CHEMOTHERAPY INDUCED NAUSEA AND VOMITING

- Motion Sickness
- Pregnancy
- Hepatitis

Variety of Conditions where Nausea and Vomiting Occurs

- Carmustine
- Cisplatin
- Dacarbazine
- Streptozocin

CHEMOTHERAPY DRUG DRUG THAT CAUSE N&V
Strong

Asparaginase
Azacitidine
Carboplatin
Cyclophosphamide
Doxorubicin
Mitomycin

CHEMOTHERAPY DRUG DRUG THAT CAUSE N&V
Moderate

- Bleomycin
- Etoposide
- Fluorouracil
- Methotrexate
- Vincristine

CHEMOTHERAPY DRUG DRUG THAT CAUSE N&V
Mild

- Chemotherapy Drug
- Dose
- Route
- Schedule of Administration
- Patient Variables

Several factors influence the incidence and severity of chemotherapy-induced nausea and vomiting (CINV):

- Young Patients
- Women

Which patient demographics are more susceptible to CINV?

Vomiting before Chemotherapy

What is anticipatory vomiting in chemotherapy patients?

- Dehydration
- Profound Metabolic Imbalances
- Nutrient Depletion

What are the consequences of uncontrolled chemotherapy-induced vomiting?

- Chemoreceptor Trigger Zone (CTZ)
- Vomiting Center

What are the two key brainstem sites involved in the vomiting reflex pathway?

Chemoreceptor Trigger Zone (CTZ)

Brainstem Sites involved in the Vomiting Reflex Pathway
- Is located in the area postrema.
- It is outside the blood–brain barrier.
- Thus, it can respond directly to chemical stimuli in the blood or cerebrospinal fluid.

Postrema

A circumventricular structure at the caudal end of the fourth ventricle.

Vomiting Center

Brainstem Sites involved in the Vomiting Reflex Pathway
- Located in the lateral reticular formation of the medulla.
- Coordinates the motor mechanisms of vomiting.
- Responds to afferent input from the vestibular system, the periphery (pharynx and GI tract), and higher brainstem and cortical structures.

Vestibular System

Functions mainly in motion sickness.

Chemotherapeutic Drugs

- Can directly activate the medullary CTZ or vomiting center.
- Can also act peripherally by causing cell damage in the GI tract and by releasing serotonin from the enterochromaffin cells of the small intestine.

- Dopamine Receptor Type 2
- Serotonin Type 3 (5-HT3)

Which neuroreceptors are critical in the emetic actions of chemotherapeutic agents?

By activating higher brain centers.

How can the color or smell of chemotherapeutic drugs trigger emesis?

Serotonin

Activates 5-HT3 receptors on vagal and splanchnic afferent fibers, which then carry sensory signals to the medulla, leading to the emetic response.

Due to the complexity of the mechanisms involved in emesis.

Why do antiemetic drugs come in a variety of classes?

Scopolamine

USEFUL IN MOTION SICKNESS
Muscarinic Receptor Antagonist

- Dimenhydrinate
- Meclizine
- Cyclizine

USEFUL IN MOTION SICKNESS
H1- Receptor Antagonist

- Muscarinic Receptor Antagonist
- H1- Receptor Antagonist

Useful in motion sickness but are ineffective against substances that act directly on the CTZ.

- Phenothiazines
- 5-HT3 Receptor Blockers
- Substituted Benzamides
- Butyrophenones
- Benzodiazepines
- Corticosteroids
- Substance P/ Neurokinin-1 Receptor Blocker
- Combination Therapy

The major categories of drugs used to control CINV include the following:

Phenothiazines

- The first group of drugs shown to be effective antiemetic agents.
- Act by blocking dopamine receptors.

Prochlorperazine

- Is effective against low or moderately emetogenic chemotherapeutic agents (for example, fluorouracil and doxorubicin).

- Fluorouracil
- Doxorubicin

Prochlorperazine is effective against low or moderately emetogenic chemotherapeutic agents such as?

Dose- Limiting

What limits (side effects) the use of higher doses of prochlorperazine to improve antiemetic activity?

- Ondansetron
- Granisteron
- Palonosetron
- Dolasetron

Examples of 5-HT3 Receptor Blockers:

5-HT3 Receptor Blockers

These agents selectively block 5-HT3 receptors in the periphery (visceral vagal afferent fibers) and in the brain (CTZ).

5-HT3 Receptor Blockers

- This class of agents is important in treating emesis linked with chemotherapy, largely because of their longer duration of action and superior efficacy.
- These drugs can be administered as a single dose prior to chemotherapy (intravenously or orally) and are efficacious against all grades of emetogenic therapy

- Ondansetron
- Granisteron

Prevent emesis in 50% to 60% of cisplatin-treated patients

5-HT3 Receptor Blockers

- These agents are also useful in the management of postoperative nausea and vomiting.
- Extensively metabolized by the liver.
- Elimination is through the urine.

Ondansetron

Examples of 5-HT3 Receptor Blockers
Requires dosage adjustments in hepatic insufficiency.

Prolonged QTc Interval

What potential cardiovascular side effect is associated with high doses of dolasetron and ondansetron?

Dolasetron

Examples of 5-HT3 Receptor Blockers
Is no longer approved for CINV prophylaxis.

Metoclopramide

Example of Substituted Benzamides

Metoclopramide

- Is effective at high doses against the emetogenic cisplatin, preventing emesis in 30% to 40% of patients and reducing emesis in the majority of patients.
- Accomplishes this through inhibition of dopamine in the CTZ.

Metoclopramide

- Was previously used as a prokinetic drug for the treatment of GERD.
- However, due to the adverse effect profile and the availability of more effective drugs, such as PPIs, it should be reserved for patients with documented gastroparesis.

Antidopaminergic side effects, including extrapyramidal symptoms.

What limits the long-term high-dose use of metoclopramide?

- Droperidol
- Haloperidol

Examples of Butyrophenones

Butyrophenones

- Act by blocking dopamine receptors.
- Moderately effective antiemetics.

Droperidol

Examples of Butyrophenones
- Had been used most often for sedation in endoscopy and surgery, usually in combination with opioids or benzodiazepines.
- However, it may prolong the QTc interval and should be reserved for patients with inadequate response to other agents.

Haloperidol

Examples of Butyrophenones
- High dose of these was found to be nearly as effective as high-dose metoclopramide in preventing cisplatin-induced emesis.

Haloperidol Lactate

Examples of Butyrophenones
Is a short acting parenteral solution for intramuscular and intravenous administration.

Haloperidol Decanoate

Examples of Butyrophenones
Is a long acting intramuscular preparation.

- Lorazepam
- Alprazolam

Examples of Benzodiazepines
- Antiemetic potency is low.
- Their beneficial effects may be due to their sedative, anxiolytic, and amnesic properties.

Benzodiazepines

Useful in treating anticipatory vomiting.

Due to their sedative, anxiolytic, and amnesic properties.

Why are benzodiazepines useful in treating anticipatory vomiting?

Concomitant use of alcohol, due to additive CNS depressant effects.

What should be avoided when using benzodiazepines for antiemetic therapy?

- Dexamethasone
- Methylprednisolone

Examples of Corticosteroids
- Used alone, are effective against mildly to moderately emetogenic chemotherapy.
- Most frequently, however, they are used in combination with other agents.

Corticosteroids

Their antiemetic mechanism is not known, but it may involve blockade of prostaglandins.

Aprepitant

- Targets the neurokinin receptor in the brain and blocks the actions of the natural substance.
- Is indicated only for highly or moderately emetogenic chemotherapy regimens.

Aprepitant

- It is usually administered orally with dexamethasone and a 5-HT3 antagonist.
- It undergoes extensive metabolism, primarily by CYP3A4, and it may affect the metabolism of other drugs that are metabolized by this enzyme, such as warfarin and oral contraceptives.

- Dexamethasone
- 5-HT3 Antagonist

Aprepitant us usually administered orally with?

- Warfarin
- Oral Contraceptives

Aprepitant may affect the metabolism of drugs metabolized by CYP3A4, such as?

To increase antiemetic activity or decrease toxicity.

Why are antiemetic drugs often combined?

- High-Dose Metoclopramide
- 5-HT3 Antagonist
- Phenothiazine
- Butyrophenone
- Benzodiazepine

With which antiemetic agents is dexamethasone (corticosteroids) commonly combined to increase antiemetic activity?

- Antihistamine (Diphenhydramine)
- High Dose Metoclopramide

DRUG COMBINATION
- To reduce extrapyramidal reactions.

- Antihistamine (Diphenhydramine)
- Corticosteroids

DRUG COMBINATION
- To counter metoclopramide-induced diarrhea.