PROKINETIC AGENTS, ANTIEMETICS,

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PROKINETIC AGENTS, ANTIEMETICS, AND AGENTS USED
IN IRRITABLE BOWEL SYNDROME 300-500
pm November 30, 2005 Dr. Wen Xie Center for
Pharmacogenetics School of Pharmacy University of
Pittsburgh 633 Salk Hall wex6_at_pitt.edu
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Gastrointestinal Motility Disorders and
Irritable Bowel Syndrome Orphan diseases
whose pathogenesis is not well understood.
There are challenges for therapeutic
development of these orphan diseases. Antiemeti
cs to treat nausea and vomiting are
more established treatments
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PROKINETICS
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PROKINETICS definition Drugs that promote
upper G.I. tract motility
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PROKINETICS

• Agents that enhance coordinated contraction of
  the antrum duodenum
• Increases gastric emptying
• Relief of gastric stasis
• Decreases reflux oesophagitis/heartburn
• ? Regurgitation of gastric contents emesis

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Examples of disorders treated by PROKINETICS

• Achalasia (esophagus spasm, lower esophageal
  sphincter (LES) fails to relax)
• GERD (gastroesophageal reflux disease)
  (insufficient LES pressure)
• Gastroparesis (delayed gastric emptying, often
  occurs in people with diabetes due to vagus nerve
  damage)

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Inhibit dopamine D2 receptors
Motor neuron
Inhibit 5HT3 receptors (e.g. ondansetron)
Stimulate 5HT4 receptors
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Prokinetic Agents
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All prokinetic drugs enhance cholinomimetic
effect by modulating cholinergic neurons
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• Comparative Pharmacology Indications
• Bethanachol (Muscarinic agonist) Neostigmine
  (Anticholinestrase)
• Disadvantage
• Non-specific muscarinic effect
• Increases salivation
• Diarrhea, gastric pancreatic secretion
• Advantage
• Dopamine D2 Blockers Metoclopramide, Domperidone
• 5-HT4 agonists Cisapride, metoclopramide
• Motilin agonist Erythromycin

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Comparative Pharmacology Indications

• Metoclopramide (Dopamine D2 blockers)
• 5HT4 receptor agonist
• D2 selective dopamine antagonist (anti-emetic)
• Crosses the blood brain barrier
• Hyperprolactinemia
• Anti-emetic effect
• Domperidone (Dopamine D2 blockers)
• D2 selective antagonist
• Does not cross blood brain barrier
• CNS related symptoms are least
• Causes hyperprolactinemia (dopamine inhibits
  prolactin release)

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• Comparative Pharmacology Indications
• Cisapride (PROPULSID) (5-HT4 agonists)
• Serotonergic agonist, activates 5-HT4 receptor
• Has no D2 receptor activity, no CNS related side
  effects
• No hyperprolactinemia, no anti-emetic effect.
• Causes upper G.I. motility, promote colonic
  hypermotility
• Relieves constipation
• Causes ventricular arrhythmia by torsades de
  pointes
• Block K channels in the heart GIT

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• Comparative Pharmacology Indications
• Erythromycin (Motilin Agonist)
• Macrolide antibiotic acts as a motilin agonist
• Increases gastric emptying duodenal contraction
• Useful in diabetic gastric paresis

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Newer Therapies

• CCK1 receptor antagonist loxiglumide
• to suppress transient lower esophageal
  relaxations (tLESRs) (in gastroesophageal reflux
  disease - GERD)
• GABA agonists baclofen
• Achalasia- lower esophageal sphincter (LES) fails
  to relax
• Agents that inhibit contractility Ca2
  channel blockers, organic nitrates, local
  injection of botulinum toxin (inhibits ACh
  release)

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ANTIEMETICS
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ANTIEMETICS definitionAgents to treat nausea
and vomiting
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Chemoreceptor Trigger Zone and Emetic Center
Antagonist
5-HT3 RAs
Droperidol
Promethazine
Atropine
NK-1 RA
Agonist
5-HT3
Muscarinic
Dopamine (D2)
Histamine
Substance P
Receptor Site
Nitrogen mustard Cisplatin Digoxin
glycoside Opioid, analgesics Vestibular
portion of 8th nerve N2O GI tract
distension Higher centers (vision, taste) Pharynx
Chemoreceptor Trigger Zone (CTZ)
Area Postrema
Mediastinum
Parvicellular Reticular Formation
Emetic Center
?
Vagus
Watcha MF, White PF. Anesthesiology.
199277162184.
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AntiemeticsMembers by Class

• Antidopamines
• Metoclopramide
• Droperidol (haloperidol)
• Phenothiazines
• Chlorpromazine, prochlorperazine, promethazine
• Others
• Dexamethasone
• Dronabinol

• 5-HT3 antagonists
• Dolasetron, granisetron, ondansetron
• Antihistamines
• Dimenhydrinate, hydroxyzine
• Anticholinergics
• Scopolamine

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Phenothiazines

• Chlorpromazine, Prochlorperazine, Promethazine
• Antipsychotic agents
• Blocks D2 receptors in CTZ and CNX
• SIDE EFFECTS sedation, dizziness, blurred
  vision, skin reactions, orthostatic hypotension

chlorpromazine
Prochlorperazine-heterocyclic side chain
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• Droperidol (antidopamines)
• D2 receptor antagonist (binds to D2 receptor)
• Acts at both CTZ and area postrema
• SIDE EFFECTS sedation, QTc prolongation

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FDA Advisory For Droperidol

• Risk of fatal cardiac arrhythmia
• The black box warns
• consider alternative medications in patients at
  high risk for cardiac arrhythmia
• use only low doses when other initially
  recommended antiemetics fail
• use as a 2nd agent when an initial treatment
  fails.

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• Metoclopramide
• Specific dopamine D2 antagonist
• ? LES tone which enhances gastric motility
• Short (1 to 2 hours) duration of action.
• SIDE EFFECTS restlessness, drowsiness, fatigue,
  agranulocytosis, methemoglobinemia

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Anticholinergics

• Scopolamine
• Inhibit cholinergic and muscarinic CNS receptors.
  
• Crosses the blood-brain barrier.
• More effective against motion-induced emesis than
  against motion-induced nausea.
• SIDE EFFECTS sedation, CNS excitation, dry
  mouth, urinary retention, blurred vision,
  confusion, disorientation, hallucinations

Night Shade
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Antihistamines

• Dimenhydrinate, Hydroxyzine, Cyclizine
• Block acetylcholine in the vestibular apparatus
  and histamine H1 receptors in the nucleus of the
  solitary tract.
• SIDE EFFECTS blurred vision, urinary retention,
  dry mouth, and sedation

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5-HT3 Antagonists

• (Ondansetron (Zofran), Granisetron (Kytril),
  Tropisetron (Navoban), and Dolasetron (Anzemet)
• No sedation, extrapyramidal reactions, adverse
  effects on vital signs or laboratory tests, or
  drug interactions with other anesthetic
  medications.
• SIDE EFFECTS Headache, dizziness, constipation

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Dexamethasone

• Synthetic steroid not indicated for treatment of
  PONV in the United States.
• Hypotheses
• inhibition of prostaglandin syn.
• ? tryptophan
• release of endorphins
• change in csf opening pressure
• psychological effects of steroids
• ACUTE SIDE EFFECTS flushing and
• perineal itching.

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DRONABINOL Marinol

• Unknown mechanism involves inhibition of CTZ
• SIDE EFFECTS dizziness, drowsiness, nausea (not
  emesis)
• Schedule II drug

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Irritable Bowel Syndrome (IBS)
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Irritable Bowel Syndrome (IBS), An Overview IBS
is one of the most common disorders that doctors
see. IBS is characterized by abdominal pain or
cramping and changes in bowel function,
including bloating, gas, diarrhea and
constipation. For many years IBS was considered
a psychological rather than a physical
Problem---WRONG. Up to one in five American
adults has IBS. For most people, signs and
symptoms of IBS are mild. Only a small
percentage of people with IBS have severe signs
and symptoms. Unlike more serious intestinal
diseases such as ulcerative colitis and Crohn's
disease, IBS doesn't cause inflammation or
changes in bowel tissue or increase risk of
colorectal cancer. In many cases, IBS can be
controlled by managing diet, lifestyle and stress.
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What is IBS? Irritable bowel syndrome, or IBS,
is a problem that affects mainly the bowel
(large intestine). IBS is a syndrome because it
can cause a group of symptoms, such as cramping,
bloating, gas, diarrhea, and constipation. IBS
is not a disease. It's a functional disorder,
which means that the bowel doesn't work as it
should. With IBS, the nerves and muscles in the
bowel are extra-sensitive. For example, the
muscles may contract too much when eating. These
contractions can cause cramping and diarrhea
during or shortly after a meal. Or the nerves
can be overly sensitive to the stretching of the
bowel (because of gas, for example). Cramping or
pain can result. IBS can be painful. But it does
not damage the bowel or cause any other disease.
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Does stress cause IBS? Emotional stress does not
cause IBS but it can trigger symptoms. The
bowel can overreact to other things, including
food, exercise, and hormones. Foods that tend
to cause symptoms include milk products,
chocolate, alcohol, caffeine, carbonated drinks,
and fatty foods. In some cases, simply eating a
large meal will trigger symptoms. Women with IBS
often have more symptoms during their menstrual
period.
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What are the symptoms of IBS? Crampy pain in
the stomach area. Painful diarrhea and/or
constipation. Other symptoms are - mucus in
the stool - swollen or bloated abdomen - the
feeling that you have not finished a bowel move
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How is IBS diagnosed? Suspect due to symptoms.
Medical tests to exclude any other diseases that
could cause the symptoms. Physical exam Blood
tests Celiac disease (nontropical sprue) is
sensitivity to wheat protein that also may cause
symptoms like those of IBS. Blood tests may help
rule out that disorder. X ray of the bowel
Barium enema or lower GI series. (barium
administration through the anus). Endoscopy.
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IBS treatment IBS has no cure! Treatments to
relieve symptoms diet changes stress
relief medicines
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Diet Changes Foods that may make IBS
worse fatty foods like French fries milk
products like cheese or ice cream chocolate al
cohol caffeine carbonated drinks Foods that
may help to relieve IBS Probiotics Probiotics
are "good" bacteria that normally live in the
intestines and are found in certain foods, such
as yogurt, and in dietary supplements. It's been
suggested that people with IBS may not have
enough good bacteria, and that adding probiotics
to your diet may help ease your symptoms.
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Stress Relief
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• Medicine
• Laxatives to treat constipation
• Fiber supplements to control constipation
• (psyllium (Metamucil) or methylcellulose
  (Citrucel))
• Anticholinergic medications to slow contractions
  
• in the bowel, which helps with diarrhea and pain
• Herbs Peppermint is a natural antispasmodic that
  relaxes smooth
• muscles in the intestines. Avoid herb-drug
  interactions.
• Antidepressants to help those who have severe
• pain.
• - Tricyclic antidepressants, such as imipramine
  (Tofranil).
• SSRIs (selective serotonin re-uptake inhibitors),
  such as
• Prozac (fluoxetine) or Paxil (paroxetine)

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Drugs Specifically for IBS Alosetron (Lotronex).
This drug is a nerve receptor antagonist that's
supposed to relax the colon and slow the
movement of waste through the lower bowel. But
the drug was removed from the market just nine
months after its approval when it was linked to
deaths and severe side effects. In June 2002, FDA
decided to allow alosetron to be sold again with
restrictions. The drug can be prescribed only by
doctors enrolled in a special program and is
intended for severe cases of diarrhea-predominant
IBS in women who haven't responded to other
treatments. Alosetron is not approved for use by
men. Tegaserod (Zelnorm). Tegaserod imitates the
action of the neurotransmitter serotonin and
helps to coordinate the nerves and muscles in the
intestine. It is intended for women who have IBS
with constipation and has not been shown to be
effective for treating men with IBS. Some reports
have suggested a risk of rare, dangerous side
effects similar to those of alosetron. Generally,
alosetron and tegaserod should only be used if
you have failed usual therapy for your IBS.
Additionally, they should only be prescribed by a
gastroenterologist with expertise in IBS because
of the potential side effect
Drugs Specifically for IBS Alosetron (Lotronex).
This drug is a nerve receptor antagonist that's
supposed to relax the colon and slow the
movement of waste through the lower bowel. But
the drug was removed from the market just nine
months after its approval when it was linked to
deaths and severe side effects. In June 2002, FDA
decided to allow alosetron to be sold again with
restrictions. The drug can be prescribed only by
doctors enrolled in a special program and is
intended for severe cases of diarrhea-predominant
IBS in women who haven't responded to other
treatments. Alosetron is not approved for use by
men. Tegaserod (Zelnorm). Tegaserod imitates the
action of the neurotransmitter serotonin and
helps to coordinate the nerves and muscles in the
intestine. It is intended for women who have IBS
with constipation and has not been shown to be
effective for treating men with IBS. Some reports
have suggested a risk of rare, dangerous side
effects similar to those of alosetron. Generally,
alosetron and tegaserod should only be used if
you have failed usual therapy for your IBS.
Additionally, they should only be prescribed by a
gastroenterologist with expertise in IBS because
of the potential side effects
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IBS Summary IBS is a functional disorder in
which the bowel doesn't work as it should. IBS
can cause cramping, bloating, gas, diarrhea, and
constipation. IBS doesn't damage the bowel. The
doctor will diagnose IBS based on your symptoms.
You might have some medical tests to rule out
other diseases. Stress doesn't cause IBS, but it
can trigger symptoms. Fatty foods, milk
products, chocolate, caffeine, carbonated drinks,
and alcohol can trigger symptoms. Eating foods
with fiber and eating smaller meals can reduce
symptoms. Treatment for IBS may include
medicine, stress relief, or changes in eating
habits.
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IBS is not IBD (Inflammatory Bowel Disease)
(IBD) refers to two chronic diseases that cause
inflammation of the intestines ulcerative
colitis and Crohn's disease. IBD IS A
DISEASE. Ulcerative colitis is an inflammatory
disease of the large Intestine. The inner lining
or mucosa of the intestine becomes inflamed and
develops ulcers. Ulcerative colitis is often the
most severe in the rectal area, which can cause
frequent diarrhea. Mucus and blood often appear
in the stool. Crohn's disease most commonly
affects the last part of the terminal ileum and
parts of the large intestine but it can attack
any part of the digestive tract. Crohn's disease
causes inflammation that extends much deeper
into the layers of the intestinal wall than
ulcerative colitis does.
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Symptoms of IBD The most common symptoms are
diarrhea and abdominal pain. Diarrhea can range
from mild to severe. If the diarrhea is extreme,
it can lead to dehydration, rapid heartbeat, and
a drop in blood pressure. And continued loss of
small amounts of blood in the stool can lead to
anemia. At times, IBD may associate to have
constipation. With Crohn's disease, this can
happen as a result of a partial obstruction in
the intestines. In ulcerative colitis,
constipation may be a symptom of proctitis
(inflammation of the rectum) Because of the
loss of fluid and nutrients from diarrhea and
chronic inflammation of the bowel, IBD patients
may also experience fever, fatigue, weight loss,
dehydration, and malnutrition. Treatments
anti-inflammatory drugs immunosuppressive
agents
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Herbal-Drug Interactions
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Case 1St. Johns wort
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St. Johns wort
Induction of Drug Metabolizing enzymes
Increased Metabolism of Oral contraceptivesImmun
osuppressant cyclosporinHIV protease inhibitor
indinavir
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St. Johns wort
?
Induction of Drug Metabolizing enzymes
Increased Metabolism of Oral contraceptivesImmun
osuppressant cyclosporinHIV protease inhibitor
indinavir
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Nuclear Hormone Receptor
DNA
LIGAND
N
C
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PXR (pregnane X receptor)
DNA
LIGAND
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Case 2Chinese herbs
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Traditional Chinese Medicines Wu Wei Zi and Gan
Cao Activate PXR and Increase Warfarin Clearance
in Rats (Mu et al., J Pharmacol Exp Ther, in
press)
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Wu Wei Zi (Five-Taste Seed, Schisandra Chinensis
Baill,)
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Constituent Chemicals of WWZ Activate PXR

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WWZ and GC Increase Warfarin Clearance In Rats

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