Pharmacology of the GIT Pharmacology of the GIT systemsystem

LECTURE OutlineLECTURE Outline

• REVIEW the Anatomy of the GIT

• REVIEW the physiology of the GIT

• Review common GI drugs in the following categories:– 1. Drugs affecting GI secretions– 2. Laxatives– 3. Anti-diarrheals– 4. Emetics and anti-emetics

Drugs affecting GI secretionsDrugs affecting GI secretions

There are five types of drugs that affect gastric acid secretions and are useful for the treatment of peptic ulcer.

1. Histamine (H2) receptor antagonist/blockers

2. Antacids

3. Proton pump inhibitors

4. Mucosal protectants

5. Prostaglandin analogs

Drugs affecting GI secretionsDrugs affecting GI secretions

Histamine (H2) receptor blockers

• These drugs BLOCK the release of hydrochloric acid in the stomach in response to gastrin

• Preventing histamine from Preventing histamine from binding to its receptor in binding to its receptor in parietal cells.parietal cells.

Drugs affecting GI secretionsDrugs affecting GI secretions

Antacids

• These drugs interact with the gastric acids at the chemical level to neutralize them

Drugs affecting GI secretionsDrugs affecting GI secretions

Proton pump inhibitors• These drugs suppress the

secretion of hydrochloric acid into the lumen of the stomach

•Stimulation of protein Stimulation of protein kinases that phosphorylate kinases that phosphorylate H*/K* ATPase.H*/K* ATPase.

Drugs affecting GI secretionsDrugs affecting GI secretions

Mucosal protectants

• These are agents that coat any injured area in the stomach to prevent further injury from acid

Drugs affecting GI secretionsDrugs affecting GI secretionsProstaglandin analogs• These are agents that inhibit the

secretion of gastrin and increase the secretion of mucus lining of the stomach, providing a buffer.

•Activate inhibitory proteins Activate inhibitory proteins that block histamine that block histamine activation of adenylate activation of adenylate cyclasecyclase

The H2 Blockers- “tidines”The H2 Blockers- “tidines”

Prototype: Cimetidine

• 1. Ranitidine

• 2. Famotidine

• 3. Nizatidine

The H2 Blockers- “tidines”The H2 Blockers- “tidines”

Pharmacodynamics: Drug Action• The H2 blockers are antagonists at the

receptors in the parietal cells of the stomach. • The blockage results to inhibition of the

hormone gastrin. • There will be decreased production of gastric

acid from the parietal cells.• Also, the chief cells will secrete less

pepsinogen.

The H2 Blockers- “tidines”The H2 Blockers- “tidines”

Therapeutic use of the H2 blockers• Short-term treatment of active duodenal ulcer or

benign gastric ulcer• Treatment of hypersecretory conditions like the

Zollinger-Ellison syndrome• Prevention of stress-induced ulcers and acute

GI bleeding• Treatment of erosive GERD (reflux disease)• Relief of Symptoms of heart burn and acid

indigestion

The H2 Blockers- “tidines”The H2 Blockers- “tidines”

Precautions and Contraindications

• Any known allergy is a clear contraindication to the use of the agents. Conditions such as pregnancy, lactation, renal dysfunction and hepatic dysfunction should warrant cautious use.

• Nizatidine can be used in hepatic dysfunction.

The H2 Blockers- “tidines”The H2 Blockers- “tidines”

Pharmocodynamics- Side effects and adverse effects

• GIT= diarrhea or constipation• CNS= Dizziness, headache, drowsiness,

confusion and hallucinations• Cardio= arrhythmias, HYPOTENSION (related to

H2 receptor blockage in the heart)• Cimetidine= Gynecomastia and impotence in

males

The H2 Blockers- “tidines”The H2 Blockers- “tidines”

Drug-drug Interactions

• Cimetidine, Famotidine, Ranitidine are metabolized in the liver- they can cause slowing of excretion of other drugs leading to their increased concentration. These drugs can be anticoagulants, phenytoin, alcohol, antidepressants.

The AntacidsThe Antacids

• These are drugs or inorganic chemicals that have been used for years to neutralize acid in the stomach. The following are the common antacids that can be bought OTC:

• Aluminum salts (hydroxide)• Calcium salts (carbonate)• Magnesium salts (milk of magnesia)• Sodium bicarbonate• Magaldrate (aluminum and magnesium

combination)

2 types2 types

• Systemic• NaHCO3, Na citrate

• alkalosis

• Non – systemic• ALOH3 – adsorbs pepsin and

removes it from solution at Ph > 3

• Relaxes stomach,delays GET

• Stimulates secretion of mucus enhancing mucosal barrier to acid

• MgOH - diarrhea

• CaCO3 – rebound acidosis

The AntacidsThe Antacids

Pharmacodynamics: drug action

• These agents act to neutralize the acidic pH in the stomach.

• They do not affect the rate of gastric acid secretion.

The AntacidsThe Antacids

Pharmacodynamics: drug action

• The administration of antacid may cause an acid rebound.

• Neutralizing the stomach content to an alkaline level stimulates gastrin production to cause an increase in acid production and return the stomach to its normal acidic state.

The AntacidsThe Antacids

Therapeutic Indications

• Symptomatic relief of upset stomach associated with hyperacidity

• Hyperacidic conditions like peptic ulcer, gastritis, esophagitis and hiatal hernia

The AntacidsThe Antacids

Precautions of Antacid Use

• Known allergy is a clear contraindication. Caution should be instituted if used in electrolyte imbalances, GI obstruction and renal dysfunction.

Antacids are combined toAntacids are combined to

• I.I. Antagonize the side effect of Antagonize the side effect of the other component the other component

II. II. Obtain a product with a Obtain a product with a rapid onset and sustained action rapid onset and sustained action

III.III. Lower the dose of each Lower the dose of each componentcomponent

• Slow onset,long duration – ALOH

• Fast onset,short duration – MgOH,Na bicarb

• Fast onset, LONG duration – CaCO3

The AntacidsThe Antacids

Pharmacokinetics

• These agents are taken orally and act locally in the stomach

The AntacidsThe AntacidsPharmacodynamics: Effects of drugs1. GIT= rebound acidity; alkalosis may occur.• Calcium salts may lead to hypercalcemia

and milk-alkali syndrome. • Magnesium salts can cause DIARRHEA• Aluminum salts may cause CONSTIPATION

and hypophosphatemia by binding with phosphates in the GIT.

2. Fluid retention due to the high sodium content of the antacids.

The PPIThe PPI

These are the newer agents for ulcer treatment

• The “prazoles”

Prototype: Omeprazole

• Lanisoprazole

• Esomeprazole

• Pantoprazole

The PPIThe PPIPharmacodynamics: drug action

• They act at specific secretory surface receptors to prevent the final step of acid production and thus decrease the level of acid in the stomach.

• The “pump” in the parietal cell is the H-K ATPase enzyme system on the secretory surface of the gastric parietal cells

3 therapy3 therapy

• Omeprazole +chlarithromycin+amoxicillin/metronidazole

The PPIThe PPIClinical use of the PPIs• Short-term treatment of active duodenal

ulcers, GERD, erosive esophagitis and benign gastric ulcer.

• Long-term- maintenance therapy for healing of erosive disorders.

Precautions with the use of the PPIs• Known allergy is a clear contraindication.

Caution if patient is pregnant

The PPIThe PPI

Pharmacodynamics: Adverse effects

• CNS- dizziness, headache, asthenia (loss of strength), vertigo, insomnia, apathy

• GIT- diarrhea, abdominal pain, nausea, vomiting, dry mouth and tongue atrophy

• Respi- cough, stuffy nose, hoarseness and epistaxis.

The Mucosal ProtectantThe Mucosal Protectant

Sucralfate

• This is given to protect the eroded ulcer sites in the GIT from further damage by acid and digestive enzymes

SucralfateSucralfate

Pharmacodynamics: Action of drug

• It forms an ulcer-adherent complex at duodenal ulcer sites, protecting the sites against acid, pepsin and bile.

• This action prevents further breakdown of proteins in the area and promotes healing.

SucralfateSucralfate

Clinical use of sucralfate

• Short and long term management of duodenal ulcer.

• NSAIDs induced gastritis

• Prevention of stress ulcer

• Treatment of oral and esophageal ulcers due to radiation, chemotherapy or sclerotherapy.

SucralfateSucralfate

Precautions on the use of Sucralfate

• This agent should NOT be given to any person with known allergy to the drug, and to those patients with renal failure/dialysis because of build-up of aluminum may occur if used with aluminum containing products.

The Mucosal ProtectantThe Mucosal Protectant

Pharmacodynamics: Side-effects & adverse reactions

• Primarily GIT= CONSTIPATION, occasionally diarrhea, nausea, indigestion, gastric discomfort, and dry mouth may also occur

• CNS= dizziness, drowsiness, vertigo

• Others= rash and back pain

The Mucosal ProtectantThe Mucosal Protectant

Drug-drug interactions

• If used with aluminum salts= high risk of accumulation of aluminum and toxicity.

• If used with phenytoin, fluoroquinolones and penicillamines- decreased levels of these drugs when taken with sucralfate

Prostaglandin analogueProstaglandin analogue

Misoprostol

• This agent is a synthetic prostaglandin E1 analog that is employed to protect the lining of the mucosa of the stomach

Prostaglandin analogueProstaglandin analogue

Misoprostol: Pharmacodynamics

• Being a prostaglandin analog, it inhibits gastric acid secretion to some degree

• It INCREASES mucus production in the stomach lining.

Prostaglandin analogueProstaglandin analogue

Misoprostol: Clinical use

• NSAIDs-induced gastric ulcers

• Duodenal ulcers unresponsive to H2 antagonists.

Prostaglandin analogueProstaglandin analogue

Precautions of Misoprostol Use• This drug is CONTRAINDICATED during

pregnancy because it is an abortifacient.• Women should be advised to have a negative

pregnancy test within 2 weeks of beginning therapy and should begin the drug on the second or third day of the next menstrual cycle.

• They should be instructed in the use of contraceptives during therapy.

Therapeutic Indications of the Therapeutic Indications of the LaxativesLaxatives

• SHORT term relief of Constipation

• Prevention of straining in conditions like CHF, post-MI, post partum, post-op

• Preparation for diagnostic examination

• Removal of poison or toxins

• Adjunct in anti-helminthic therapy

Contraindications in Laxative useContraindications in Laxative use

• ACUTE abdominal disorders– Appendicitis– Diverticulitis– Ulcerative colitis

Pharmacokinetics: Pharmacokinetics: Common Side-effects of the LaxativesCommon Side-effects of the Laxatives

• Diarrhea

• Abdominal cramping

• Nausea

• Fluid and electrolyte imbalance

• Sympathetic reactions- sweating, palpitations, flushing and fainting

• CATHARTIC dependence

LaxativesLaxatives

• Generally used to INCREASE the passage of the colonic contents

• The general classifications is as follows:

1. dietary fibers/Bulk formers

2. Mechanical /stimulant

3. Lubricants/emolient

4. Osmotic and saline laxatives

Bulk-forming LaxativesBulk-forming Laxatives

• - fiber (fruits, vegetables, cereals), bran, methyl cellulose, psyllium

• - increases stool bulk causing peristalsis

• Increase bacteria

Osmotic LaxativesOsmotic Laxatives

• saccharides: lactulose, sorbitol

• saline: magnesium hydroxide/citrate/sulfate (PO, enema)• Na and K SO4,PO4• glycerin (suppository)• Causes duodenal secretion of cholecystokinin – inc fluid

secretion and motility

Stool Softeners/Emollient Stool Softeners/Emollient LaxativesLaxatives

• - docusate

• - surfactant which facilitates mixing of water and oily materials

• - used to prevent constipation

• (post-MI, rectal surgery etc)

Stimulant LaxativesStimulant Laxatives

• - stimulates mucosal nerves in the colon

• diphenylmethane derivatives:bisacodyl, phenolphthalein

• anthraquinone derivatives: cascara sagrada, sennosides, casanthrol

• castor oil- active: ricinoleic acid

• S/E: dependence on laxatives; daily use is discouraged

Lubricant laxativesLubricant laxatives

• Ex. Mineral oil

• Interferes with H2O and fat absorption

The Anti-diarrhealsThe Anti-diarrheals

• These are agents used to calm the irritation of the GIT for the symptomatic relief of diarrhea

• General Classifications

Clinical Indications of drug useClinical Indications of drug use

• Relief of symptoms of acute and chronic diarrhea

• Reduction of fecal volume discharges from ileostomies

• Prevention and treatment of traveler's diarrhea

Contraindications of anti-diarrheal Contraindications of anti-diarrheal UseUse

• Poisoning

• Drug allergy

• GI obstruction

• Acute abdominal conditions

Pharmacokinetics: Side effectsPharmacokinetics: Side effects

• Constipation

• Nausea, vomiting

• Abdominal distention and discomfort

• TOXIC MEGACOLON

Oral Rehydration Salts/ Oral Glucose-Oral Rehydration Salts/ Oral Glucose-Electrolyte Solution (Oresol)Electrolyte Solution (Oresol)

• prevents dehydration

• - contains sodium, chloride, potassium, glucose and citrate (245 mOsm/L)

AdsorbentsAdsorbents

• kaolin-pectin mixture, polycarbophil, attapulgite

• Traditional remedies

Antimotility agents/Opiods

• - opiods: diphenoxylate (+ atropine), loperamide, paregoric, opium tincture, difenoxin (metabolite of diphenoxylate)

• Inc GIT contraction but non propulsive and they close the sphincter

Antisecretory/ Astringents

• a. bismuth subsalicylate- treatment and prevention of traveler’s diarrhea

• Local anti- inflammatory effect of salicylate

• Antibacterial effect of bismuth

The Anti-diarrhealsThe Anti-diarrhealsType Prototype Action

Local reflex inhibitor

Bismuth subsalicylate

Locally coats the lining of the GIT to soothe irritation that may stimulate the reflex

Local anti-motility

Loperamide Directly inhibits the intestinal muscle activity to SLOW peristalsis

Central acting agent

Opium derivatives (paregoric)

Stops GIT spasm by CNS action

Emetics and Anti-emeticsEmetics and Anti-emetics

Emetic Agent• Ipecac

Anti-emetics• 1. Phenothiazines• 2. Non-phenothiazines• 3. Anticholinergics/Antihistamines• 4. Serotonin receptor Blockers• 5. Miscellaneous

EMETICEMETIC

• Prototype: Ipecac Syrup

EMETICEMETIC

Pharmacodynamics

• Ipecac syrup irritates the GI mucosa locally, resulting to stimulation of the vomiting center

• It acts within 20 minutes

EMETICEMETIC

Clinical Use of ipecac

• To induce vomiting as a treatment for drug overdose and certain poisonings

EMETICEMETIC

Contraindications of Ipecac use

• Ingestion of CORROSIVE chemicals

• Ingestion of petroleum products

• Unconscious and convulsing patient

EMETICEMETIC

Pharmacokinetics: side effects of Ipecac

• Nausea

• Diarrhea

• GI upset

• Mild CNS depression

• CARDIOTOXICITY if large amounts are absorbed in the body

ANTI-EMETICSANTI-EMETICS

• These are agents used to manage nausea and vomiting

• They act either locally or centrally

ANTIEMETICSANTIEMETICS

Anti-emetic types Common examples

Phenothiazines Prochlorperazine, promethazine

Non-phenothiazines Metoclopramide

Anticholinergics and Antihistaminics

Meclizine, buclizine

Serotonin Receptor blockers

“setron”- dolasetron

Miscellaneous Dronabinol, hydroxyzine

ANTIEMETICSANTIEMETICSTypes Pharmacodynamics

Phenothiazines Centrally block the vomiting center in the medulla

Non-phenothiazine Reduces the responsiveness of the nerve cell in the medulla

Anticholinergics Block the transmission of the impulses to the medulla

Serotonin receptor blockers

Centrally and locally inhibits the serotonin receptors

Miscellaneous Act in the CNS , either in the medulla or in the cortex

ANTIEMETICSANTIEMETICSTypes Clinical Use

Phenothiazines N/V associated with anesthesia, intractable hiccups

Non-phenothiazine N/V associated with chemical stimulation

Anticholinergics N/V associated with motion sickness

Serotonin-receptor Blockers

N/V associated with chemotherapy

Miscellaneous N/V associated with chemotherapy

ANTIEMETICSANTIEMETICS

Contraindications

• 1. Severe CNS depression

• 2. Severe liver dysfunction

ANTIEMETICSANTIEMETICS

Pharmacokinetics: Side-effects

1. PHOTHOSENSITIVITY

2. Drowsiness, dizziness, weakness and tremors and DEHYDRATON

3. Phenothiazines= autonomic effects like dry mouth, nasal congestion and urinary retention

An example of a weakly basic prodrug that An example of a weakly basic prodrug that when protonated,form covalent disulfide when protonated,form covalent disulfide linkages with H+/K+ ATPase and inactivateslinkages with H+/K+ ATPase and inactivates

• A. maalox

• B. nexium

• C. tagamet

• D. buscopan

Anti – ulcerant drugs exert their effort Anti – ulcerant drugs exert their effort through which of the ff mechanismsthrough which of the ff mechanisms

• I. stimulation of protein kinases that phosphorylates H/K ATPase

• II. Prevent the histamine from binding to its receptor in parietal cells

• III. Activate inhibitory proteins that block histamine activation of adenylate cyclase

• A. I only C. I and II

• B. II only D. II and III only

• E. I , II, III

• .

Which of the H2 receptor blocker has almost Which of the H2 receptor blocker has almost complete oral bioavailabiltycomplete oral bioavailabilty

• A. nizatidine

• B. famotidine

• C. ranitidine

• D. cimetidine

Evaluate the ff regarding emeticsEvaluate the ff regarding emetics

• I. they induce vomiting

• II. They cause vomiting reflex by irritating the upper GI tract

• A. I only

• B. II only

• C. both

• D. none

Evaluate the ff statements regarding Evaluate the ff statements regarding laxativeslaxatives

• I. they accelerate fecal passage in the colon

• II. They increase fecal consistency

• A. I only

• B. II only

• C. both

• D. none

Different antacids are combined in one Different antacids are combined in one preparation topreparation to

• I. antagonize the side effect of one component

• II. Obtain a product with rapid onset and sustained action

• III. Lower the dose of each component

A. I only C. I and II

• B. II only D. II and III only

• E. I , II, III

Antacids prevent the formation of this Antacids prevent the formation of this proteolytic enzyme that is thought to proteolytic enzyme that is thought to mediate tissue injury in gastric ulcerationmediate tissue injury in gastric ulceration

• A. pepsin

• B. pepsinogen

• C. chymotrypsin

• D. chymotrypsinogen

Gastric acid by parietal cells is/are regulated Gastric acid by parietal cells is/are regulated byby

• I. neurocrine cells

• II. Paracrine cells

III. Endocrine cells

A. I only C. I and II

• B. II only D. II and III only

• E. I , II, III

This acts as the most common mediator and This acts as the most common mediator and the most potent stimulus of gastric acid the most potent stimulus of gastric acid secretionsecretion

• A. acetylcholine

• B. Histamine

• C. gastrin

• D. none

Prostaglandin analogs increases gastric Prostaglandin analogs increases gastric mucosal resistance to injury bymucosal resistance to injury by

• I. increasing mucus secretion

• II. Increasing bicarbonate secretion

• III. Increasing gastric emptying time

A. I only C. I and II

• B. II only D. II and III only

• E. I , II, III