Nausea and Vomiting Part1 dr..lamia nagy

Nausea and Vomiting
Dr. Lamiaa Nagy
Lecturer of clinical pharmacy
Faculty of Pharmacy
October 6 University

 Nausea is an unpleasant sensation that may precedes vomiting.
 Retching is an involuntary contraction of the diaphragm and
abdominal muscles associated with vomiting without the
expulsion of vomitus.
 Vomiting (emesis): is the outward expulsion of gastric contents
through the esophagus and pharynx to the mouth.

Etiology of nausea and vomiting
 Nausea and vomiting are symptoms with various etiologies such
as gastrointestinal, cardiovascular, neurological, metabolic and
endocrinal disorders.
 Vomiting can be a sign of serious conditions such as
concussions, brain tumors, meningitis, intestinal obstruction and
appendicitis.
 Chemotherapeutic agents
 Radiotherapy
 Postoperative nausea and vomiting
 Some medications such as digoxin and theophylline.

Etiology of nausea and vomiting
continued…
 Pregnancy:
o nausea occurs in 50-90% of pregnancies while vomiting occurs in
22-55%.
o Hyperemesis gravidarum -which is a life-threatening condition to
the mother and her fetus due to recurrent severe vomiting - occurs
in up to 2% of pregnancies. It is characterized by fluid and
electrolyte imbalance.
 Ethanol and other toxic agents.
 Oral contraceptives and other hormonal therapy.
 Motion sickness or seasickness.

Pathophysiology of nausea and vomiting
continued

 Vomiting is a complex reflex which results from stimulation of the
central vomiting center (VC) located in the medulla.
 Vomiting center has five primary afferents which send impulses
to the salivation center, abdominal muscles, respiratory center
and cranial nerves to produce vomiting.
 The five primary afferents are chemoreceptor trigger zone (CTZ)
in the area postrema of the fourth ventricle of the brain,
pharynx, vestibular apparatus, visceral afferents from GI tract
and cerebral cortex.
 These afferents have many neurotransmitter receptors.
 Activation of these receptors leads to vomiting.

continued
 CTZ is located outside the blood brain barrier and is exposed to
cerebrospinal fluid emetogenic chemicals and blood. So it is
stimulated by uremia, acidosis and other circulating toxins.
 The CTZ has many receptors including dopamine (D2) receptors,
neurokinin-1 (NK1) receptors and serotonin (5HT3) receptors.
 Visceral vagal nerve fibers are rich in 5HT3 receptors.
 Vestibular system, which is located in the inner ear, is rich in
histamine (H1) receptors and muscarinic receptors, and upon
stimulation, it causes motion sickness.
 The cerebral cortical afferents with information such as stress,
anticipation and psychiatric disorders are involved in
anticipatory nausea and vomiting.

continued
 Antiemetics block one or more of these afferents to reduce the
activity of the vomiting center.

Classification of nausea and vomiting
 Simple nausea and vomiting: relieved by minimal therapy or self-
limiting.
 Complex nausea and vomiting:
 Require more aggressive therapy due to risk of dehydration and
electrolyte imbalance.
 Excessive vomiting leads to dehydration (treated by fluid and
electrolyte intake), hypokalemia (give potassium supplement),
sodium and chloride loss (give saline), alkalosis (give NH4Cl due to
HCl loss) and weight loss.
 Signs of dehydration are dry mouth and lips sunken eyes, dry skin,
tachycardia, elevated temperature, rapid breathing and
decreased urination.

Management of vomiting
The goal of treatment is to relieve the symptoms regardless of its
etiology and prevent complications such as dehydration or
malnutrition.
 Non pharmacological therapy
 Control vomiting regardless of its cause
 Identify and treat the cause
 Adequate hydration and electrolyte replacement (gradual intake)
 Avoid large meals, spicy or fatty food
 High-protein meals
 Correction of hypokalemia, alkalosis
 Administration of rehydrating solutions when vomiting lasts for > 20 hours.

Management of vomiting
continued…
 Pharmacological therapy
Include usage of suitable antiemetic drugs. It is better to use
combinations of different drugs acting on different receptors.

Antiemetic drugs
1) Dopamine D2 receptor antagonists
2) Serotonin receptor antagonists (setrons)
3) Neurokinin (NK1) receptor antagonist [pitants] [substance P
receptor antagonist]
4) Anticholinergic (muscarinic) antagonists
5) Antihistaminics (histamine H1 receptor antagonist)
6) Corticosteroids (steroid receptor antagonists)
7) Cannabinoids
8) Benzodiazepines
9) Atypical antipsychotic (olanzapine)

Abbreviations
 PONV = Postoperative nausea and vomiting.
 CINV = Chemotherapy-induced nausea and vomiting.
 RINV = Radiotherapy-induced nausea and vomiting.
 PANV = Pregnancy-associated N & V nausea

Dopamine D2 receptor antagonists
A. Phenothiazines
• Include chlorpromazine, prochlorperazine, and methotrimeprazine.
• Has antihistaminic/antimuscarinic activity
• Used for PONV, mild CINV, GI induced emesis.
• Adverse effects: dystonia (involuntary muscle contraction), akathisia
(feeling of inner restlessness), tardive dyskinesia (movement disorders),
hypotension, drowsiness.
B. Benzamides
• Include metoclopramide and dompridone.
• Used for CINV, GI induced emesis.
• Side effects: dystonia, akathisia, tardive dyskinesia
• Dystonia rarely occurs with dompridone (as it poorly penetrates BBB)

Dopamine D2 receptor antagonists
continued…
C. Butyrophenones:
• Include haloperidol.
• Used for PONV
• Has long half life (18 hours)
• Main side effects are dyskinesia and sedation

Serotonin receptor antagonists (setrons)
 Indicated mainly in CINV, PONV, RINV
 Include Ondansetron, Granisetron, Dolasetron and Palonosetron.
 They block serotonin receptors peripherally in the GIT and centrally in
the medulla.
 Side effects are headache, dizziness, agitation, diarrhea, constipation
and QT prolongation, so, ECG monitoring is recommended specially
for patients receiving ondansetron or dolasetron.
 Palonosetron is the first 5HT3 antagonist used for acute and delayed
CINV.
 Palonosetron is used as a component of NEPA and is preferred due to
its long half life (approx. 40 hours) and minimal toxicity profile.

Neurokinin (NK1) receptor antagonists [pitants]
[substance P receptor antagonists]
 Include aprepitant, fosaprepitant, netupitant and rolapitant.
 They block neurokinin NK1 subtype of substance P receptors
 Used for acute and delayed nausea and vomiting
 Aprepitant was the first NK1 receptor antagonist and is used for preventing
acute and delayed CINV when used with 5HT3 antagonist and
corticosteroid
 Netupitant Is the second NK1 receptor antagonist and is available only in
an oral fixed-dose combination (NEPA) with palonosetron for preventing
acute and delayed CINV following moderately or highly emetogenic
chemotherapy (e.g. cisplatin or combined anthracycline plus
cyclophosphamide regimens.
 Useful for patients receiving multiple cycles of high dose chemotherapy
(e.g. cisplatin)

Anticholinergic (muscarinic) antagonists
 Include hyoscine (scopolamine)
 Used for treatment of motion sickness
 The most common side effects are dry mouth, blurred vision,
constipation, drowsiness, urinary retention.

Antihistaminics
(histamine H1 receptor antagonists)
 Include cyclizine, promethazine, dimenhydrinate,
diphenhydramine, meclizine and cinnarizine.
 Used for motion sickness, PONV, hyperemesis gravidarum.
 Side effects are sedation, dry mouth, constipation.

Corticosteroids (steroid receptor antagonists)
 Examples: dexamethasone and methylprednisolone
 Used for PONV, CINV
 Side effects are insomnia, mode change, increased appetite
 Act by inhibiting prostaglandin synthesis in the cortex

Cannabinoids
 Examples: oral dronabinol and nabilone
 Used to treat refractory CINV
 Act by stimulating CB1 subtype of cannabinoid receptors on
neurons in and around the vomiting center.
 Side effects: sedation, euphoria, depression, hypotension,
ataxia, dizziness and vision difficulties.

Benzodiazepines
 Short acting benzodiazepines especially lorazepam and
midazolam act as adjuvants to antiemetic drugs.
 Used to treat anticipatory CINV by causing sedation and reduce
anxiety
 Adverse effects are amnesia, sedation and hypotension.

Atypical antipsychotic (olanzapine)
 Alternative agents for preventing nausea and vomiting in highly
emetogenic agent and useful in breakthrough CINV.
 Act by blocking multiple neurotransmitters including dopamine,
serotonin, cholinergic and histaminic receptors.
 Side effects are sedation, dry mouth, increased appetite, weight
gain, dizziness and GIT prolongation

Chemotherapy-induced nausea and vomiting
CINV
 Types of CINV
 Acute CINV:
 Occurs within the first 24 hours of chemotherapy
 Mediated by serotonin antagonist and substance P antagonist
 Delayed CINV:
 Occurs between 1-5 days after chemotherapy administration.
 Mediated by substance P antagonists.
 Occurs with high dose cisplatin and cyclophosphamide based regimen.
 Anticipatory CINV:
 Occurs before treatment and developed as conditioned response when
patient has experienced CINV from previous treatment.
 Related to bad memory and treated by lorazepam.

CINV continued…
 Breakthrough CINV:
 Occurs within 5 days of chemotherapy administration when patient
experience nausea and vomiting despite the use of prophylactic antiemetic
drugs.
 Need additional rescue medication with additional antiemetics (e.g.
metoclopramide)
 Refractory CINV:
 Occurs after chemotherapy in subsequent cycles and failure of prophylactic
agent in earlier cycles.

CINV continued…
Risk factors for CINV
 Patient age (<50 years)
 Female gender
 History of motion sickness
 History of nausea and vomiting during pregnancy
 Poor control of nausea and vomiting in previous cycles
 History of chronic alcoholism

Emetogenicity of chemotherapeutic agents
Chemotherapeutic agents are divided into four
emetogenic levels according to ASCO guidelines:
Highly emetogenic therapy (HEC) >90% incidence of
CINV
Moderately emetogenic therapy (MEC) 30-90%
incidence of CINV
Low emetogenic therapy (LEC) 10-30% incidence of
CINV
Minimal emetogenic therapy (VLEC) <10% incidence
of CINV

Nausea and Vomiting Part1 dr..lamia nagy

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