Dolasetron is an indole derivative and a potent serotonin 5-HT3 receptor antagonist with the anti-emetic property. Dolasetron blocks the activity of serotonin released from the enterochromaffin cells of the small intestine by selectively inhibiting and inactivating 5-HT3 receptors located on the nerve terminals of the vagus nerve in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. This results in suppression of signaling to trigger chemo- and radiotherapy-induced nausea and vomiting.
Dolasetron is an antinauseant and antiemetic agent indicated for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy and for the prevention of postoperative nausea and vomiting. Dolasetron is a highly specific and selective serotonin 5-HT3 receptor antagonist. This drug is not shown to have activity at other known serotonin receptors and has low affinity for dopamine receptors.
Mechanism of Action of Dolasetron
Dolasetron is a selective serotonin 5-HT3 receptor antagonist. In vivo, the drug is rapidly converted into its major active metabolite, hydrodolasetron, which seems to be largely responsible for the drug’s pharmacological activity. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting.
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Dolasetron, and its active metabolite hydrodolasetron, are highly specific and selective antagonist of serotonin subtype 3 (5-HT3) receptors. 5-HT3 receptors are present peripherally on vagal nerve terminals and centrally in the area postrema of the brain. Chemotherapeutic medications appear to precipitate release of serotonin from the enterochromaffin cells of the small intestine, which activates 5-HT3 receptors on vagal afferents to initiate the vomiting reflex. Dolasetron has not been shown to have activity at other known serotonin receptors and has low affinity for dopamine receptors.
Indications of Dolasetron
- Nausea/Vomiting, Chemotherapy Induced
- Nausea/Vomiting, Postoperative
- Prophylaxis against postoperative nausea and vomiting
- Post-operative and post-radiation nausea and vomiting
- Is a possible therapy for nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis
- Unlike most other 5HT3 antagonists, data is lacking for use of dolasetron with aprepitant in chemotherapy-induced nausea and vomiting (CINV).
- It is also sometimes used as an antiemetic (anti-vomiting medication) in veterinary medicine for dogs and cats.
- Uremic Pruritus
- Radiation-induced nausea and vomiting
- Severe Hyperemesis gravidarum
- Alcohol Dependence
- Cyclic vomiting syndrome.
- Gastroparesis
- Functional dyspepsia
- For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including initial and repeat courses of chemotherapy. Also used for the prevention of postoperative nausea and vomiting. This drug can be used intravenously for the treatment of postoperative nausea and vomiting.
Therapeutic Indications
- Dolasetron injection is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Dolasetrontablets are indicated for the prevention of nausea and vomiting associated with moderate-emetogenic cancer chemotherapy, including initial and repeat courses.
- Dolasetron injection and tablets are indicated for the prevention of postoperative nausea and/or vomiting. Routine prophylaxis is not recommended when there is little risk of nausea and/or vomiting developing postoperatively, except in patients in whom nausea and/or vomiting must be avoided.
- Dolasetron injection is indicated for the treatment of postoperative nausea and/or vomiting.
- Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary. Monitor for shock and treat if necessary. Anticipate seizures and treat if necessary. For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport. Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Cover skin burns with dry sterile dressings after decontamination.
- Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema. Consider administering a beta agonist such as albuterol for severe bronchospasm. Monitor cardiac rhythm and treat arrhythmias as necessary. Start IV administration of D5W /SRP: “To keep open”, minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer’s if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload. Treat seizures with diazepam or lorazepam. Use proparacaine hydrochloride to assist eye irrigation.
- Immediate first aid: Ensure that adequate decontamination has been carried out. If the patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention
Contra-Indications of Dolasetron
- Low amount of magnesium in the blood
- Low amount of potassium in the blood
- Neuroleptic Malignant Syndrome
- Serotonin syndrome – adverse drug interaction
- Heart Muscle Disease caused by the Medication Doxorubicin
- Complete Heart Block
- Very Rapid Heartbeat – Torsades de Pointes
- Slow Heartbeat
- Prolonged QT interval on EKG
- Chronic heart failure
- Abnormal EKG with QT changes from Birth
- kidney disease with a reduction in kidney function
- Allergies to Serotonin 5HT-3 Antagonists
Dosage of Dolasetron
Strengths: 50 mg; 100 mg, 20 mg/mL;
Postoperative Nausea/Vomiting
Recommended dose: 12.5 mg IV approximately 15 minutes before the cessation of anesthesia or as soon as nausea and vomiting presents
2 to 16 years
- Recommended dose: 0.35 mg/kg IV approximately 15 minutes before the cessation of anesthesia or as soon as nausea and vomiting presents
- Maximum dose: 12.5 mg
- Alternative dose: 1.2 mg/kg (of the IV injection solution) given orally within 2 hours before surgery, up to a maximum dose of 100 mg
Chemotherapy Induced Nausea/Vomiting
2 to 16 years
- Recommended dose: 1.8 mg/kg orally within 1 hour before chemotherapy
- Maximum dose: 100 mg
Side Effects of Dolasetron
More common
- Diarrhea
- muscle twitching
- weakness
- Any signs of infection, or a skin rash.
- Stomach pain, especially if it comes along with fever and diarrhea or constipation
- Yellowing of the skin or eyes
- Loss of appetite
- Constipation
- Chest pain or discomfort
- lightheadedness, dizziness, or fainting
- slow or irregular heartbeat
- unusual tiredness or weakness
- the decrease in the amount of urine
- fast, pounding, or irregular heartbeat or pulse
- false sense of well-being
- increased watering of mouth
- lightheadedness
- constipation;
- vision changes;
- breast swelling (in men or women); or
- decreased sex drive, impotence, or difficulty having an orgasm.
- blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- restless muscle movements in your eyes, tongue, jaw, or neck;
Common
- Drowsiness and lightheadedness the day after taking the medicine.
- Confusion.
- Numbed emotions.
- Visual disturbances such as blurred vision or double vision.
- Shaky movements and unsteady walk (ataxia).
- Muscle weakness.
- Dizziness.
- A headache.
- Skin rashes.
- Disturbances of the gut such as diarrhea, constipation, nausea, vomiting or abdominal pain.
- Changes in sex drive.
- Low blood pressure (hypotension).
- Blood disorders.
- Unexpected aggression, restlessness or irritability.
- Nightmares or hallucinations
Rare
- agitation
- anxiety
- behavioral changes, including aggressiveness, angry outbursts,
- confusion
- increased trouble sleeping
- muscle spasms
- shortness of breath
- difficult or labored breathing
- difficulty with swallowing
- dizziness, faintness, or lightheadedness
- frequent urination
- hallucinations
- bloating or swelling of the face, arms, hands, lower legs, or feet
- blurred vision
- hives or welts, itching, or skin rash
- the increased volume of pale, dilute urine
Drug Interactions of Dolasetron
Dolasetron may interact with following drugs, supplements, & may change the efficacy of drugs
- antipsychotics (e.g. haloperidol, ziprasidone)
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- beta-agonists (e.g., formoterol, salmeterol)
- cimetidine
- corticosteroids (high dose; e.g., hydrocortisone, methylprednisolone, prednisone)
- diuretics (water pills; e.g., furosemide, hydrochlorothiazide, indapamide)
- domperidone
- famotidine
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- other serotonin receptor antagonists (e.g., granisetron, ondansetron)
- quinolone antibiotics (e.g., ciprofloxacin, levofloxacin)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine)
- sotalol
- tapentadol
- tramadol
- tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline)
- trimethoprim
- tyrosine kinase inhibitors (e.g., nilotinib, sunitinib)
Pregnancy & Lactation of Dolasetron
Dolasetron has been classified as FDA pregnancy risk category B. Animal studies have not revealed any teratogenic effects associated with dolasetron. There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Other alternatives exist
According to the manufacturer, it is not known whether dolasetron is excreted in human milk. However, because of its low molecular weight, transfer into breast milk should be expected. Caution should be exercised when administering dolasetron to a breastfeeding woman. Consider the benefits of breastfeeding
Dolasetron has been used in children age 2 to 16 years and has, overall, has been well tolerated. However, dolasetron should be used cautiously in pediatric patients who have preexisting or are at risk of developing, prolonged cardiac conduction intervals, particularly QTc.
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