CB Chapter 20

• Chemotherapy

• Radiation therapy

• Oral contraceptives

• Hormone therapy

• Opioids

Nausea and vomiting are symptoms that can be due to many different causes such as GI, cardiac, neurologic, and endocrine disorders

• Whay are some agents that induce n&v

• Diaphoresis

• Disinterest in surroundings

• Pallor

• Faintness

• Salivation

Patients with nausea often complain of autonomic symptoms such as

chemoreceptor trigger zone (CTZ)

— located outside the blood–brain barrier, is exposed to cerebrospinal fluid and blood. Therefore, it is easily stimulated by uremia, acidosis, and circulating toxins such as chemotherapeutic agents.

• Female sex

• History of motion sickness or PONV

• Nonsmokingstatus

• Opioidsp use postoperation

Postoperative nausea and vomiting (PONV) occurs in 30% of surgical patients overall and in up to 70% of high-risk patients.5,6 Risk factors for PONV include:

digoxin and theophylline

Some medications, such as — and —, cause nausea and vomiting in a dose-related fashion, which may indicate excessive drug concentrations.

hyperemesis gravidarum

Nausea and vomiting of pregnancy (NVP) affects 70% to 85% of pregnant women, especially early in pregnancy. In up to 2% of pregnancies, this can lead to —, a potentially life-threatening condition of prolonged nausea, vomiting, and resultant malnutrition.9

• Nausea

• Retching

• Vomiting

Nausea and vomiting consist of three stages:

Nausea

It is the subjective feeling of a need to vomit.1,4 It is often accompanied by autonomic symptoms of pallor, tachycardia, diaphoresis, and salivation

Retching

It follows nausea and consists of contractions of the diaphragm, abdominal wall, and chest wall and spasmodic breathing against a closed glottis. It can occur without vomiting and produce the pressure gradient needed for vomiting, although no gastric contents are expelled.

Vomiting/Emesis

It is a reflexive, rapid, and forceful oral expulsion of upper GI contents due to sustained contractions in the abdominal and thoracic musculature

Chemoreceptor trigger zone (CTZ), the vestibular apparatus, visceral afferents from the GI tract, and the cerebral cortex.

Specific areas in the brain and GI tract are stimulated when the body is exposed to noxious stimuli or GI irritants:

central vomiting center

These in turn stimulate regions of the reticular areas of the medulla within the brain stem. This area is the —, which coordinates the impulses sent to the salivation and respiratory centers, and the pharyngeal, GI, and abdominal muscles that lead to vomiting

• 5-HT3

• NK-1

• D2

The CTZ has many receptors of:

Motion sickness

It is caused by stimulation of the vestibular system, rich in histaminic (H1 ) and muscarinic cholinergic receptors

Cerebral Cortex

It is affected by sensory input such as sights, smells, or emotions that can lead to vomiting. This area is involved in anticipatory nausea and vomiting associated with chemotherapy.

Simple N&V

It occurs occasionally and is either self-limiting or relieved by minimal therapy. It does not detrimentally affect hydration status, electrolyte balance, or weight.

Complex N&V

It requires more aggressive therapy because electrolyte imbalances, dehydration, and weight loss may occur.

• Eating small frequent meals

• Avoiding spicy or fatty foods

• Eating bland or dry food first thing in the morning

• Eating high protein snacks

Dietary management is important when treating NVP due to concern for teratogenic effects with drug therapies. Recommendations include:

Scopolamine

It blocks muscarinic receptors in the vestibular system, thereby halting signaling to the CNS. It is effective for preventing and treating motion sickness and has some efficacy in preventing PONV.

Scopolamine

It is available as an adhesive transdermal patch that is effective for up to 72 hours after application. Transdermal formulation should be applied 4 hours prior to motion sickness triggers and the evening before surgery if used to prevent PONV.

• It is associated with adverse anticholinergic effects such as sedation, visual disturbances, dry mouth, and dizziness.

Antihistamines

These are used to prevent and treat nausea and vomiting due to motion sickness, vertigo, or migraine headache. Their efficacy is presumably due to the high concentration of H1 and muscarinic cholinergic receptors within the vestibular system.

• Cetirizine

• Fexofenadine

What second-generation antihistamines without CNS depressant properties, were found to be ineffective for treating motion sickness, perhaps because they lack CNS effects.20

Phenothiazines (Promethazine, prochlorperazine, chlorpromazine)

Stimulation of D2 receptors in the CTZ leads to nausea and vomiting. These drugs act primarily via a central anti dopaminergic mechanism in the CTZ

Butyrophenone (Droperidol)

It is another centrally acting antidopaminergic agent effective for preventing PONV. It may also be used for treating CINV for patients who are intolerant to serotonin receptor antagonists and corticosteroids.3 Its adverse effects include sedation, agitation, and restlessness.

Butyrophenone (Droperidol)

IT carries a US FDA black box warning regarding the potential for QT interval prolongation and cardiac arrhythmias that may result in torsades de pointes and sudden cardiac death.

Butyrophenone (Haloperidol)

It is another butyrophenone with some antiemetic effects at low doses (0.5–2 mg). It has been explored as an alternative to droperidol.

• Metoclopramide

• Domperidone

They act as D2-receptor antagonists centrally in the CTZ and peripherally in the GI tract.1,28 They also display cholinergic activity, which increases lower esophageal sphincter tone and promotes gastric motility. Their antiemetic and prokinetic effects are useful in PONV, CINV, NVP, gastroparesis, and gastroesophageal reflux disease (GERD).

Metoclopramide

This drug crosses the blood–brain barrier and has centrally mediated adverse effects. Young children and the elderly are especially susceptible to these effects, which include somnolence, reduced mental acuity, anxiety, depression, and EPS and occur in 10% to 20% of patients

Domperidone

It minimally crosses the blood–brain barrier and is less likely to cause centrally mediated adverse effects.1,29 It should not be used for patients with underlying long QT interval or for those taking medications that prolong the QT interval.

• Hyperprolactinemia

• Galactorrhea

• Gynecomastia

Both metoclopramide and domperidone can cause what side effects

Corticosteroids (Dexamethasone, Methylprednisolone)

These are used alone or in combination with other antiemetics for preventing and treating PONV, CINV, or radiationinduced nausea and vomiting.3,6,11,30 Efficacy is thought to be due to release of 5-HT, reduced permeability of the blood–brain barrier, and decreased inflammation

Cannabinoids (Dronabinol, Nabilone)

These have antiemetic and appetite stimulant activity when used alone or in combination with other antiemetics. Oral formultaions are used for preventing and treating refractory CINV. They are thought to exert their antiemetic effect centrally, although the exact mechanism of action is unknown.

Benzodiazepines (Lorazepam)

These are used to prevent and treat CINV. It is used as an adjunct to antiemetic agents. Sedation and amnesia are common side effects. Respiratory depression can occur with high doses or when other central depressants such as alcohol are used concomitantly.

Serotonin (5-HT)

It is a neurotransmitter synthesized in neurons in the CNS and in enterochromaffin cells of the GI tract. Chemotherapeutic agents release this, which is a predominant mediator in nausea and vomiting. This increase in concentrations stimulates the visceral vagal nerve fibers and CTZ, thereby triggering nausea and vomiting.

• Ondansetron

• Granisetron

• Palonoseton

• Dolasetron

Selective 5-HT3 receptor antagonists such as — prevent and treat nausea and vomiting due to stimulation of these receptors, especially for CINV and PONV

• These agents are well tolerated; the most common adverse effects are headache, somnolence, diarrhea, constipation

• Ondansetron

• Dolasetron

SEROTONIN AGONISTS

• Dose-related QT changes (including torsades de pointes) have been reported, and ECG monitoring is recommended for patients with risk factors for QT prolongation who will receive —

• Granisetron

• Palonosteorn

SEROTONIN ANTAGONISTS

• — labeling does not include a recommendation for ECG monitoring

• — has not been associated with QT prolongation.

Palonosetron

It is the first 5-HT3 antagonist to be approved for preventing both acute and delayed CINV. Compared to other 5-HT3 antagonists, it has a longer serum half-life (40 hours compared to 4–9 hours) and a higher receptor-binding affinity, which may contribute to its efficacy in preventing delayed CINV

Palonosetron with dexamethasone

What is the 5-HT3 antagonist of choice for preventing CINV due to moderately emetogenic chemotherapy.

Substance P

It is a neurokinin neurotransmitter that binds to neurokinin-1 (NK1 ) receptors in the GI tract and the brain and is believed to mediate both acute and delayed nausea and vomiting.

Aprepitant

It was the first NK1 receptor antagonist antiemetic and is effective for preventing acute and delayed CINV when used with a 5-HT3 antagonist and a corticosteroid. It is also effective for preventing PONV.

Netupitant (Akynzeo)

It is the second NK1 receptor antagonist; it is available only as a combination product with palonosetron for preventing acute and delayed CINV following moderately or highly emetogenic chemotherapy

• Acute (within 24 hours after chemotherapy)

• Delayed (greater than 24 hours after chemotherapy)

• Anticipated (prior to chemotherapy)

CINV is classified as:

True

True or false

• A combination of antiemetics with different mechanisms of action is recommended to prevent acute CINV for patients receiving moderately or highly emetogenic chemotherapy

• Corticosteroid

• Prophylaxis

• Patients receiving chemotherapeutic agents with low emetogenic potential should receive a — as CINV prophylaxis

• Those receiving chemotherapy with minimal emetogenic risk do not require —.

• Cisplatin regimen

• Cyclophospahmide-based regimen

Delayed nausea and vomiting is more difficult to prevent and treat.

• It occurs most often with what regimens especially if delayed nausea and vomiting occurred with previous chemotherapy courses

False

True or false

• Patients who had poorly controlled acute CINV in the past are at lower risk for delayed CINC

Breakthrough CINV

Patients undergoing chemotherapy should have antiemetics available to treat — even if prophylactic antiemetics were given. If it occurs despite prophylaxis, treatment with an antiemetic with a different mechanism of action is recommended.

True

True or false

• The best strategy for preventing anticipatory nausea and vomiting is to prevent acute and delayed CINV by using the most effective antiemetic regimens based on the emetogenic potential of the chemotherapy and patient factors.

• Patient factors

• Anesthetic factors

• Surgical factors

PONV is a common complication of surgery that can lead to delayed discharge and unanticipated hospitalization. Risk factors include:

• Aprepitant, Palonosetron, Dexamethasone

• Droperidol, 5-HT3 antagonists

• Scopolamine

• Some agents should be administered prior to induction of anesthesia such as —

• Others are more effective when administered at the end of surgery such as —

• — should be administered the evening prior to surgery or 2 hours prior to surgery.

Aprepitant

What drug prevents PONV, but it is not more effective than other agents and is costly.

• 5-HT3 + droperidol/dexamethasone

• Droperidol + dexamethasone

Combinations of antiemetics are recommended to prevent PONV for high-risk patients, such as:

5-HT3 antagonist

If PONV occurs despite appropriate prophylaxis, it should be treated with an antiemetic from a pharmacologic class not already administered.If no prophylaxis was used, a low-dose — should be used.

Teratogenicity

Nausea and vomiting affect the majority of pregnant women; what potential of the therapy is the primary consideration in drug selection.

(Diclegis)

Pyridoxine (vitamin B6 ) 10 to 25 mg four times daily alone or in combination with an antihistamine such as doxylamine is often used for NVP. What combination product of this recommend a dose of two 10 mg/ 10 mg at bedtime

• Promethazine

• Metoclopramide

• Trimethobenzamide

For more severe NVP, what drugs ma be effective and have not been associated with teratogenic effects

hyperemesis gravidarum

In rare instances (0.5%–2% of pregnancies), NVP progresses to —. Enteral or parenteral nutrition may be required if weight loss occurs. A corticosteroid such as methylprednisolone may be considered

Methylprednisolone

Because this drug is associated with oral clefts in the fetus when used during the first trimester, corticosteroids should be reserved as a last resort and should be avoided during the first 10 weeks of gestation.

• Anticholinergics

• Antihistamines

Because the vestibular system is replete with muscarinic type cholinergic and histaminic (H1 ) receptors, what drug classes are the most commonly used agents to prevent and treat motion sickness