Drugs For Constipation, AntiEmetics and Emetics Daniel Chans AUG 2022

LAXATIVES (Aperients, Purgatives,
Cathartics)
Daniel Chans M (MPS)

BPharm, MSc, MPharm
Dept of Pharmacology and

Therapeutics
MUST
danielchans@must.ac.ug
8/3/2022 DANIEL CHANS M MPS 2021 1

• A 70-year-old man complains of small, hard stools for the past 2
weeks. He also states that his bowel movements are less
frequent than normal and that he has not had constipation
previously. He has a history of hypertension, angina pectoris, and
osteoarthritis and began a new medication 3 weeks ago.
• State your Dx & possible causes
• What are the special considerations in this older man?
• What nonpharmacological and pharmacologic therapies would be
appropriate for his condition?
CONSTIPATION
Dfn:
• Is altered frequency of defecation and sometimes; as difficulty in defecation.
• Normal defecation of formed stool can vary from three times a day to only once
every 3 days.
• Constipation presents more in women than men.
• Constipation is a symptom rather than a disease, generally defined as when
bowel movements occur three or fewer times a week and are difficult to
pass
Causes of Constipation
• Absence of propagating contractions in the colon, which may be associated
with increased segmenting contractions.
• Abnormalities of propulsion in the distal or proximal parts of the colon.
• Inadequate diet fibre intake, fluid intake, regular exercise, and failure to take
heeding to nature's call.
CAUSES OF COSNTIPATION…

Signs and symptoms
• According to the Rome IV criteria for constipation, a patient must have
experienced at least two of the following symptoms over the preceding 6
months:
• Fewer than three spontaneous bowel movements per week
• Straining for more than 25% of defecation attempts
• Lumpy or hard stools for at least 25% of defecation attempts
• Sensation of anorectal obstruction or blockage for at least 25% of
defecation attempts
• Sensation of incomplete defecation for at least 25% of defecation
attempts
• Manual maneuvering required to defecate for at least 25% of
defecation attempts

Possible Causes of Constipation
1. GI disorders • GI disorders
• Possible Causes • Possible Causes
• Irritable bowel syndrome • Volvulus of the bowel
• Diverticulitis • Syphilis
• Upper GI tract diseases • Tuberculosis
• Anal and rectal diseases • Helminthic infections
• Hemorrhoids • Lymphogranuloma venereum
• Anal fissures • Hirschsprung’s disease
• Ulcerative proctitis
• Tumors
• Hernia
2. Metabolic and endocrine 3.Pregnancy
disorders Possible causes
Possible causes • Depressed gut motility
• Diabetes mellitus with • Increased fluid absorption
neuropathy from colon
• Hypothyroidism • Decreased physical activity
• Panhypopituitarism • Dietary changes
• Pheochromocytoma • Inadequate fluid intake
• Hypercalcemia • Low dietary fiber
• Enteric glucagon excess • Use of iron salts
4. Neurogenic causes 5.Psychogenic cause
Possible causes Possible causes
• CNS diseases • Ignoring or postponing urge to
• Trauma to the brain (particularly defecate
the medulla) • Psychiatric diseases
• Spinal cord injury 6. Drug induced
• CNS tumors
• Cerebrovascular accidents
• Parkinson’s disease
6. Drug induced constipation • Antacids containing calcium carbonate
• Possible causes or aluminum hydroxide
• Analgesics • Barium sulfate
• Inhibitors of prostaglandin • Calcium channel blockers
synthesis • Clonidine
• Opiates • Diuretics (non–potassium-sparing)
• Anticholinergics • Ganglionic blockers
• Antihistamines • Iron preparations
• Anti-Parkinsonian agents/ACs • Muscle blockers ( -tubocurarine,
D
(e.g., benztropine or succinylcholine)

trihexyphenidyl) • Nonsteroidal antiinflammatory agents
• Phenothiazines • Polystyrene sodium sulfonate
• Tricyclic antidepressants
Indications
• Facilitation of bowel movements in patients with inactive colon or anorectal
disorders
• Reduction of ammonia absorption in hepatic encephalopathy (lactulose only)
• Treatment of drug-induced constipation
• Treatment of constipation associated with pregnancy and/or post-obstetric period
• Treatment of constipation caused by reduced physical activity or poor dietary habits
• Removal of toxic substances from the body
• Facilitation of defecation in megacolon
• Preparation for colonic diagnostic procedures or surgery
Contraindications
• MOST categories of laxatives share the same general
contraindications and precautions, including avoidance in cases
of drug allergy and the need for cautious use in the presence of
the following:
• Acute surgical abdomen;
• Appendicitis symptoms such as abdominal pain, nausea, and
vomiting; fecal impaction (mineral oil enemas excepted);
• Intestinal obstruction; fecal impaction, bowel obstruction
• Undiagnosed abdominal pain.
CLASSIFICATION
• 1. Bulk forming • 4. Osmotic purgatives

• Dietary fibre: Bran, Psyllium • Magnesium salts: sulfate, hydroxide
(Plantago) • Sodium salts: sulfate, phosphate
• Ispaghula, Methylcellulose • Sod. pot. tartrate
• 2. Stool softener • Lactulose
• Docusates (DOSS), Liquid paraffin
• 3. Stimulant purgatives
• a) Diphenylmethanes Phenolphthalein,
Bisacodyl, Sodium picosulfate
• b) Anthraquinones (Emodins) Senna,
Cascara sagrada
• c) 5-HT4 agonist,Tegaserod
• d) Fixed oil Castor oil
Classification of laxatives
• Classification
• 1. Bulk laxatives
• Dietary fibre—Bran, methylcellulose, ispaghula (isabgol).
• 2. Stool softeners (stool-wetting agents)
• Docusates, liquid paraffin.
• 3. Stimulant or irritant laxatives
• Phenolphthalein, bisacodyl, sodium picosulphate.
• Anthraquinone derivatives—Senna, cascara sagrada.
• 4. Osmotic laxatives
• Magnesium sulphate, magnesium hydroxide, sodium phosphate, sodium sulphate,
sodium potassium tartarate, lactulose.
Laxatives / Purgatives/ Evacuants / Apperiants
• Drugs that promote defecation hence used in management of
constipation.
• For most people, intermittent constipation is best prevented with
a high fiber diet, adequate fluid intake, regular exercise.
• Patients not responding to dietary changes or fiber supplements
should undergo medical evaluation prior to the initiation of long-
term laxative treatment.
Classes of laxatives
1. Bulking agents
2. Osmotic laxatives
3. Stimulant drugs
4. Stool softners

Laxatives

Bulk Laxatives
Being Insoluble, non digestible and non-absorbable, they Increase the bowel content volume
which triggers stretch receptors in the intestinal wall to causes reflex contraction (peristalsis) that
propels the bowel content forward
Psyllium
Bran
Methylcellulose
Sterculia
Agar
Ispaghula husk
•Must be taken with lots of water! (or it will make
constipation worse)
•They take several days to work but have no
serious unwanted effects.
•Bacterial digestion of plant fibers within the
colon may lead to increased bloating and flatus.
Bulk Laxatives
• Bulk laxatives (also called mechanical stimulants) are aggressive laxatives that
cause the fecal matter to increase in bulk.
• They increase the motility of the GI tract by increasing the fluid in the intestinal
contents, which enlarges bulk, stimulates local stretch receptors, and activates
local activity.
Pharmacokinetics
• These drugs are all taken orally.
• They are directly effective within the GI tract and are not generally absorbed
systemically.
• Contraindications and Cautions
• Bulk laxatives are contraindicated with allergy to any component of the drug to
prevent hypersensitivity reactions and in acute abdominal disorders, including
appendicitis, diverticulitis, and ulcerative colitis.
• Laxatives should be used with caution in heart block, CAD and debilitation(which
could be affected by the decrease in absorption and changes in electrolyte levels
that can occur)
• Great caution during pregnancy and lactation because, in some cases,

stimulation of the GI tract can precipitate labor and many of these agents cross
the placenta and are excreted in breast milk.
Adverse Effects
• The adverse effects most commonly associated with bulk laxatives are GI effects such as
diarrhea, abdominal cramping, and nausea
• CNS effects, including dizziness, headache, and weakness may relate to loss of fluid and
electrolyte imbalances.
• Sweating, palpitations, flushing, and even fainting have been reported after laxative use.
• These effects may be related to a sympathetic stress reaction to intense
neurostimulation of the GI tract or to the loss of fluid and electrolyte imbalance.
• Clinically Important Drug–Drug Interactions
• It is advisable not to take laxatives with other prescribed medications.
• The administration of laxatives and other medications should be separated by at least 30
minutes.
Saline and Osmotic Laxatives
-Used to purge intestine (e.g. surgery, poisoning)
-They draw water into the lumen, distend the bowel, which then stimulates peristalsis resulting in
purgation.
-Fluid is drawn into the bowel by osmotic force, increasing volume and triggering peristalsis
•Non-digestible sugars and alcohols
•Lactulose (broken down by bacteria to acetic and lactic acid, which
causes the osmotic effect)
•Salts
•Milk of Magnesia (Mg(OH)2)
•Epsom Salt (MgSO4)
•Glauber’s Salt (Na2SO4)
•Sodium Phosphates (used as enema)
•Sodium Citrate (used as enema)
•Polyethylene glycol
•Polyethylene glycol electrolyte solution should be used with caution in any Disodium Phosphate and Mono
Sodium Phosphate
patient with a history of seizures because of the risk of electrolyte
absorption causing neuronal instability and precipitating seizures.

OSMOTIC LAXATIVES
Egs: Lactulose, sodium salts, magnesium salts
Osmotic diuretics are poorly absorbed and increase the small and large bowel fluid
volume by osmosis and as a result increase peristaltic motility. This leads to distension
and purgation in about an hour later.
Effective within 48 hours and their side effects include: abdominal cramps and
vomiting.
Lactulose
Widely used and is semisynthetic disaccharide of galactose and fructose. It passes

unchanged to the colon and is then broken down by bacteria to lactic and acetic
acids which act osmotically to increase fluid volume and lower pH. It is effective within
2-3 days.
Side effects: With high doses include: Flatulence, cramps, diarrhoea and electrolyte
disturbance.
DANIEL CHANS M MPS 2021 22
Tolerance can develop.
Magnesium salts and sodium acid phosphate
• Used less often than lactulose. They are poorly absorbed and osmotically active.
• They remain in the lumen and retain water, increasing the volume of the faeces.
• Magnesium also increases the synthesis of cholecystokinin, which increases colon motility
and fluid secretion into the lumen.
• The amount of magnesium absorbed after an oral dose is usually too small to have adverse
systemic effects.
• Sodium phosphate is commonly used orally for colon preparation before surgery or
colonoscopy.
• There is an increased risk of neuromuscular blockade when using nondepolarizing
neuromuscular junction blockers with magnesium salts
Contraindications:
• In young children
• In patients with poor renal function, in whom they can cause heart block, neuromuscular
block or CNS depression.
• Sodium salts should be avoided in cardiac patients
Stool Softners - Emollients
• Surface-active compounds that acts in the gastrointestinal

tract in a manner similar to a detergent and produces
softer faeces
•Docusate sodium (surfactant and stimulant)
•Liquid Paraffin (oral solution)
•Glycerin suppositories (- Also hyperosmotic laxative)
Docusate
Stool softeners (stool-wetting agents)
• These are sometimes known as emollients, surfactants or stool
softeners
• Mechanism of action
• They lower the surface tension of stool & cause accumulation of
fluid and fatty substance, thus softening the stools.
• They act mainly by holding water molecules in the fecal material, thus
rendering them softer and easier to pass.
• May also act on the intestinal wall to inhibit water absorption and
promote water and electrolyte secretion, thus also having some
stimulant properties.
• Liquid Paraffin
• Liquid paraffin is a mineral oil and is administered orally.
• It softens stools.
• It also has a Lubricant effect, and thus helps in smooth defaecation. It is useful in
patients with cardiac disease because it prevents straining during defecation
• Adverse effects of liquid paraffin
• 1. Lipid pneumonia may occur due to entry of the drug into lungs; hence, liquid
paraffin should not be given at bed time and in lying down position.
• 2. Long-term use may cause malabsorption of vitamin A, D, E and K (fat-soluble

vitamins).
• 3. Leakage of fecal matter through anal sphincter may lead to soiling of clothes.
Common adverse effects
• Having detergent properties, these substances can affect the cell

membranes of gastrointestinal mucosal cells, causing an increase in
absorption of other medicines administered concurrently.
• This increased absorption, in turn, could increase the toxicity of the
other medicines.
• Docusate is itself absorbed and has been reported as being
hepatotoxic
• Docusates increase the absorption of liquid paraffin, hence should
not be given together.
Irritant/Stimulant Laxatives-Cathartics
-Increases intestinal motility by stimulating enteric nerves.
-Irritate the GI mucosa and pull water into the lumen
-Indicated for severe constipation where more rapid effect is required (6-8
hours)
•Castor Oil - From the Castor Bean
•Senna - Plant derivative
•Bisacodyl (Dulcolax), Sodium Picosulphate
•danthron,ricinoleic acid.
•Lubiprostone -PGE1 derivative that stimulates chloride channels, producing chloride
(efflux) rich secretions (Used in Idiopathic Chronic Constipation e.g. > 3months)
Induces SBMSpontaneous Bowel Movts
8/3/2022
Bisacodyl Senna
DANIEL CHANS M MPS 2021
Lubiprostone 28
Stimulant or irritant laxatives
• Mechanism of action
• They directly affect the walls of either the small or large intestine, and cause an
increase in peristaltic movements, leading to defecation
• Interference with enzyme systems involved in ion transport, which increases the
concentration of the intestinal fluid and leads to an osmotic effect.
• Some may directly prevent water reabsorption in the colon and may even
promote water excretion directly from the intestinal cells to the lumen
• Others may simply irritate the smooth muscle of the intestinal wall or even the
mucosal cells, leading to a defecation reflex arc.
• Clinical considerations
• Stimulant laxatives are not recommended for use on a regular basis
because this may lead to a dilated colon with reduced
peristalsis, as well as the need to increase the dose…
• Chronic use is acceptable in particular cases, such as in people
with spinal damage or neuromuscular disease, or in people
taking opioids.
• Use of stimulant laxatives is contraindicated in intestinal obstruction
• Common adverse effects
• A problem with the use of these laxatives is rebound
constipation because the intestines adapt to being strongly
stimulated and the normal diet does not cause enough stimulation,
As a result, the afferent messages from the intestine to the brain
are ignored.
• Following muscle contraction, faecal contents are propelled
through the intestine, allowing less time for water absorption.
NOTE
• Bisacodyl can be given orally but in severe constipation it is usually given by suppository,
causing stimulation of the rectal mucosa, which results in peristaltic action and
defaecation in 15-30 minutes.
• Sodium picosulfate has a similar action; it is given orally and is often used in preparation
for intestinal surgery.
• Senna has laxative activity because it contains derivatives of anthracene (e.g. emodin)
combined with sugars to form glycosides. The drug passes unchanged into the colon,
where bacteria hydrolyze the glycoside bond, releasing the free anthracene derivatives.
These are absorbed and have a direct stimulant effect on the myenteric plexus, resulting
in smooth muscle activity and thus defecation.
• Some emodin is excreted in the urine and some may appear in the milk of women who
are breast-feeding.
• Castor Oil
• This oil is a potent stimulant laxative which is hydrolyzed in the upper small intestine to
ricinoleic acid, a local irritant that stimulates intestinal motility. Formerly used as a
purgative to clean the colon before procedures, it is now seldomly used.
Cathartic Colon: Long-term use of Stimulant Laxatives
• Cathartic colon is the anatomic and physiologic change in the colon that occurs with
chronic use of stimulant laxatives (> 3 times per week for at least 1 year).
• Signs and symptoms of cathartic colon include bloating, a feeling of fullness, abdominal
pain, and incomplete faecal evacuation.
• Radiologic studies show an atonic and redundant colon.
• Chronic use of stimulant laxatives can lead to serious medical consequences such as
fluid and electrolyte imbalance, steatorrhea, protein-losing gastroenteropathy,
osteomalacia, and vitamin and mineral deficiencies.
• When the drug is discontinued, radiographic and functional changes in the colon may only
partially return to normal because of drug-induced neuromuscular damage to the colon.

Semanticscholar.com
Cathartic colon: Laxative abuse

Melanosis coli and Gastric Ca risk
• Anthranoid laxatives (aloe, cascara sagrada,

and senna) are derived from naturally occurring
plants and are considered to be stimulant
laxatives.
• Short-term use of stimulant laxatives is safe, but

abuse of these drugs can cause melanosis coli
and possibly increases the risk of colonic
cancer.
• Melanosis coli, a benign condition, is

characterized by dark pigmentation of the
colonic mucosa that usually develops 9 months
after initiating the use of these drugs and
disappears just as quickly after the drug is
discontinued.
Slideshare.com
Laxative abuse
• Can cause of constipation!
• Longer interval needed to refill colon is misinterpreted as constipation
• => repeated use
• Enteral loss of water and salts causes release of aldosterone

• => stimulates reabsorption in intestine, but increases renal excretion of
K+
• => double loss of K+ causes hypokalemia, which in turn reduces
peristalsis.
• =>This is then often misinterpreted as constipation
• => repeated laxative use

NOTE
• Bulk-forming agents (fibers; eg, psyllium): arguably the best and least
expensive medication for long-term treatment
• Emollient stool softeners (eg, docusate): Best used for short-term
prophylaxis (eg, postoperative)
• Rapidly acting lubricants (eg, mineral oil): Used for acute or subacute
management of constipation
• Prokinetics (eg, tegaserod): Proposed for use with severe constipation-
predominant symptoms
• Stimulant laxatives (eg, senna): Over-the-counter agents commonly
but inappropriately used for long-term treatment of constipation

Newer therapies for constipation
• Prucalopride is a prokinetic selective 5-hydroxytryptamine-4 (5-HT4)
receptor agonist that stimulates colonic motility and decreases the transit
time
• Lubiprostone (Osmotic Agent) is FDA approved for constipation caused by
IBS and opioid-induced constipation in adults with chronic, noncancer pain
• Another osmotic laxative is lactitol, which is indicated for adults with
chronic idiopathic constipation (CIC)
• Linaclotide and plecanatide are guanylate cyclase C (GC-C) agonists
• they are indicated for chronic idiopathic constipation. Additionally, linaclotide is
indicated for constipation caused by IBS in adults
• Peripherally-acting mu-opioid receptor antagonists (PAMORA)
eg, naloxegol, methylnaltrexone, naldemedine
• have been approved by the FDA for opioid-induced constipation in adults with chronic
noncancer pain and/or for palliative care
Non Pharmacological management?
US Pharmacist.com

Choice of laxatives
1. Acute functional constipation (atonic or spastic)—bulk laxatives.
2. To avoid straining during defaecation in patients with cardiovascular disease, eye

surgery, hernia, etc.—docusates or bulk laxatives.
3. In patients with hepatic coma to reduce the blood ammonia level—lactulose.
4. Preoperatively in bowel surgery, colonoscopy and abdominal X-ray—
osmotic laxatives or bisacodyl.
5. Following certain anthelmintics (e.g. for Taenia solium)—osmotic laxatives to

expel the worm segments.
6. In drug poisoning to wash out the poisonous material from the gut—osmotic
laxatives.
7. To treat constipation in children and pregnant women— lactulose.

UCG 2016 GUIDELINES

EMESIS (VOMITING)

PROBLEM DIRECTED STUDY 3
• A 4-year-old girl is brought to the hospital emergency. The parents are very
alarmed by her condition that has developed over the past one hour, when
she started making bizarre faces.
• The neck has become rigid and head has tilted to one side. The teeth are
clinched and she is not speaking.
• The eyes are staring in one direction and there are intermittent
purposeless movements of the upper limbs.
• The parents inform that she had vomited twice in the morning and was
taken to a local doctor, who had given her an injection. The vomiting had
stopped, but after about 2 hours of the injection she developed the above
symptoms.
(a) What is the most likely cause of her symptoms? Could it be due to the
injection given to her? If so, which drug could have caused it?
(b) How should this patient be treated?
SOLUTION 3

EMESIS (VOMITING)
• Vomiting is a forceful expulsion of gastric contents through the
mouth.
• Vomiting may be due to;
• Adverse effects from medications;
• Systemic disorders or infections;
• Pregnancy;
• Vestibular dysfunction;
• Central nervous system infection or increased pressure;
• Peritonitis;
• Hepatobiliary disorders;
• GIT obstruction, dysmotility, or infections.
• Radiation or chemotherapy;
PATHOPHYSIOLOGY OF VOMITING
• There are four sources of afferent input to the vomiting center:
• The chemoreceptor trigger zone (CTZ) in the area postrema. This is
outside the blood-brain barrier and is accessible to emetogenic stimuli in the
blood or cerebrospinal fluid.
• The CTZ is rich in dopamine (D2) receptors, serotonin (5-HT3) receptors,
neurokinin 1 (NK1), and opioid receptors. It’s connected to the emetic
center through the fasciculus solitarius.
• The vestibular system is important in motion sickness via cranial nerve
VIII. It is rich in muscarinic and histamine H1 receptors.
• Irritation of the gastrointestinal mucosa by chemotherapy, radiation
therapy, distention, or acute infectious gastroenteritis leads to release of
mucosal serotonin and activation of these receptors, which stimulate vagal
afferent input to the vomiting center and CTZ.
• The CNS plays a role in vomiting due to psychiatric disorders, stress, and
anticipatory vomiting prior to cancer chemotherapy.
8/3/2022 48
Emesis
(seeing something repulsive)
(motion sickness)
8/3/2022 (Ingesting a toxin) DANIEL CHANS M MPS 2021 50

Neurotransmitters involved in vomiting
• Dopamine - D2receptors
• Serotonin - 5HT3 receptors
• Histamine - H1 receptors
• Acetyl choline - M1 receptors
• Neurokinin 1-NK1 receptor

Classification of Antiemetics
• Serotonin 5-HT3 antagonists: ondansetron, granisetron, dolasetron
• Dopamine receptor antagonists: metoclopramide, domperidone
• H1 Antihistamines: promethazine, meclizine, diphenhydramine, doxylamine etc
• Anticholinergics: scopolamine (hyoscine).
• Benzodiazepines: lorazepam and diazepam
• Neurokinin Receptor Antagonists: aprepitant
• Cannabinoids: nabilone & dronabinol
• Corticosteroids: dexamethasone and methylprednisolone
• Others: prochlorperazine, Chlopromazine, thiethylperazine, droperidol,
trimethobenzamide,pyridoxine
• Combinations exist eg Doxylamine-Pyridoxine (VitB6) for N&V in Pregnancy

Prokinetic Drugs
• Substances which enhance transit of

materials through the GI tract;
• Increase neuromuscular transmission

Prokinetic Drugs are Often Used for:
Gastroesophageal reflux disease (GERD)
Gastroparesis
Nighttime heartburn
Severe refractory constipation (sometimes caused by

irritable bowel syndrome (IBS))
Emesis

Prokinetic Drugs – Metoclopramide (Reglan)
Metoclopramide is an antiemetic and improves gastric emptying
•
– indirectly releases acetylcholine
• Actions
• Dopamine D2 receptor antagonist
• 5-HT4 receptor agonist
• Ganglionic stimulant
• Pharmacokinetics O
CH 2 CH 3
• Oral bioavailability Cl C NH CH 2 CH 2 N
• Crosses blood-brain barrier CH 2 CH 3
• Metabolised in the kidney
• Excreted in the urine.
NH 2 OCH 3
• Adverse Side-effects
• Sedation
• Dystonic reactions
• Anxiety reactions
• Gynecomastia
8/3/2022 • Galactorrhea DANIEL CHANS M MPS 2021 55
Prokinetic Drugs – Domperidone (Motilium)
Domperidone is an antiemetic and improves gastric emptying
• Actions
Dopamine receptor antagonist
Ganglionic stimulant
• Pharmacokinetics
Low oral bioavailability
Does not cross blood-brain barrier
• Adverse Side-effects
Headaches
Gynecomastia
Galactorrhea
Serotonin (5-HT3) antagonists
• Selective 5-HT3-receptor antagonists have potent antiemetic

properties that are mediated mainly through central 5-HT3-
receptor blockade in the vomiting center and chemoreceptor
trigger zone and blockade of peripheral 5-HT3 receptors on
extrinsic intestinal vagal and spinal afferent nerves.

Serotonin (5-HT3) antagonists
Pharmacokinetics
• Four agents are available: ondansetron, granisetron, dolasetron, and

palonosetron.
• The first three agents have a serum half-life of 4–9 hours and may be administered
once daily by oral or intravenous routes.
• Palonosetron is a newer intravenous agent that has greater affinity for the 5-HT3
receptor and a long serum half-life of 40 hours.
• All four drugs undergo extensive hepatic metabolism and are eliminated by renal
and hepatic excretion.
• Dose reduction is required for patients with hepatic insufficiency on ondansetron

Clinical Uses
• Chemotherapy-Induced Nausea and Vomiting
• Postoperative and Post radiation Nausea and Vomiting
• Other Nausea and vomitting
N.B Their efficacy is enhanced by combination therapy with a corticosteroid
(dexamethasone) and NK1 receptor antagonist.
Adverse Effects
Headache, dizziness, and constipation.
Drug Interactions
Dolasetron shouldn’t be administered to patients with prolonged QT or in
conjunction with other medications that may prolong the QT interval.
Anticholinergics
• Hyoscine (scopolamine)
Effective treatment for
• Motion sickness
• Vomiting caused by irritants in the GIT.
N.B. Hyoscine is employed principally for prophylaxis and treatment of motion
sickness and is often administered as a transdermal patch because of a very high
incidence of anticholinergic effects when given orally or parenterally.
Side effects
Dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention

Antihistamines
• Meclizine - motion sickness and treatment of vertigo due to labyrinth
dysfunction.
• Promethazine – motion sickness
• Diphenhydramine is commonly used in conjunction with other antiemetics

for treatment of emesis due to chemotherapy.
• Doxylamine
• Etc.
N.B Their use is limited by dizziness, sedation, confusion, dry mouth,

cycloplegia, and urinary retention

Droperidol
• Given by intramuscular or intravenous injection.
• it is a Butyrophenone, centrally acting Anti-emetic with Dopamine Blocking action
• Also has anti-adrenergic and Anti-Histaminergic effects
• In antiemetic doses, droperidol is extremely sedating.
Clinical uses
• Used for prevention and treatment of postoperative nausea and vomiting
• For induction and maintenance of general anesthesia
Adverse effects
• Extrapyramidal effects, drowsiness, dizziness, restlessness, anxiety occur.
• May prolong the QT interval, rarely resulting in fatal episodes of ventricular tachycardia
including torsade de pointe
Contraindication
• Should not be used in patients with QT prolongation and should only be used in patients who
have not responded adequately to alternative agents.

Corticosteroids
Dexamethasone, methylprednisolone
• These agents appear to enhance the efficacy of 5-HT3-receptor antagonists
for prevention of acute and delayed nausea and vomiting in patients receiving
moderately to highly emetogenic chemotherapy regimens.
• Although a number of corticosteroids have been used, dexamethasone, 8–20
mg intravenously before chemotherapy, followed by 8 mg/d orally for 2–4
days, is commonly administered.
• Dexamethasone, one of the glucocorticoids, has been suggested as a first-
line drug for preventing low-level emetogenic chemotherapy- and
radiotherapy-induced nausea and vomiting, and in patients with only one or
two risks for postoperative nausea and vomiting (PONV). (Chu et al., 2013)
• Dexamethasone combined with 5-HT3 or tachykinin NK1 antagonists is also
suggested for higher-level emetogenic chemotherapy and radiotherapy and
for patients at high risk for PONV. (Chu et al., 2013)

Moa of corticosteroids (Chu et al., 2013)
• (1) anti-inflammatory effect; inhibiting PG synthesis
• (2) direct central action at the solitary tract nucleus,
• (3) interaction with the neurotransmitter serotonin, and receptor
proteins tachykinin NK1 and NK2 (boosts other AntiEmetics)
• (4) maintaining the normal physiological functions of organs and
systems;
• (5) regulation of the hypothalamic-pituitary-adrenal axis;
• (6) reducing pain; endogenous opiates and the concomitant use of
opioids, which in turn reduces opioid-related nausea and vomiting.

Neurokinin receptor antagonists
Eg. Aprepitant, Fosapreitant, Cosaprepitant,netupitant, rolapitant
• Aprepitant, which is given orally, and its water-soluble prodrug fosaprepitant, given intravenously
• They block the release of substance P
• Aprepitant is a highly selective NK1 receptor antagonist that crosses the blood-brain barrier and
occupies brain NK1 receptors. It has no affinity for serotonin, dopamine, or corticosteroid
receptors.
Pharmacokinetics
• The oral bioavailability is 65%, and the serum half-life is 12 hours. Aprepitant is metabolized by the
liver, primarily by the CYP3A4 pathway.
Clinical Uses
• In combination with 5-HT3-receptor antagonists and corticosteroids , it is used for the prevention
of acute and delayed nausea and vomiting from highly emetogenic chemotherapeutic regimens.
• Aprepitant is administered orally for 3 days as follows: 125 mg given 1 hour prior to chemotherapy,
followed by 80 mg/d for 2 days after chemotherapy.
…
• The most common side effects of aprepitant are headache, anorexia,
diarrhea, hiccups, fatigue, and a mild elevation of serum transaminase levels.
• Aprepitant is a moderate inhibitor and an inducer of cytochrome P450 (CYP)
3A4, as well as an inducer of CYP2C9.
• For this reason the dosage of dexamethasone has to be decreased by 50%
when co-administered with aprepitant.
• Precautions are recommended with the concomitant use of warfarin, as
aprepitant induces its metabolism, causing low international normalized
ratio values.
• It inhibits the metabolism of docetaxel, paclitaxel, etoposide, irinotecan,
imatinib, vinblastine, and vincristine, hence increasing their level and toxicity.
• Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant
plasma levels (eg, ketoconazole, ciprofloxacin, clarithromycin, nefazodone,
ritonavir, nelfinavir, verapamil, and quinidine).

CANNABINOIDS
• Nabilone and dronabinol are synthetic cannabinol derivatives have been found to decrease vomiting
caused by agents which stimulate the CTZ.
• The antiemetic effects of these agents are antagonized by naloxone.
Pharmacokinetics
• Nabilone is given orally, is well absorbed from the gastrointestinal tract and is metabolised in many
tissues. Its plasma half-life is approximately 120 minutes, and its metabolites are excreted in the urine and
faeces.
• Dronabinol is usually administered prior to chemotherapy and every 2–4 hours as needed, but becoz of
better drugs, it’s uncommonly used.
Unwanted effects
• Drowsiness, dizziness and dry mouth.
• Sedation, euphoria
• Mood changes and postural hypotension are also fairly frequent.
• Some patients experience hallucinations and psychotic reactions, resembling the effect of other
cannabinoids.

Assignment
• Other drugs used in N&V
• Chemotherapy Induced Nausea and Vomiting
• Drugs for Pregnancy Induced Nausea and Vomiting
• Pharmacology of drugs used in IBD and IBS
• Drugs used for Hemorrhoids
• Drugs for GIT disorders in Pregnancy

EMETIC DRUGS
• In some circumstances, such as when a toxic substance has been
swallowed, it may be necessary to stimulate vomiting.
• This should never be attempted if the patient is not fully conscious or if the
substance is corrosive.
• The drug usually used to produce vomiting is ipecacuanha, which acts
locally in the stomach.
• Its irritant action results from the presence of two alkaloids emetine and
cephaeline.
• In cases of poisoning, activated charcoal can also be given to sequester the
toxic drug.
• Also apomorphine hydochloride can be used

Syrup of Ipecac Emetic
• Prepared from the root of the ipecacuanha plant
• Induces emesis
• Side effects include drowsiness, diarrhea, and stomach ache
• Acceptable for use when:
• There is no contraindication to the use of ipecac
• There is substantial risk of serious toxicity to the victim
• There is no alternative therapy available or effective to decrease
gastrointestinal absorption (e.g., activated charcoal)
• There will be a delay of greater than 1 hour before the patient will
arrive at an emergency medical facility and ipecac syrup can be
administered within 30-90 minutes of the ingestion
• Ipecac syrup administration will not adversely affect more definitive
8/3/2022 treatment that might be provided at a hospital 70
ASSIGNMENT: READ AND MAKE NOTES ABOUT PHARMACOLOGY OF DRUGS USED
IN IBS and IBD
• Difference between IBS and IBD
• Surgery
• 5-Aminosalicylic acid derivatives (are sulfasalazine, mesalamine, balsalazide, and olsalazine)
• Tumor Necrosis Factor Inhibitors eg infliximab, golimumab, adalimumab
• Immunosuppressants: azathioprine, 6-mercaptopurine, Calicuneurin inhibitors (cyclosporine,
tacrolimus)
• Corticosteroids: methylpred, pred, hydrocortisone, budesonide
• Alpha 4 Integrin Inhibitors: Vedolizumab
• JAK Inhibitors: Tofacitinib
• Interleukin Inhibitors:Ustekinumab
• Antimicrobials: Ciprofloxacin, Metronidazole, rifaximin
• Antidiarrheals: Diphenoxylate hcl/atropine

Inflammatory Bowel Disease
• Ulcerative colitis
• Diffuse mucosal inflammation limited to the
colon
• Bloody diarrhea, colicky pain,
urgency,tenesmus
• Crohn’s Disease
• Patchy transmural inflammation
• May affect any part of GI tract
• Abdominal pain, diarrhea, weight loss,
intestinal obstruction

Inflammatory Bowel Disease
Treatment = Resolve acute episodes and prolong remission
Drugs used:
• Aminosalicylates - for mild symptoms
• Corticosteroids - for moderate symptoms
• Thiopurines - for active and chronic symptoms
• Methotrexate - for active and chronic symptoms
• Cyclosporine - for active and chronic symptoms refractory to corticorsteroids- (significant
side effects)
• Infliximab - antibody infusion

Aminosalicylates
Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance)
Mesalazine (5-ASA), eg Asacol, Pentasa
Balsalazide (prodrug of 5-ASA)
Olsalazine (5-ASA dimer cleaves in colon)
Oral, rectal preparation
Use
 Maintaining remission
 Active disease
 May reduce risk of colorectal cancer
Adverse effects
 10-45%
 Nausea, headache, epigastric pain, diarrhoea, hypersensitivity, pancreatitis, blood disorders, lung
disorders, myo/pericarditis
 Caution in renal impairment, pregnancy, breast feeding

Corticosteroids
• Anti-inflammatory agents for moderate to severe relapses
• eg 40mg Prednisolone
• Inhibition of inflammatory pathways (↓IL transcription, suppression of arachidonic
acid metabolism, lymphocyte apoptosis)
• Side effects
• Acne, moon face
• Sleep, mode disturbance
• Dyspepsia, glucose intolerance
• Cataracts, osteoporosis, myopathy…

Thiopurines
Azathioprine, mercaptopurine
• Inhibit ribonucleotide synthesis
• Inducing T cell apoptosis by modulating cell signalling
• Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides
Use
• Active and chronic disease
• Steroid sparing
Side effects
• Leucopaenia (myelotoxic)
• Monitor for signs of infection, sore throat
• Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity

Methotrexate
Inhibits dihydrofolate reductase
Probably inhibition of cytokine and eicosanoid synthesis
 Use
Relapsing or active CD refractory or intolerant to AZA or thiopurine
Side effects
 GI
 Hepatotoxicity, pneumonitis

Infliximab
• Anti TNF-α monoclonal antibody
• Potent anti inflammatory effects
• Use
• Fistulizing CD
• Severe active CD refractory/intolerant of steroids or immunosuppression
• Iv infusion
• Side effects
• Infusion reactions
• Sepsis
• Reactivation of Tb, increased risk of Tb

END

Drugs For Constipation, AntiEmetics and Emetics Daniel Chans AUG 2022

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Drugs For Constipation, AntiEmetics and Emetics Daniel Chans AUG 2022

Uploaded by

Copyright:

Available Formats

LAXATIVES (Aperients, Purgatives,

Daniel Chans M (MPS)

Dept of Pharmacology and

8/3/2022 DANIEL CHANS M MPS 2021 1

8/3/2022 DANIEL CHANS M MPS 2021 4

8/3/2022 DANIEL CHANS M MPS 2021 5

(e.g., benztropine or succinylcholine)

• 1. Bulk forming • 4. Osmotic purgatives

8/3/2022 DANIEL CHANS M MPS 2021 15

8/3/2022 DANIEL CHANS M MPS 2021 16

• These drugs are all taken orally.

• Great caution during pregnancy and lactation because, in some cases,

8/3/2022 DANIEL CHANS M MPS 2021 21

Egs: Lactulose, sodium salts, magnesium salts

Widely used and is semisynthetic disaccharide of galactose and fructose. It passes

• Surface-active compounds that acts in the gastrointestinal

• 2. Long-term use may cause malabsorption of vitamin A, D, E and K (fat-soluble

• Having detergent properties, these substances can affect the cell

• Radiologic studies show an atonic and redundant colon.

8/3/2022 DANIEL CHANS M MPS 2021 33

8/3/2022 DANIEL CHANS M MPS 2021 34

• Anthranoid laxatives (aloe, cascara sagrada,

• Short-term use of stimulant laxatives is safe, but

• Melanosis coli, a benign condition, is

• Enteral loss of water and salts causes release of aldosterone

8/3/2022 DANIEL CHANS M MPS 2021 36

8/3/2022 DANIEL CHANS M MPS 2021 38

8/3/2022 DANIEL CHANS M MPS 2021 40

2. To avoid straining during defaecation in patients with cardiovascular disease, eye

3. In patients with hepatic coma to reduce the blood ammonia level—lactulose.

4. Preoperatively in bowel surgery, colonoscopy and abdominal X-ray—

osmotic laxatives or bisacodyl.

5. Following certain anthelmintics (e.g. for Taenia solium)—osmotic laxatives to

7. To treat constipation in children and pregnant women— lactulose.

8/3/2022 DANIEL CHANS M MPS 2021 42

8/3/2022 DANIEL CHANS M MPS 2021 44

8/3/2022 DANIEL CHANS M MPS 2021 46

8/3/2022 (Ingesting a toxin) DANIEL CHANS M MPS 2021 50

8/3/2022 DANIEL CHANS M MPS 2021 51

8/3/2022 DANIEL CHANS M MPS 2021 52

• Substances which enhance transit of

• Increase neuromuscular transmission

8/3/2022 DANIEL CHANS M MPS 2021 53

Severe refractory constipation (sometimes caused by

8/3/2022 DANIEL CHANS M MPS 2021 54

• Selective 5-HT3-receptor antagonists have potent antiemetic

8/3/2022 DANIEL CHANS M MPS 2021 57

• Four agents are available: ondansetron, granisetron, dolasetron, and

• Dose reduction is required for patients with hepatic insufficiency on ondansetron

8/3/2022 DANIEL CHANS M MPS 2021 60

• Promethazine – motion sickness

• Diphenhydramine is commonly used in conjunction with other antiemetics

N.B Their use is limited by dizziness, sedation, confusion, dry mouth,

8/3/2022 DANIEL CHANS M MPS 2021 61

8/3/2022 DANIEL CHANS M MPS 2021 62

8/3/2022 DANIEL CHANS M MPS 2021 63

8/3/2022 DANIEL CHANS M MPS 2021 64

8/3/2022 DANIEL CHANS M MPS 2021 66

8/3/2022 DANIEL CHANS M MPS 2021 67

8/3/2022 DANIEL CHANS M MPS 2021 68

8/3/2022 DANIEL CHANS M MPS 2021 69

8/3/2022 DANIEL CHANS M MPS 2021 71

8/3/2022 DANIEL CHANS M MPS 2021 72