Nausea and Vomiting

Dr. Sun - Week 1

Nausea

The inclination to vomit or as a feeling in the throat or epigastric region alerting an individual that vomiting is imminent

Vomiting

The ejection or expulsion of gastric contents through the mouth; often a forceful event

What two common complications can occur with excess N/V?

Dehydration & Loss of electrolytes

What are the common causes of N/V?

• GI — obstruction, gastroparesis, gastroenteritis, pancreatitis, cholecystitis

• CNS — ↑ intracranial pressure, migraine, vestibular disorders (e.g., motion sickness)

• Metabolic — DKA, uremia, adrenal insufficiency

• CV — acute MI

• Psychiatric/functional — anxiety, eating disorders

• Pregnancy/postoperative

• Medications — opioids, antibiotics, digoxin, anesthetics, chemotherapy

N/V is a ______, not a _______.

symptom; diagnosis

What 2 things should treatment of N/V address?

Underlying cause & symptom control

Chemotherapy-Induced Nausea & Vomiting (CINV)

The probability of causing emesis without prophylaxis via chemotherapy

What are the 3 phases of N/V?

1. Nausea — subjective sensation that you’re about to vomit

2. Retching — repetitive contractions of abdominal and respiratory muscles, but no expulsion

3. Vomiting — forceful expulsion of gastric contents

What part of the body coordinates vomiting?

Brainstem → the vomiting center (VC) in the medulla

What are the 4 major sources of input for vomiting?

• GI tract / visceral afferents

  • e.g., gastroenteritis, gastric irritation, chemotherapy

  • ↓ primarily through vagal pathways

• Chemoreceptor trigger zone (CTZ)

  • detects drugs and toxins in blood/CSF

• Vestibular system — inner ear

  • important in motion sickness

• Higher cortical centers

  • sight, smell, pain, anxiety, memories, anticipatory nausea

Chemical detector (CTZ)

• Located in the area postrema, near the fourth ventricle; has a relatively permeable BBB

• Drug/toxin in the blood → CTZ detects it → vomiting circuitry activated

Reason behind why systemic medications can cause N/V

What drug class can you select to stop/prevent chemotherapeutic drug-induced nausea and vomiting (CINV)?

5-HT3 receptor antagonist → Ondansetron (Zofran)

What do chemotherapy drugs do to the GI tract?

Damage or stimulate the enterochromaffin cells, causing release of serotonin (5-HT)

How does the release of serotonin produce an emetic response?

Serotonin activates the 5-HT3 receptors on vagal afferents → signal travels to the brainstem → emetic response

What is the pathway of reactions that result in CINV?

Chemotherapy → GI serotonin release → 5-HT3 receptor → vagus → brainstem → vomiting

What is the treatment strategy for treating CINV via the 5-HT₃ receptor?

Ondansetron, Granisetron, Palonosetron

What is the treatment strategy for treating CINV via NK₁ (substance P) receptor?

Aprepitant/fosaprepitant

What is the treatment strategy for treating CINV via D₂ receptor?

Metoclopramide, Prochlorperazine

What is the treatment strategy for treating CINV via H₁ receptor?

1st generation antihistamine H1 receptor antagonists — Meclizine, Dimenhydrinate

What is the treatment strategy for treating CINV via M₁ receptor?

Muscarinic antagonist — Scopolamine

Simple symptoms of N/V

Self-limiting, resolves spontaneously, and requires only symptomatic therapy

Complex symptoms of N/V

Not relieved after administration of antiemetics; progressive deterioration of the patient secondary to fluid-electrolyte imbalances; usually associated with noxious agents or psychogenic events

What are the simple signs of N/V?

Patient complains of queasiness or discomfort

What are the complex signs of N/V?

Weight loss, fever, abdominal pain

What are laboratory tests that can be done to confirm N/V?

Serum electrolyte concentrations; upper/lower GI evaluation

How should N/V be treated?

Treat the cause first, then select an antiemetic

What are the goals of N/V treatment?

• Prevent or eliminate N/V

• Maintain hydration and electrolytes

• In chemotherapy → allow patients to continue cancer treatment

What are potential causes of N/V?

• Gastroenteritis/dehydration → fluids/electrolytes + symptomatic treatment

  • ← LR or NS (never dextrose)

• Bowel obstruction → treat the obstruction; don’t give an antiemetic and send the patient home

• DKA → insulin + fluids + electrolyte management

• Medication-induced → stop, reduce, or change the offending drug when possible

• Moton sickness → vestibular-directed therapy (i.e., Scopolamine)

• Chemotherapy → prophylactic multi-drug antiemetic regimen based on emetic risk (not treating, just preventing)

Nonpharmacologic treatment for mild or self-limited N/V

• Hydration

  • Oral fluids if tolerated

  • IV fluids when significant dehydration or inability to tolerate PO

  • Correct electrolyte abnormalities

• Diet

  • Small, frequent meals (especially pregnant women)

  • Bland/easily digested foods

  • Avoid large, fatty, spicy, or triggering meals

  • Gradually return to normal diet

• Environmental/behavioral

  • Avoid triggering smells or foods

  • Stable position for motion-related symptoms

  • Acupuncture/acupressure in selected settings

What is the treatment approach for anticipatory N/V?

Behavioral approaches can be useful — conditioning and anxiety contribute to the symptoms

For motion sickness/vertigo, what are the common drug options that target H1 and M1 receptors?

Meclizine, Dimenhydrinate, Scopolamine

For drug-induced/general N/V, what are the common drug options that target D2 ± 5-HT3 receptors?

Prochlorperazine, Metoclopramide, Ondansetron

For gastroparesis, what are the common drug options that target D2 receptor + impaired motility?

Metoclopramide

For CINV, what are the common drug options that target 5-HT3 and NK1 receptors?

5-HT3 antagonist + dexamethasone ± NK1 antagonist ± olanzapine

For PONV, what are the common drug options that target multiple pathways?

Ondansetron, dexamethasone, scopolamine, etc.

For pregnancy, what are the common drug options that target multiple receptors?

Pyridoxine ± doxylamine (commonly first-line)

Antihistamines/Anticholinergics such as Meclizine, Dimenhydrinate, and Scopolamine are common drugs that treat what cause of N/V?

Motion sickness, vertigo

Phenothiazines such as Prochlorperazine and Promethazine are common drugs that treat what cause of N/V?

Simple/general N/V

Haloperidol and droperidol are common drugs that treat what cause of N/V?

PONV — known to cause QT prolongation and EPS

Metoclopramide is a common drug that treats what cause of N/V?

Gastroparesis

5-HT3 antagonists such as Ondansetron, Granisetron, and Palonosetron are common drugs that treat what cause of N/V?

CINV/PONV

NK1 antagonists such as Aprepitant and Fosaprepitant are common drugs that treat what cause of N/V?

CINV — especially delayed

Dexamethasone is a common drug that treats what cause of N/V?

CINV/PONV as a part of combination therapy

Olanzapine is a common drug that treats what cause of N/V?

CINV / breakthrough N/V — causes sedation

How do antihistamine-anticholinergic drugs work in motion sickness?

Act at muscarinic (M1) and histamine (H1) receptors in the vomiting center and vestibular system

• e.g., Meclizine, Scopolamine

Dopamine antagonists → CTZ

Block D2 receptors in the CTZ

• Used for relatively uncomplicated N/V and are inexpensive

• Rectal administration can be useful when PO isn’t feasible

• e.g., Prochlorperazine, Promethazine

• Watch for:

  • EPS → involuntary muscle movements

Metoclopramide

Plays 2 major roles:

• Central: D2 blockade in CTZ → antiemetic

• GI: Increases gastric emptying + GI transit + LES tone

Gastroparesis (esp. diabetic) + N/V**

• Watch for:

  • EPS

  • Tardive dyskinesia (long exposure risk)

What’s the major class for CINV?

5-HT3 antagonists

5-HT3 antagonists

• Ondansetron (PO and IV)

  • IV doses should not exceed 16 mg because of QT prolongation (for pts with underlying cardiac issues)

• Granisetron (transdermal patch)

• Palonosetron

  • longer half-life and less QTc effect

How do 5-HT3 antagonists prevent CINV?

Chemotherapy → serotonin release → 5-HT3 on vagal afferents → brainstem → vomiting

• Antagonists block 5-HT3, preventing CINV (chemotherapy-induced N/V)

What is the main drug class used for both CINV and PONV?

5-HT3 antagonists

NK1 Antagonists

Particularly for delayed CINV

• Block NK1 receptor, preventing Substance P from producing its emetic effect

• e.g.,

  • Aprepitant (PO) → dosing on days 1-3 surrounding chemotherapy

  • Fosaprepitant (IV prodrug) → single dose on day 1

What DDIs are potential with Aprepitant?

• CYP3A4 and CYP2C9

• Dexamethasone → Reduce antiemetic dexamethasone dosing when given with aprepitant

Dexamethasone

For CINV + PONV

• Antiemetic MOA isn’t well defined

• Combined with other antiemetics, particularly 5-HT3 and NK1-directed therapy

• Not routinely used for uncomplicated everyday nausea

Olanzapine

Blocks multiple receptors (dopamine, serotonin, H1, etc.)

• Broad-spectrum antiemetic activity

• Part of the four-drug approach for highly emetogenic chemotherapy (has high potential for inducing N/V)

• Watch for:

  • Sedation (in older adults especially)

Lorazepam

Anticipatory CINV adjunct — for anxious pts who get N/V

• Does not work by strongly blocking an emetic receptor — acts on GABA receptor

• Anxiety/condition → anticipatory N/V — Lorazepam reduces anxiety

• Benzodiazepines as weak antiemetics used primarily for anxiolysis in anticipatory N/V

Cannabinoids

Reserved for when CINV is refractory to other antiemetics; NOT first-line

• Act on CD1 receptor in the brain

• e.g., Dronabinol and Nabilone

• Watch for:

  • Chronic cannabis use can itself cause cannabinoid hyperemesis syndrome

“The 6 associations”

1. Motion sickness → H1/M1 → meclizine/scopolamine

2. Gastroparesis → metoclopramide

3. General N/V / CTZ → D2 antagonist

4. Acute CINV → 5-HT3

5. Delayed CINV → NK1

6. Anticipatory CINV → lorazepam

**Highly emetogenic chemotherapy activates multiple pathways → combination therapy, not one antiemetic

Postoperative N/V (PONV)

Occurs in ~30% of adult surgical patients

• Usually within the first 24 hours post-anesthesia

• Predictable → should prevent in patients at risk!

What patient populations are at the most risk for developing PONV?

• Female

• Nonsmoker

• Previous PONV/motion sickness

• Opioids

What are some risk factors associated with PONV, aside from the top 4?

• Age <50 years old

• General anesthesia

• Hydration status

• Incidence of PONV can get as high as 80% when a patient has at least 4 risk factors

How to manage PONV

• Regional anesthesia rather than general anesthesia

• Propofol-based anesthesia rather than emetogenic volatile anesthetics

• Reduce perioperative opioids

• Adequate hydration

Reduce emetic stimulus + give prophylactic antiemetics when indicated

If a patient has 0-1 risk factors (low risk), what prophylaxis is used?

Little/none, depending on the clinical situation

If a patient has 2 risk factors (moderate risk), what prophylaxis is used?

2 antiemetics from different classes:

• Dexamethasone + Ondansetron (5-HT₃ antagonist)

If a patient has ≥3 risk factors (high risk), what prophylaxis is used?

Multimodal prophylaxis → 3 or more interventions/classes in very high-risk patients

Why are we using combination therapy for PONV patients?

PONV involves multiple neurotransmitter pathways; multiple drugs can target these different pathways

• 5-HT₃ blockade

• Corticosteroid

• NK₁/D₂/M₁ blockade

More effective than targeting the same receptor

PONV Combination Therapy w/ Ondansetron + Dexamethasone

• ondansetron 4 mg IV near end of surgery

• dexamethasone 4-8 mg IV at induction/early in surgery

What commonly used antiemetic is given before surgery to prevent PONV?

Scopolamine patch

What commonly used antiemetic is given at induction of anesthesia/early in surgery to prevent PONV?

Dexamethasone

What commonly used antiemetic is given before surgery to prevent PONV?

Ondansetron

Scopolamine

Blocks M₁ receptor, as part of the multimodal PONV prophylaxis

• Transdermal patch has slow onset; needs to be placed well before its effect is needed

• Watch for:

  • Dry mouth

  • Blurred vision

  • Urinary retention

  • Confusion (CNS effect)

Droperidol/Haloperidol

Blocks D₂ receptor

• Use when a 3rd drug is needed in high-risk patients (combination therapy)

• Watch for:

  • EPS

  • QT prolongation (black box warning for droperidol)

Not simply interchangeable with ondansetron without considering patient-specific risks

What should be done if prophylaxis fails using dexamethasone + ondansetron?

Use a rescue antiemetic from a DIFFERENT drug class

• e.g., Ondansetron already given → don’t repeat 5-HT₃ blockade

  • Consider D₂ antagonist, phenothiazine, droperidol, etc.

Prophylaxis failed → change receptor/class

What is the “6-hour concept”?

If prophylactic antiemetic was administered recently (<6 hours)

• Don’t repeat the same agent

• Repeating 5-HT₃ antagonist generally provides little additional benefit

If prophylactic antiemetic was administered >6 hours ago

• Repeat dose of a short-acting agent such as 5-HT₃ antagonist

  • Do NOT repeat dexamethasone or the scopolamine patch simply as rescue therapy

What should be done if a patient receives no prophylaxis for PONV?

5-HT₃ antagonist as first-line choice

• e.g., Ondansetron 4 mg

If patient had already received ondansetron and was still vomiting, choose another class

Case: A 35-year-old nonsmoking woman with a history of motion sickness is undergoing laparoscopic surgery and will receive postoperative opioids.

(a) Prophylaxis?

(b) If she received dexamethasone + ondansetron and develops PONV shortly after surgery, what is the next step?

(a) 3-drug combination therapy

(b) Bring in another rescue drug from a different class

What 4 things can result from motion sickness causing a sensory mismatch in the brainstem vomiting circuitry?

Dizziness → nausea → autonomic symptoms → vomiting

Which receptors matter when it comes to motion sickness?

• Vestibular system

• H1 receptors

• M1 receptors

Best drugs for this disorder = H₁ antagonists + M₁ antagonists

What is first-line for prevention of motion sickness?

Scopolamine (M₁ antimuscarinic) — blocks cholinergic transmission from vestibular system to the vomiting center

• Transdermal patch — provides prolonged drug delivery and is convenient for situations such as traveling

  • Apply BEFORE motion exposure

First-generation antihistamines

Dimenhydrinate, Meclizine, Diphenhydramine

• Block H₁ receptors; anticholinergic activity

• Major ADE: Sedation

Are second-generation nonsedating antihistamines effective for motion sickness?

No ma’am

Incidence of NVP (pregnancy-induced N/V)?

• Up to 80% experience nausea

• ~50% experience vomiting or retching

• Up to 3% develop hyperemesis gravidarum

Hyperemesis gravidarum

Severe NVP associated with significant clinical consequences:

• Persistent vomiting

• Dehydration/volume contraction

• Starvation/weight problems

• Electrolyte abnormalities

How to manage mild NVP (nonpharmacologic)

• Diet/lifestyle

• Small, frequent meals

• Eat every 1-2 hours

• Avoid triggering foods and odors

• Ginger (for nausea, not vomiting)

• Prenatal vitamin 1 month before conception (when planned)

First-line pharmacotherapy for NVP

Vitamin B6 ± doxylamine

• Step 1: Pyridoxine (Vitamin B6)

If inadequate:

• Step 2: Pyridoxine + doxylamine

1st gen antihistamines (Dimenhydrinate) or Phenothiazines (Promethazine, Prochlorperazine) may be considered if the prior steps do not work

Treatment approach to NVP

1. Lifestyle/diet

2. B6 ± doxylamine

3. Add/change antiemetic therapy if persistent

For severe/persistent NVP symptoms (particularly hyperemesis gravidarum), what should be the treatment approach?

• Ondansetron — 5-HT₃ antagonist

• Metoclopramide — D₂ antagonist + prokinetic

• Promethazine — primarily antihistaminic/phenothiazine effects

If a patient with NVP is dehydrated, how does this change treatment?

IV fluids + electrolyte correction

• THIAMINE BEFORE DEXTROSE

  • Giving carb load to a thiamine deficient patient (due to prolonged vomiting/dehydration) can worsen Wernicke encephalopathy

    • Hyperemesis + prolonged poor intake → thiamine before dextrose

Severe refractory hyperemesis in NVP

If a patient cannot maintain adequate nutrition/weight despite therapy → enteral tube feeding

• Hydration + electrolytes + nutrition + vitamin replacement + control of N/V

  • Consider methylprednisolone (glucocorticoid)

    • Avoid before 10 weeks of gestation

    • Refractory severe disease — not routine NVP treatment (best in hospital setting)

Gastroenteritis in children

Usually self-limited and improves with correction of dehydration (oral rehydration therapy)

• Antiemetics for intractable vomiting

• Ondansetron is the safest option for children — associated with decreased vomiting, reduced need for IV rehydration therapy, and prevents hospital admissions

• Promethazine is contraindicated in patients <2 years of age; use with caution in older children due to the potential risk of fatal respiratory depression

Use of Antiemetics in Older Patients

Ondansetron is preferred

• Possibly inappropriate medications:

  • 1st generation antihistamines and scopolamine — anticholinergic effect

  • Metoclopramide — may cause extrapyramidal effects (tardive dyskinesia)