Drugs Affecting the

Gastrointestinal

System

Antacids, Constipation,

Increasing gastrointestinal

motility

Cells of the Gastric Gland

• parietal cells:

• produce & secrete HCl

• primary site of action for many drugs

• chief cells:

• secrete pepsinogen [= a proenzyme]

• pepsinogen acid pepsin[ breaks

down proteins]

• mucoid cells:

• mucus-secreting cells

• purpose = protective mucous coat [HCl]

Hydrochloric Acid

• secreted by parietal cells

• maintains stomach pH at 1 to 4

• stimulants to secretion:

• large, fatty meals

• excessive amounts of ETOH

• emotional stress

Parietal Cell Stimulation & Secretion

Histamine

H-2 Blocker

Gastric Gland

Illustrations from LifeART, MediClip, © Williams & Wilkins, a Waverly Company.

Histamine

H-2 Blocker

Ca++ Ca++

Energy

H+/K+ ATPase

Pump

H+

K+

mast

cell Vagus

Nerve

from circulation

Management

• Therapy is aimed at • Healing the ulcer • Preventing recurrence

• Drug therapy has several major thrusts

• Raising gastric pH • antacids • Inhibitors of acid secretion

• H2 antagonists • Proton pump inhibitors

• Mucosal protection • H Pylori eradication

• The predominant causes of peptic ulcer disease are H pylori

infection and use of NSAIDs accounting for 48% and 24% of cases, respectively.

Antacids

• Neutralize gastric pH

• Largely replaced in recent years by other drugs

• Used for fast relief of gastric discomfort, often in combination with other therapies

• Onset: 5-15 minutes

• Duration: 2 hours

• must be used repeatedly to reduce acidity

Antacids • Formulations: chewable tablets, liquids

• liquids are more effective

• Formulations of aluminum, magnesium and

calcium, often combinations are made

MOA Antacids • Do nothing to stop overproduction of acid

• Promote gastric mucosal defenses by:

• stimulating mucus,

• prostaglandins, and

• bicarbonate secretion from the gastric

glands

Effects of Antacids • raising pH 1.3 to 1.6

• acid in gastric juices 50% neutralized

• raising pH 1.3 to 2.3

• reduction of acid by 90%

• reduces pain assoc. with acid-release

Therapeutic Uses • Heart burn

• DU

• GU

Doses: 1 -2 tablespoon 1-3 hours after meals

(140 -156 mEq)

Side Effects • Minimal and depend upon compound

• May be unpleasant or chalky tasting

• flavors are better tolerated

• magnesium:

• Diarrhea, in RF causes CNS toxicity

• aluminum & calcium

• constipation

Drug Interactions

• Four basic mechanisms • chelation:

• binding or inactivation of another drug

• chemical inactivation:

• produces insoluble complexes

• increased stomach pH:

• increases absorption of basic drugs

• decreases absorption of acidic drugs

• increased urinary pH

• increases excretion of acidic drugs

• decreases excretion of basic drugs

Cimetidine

Ranitidine

Famotidine

Nizatidine

H2 Antagonists • Histamine type 2 receptor [H2] competitive

antagonist

• prototypical acid secretory antagonists

• Reduce, but not abolish acid secretion

• one of most frequently Rx’d drugs

MOA

• 2 mechanism: • Competitively block the histamine (H2)

receptor of acid-producing parietal cells

• Also up to 90% inhibition of vagal

stimulated and gastrin stimulated acid

secretion

Therapeutic Effects

• Proven effective: • PUD = gastric & duodenal ulcer

• Gastroesophageal reflux disease [GERD]

• Upper GI bleed [GIB]

• May be effective: • Prevention of stress ulcers

• Peptic esophagitis

• Less potent than PPIs but still suppress acid by 60- 70% over 24 hrs

• Complete inhibition has not been shown.

• 70-85% of patients with DU respond in 4-6 weeks and 87% to 94% after 8 weeks.

• Suppression of acid secretion during night.

• 60-80% of patients with GU respond in 6-8 weeks.

• It is used in half of usual dose to prevent recurrence of ulcer.

Side Effects

• Cimetidine:

• Overall low < 3%

• Headache, dizziness, confusion, rash, liver

& kidney impairment, muscle cramp, fever

• Impotence, increased prolactin, &

gynecomastia

• Dosage: qid or at hs

• Ranitidine:

• Headache, arrhythmia, confusion

• Dosage: bid or at hs

Drug Interactions

• Cimetidine:

• Decrease the activity of cytochrome

P450

• Ranitidine

• Inhibits CYP450 , 4- 10 times less than

cimetidine.

• Concurrent use with omeprazole

decreases its effect

• Cigarette decreases their effects

Anticholenergics

• Clidinium, Dicyclomine, Glycopyrrolate,

Propanthelene, Pirenzepine

• Decreases the effect of Ach on the parietal

cells

• Therapeutic Uses:

• Not a mainstay of therapy

• Should not be used in GERD

• Side effects:

• Blurred vision, dry mouth, tachycardia, urinary

retention, constipation

Omeprazole

Rabeprazole

Pantoprazole

Lansoprazole

Esomeprazole

H+/K+ATPase = site of action

Final common step in acid production

Acetylc

holine

Histamine Gastrin

atro

pine

H-2 Blocker

ATP cAMP

Ca++Ca++

Energy

H+/K+ ATPase

Pump

H+

K+

mast

cellVagus

Nerve

from circulation

MOA Proton Pump Inhibitors

• convert in to their active form in the acidic

environment (Activated only when pH

decreases below 4)

• irreversibly bind to H+/K+ATPase

• prevent H+ ion production & secretion

• block all acid secretion = achlorhydria

• to return to normal must synthesize new

H+/K+ ATPase

• Delayed effect

• should be administered approximately 1 hour

before a meal

• have a short serum half-life

• concentrated and activated near their site of

action

• have a long duration of action.

Therapeutic Effects

• GERD • Drug of choice

• PUD • recurrent [Helicobacter pylori]

• Better than H2 antagonists

• Erosive esophagitis

• Zollinger-Ellison syndrome [ZE]

• NSAID associated ulcers

• Prevention of Rebleeding from Peptic

Ulcers

• Prevention of stress related mucosal

bleeding

Dosage: 20 mg qd for 4- 8 weeks Most effective after a prolonged fast when large amounts of active proton pumps are present (i.e. breakfast)

PPIs provide superior acid suppression, healing

rates, and symptom relief vs H2 blockers and

heal 95% of duodenal ulcers and 80% to 90% of

gastric ulcers by 4 weeks

Side Effects & Interactions • Side effects: (mild) nausea, headache,

diarrhea, constipation, flatulence,

hypergastrinemia ECL hypeplasia

• May affect absorption of other drug

• May decrease calcium absorption or

osteoclast, which may lead to hip fracture.

• nosocomial pneumonia

Sucralfate • cytoprotective agent

• once comes in contact with acid in stomach

• dissociate into aluminum hydroxide &

sulfate anions

• attracted to and bind to the base of ulcers &

erosions

• forms a protective barrier over the base of

this area

• binds to exposed proteins of ulcers

• limits pepsin’s proteolytic action here

• Prevents H+ reflux

• Increases production of PGs and

bicarbonate secretion

Sucralfate • Uses: gastric, duodenal and oral ulcers, GI

bleed, stress ulcer prevention

• Minimal absorption

• Dosing: 1 g qid, 1 hr before meals & hs on

empty stomach

• Side effects: constipation, sleepiness,

hypophosphatemia

• Drug interaction: decreases absorption of

many drugs and fat soluble vitamins

Bismuth subcitrate

• Coats ulcer at low pH

• Assists H Pylori eradication

• Causes black tongue and stool

• Must be taken at least half an hour before meals

• Bismuth based preparations have more adverse effects, and also ~85% success.

However cheapest. • Bismuth, metronidazole and tetracycline,

and a proton pump inhibitor for 2 weeks

H Pylori eradication

regimens

• Clarithromycin based quadruple therapy has

highest eradication rate (~95%)

• Omeprazole (any PPI), clarithromycin,

amoxicillin and metronidazole, all twice

daily for a week

• Non-clarithromycin based regimens: cheaper,

but lower eradication rate (~85%)

• Omeprazole (or high dose ranitidine),

amoxicillin and metronidazole for 2 weeks

Eradication of H pylori reduces the incidence of peptic ulcer disease recurrence, from 67% to 6% for DU and from 59% to 4% for GU. Continue PPIs after 6 weeks of triple therapy, especially if ulcer is >1 cm.

• Bulk-formers

• Osmotic laxatives

• Stool softeners

• Stimulant Laxatives

Laxatives

Bulk-forming Laxatives

• Psyllium, bran, etc.

• Swells in water to form gel that increases

bulk and softens stool, increase peristalsis

– Similar to the action of dietary fiber

• Useful in chronic constipation, and in irritable

bowel syndrome

• Onset: 12-24 hrs

• Powder needs reconstitution in at

least 8 oz (1 glass) water or juice

• Drink 6-8 glasses of water

Osmotic laxatives

• Increase colonic fluid retention

• Nonabsorbable

• Stimulate peristalsis

• Include two types:

– Nonabsorbable Sugars

– Nonabsorbable salts

Nonabsorbable Sugars

• Lactulose – In the colon hydrolyzes to lactic acid, formic acid, and

acetic acid

– Onset: 24-48 hr

• Sorbital – Side effects: flatulence, abdominal bloating, diarrhea

• Polyethylene Glycol

- does not produce significant cramps or flatus.

Nonabsorbable salts

Milk of Magnesia, Magnesium oxide

• Used in simple constipation & postop

• Onset: 0.5-3 hours

• Use cautiously in renal impairment

– Potential for hypermagnesemia due to reduced

excretion

Stool softeners

• Docusate , Paraffin (Mineral oil), Glycerin

• Reduce surface tension in the bowel increasing water absorption into stool

• Onset: 6-8 hrs

• Side effects:

– (rare) GI pain, cramping, rash, decrease absorption of fat soluble vitamins

• Administer with adequate fluids

Stimulant Laxatives

• May stimulate myenteric plexus

• Increase intestinal peristaltic motility and secretion

• Onset: 2-6 hours

• Potent, may cause watery stools, cramping

• Often used for preprocedure bowel preps, postop

• Side effects: abdominal discomfort,

nausea, cramps

Castor oil

• Besides irritation, it has surfactant

activity

• It may acts through inhibition of Na+/k+

ATPase, cAMp, PGs

Bisacodyl (Dulcolax)

• inhibition of Na+/k+ ATPase, cAMp,

PGs

• Tablets

– Onset: 6-12 hrs

• Suppository

– Onset: 15-60 minutes

• Used in conjunction with PEG

Senokot (senna)

• Natural, obtained from dried cassia leaflets

• Used for simple constipation, postop, other

• Onset: 6-12 hours (up to 24)

Drugs promoting

gastrointestinal motility

Time to empty half of liquid is half an hour

and to empty solids is 2 hours

Factors that delay the gastric emptying:

Neuropathy, myopathy, electrolyte disturbances, gastroenteritis, anticholenergics, TCA, levodopa, β agonists

Factors that enhance the gastric emptying:

Metoclopramide, Cisapride, Domperidone, cholinomimetics

Metoclopramide Mechanism:

CNS: D2 antagonist

Peripheral: cholinergic agonist, dopamine antagonist, 5-HT4 agonist, 5-HT3 blocker, sensitize intestinal smooth muscles to the Ach

Increases gastric contractions, gastric emptying and peristaltic movement, raises pressure of lower esophageal sphincter

block dopamine D2 receptors in the CTZ of the medulla, resulting in potent anti N/V

Indications:

1. Decreases gastric emptying time

2. GERD

3. Nausea

4. Before induction of anesthesia

5. Facilitates small bowel intubation

6. Increases lactation

Side effects

Insomnia, fatigue, restlessness,

unordinary weakness

Galactorrhea, menstrual disorders

Extraperimedial side effects: parkinson,

dystonic reactions, akatesia, tardive

dyskenesia

Especially in elders and youngsters

Drug Interactions

Increases the effect of CNS depressant

Increases the EP side effects of

haloperidol, phenothiazines,

thioxanthins

Antimuscarinics neutralize the effects

of metoclopramide

Other drugs Domperidone

Like metoclopramide except it does not

enter the CNS

Cisapride

No effect on DA, activation of 5-HT4 and Ach

Causes fatal ventricular arrhythmia,

diarrhea

Cholinergic agonists

Increase the effect of metoclopramide

Erythromycin

Prokinetic activity