Drug therapy

for
GIT Disorders

1
Common GIT medical conditions
 Thereare six common medical conditions involving the
gastrointestinal (GI) tract:
Acid-peptic diseases (PUD and GERD)
 constipation
 diarrhea,
 Emesis,
 Irritable bowel syndrome (IBS),
 Inflammatory bowel disease (IBD),
 Gastropraresis

2
1.Treatment of PUD and GERD
 Treatment approaches include :
1) Eradicating the H. pylori infection,
2) Reducing secretion of gastric acid with the use of PPIs
or H2 receptor antagonists, and/or
3) Providing agents that protect the gastric mucosa from
damage

3
Drugs Used to Treat PUD and GERD
◦ Antacids,
◦ PPIs,
◦ H2 receptor antagonists,
◦ Mucosal protectants
◦ Metoclopramide
◦ Antimicrobials

4
 1. Antacids
 Are weak bases that react with gastric hydrochloric acid to
form a salt and water to diminish gastric acidity.
 Antacids also reduce pepsin activity.
◦ Because pepsin is inactive at a pH greater than 4
 They are used for symptomatic relief of peptic ulcer disease,
heartburn, and GERD.
 Antacids have a rapid onset of action
 But their neutralizing capacity lasts only approximately 30
minutes on an empty (fasted) stomach.
◦ They should be administered after meals for maximum effectiveness.

5
Cont’d
 Commonly used antacids are:
◦ combinations of aluminum hydroxide and magnesium
hydroxide
◦ Calcium carbonate [CaCO3 ]
 Sodium bicarbonate [NaHCO3 ] is not recommended.
◦ can produce transient metabolic alkalosis and produce a
significant sodium load.

6
Adverse effects of antacids and drug interactions
 Gastric distention and belching
 Metabolic alkalosis
 All antacids may affect the absorption of other
medications by
 binding the drug (reducing its absorption) or
 increasing intra gastric PH
 Should not be given within 2 hours of doses of tetracyclines,
fluoroquinolones, itraconazole, and iron.
• Calcium-containing antacids may cause acid rebound (i.e.,
an increase in acid secretion) after their effects wear off.
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2. H2-receptor antagonists
 Four H2 antagonists are in clinical use:
 Cimetidine,
 Famotidine,
 Nizatidine , and
 Ranitidine
 Exhibit competitive inhibition at the parietal cell H2
receptor
 Inhibit basal, food-stimulated, and nocturnal secretion of
gastric acid,
◦ especially effective at inhibiting nocturnal acid secretion
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Cont’d
 All four agents are equally effective
◦ all inhibit 60–70% of total 24-hour acid secretion.

 However, the potencies of the four H2-receptor antagonists

vary over a 50-fold range
 Recommended prescription doses maintain greater than 50%
acid inhibition for 10 hours;
 hence, these drugs are commonly given twice daily.

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Pharmacokinetics
 After oral administration ,all four agents are rapidly absorbed from the
intestine.
◦ Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism
resulting in a bioavailability of approximately 50%.
◦ Nizatidine has little first-pass metabolism.
 Cimetidine, ranitidine, and famotidine are also available in intravenous
formulations.
 Distribute widely throughout the body (including into breast milk and
across the placenta)
 Are cleared by a combination of hepatic metabolism, glomerular
filtration, and renal tubular secretion.
◦ are excreted mainly in the urine.
 Dose reduction is required in patients with moderate to severe renal
(and possibly severe hepatic) insufficiency.
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Clinical use and dosage

11
 Drug Interactions
 Cimetidine inhibits CYP1A2, CYP2C9, CYP2D6, and
CYP3A4
 Ranitidine binds 4–10 times less avidly than cimetidine to
cytochrome P450.
 Negligible CYP interaction occurs with nizatidine and
famotidine
 H2 antagonists compete with creatinine and certain
drugs (eg, procainamide) for renal tubular secretion.
 All of these agents except famotidine inhibit gastric first-
pass metabolism of ethanol, especially in women.
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Adverse Effects
 H2 antagonists are extremely safe drugs.
 Rare adverse effects include diarrhea, headache, fatigue, myalgias,
and constipation.
 Cimetidine may cause
gynecomastia or impotence in men and galactorrhea in women.
confusion, hallucinations, agitation
 Rapid intravenous infusion may cause bradycardia and hypotension
through blockade of cardiac H2 receptors
 H2 antagonists cross the placenta and secreted into breast milk
they should not be administered to pregnant women unless absolutely
necessary.

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3. Proton-pump inhibitors (PPIs)
 Six PPIs are available for
clinical use:
 Omeprazole,
 esomeprazole,
 lansoprazole,
 dexlansoprazole,
 rabeprazole, and,
 pantoprazole.

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Pharmacokinetics of PPIs
 Are lipophilic weak base prodrugs
 All are available in oral formulations
◦ formulated for delayed release as acid-resistant, enteric-coated
capsules or tablets
◦ Omeprazole combined with sodium bicarbonate for faster
absorption is also available.
◦ Esomeprazole, omeprazole, and pantoprazole are also available as
oral suspensions.
◦ Lansoprazole is available as a tablet formulation that disintegrates in
the mouth
◦ Rabeprazole is available in a formulation that may be sprinkled on
food.

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Cont’d
 Esomeprazole , lansoprazole, and pantoprazole are also
available in intravenous formulations
 Oral PPIs should be taken 30 to 60 minutes before breakfast
or the largest meal of the day.
 PPIs undergo rapid first-pass and systemic hepatic
metabolism
 All PPIs are metabolized by hepatic P450 cytochromes,
including CYP2C19 and CYP3A4.
 Metabolites of these agents are excreted in urine and feces.
 The drugs have a short serum half-life of about 1.5 hours

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Activation and Pharmacodynamics of PPIs
 The coating is removed in the alkaline duodenum,
 The prodrug is absorbed and transported to the parietal
cell
 In the parietal cell(acidified compartments) the prodrug
activated in to thiophilic sulfenamide cation,
 which forms a covalent disulfide bond with the actively
secreting H+ /K+ - ATPase,
 irreversibly inactivating the enzyme.

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Cont’d
 PPIs inhibit both basal and stimulated gastric acid
secretion by more than 90%.
 Acid inhibition lasts up to 24 hours
 Up to 3–4 days of daily medication are required before
the full acid-inhibiting potential is reached.
 Similarly, after stopping the drug, it takes 3–4 days for full
acid secretion to return

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 Clinical Uses
 GERD
 Peptic ulcer disease
a. H pylori-associated ulcers
b. NSAID-associated ulcers
 Prevention of rebleeding from peptic ulcers
 Prevention of stress-related mucosal bleeding
 Gastrinoma and other hypersecretory conditions

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Cont’d

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 Drug Interactions
 Because of the short half-lives of PPIs, clinically significant
drug interactions are rare
 May alter absorption of drugs eg, ketoconazole, itraconazole,
digoxin, and atazanavir
 Omeprazole and esomeprazole may decrease the
effectiveness of clopidogrel because they inhibit CYP2C19
 Esomeprazole also may decrease metabolism of diazepam.
 Lansoprazole may enhance clearance of theophylline.
 Rabeprazole and pantoprazole have no significant drug
interactions.

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Adverse Effects
 PPIs have been considered to be extremely safe
◦ Diarrhea, headache, and abdominal pain
 Acute interstitial nephritis and chronic kidney disease
 Increased risk of dementia in long-term, 1 year or greater, PPI users
 Affect absorption of food-bound minerals (non-heme iron, insoluble
calcium carbonate , magnesium
 Increase in the risk of hip fracture in patients taking long-term PPIs
 Reduction in oral cyanocobalamin (vitamin B12) absorption
 Respiratory and enteric infections
 Increased serum gastrin; may cause transient rebound acid
hypersecretion

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Anticholinergics
 Pirenzepine
 Block muscarinic receptors, decrease acid secretion

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Mucosal protective agents
A. Sucralfate
B. Prostaglandin analogs
C. Bismuth compounds

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A. Sucralfate
 Sucralfate is a salt of sucrose complexed to sulfated
aluminum hydroxide.
 Breaking down into sucrose sulfate (strongly negatively
charged) and an aluminum salt in water or acidic
solutions.
 sucrose sulfate binds to positively charged proteins in
the base of ulcers or erosion,
◦ forming a physical barrier that restricts further caustic damage
and
◦ stimulates mucosal prostaglandin and bicarbonate secretion.

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Con
 Sucralfate is used for prevention of stress-related
bleeding
◦ Lower risk of nosocomial pneumonia than antacids, H2
antagonists, and PPIs
 Sucralfate it is not absorbed,
◦ devoid of systemic adverse effects.
 Constipation occurs in 2% of patients due to the
aluminum salt.
 Sucralfate may bind to other medications, impairing their
absorption.
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B. Prostaglandin analogs
 Misoprostol, a methyl analog of PGE1, has been approved
for gastrointestinal conditions
 The serum half-life is less than 30 minutes
 It has both acid inhibitory and mucosal protective properties.
 It is believed to stimulate mucus and bicarbonate secretion
and enhance mucosal blood flow
 misoprostol has never achieved widespread use owing to:
◦ its high adverse-effect profile and
◦ need for multiple daily dosing

27
C. Bismuth compounds
 Two bismuth compounds are available:
 bismuth subsalicylate, and
 bismuth subcitrate potassium.
 Bismuth subsalicylate undergoes rapid dissociation within the
stomach, allowing absorption of salicylate.
 Bismuth coats ulcers and erosions, creating a protective layer
against acid and pepsin.
 It may also stimulate prostaglandin, mucus, and bicarbonate
secretion.
 Bismuth compounds have direct antimicrobial activity against
H pylori.

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H pylori-eradication
 For H pylori-associated ulcers, there are two therapeutic
goals:
 to heal the ulcer and
 to eradicate the organism.
 The most effective 14 days regimens for H pylori
eradication are
1. Triple therapy: PPI + clarithromycin 500 mg +
amoxicillin, 1 g or metronidazole 500 mg twice daily.

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Cont’d
2. Quadruple therapy: a PPI twice daily with either:
A. Bismuth subsalicylate 524 mg + metronidazole 500 mg,
+ tetracycline 500 mg four times daily; or
B. Amoxicillin 1 g +clarithromycin 500 mg +
metronidazole 500 mg, twice daily.
 After completion of antibiotic therapy, the PPI should be
continued once daily for a total of 4–6 weeks to ensure
complete ulcer healing.

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Reading assignment
 Gastric ulcer vs duodenal ulcer
 Effect of PPI on vit B12 absorption and bone
 Does bismuth compounds cause Ray’s syndrome?

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Drugs used in the treatment of
constipation

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Classes of drugs for constipation treatment
1. Laxatives
2. Cholinomimetic agents
3. Opioid receptor antagonists
4. Serotonin 5-HT4-receptor agonists

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1. Laxatives
 These drugs
are classified on the basis of their
mechanism of action into:
I. Osmotic laxatives
II. Stimulant laxatives
III. Lubricant laxatives
IV. Bulk laxatives
V. Chloride channel activators
 Laxatives should never be prescribed for patients with
undiagnosed abdominal pain or intestinal obstruction

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I. Osmotic laxatives
 Osmotic laxatives are soluble but nonabsorbable compounds
that result in increased stool liquidity due to an obligate
increase in fecal fluid.
 These include
 magnesium hydroxide, magnesium citrate, magnesium sulphate
solution,
 Sorbitol, lactulose, and polyethylene glycol (PEG)
 High doses of osmotically active agents produce prompt
bowel evacuation (purgation) within 1–3 hours.

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Cont’d
 Osmotic laxatives are the first choice in the pharmacological
treatment of FC
 Lactulose and sorbitol undergo bacterial fermentation in the
colon to
◦ organic acids [lactic, formic, and acetic acids] and CO2 .
◦ Abdominal bloating and flatulence are common side effects.
 PEG is not metabolized by colonic bacteria.
 cause less cramping and gas than other laxatives.
 is the first-choice osmotic laxative in children with FC
 Side effects include fecal incontinence (especially during
disimpaction), flatulence, abdominal
pain, nausea, and abdominal bloating.

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II. Stimulant Laxatives
 Castor oil, senna, and bisacodyl
 Stimulant laxatives can be considered as additional or
second-line treatment.
 Stimulant laxatives act directly on the intestinal mucosa,
◦ stimulating intestinal motility and/or increasing water and
electrolyte secretion.
 Castor oil is broken down in the small intestine by lipase to
ricinoleic acid, which is very irritating to the stomach
promptly increases peristalsis and intestinal secretion
Because castor oil causes severe intestinal cramping and diarrhea, its
use should be avoided.
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Bisacodyl
 Bisacodyl can be administered orally or rectally.
 Is non-absorbable agent
 In the colon bisacody is hydrolyzed to its active metabolites,
◦ which exert a local prokinetic effect and stimulate intestinal
secretion
 The laxative effect of ingested bisacodyl generally
occurs within 6–8 h; therefore it is recommended to
administer oral bisacodyl ante noctum.
 Rectally administered bisacodyl induces a fast effect (sometimes within
30–60 min).
 The most common side effects are abdominal pain, nausea, and diarrhea.
 Rectal administration of bisacodyl is contraindicated in children with
proctitis or anal fissures.

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III. Lubricant laxatives
◦ Mineral oil, Sodium docusate, and glycerin suppositories
 Lubricants are a class of laxatives that mainly soften or
lubricate stools.
 Nonabsorbable laxatives that act by lubricating the stool
to facilitate passage.
 They may also act on the colonic epithelium to reduce
water absorption from the stool.

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Mineral Oil
 Mineral oil (or liquid paraffin) is a derivative of petroleum.
 It is not absorbed by the intestines, and it functions as a
lubricant.
 Mineral oil may also exert an osmotic effect when it is converted to
fatty acids.
 It can be administered orally or rectally;
◦ the laxative effect generally occurs within 1–2 days for both administration
routes.
 Liquid paraffin should not be administered to
children under 3 years of age
 can reduce absorption of fat-soluble vita-
mins (A, D, E, and K),
 severe side effects, such as granulomata following absorption, and
lipoid pneumonia following aspiration

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Iv. Bulk-forming laxatives
 Are indigestible, hydrophilic colloids that absorb water,
forming a bulky, emollient gel that distends the colon and
promotes peristalsis.
 Common preparations include:
 natural plant products (psyllium, methylcellulose) and
 synthetic fibers (polycarbophil)
 They should be used cautiously in patients who are
immobile because of their potential for causing
intestinal obstruction
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V. Chloride secretion activators
 Lubiprostone, Linaclotide, and plecanatide
 Increases chloride rich fluid secretion into the intestine,
which stimulates intestinal motility and shortens intestinal
transit time
 Lubiprostone is a pros-taglandin E1 derivative acts by
stimulating the type 2 chloride channel (ClC-2) in the small
intestine.
 Linaclotide and plecanatide are a synthetic peptide, act by
binding to and activating guanylate cyclase-C on the luminal
surface
 increased intracellular and extracellular cGMP thereby
promotes fluid secretion

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Cont’d
 Used in the treatment of chronic constipation and
irritable bowel syndrome with constipation (IBS-C)
 particularly because
 tolerance or dependency has not been associated with this
drug.
 Also, drug–drug interactions are minimal because metabolism
occurs quickly in the stomach and jejunum.
 Lubiprostone may cause nausea in up to 30% of patients
due to delayed gastric emptying

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 2. Cholinomimetic agonists
 Cholinomimetic agonists stimulate muscarinic M3
receptors
 Bethanechol, neostigmine
 neostigmine can enhance gastric, small intestine, and colonic
emptying.
 These drugs are no longer used because they produce
excessive secretions and
fail to produce coordinated contractions required for effective
gastric emptying.

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3. Opioid receptor antagonists
 methylnaltrexone bromide and alvimopan.
 selective antagonists of the μ-opioid receptor
 Methylnaltrexone is approved for the treatment of opioid-induced
constipation
 It is administered as a subcutaneous injection (0.15 mg/ kg) every 2
days.
 Alvimopan is approved for short-term use to shorten the period of
postoperative ileus in hospitalized patients who have undergone
small or large bowel resection.
 Alvimopan (12 mg capsule) is administered orally within 5 hours
before surgery and twice daily after surgery until bowel function
has recovered, but for no more than 7 days

45
4. 5-HT4-receptor agonists
 Tegaserod and
Prucalopride
 stimulate proximal bowel
contraction (via acetylcholine
and substance P)

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Drugs used in the treatment of diarrhea

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Introduction
 Diarrhea is the abnormally frequent passage of loose
watery feces.
 Diarrhea can be caused by:
1) Increase osmotic load in the intestine
2) Excessive secretion of water and electrolyte
3) Exudation of protein and fluid from the mucosa,and
4) Increased motility of the GI tract

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Treatment of diarrhea
 Many forms of diarrhea are self-limiting and do not require
treatment.
 However, more severe or chronic diarrhea requires
treatment because
◦ it can result in serious electrolyte imbalances and morbidity.
 Diarrhea can often be managed with classic antidiarrheal
medications,
◦ but antimicrobial or antiinflammatory agents may also be
needed.
 Replacement of fluid and electrolytes is an essential
component of treatment.

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Replacement of fluid and electrolytes
A. Oral Rehydration
◦ Mild-fluid lose up to 5% of body weight or
<50 ml/kg
◦ Moderate-fluid lose up to 6-10% of body weight or 50-100
ml/kg

B. Intravenous therapy
◦ Fluid lose more than 10% of body weight or >100 ml/kg

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Composition by weight and molar
concentrations of reduced (low) osmolarity
ORS solution

11/12/2023 51
ORS plus zinc
 Zn blocking basolateral membrane K+ channels
◦ inhibits cAMP-induced chloride ion secretion
 Zinc
◦ reduces duration and severity
◦ Continued supplementation reduces recurrence
◦ Strengthen immune response and regenerate intestinal mucosa

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Solutions for intravenous infusion
 Ringer’s lactate
 Ringer’s lactate With 5% dextrose
 Normal saline (0.9% NaCl)

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Classes of antidiarrheal drugs
 Antimotility agents
 Opioid agonists; diphenoxylate, loperamide, Eluxadoline
 5-HT3 antagonists; alosetron
 Antisecretory agents;
 bismuth subsalicylate, octreotide
 Adsorbents;
 kaolin, Aluminum hydroxide, and methylcellulose
 Ion exchange resins /bile acid sequestrant;
Cholestyramine, colestipol, or colesevelam
 Antimicrobials

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1.Antimotility agents

 May be used safely in patients with mild to moderate

acute diarrhea.
 However, these agents should not be used in patients
with
◦ bloody diarrhea, high fever, or systemic toxicity

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I. Opioids
 Loperamide and diphenoxylate are widely used to
control diarrhea
 Both are analogs of meperidine and have opioid-like actions
on the gut.
 Are more potent than morphine for diarrhea
 At the usual doses, they lack analgesic effects.
 They inhibit presynaptic cholinergic nerves in the
submucosal and myenteric plexuses lead to
decrease mass colonic movements and the gastrocolic reflex and
increased colonic transit time and fecal water absorption.

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A. Loperamide
 Is a nonprescription opioid agonist
◦ It does not cross the blood-brain barrier and has no potential
for addiction
 It is also more effective than diphenoxylate
 Loperamide also increase anal sphincter tone
◦ May has therapeutic value for patients with anal inconsistence
 In addition, loperamide has antisecretory effect against
cholera and E.coli toxins
◦ Mediated through Gi-receptor and decrease cAMP.
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Cont’d
 Loperamide is available in capsule,solution,and chewable
tablet forms
 It is typically administered in doses of 2 mg taken one to
four times daily after each subsequent loose stool up to
16 mg/day.
 It undergoes extensive hepatic metabolism
 Has t1/2 of 11 hours

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Cont’d
 Loperamide is used for the general treatment of acute
diarrhea, including traveler’s diarrhea.
 should not be used in children <2 years or in patients
with severe colitis.
◦ Can contribute to toxic megacolon,

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B. Diphenoxylate
 Isa prescription opioid agonist
 Dosage commonly contain small amounts of atropine ;
◦ 2.5 mg diphenoxylate with 0.025 mg atropine.
 Extensively absorbed after oral administration
 Diphenoxylate is rapidly deesterified in to difenoxin
(active)

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C. Eluxadoline
 Is a prescription opioid agonist with high affinity for the
mu receptor
 Eluxadoline is approved for the treatment of patients
with diarrhea-predominant IBS at a dose of 75–100 mg
twice daily.

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2.Antisecretory agents
 Bismuth subsalicylate decreases fluid secretion in the
bowel.
 Its action may be due to its salicylate component as well as
its coating action
 In addition, it has weak antacid properties and possesses
antibacterial properties.
 Used for prevention and treatment of traveler’s diarrhea.
 Adverse effects may include black tongue and black stools.
◦ Caused by bimuth sulfide formed in a reaction between the drug
and bacterial sulfides in AGI tract

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Cont’d
 Octreotide is a synthetic octapeptide with actions
similar to somatostatin.
 It slows gastrointestinal motility and reduces intestinal
fluid secretion and pancreatic secretion.
 When administered intravenously, it has a serum half-life
of 1.5 hours.
 It also may be administered by subcutaneous injection,
resulting in a 6- to 12-hour duration of action.
 A longer-acting formulation is available for once-monthly
depot intramuscular injection.
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3. Adsorbents
 Aluminum hydroxide and methylcellulose are used
to control diarrhea.
 Presumably, these agents act by:
◦ adsorbing intestinal toxins or microorganisms and/or
◦ coating or protecting the intestinal mucosa.
 They are much less effective than antimotility agents
 They can interfere with the absorption of other drugs.

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4. Bile acid sequestrant
 Bile salts are normally absorbed in the terminal ileum
 Malabsorption of bile salts may cause colonic secretory
diarrhea.
 Cholestyramine, colestipol, or colesevelam, may
decrease diarrhea caused by excess fecal bile acids.

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Cont’d
 These products come in a variety of powder and pill
formulations that may be taken one to three times daily
before meals.
 Adverse effects include bloating, flatulence, constipation, and
fecal impaction
 Further removal of bile acids may lead to an exacerbation of
fat malabsorption.
 Cholestyramine and colestipol bind a number of drugs and
reduce their absorption.
 Colesevelam does not appear to have significant effects on
absorption of other drugs

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Antimicrobials
 Usedto treat specific causes of diarrhea
 Cholera
◦ Doxycycline 300 mg once or Tetracycline 500 mg 4 times a day
x 3 days or Erythromycin 250 mg 4 times a day x 3 days for
adult
◦ Erythromycin 12.5 mg/kg 4 times a day x 3 days for children
 Shigella dysentery
◦ Ciprofloxacin 500 mg 2 times a day x 3 days for adults
◦ Ciprofloxacin 15 mg/kg 2 times a day x 3 days for children

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Cont’d
 Amoebiasis
 Metronidazole
◦ Children: 10 mg/kg 3 times a day x 5 days (10 days for severe
disease)
◦ Adults: 750 mg 3 times a day x 5 days (10 days for severe
disease
 Giardiasis
Metronidazole
◦ Children: 5 mg/kg 3 times a day x 5 days
◦ Adults: 250 mg 3 times a day x 5 days

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Quize
1. mention different classes of drugs for constipation
2. Mention different classes of antidiarrheal drugs
3. Describe the use of opioid agonists and antagonists for
constipation and diarrhea
4. List different classes of laxatives
5. Classify diarrhea based on underlying mechanism

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Antiemetic drugs

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Induction
 Nausea and vomiting are caused by multiple factors, such
as
gastroenteritis,
 motion sickness and vertigo,
 pregnancy (morning sickness), or
 as adverse effects of drugs[Chemotherapy] or radiation
treatments.

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Neurologic pathways involved in pathogenesis of
nausea and vomiting

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Classes of antiemetic drugs
 Serotonin 5-HT3 antagonists
 D2-receptor antagonists
 Neurokinin 1 (NK1)-receptor antagonists
 H1 antihistamines
 Anticholinergic drugs/M1 antagonists
 Corticosteroids (dexamethasone, methylprednisolone)
 Benzodiazepines such as lorazepam or diazepam

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Cont’d

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A. Serotonin 5-HT3 antagonists
 ondansetron, granisetron, dolasetron, and palonosetron
 Have potent antiemetic properties
 These agents selectively block 5-HT3 receptors in the periphery
and central 5-HT3- receptor
 ondansetron, granisetron, and dolasetron can be administered
intravenously or orally
 Palonosetron is a newer intravenous agent
 Extensively metabolized by the liver
 Eliminated by renal and hepatic excretion.
 ondansetron, granisetron, and dolasetron have a serum half-life of
4–9 hours
 Palonosetron has serum half-life of 40 hours.

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Clinical use
 Are the primary agents for the
 prevention of acute chemotherapy-induced nausea and emesis
and
 prevention or treatment of postoperative and postradiation
nausea and vomiting
 Have little or no efficacy for the prevention of delayed
nausea and vomiting (ie, occurring >24 hours after
chemotherapy).
 Other emetic stimuli such as motion sickness are poorly
controlled.

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Adverse Effects
 Are well-tolerated agents with excellent safety profiles.
 The most commonly reported adverse effects are
 headache, dizziness, and constipation.
 All four agents cause a small but statistically significant
prolongation of the QT
 this is most pronounced with dolasetron.
 Serotonin syndrome has been reported in patients taking 5-
HT3-receptor antagonists in combination with other
serotonergic drugs
 For patients with hepatic insufficiency, dose reduction may be
required with ondansetron.

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B. D2-receptor antagonists
 Phenothiazines
 prochlorperazine, promethazine, and thiethylperazine.
 Butyrophenones
 droperidol
 Substituted benzamides
 metoclopramide and trimethobenzamide.
 All possess antiemetic properties due to their central
dopaminergic blockade
 Phenothiazines also have antimuscarinic and antihistamine
activity
 Trimethobenzamide also has weak antihistaminic activity.

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Adverse effects
 Theprincipal adverse effects of these central dopamine
antagonists are
◦ extrapyramidal: restlessness, dystonias, and parkinsonian
symptoms.

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C. Substance P/neurokinin-1 receptor
antagonists
 Aprepitant, fosaprepitant, netupitant, rolapitant
 Aprepitant, netupitant, and rolapitant are oral agents
 Fosaprepitant is a prodrug of aprepitant that is administered
intravenously.
 All three agents are metabolized by the liver, primarily by the
CYP3A4 pathway.
 The serum halfife of aprepitant, netupitant, and rolapitant is
12,90, and 180 hours, respectively
 They are usually administered with dexamethasone and a 5-
HT3 antagonists for the prevention of acute and delayed
nausea and vomiting.

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H1 antihistamines & anticholinergic drugs
 Diphenhydramine, dimenhydrinate, Meclizine
 Hyoscine (scopolamine)
 Used for the prevention of motion sickness and the
treatment of vertigo

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