1. Antiemetic agents
Domina Petric, MD

2. Introduction Causes of nausea and vomiting:
adverse effects from medicinations
systemic disorders or infections
pregnancy
vestibular dysfunction
central nervous system infection or increased intracranial pressure
peritonitis
hepatobiliary disorders
radiation or chemotherapy
gastrointestinal obstruction
dysmotility, infections

3. Pathophysiology
The brainstem ˝vomiting center˝ is loosely organized neuronal region within the lateral medullary reticular formation.
It coordinates the complex act of vomiting through interactions with cranial nerves VIII and X, and neural networks in the nucleus tractus solitarius, that control respiratory, salivatory and vasomotor centers.
High concentrations of muscarinic M1, histamine H1, neurokinin 1 (NK1) and serotonin 5-HT3 receptors are present in the vomiting center.

4. Pathophysiology
Important sources of afferent input to the vomiting center are:
chemoreceptor trigger zone
vestibular system
vagal and spinal afferent nerves from the GI tract
central nervous system

5. Chemoreceptor trigger zone
It is also called area postrema.
It is located at the caudal end of the fourth ventricle.
It is outside the blood-brain barrier, but accessible to emetogenic stimuli in the blood and cerebrospinal fluid.

6. Source: Pinterest.com

7. Chemoreceptor trigger zone
It is rich in dopamine D2 receptors and opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors.

8. The vestibular system
It is important in motion sikness via cranial nerve VIII.
It is rich in muscarinic M1 and histamine H1 receptors.

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10. Vagal and spinal nerves
Vagal ans spinal afferent nerves from the gastrointestinal tract are rich in 5-HT3 receptors.
Irritation of the GI mucosa by chemotherapy, radiation therapy, distention or acute infectious gastroenteritis leads to release of mucosal serotonin.

11. Vagal and spinal nerves
Mucosal serotonin activates serotonin receptors.
Activation of receptors stimulates vagal afferent input to the vomiting center and chemoreceptor trigger zone.

12. CNS
The central nervous system plays a role in vomiting due to psychiatric disorders, stress and anticipatory vomiting prior to cancer chemotherapy.

13. Serotonin 5-ht3 antagonists

14. Pharmacology Selective
5-HT3 receptor antagonists have potent antiemetic properties that are mediated through:
central 5-HT3 receptors blockade in the vomiting center
chemoreceptor trigger zone
blockade of peripheral 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves
PARTIALLY
MAINLY

15. Pharmacology
The antiemetic action of these agents is restricted to emesis atributable to vagal stimulation (postoperative) and chemotherapy.
Other emetic stimuli (motion sikness) are poorly controlled.

16. Pharmacology
Ondansetron, granisetron and dolasetron have a serum half-life of 4-9 hours so they may be administered once daily by oral or intravenous routes.
Palonosetron (iv. agent) has greater affinity for the 5-HT3 receptor and a long serum half-life of 40 hours.

17. Pharmacology
All 4 drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion.
Dose reduction is not required in geriatric patients or patients with renal insufficiency.

18. Pharmacology
Dose reduction of ondansetron is necessary for the patients with hepatic insufficiency.
5-HT3 receptor antagonists do not inhibit dopamine and muscarinic receptors.
They do not have effects on esophageal or gastric motility, but may slow colonic transit.

19. Clinical uses Indications are:
chemotherapy-induced nausea and vomiting
postoperative and postradiation nausea and vomiting

20. Chemotherapy
5-HT3 receptor antagonists are the primary agents for the prevention of acute chemotherapy-induced nausea and vomiting.
The drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy.

21. Chemotherapy
Iv. doses are:
ondansetron 8 mg
granisetron 1 mg
dolasetron 100 mg
palonosetron 0,25 mg

22. Chemotherapy Oral doses (1 hour before chemotherapy):
ondansetron 8 mg twice daily or 24 mg once daily
granisetron 2 mg
dolasetron 100 mg

23. Chemotherapy
Efficacy is enhanced by combination therapy with a corticosteroid (dexamethasone) and NK1 receptor antagonist.

24. Postoperative, postradiation
These agents are used to prevent and treat postoperative nausea and vomiting.
They are also effective in the prevention and treatment of nausea and vomiting in patients undergoing radiation therapy to the whole body or abdomen.

25. Adverse effects Well-tolerated agents with excelent safety profiles.
Most commonly reported are headache, dizziness and constipation.
Prolongation of the QT interval: all four agents, most pronounced with dolasetron.

26. Adverse effects
Dolasetron should not be administered to patients with prolonged QT interval or in conjunction with other medicinations that may prolong the QT interval.

27. Drug interactions There are no significant drug interactions.
All four agents undergo some metabolism by hepatic cytochrome P450 system.
Other drugs may reduce hepatic clearance of the 5-HT3 receptor antagonists, altering their half-life.

28. corticosteroids

29. Corticosteroids
Corticosteroids (dexamethasone, methylprednisolone) have antiemetic properties.
These agents 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.

30. Corticosteroids
Dexamethasone 8-20 mg iv. before chemotherapy, followed by 8 mg/d orally for 2-4 days, is commonly administered.

31. Neurokinin receptor antagonists (NK1-receptor antagonists)

32. NK1-receptor antagonists
Neurokinin 1 receptor antagonists have antiemetic properties that are mediated through central blockade in the area postrema.
Aprepitant is an oral formulation, highly selective and crosses the blood-brain barrier.

33. NK1-receptor antagonists
Aprepitant occupies brain NK1-receptors.
It has no affinity for setononin, dopamine or corticosteroid receptors.
Fosaprepitant is an iv. formulation.
It is converted within 30 minutes after infusion to aprepitant.

34. Pharmacokinetics The oral bioavailability of aprepitant is 65%.
The serum half-life is 12 hours.
Aprepitant is metabolized by the liver, primarily by the CYP3A4 pathway.

35. Clinical use
Aprepitant is used in combination with 5-HT3 receptor antagonists and corticosteroids for the prevention of acute and delayed nausea and vomiting from highly emetogenic chemotherapeutic regimens.

36. Clinical use 3-days dose regime:
oral aprepitant 125 mg or iv. fosaprepitant 115 mg, given 1 hour before chemotherapy
followed by oral aprepitant in the dose of 80 mg/d for 2 days after chemotherapy

37. Aprepitant may be associated with fatigue, dizziness and diarrhea.
Adverse effects
Aprepitant may be associated with fatigue, dizziness and diarrhea.

38. Drug interactions
Aprepitant is metabolized by CYP3A4 and may inhibit the metabolism of other drugs metabolized by the same enzyme:
docetaxel, paclitaxel, etoposide
irinotecan, imatinib, vinblastine
vincristine

39. Drug interactions
Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant plasma levels:
ketoconazole, ciprofloxacin
clarithromycin, nefazodone
ritonavir, nelfinavir
verapamil, quinidine

40. Drug interactions
Aprepitant decreases the international normalized ratio (INR) in patients taking warfarin.

41. Phenothiazines, butyrophenones

42. Phenothiazines
Antipsychotics that can be used for their potent antiemetic and sedative properties.
The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors.

43. Phenothiazines
Sedative properties are due to their antihistamine activity.
The agents most commonly used as antiemetics are prochlorperazine, promethazine and thiethylperazine.

44. Butyrophenones
Antipsychotics that have antiemetic properties due to their central dopaminergic blockade.
Droperidol can be given by intramuscular or intravenous injection.
In antiemetic doses, droperidol is extremely sedating.

45. Butyrophenones It is not used as much as in the past.
Droperidol may prolong the QT interval, rarely resulting in fatal episodes of ventricular tachycardia (torsades de pointes).
It should not be used in patients with QT prolongation.

46. Substituted benzamides

47. Substituted benzamides
Those are metoclopramide and trimethobenzamide.
Their primary mechanism of antiemetic action is dopamine-receptor blockade.
Trimethobenzamide has also weak antihistaminic activity.

48. Substituted benzamides
Metoclopramide is used for prevention and treatment of nausea and vomiting mg orally or iv. every 6 hours.
The usual dose of trimethobenzamide is 300 mg orally or 200 mg im. injection.

49. Substituted benzamides
The principal adverse effects are extrapyramidal: restlesness, dystonias and parkinsonian symptoms.

50. Anticholinergics, antihistamines

51. Anticholinergics
As single agents, these drugs have weak antiemetic activity.
Despite that, they are particularly useful for the prevention or treatment of motion sickness.
Adverse effects: dizziness, sedation, confusion, dry mouth, cycloplegia, urinary retention.

52. H1 antihistamines
Diphenhydramine and its salt, dimenhydrinate, are first generation histamine H1 antagonists that have significant anticholinergic properties.
Diphenhydramine has sedating properties and it is commonly used together with other antiemetics for treatment of emesis due to chemotherapy.

53. H1 antihistamines
Meclizine has minimal anticholinergic properties and causes less sedation.
It is used for the prevention of motion sickness and the treatment of vertigo due to labyrinth dysfunction.

54. H1 antihistamines
Hyoscine (scopolamine) is a prototypic muscarinic receptor antagonist.
It is one of the best agents for the prevention of motion sickness.
It has a very high incidence of anticholinergic effects when given orally or parenterally.

55. Hyoscine is better tolerated as a transdermal patch.
H1 antihistamines
Hyoscine is better tolerated as a transdermal patch.

56. benzodiazepines

57. Benzodiazepines
Lorazepam and diazepam are used before the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety.

58. cannabinoids

59. Cannabinoids
Dronabinol is ∆9-tetrahydrocannabinol (THC), the major psychoactive chemical in marijuana.
After oral ingestion, the drug is almost completely absorbed, but undergoes significant first-pass hepatic metabolism.

60. Cannabinoids
Metabolites of dronabinol are excreted slowly over days to weeks in the feces and urine.
Dronabinol is used medically as an appetite stimulant and as an antiemetic.

61. Cannabinoids
Combination therapy of dronabinol and phenothiazines provides synergistic antiemetic action and appears to attenuate the adverse effects of both agents.
Dosage is 5 mg/m2 just prior to chemotherapy and every 2-4 hours as needed.

62. Cannabinoids
Adverse effects: euphoria, dysphoria, sedation, hallucinations, dry mouth and increased appetite.
It has some autonomic effects that may result in tachycardia, conjunctival injection and orthostatic hypotension.

63. Cannabinoids
Dronabinol has no significant drug-drug interactions, but may potentiate the clinical effects of other psychoactive agents.
Nabilone is a closely related THC analog.

64. Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.
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