, hypokalemia, hypertension)

Misoprostol PG analogue Increase secretion of

mucus & bicarbonate Inhibit acid secretion Effective for long term

usage of NSAIDs SE: uterine stimulation

(IV) Eradication of H.pylori

Triple therapy:- PPI + clarithromycin + amoxycillin (or metronidazole)

G- curved rod dyspepsia gastritis duodenal ulcer painful stomach

Helicobacter pylori

Other dugs Cimethicone Motilium Magesto M.carminative Cisapride

PUD complications Hemorrhage Perforation Obstruction Cancer

4-8 weeks Avoid special food: coca cola, chilly Stress control

PU / GU/DU treatment

Antidiarrheal Drugs

Used when necessary Routine diarrheal treatment : Rehydration ->

antimicrobial agents -> Antidiarrheal agents (antispasmodic / antimotility agents)

Classification : Opioids & others Opioids - opium tincture, diphenoxylate, loperamide Others - Bismuth subsalicylate, octreotide, adsorbent,

astringent

(I) Opioids Agonist at opioid receptors of GI muscle Reduce muscle movement, but increase tone of

contraction of rectal sphincter Reduce fluid & electrolyte secretion in GI Fast action Cause addiction (long term usage) Careful usage in children Lomeramide (ImodiumR), diphenoxylate (LomotilR) -

potency > opium tr.

(II) Other antidiarrheal

Bismuth subsalicylate: inhibit PG secretion -> inhibit diarrhea

Octreotide: somatostatin receptor binding -> inhibit GI fluid secretion

Adsorbent - charcoal, kaolin, chalk: trap toxin, substance into their suface

Astringent - tea leaves: precipitate surface protein -> reduce diarrhea

Atropine: M-receptor SE

Laxatives Drugs

Foods (mainly plant-based foods Bulk laxative Hydrating agents Stimulant laxative Surfactant laxative Others

Laxative - Purgative - Cathartic

Mostly need water

(I) Foods Laxative

Plant-based foods Almonds, Aloe Vera, Apples, Bananas, Blueberry,

Coconut, Coffee, Grapes, Mangos, Oranges, Papayas Preventing constipation than treating it.

(II) Bulk Laxative

Dietary fiber (natural cellulose), polysaccharide, psyllium seed (MetamucilR), Lemon basil ()

Bind to water ---> increase bulk (mass) ---> stimulate local reflex in colon

Needs water (retain more water) Not absorbed in GI Reduces absorption of other drugs Quite safe (except GI obstruction) Takes days for action (12-72 hrs.)

(III) Hydrating agents (osmotics)

Hyperosmotic agents Sorbitol, glycerin, lactulose drawing water into the bowel SE- withdraw water &

electrolytes into colon lumen Poorly absorbed in GI Fast action (30 min. to 3 hrs.)

Saline laxatives Magnesium salts - Mg(OH)2,

MgSO4, sodium phosphate, sodium biphosphate

Attract and retain water in the hollow of the intestinestool softening .increase intraluminal pressure

Poorly absorbed in GI SE- withdraw water & electrolytes

into colon lumen Fast action (30 min. to 6 hrs.)

(IV) Stimulant Laxative (irritants)

Diphenylmethane derivatives - bisacodyl (DulcolaxR), phenolphthalein

Anthraquinone glycosides - senna, aloe, etc Stimulate local reflex in colon Poorly absorbed Medium action (6-8 hr) Suppository (1-2 hr) SE: abdominal cramp, phenolphthalein ->liver toxic (not

in use now)

(V) Surfactant Laxative (stool-softeners)

Docusate, castor oil Wetting & softening agent - increase water

permeability (fats & water to penetrate the stool) Needs water for effect Slow action (1-3 days) Castor oil also increase peristalsis -> fast action (1-3

hr) --> bowel evacuation before operation SE: abdominal cramp, electrolyte imbalance (castor

oil)

(VI) Other Laxatives

Mineral oil - non absorbed, work as lubricant, slow action (6-8 hrs.), SE: interfere oil-soluble vitamin absorption, oil leakage

Laxative Abuse: Weight control - loss of fluid & electrolytes, interfere normal habit

Controlling System for Emesis Vomiting

Center Sensory Aff.

CNS Pways

CTZ mood

Special sensation

Labyrinth

Motion sickness

Solitary tract nuclei

Endotoxin Drugs

Local Irritants in GI by chemical, bacteria,

virus and cytotoxic drugs

radiation

Emetic & Antiemetic Drugs

Stimulate vomiting center in medulla or outside (CTZ, GI)

Ipecac is used as an antidote for toxic substant ingestion (GI)

Apomorphine (CTZ) & CuSO4 (GI) are mainly used in experiment but not for medicated purpose

Emetic Drugs

Antiemetic Drugs

Block vomiting center or pathways outside medulla Mainly used in motion sickness, pregnancy (morning

sickness), chemotherapy, food poisoning, radiation & post-operation

Antiemesis: D2 antagonist, 5-HT antagonist, H1 antagonist, M antagonist & miscellaneous

dimenhydrinate (DramamineR), diphenhydramine (BenadrylR) -> Motion sickness

SE: Antihistamine SE

H1antagonist

M- antagonist promethazine (PhenerganR), scopolamine (ScopodermR) -

> Motion sickness (caused by labyrynth) SE: similar to Antihistamine SE

D2 antagonist Chlorpromazine (ChlorpromedR), domperidone

(MotiliumR) -> Local irritants, cytotoxic drugs, radiation SE: BP drop , dizziness, abnormal movement in

extrapyramidal system

Ondansetron (ZofranR) -> cytotoxic drugs SE: headache, dizziness

5HT- antagonist

Prokinetics Metoclopramide (PlasilR), -> general vomiting and

morning sickness (careful use) SE: depression, dizziness, abnormal movement in

extrapyramidal system domperidone (MotiliumR)

Dronabinol (MarinolR) -> block CTZ SE: dizziness, dry mouth, hallucination

Misc. The end