Nausea & Vomiting Pharmacotherapy

Define nausea

Unpleasant sensation associated with an inclination to vomit

Define vomiting or emesis

Autonomic response that results in the forceful expulsion of gastric contents through the mouth

What drugs can cause drug induced nausea/vomiting?

Cancer therapies, digoxin, opioids, antibiotics, volatile general anesthetics, anticonvulsants, oral contraceptives, oral hypoglycemics

What cancer therapies can cause DINV?

Radiation therapy, chemotherapy (antineoplastic agents)

What is the 4-level classification system used for?

Defines risk for emesis among agents used in oncology

How does the 4-level classification system classify risk?

High risk = > 90%

Moderate risk = 30-90%

Low risk = 10-30%

Minimal risk = < 10%

What are common risk factors for N/V?

Surgery (PONV), pregnancy, chemotherapy (CINV)

Describe the clinical presentation of N/V

Symptoms = diaphoresis, pallor, faintness, salivation

Signs = dehydration

Labs = electrolyte imbalances, elevated BUN and Cr

Describe simple N/V

Occurs occasionally, self-limiting

Describe complex N/V

Can cause complications, needs treatment

What are metabolic complications of complex vomiting?

Dehydration, electrolyte abnormalities, acid/base abnormalities

What are GI-related complications of complex vomiting?

Esophageal tears, aspiration

What is another complication of complex vomiting?

Malnutrition

What are treatment goals of N/V?

Prevent/eliminate nausea and vomiting

Identify underlying cause

Minimize adverse effects and limit drug interactions

Assessment of fluid and electrolyte status with appropriate replacement

Describe non-pharmacologic diet interventions for N/V

Identify/reduce dietary triggers

Eat frequent, small meals

Avoid large, fatty, spicy meals, and fried foods

BRAT diet

Electrolyte drinks

Describe non-pharmacologic behavioral interventions for N/V

Identify/avoid any other triggers

Relaxations, biofeedback, hypnosis, acupuncture, yoga, chewing gum

What are three alternative treatments for N/V?

Acupuncture, ginger, pyridoxine (vitamin B6)

What are indications for acupuncture?

CINV, PONV, early pregnancy-related N/V

What is the dosing and indication for ginger?

250 mg (powdered root) prior to meals + at bedtime

Pregnancy-related N/V

What is the indication for pyridoxine (vitamin B6)?

Early pregnancy-related N/V

What is the general treatment approach for simple N/V?

Oral fluid intake/hydration

OTC treatment if needed

Non-pharmacologic treatments

What is the general treatment approach for complex N/V?

Oral to IV fluid/electrolytes

Combination medication regimen with different MOAs

What is the treatment approach for motion sickness?

Antihistamines/antimuscarinics

Use 30-60 min prior to anticipated motion event, as medication is more effective when given prophylactically

Compare prescription vs. OTC treatments for motion sickness

Rx = scopolamine

OTC = diphenhydramine, meclizine, dimenhydrinate

What are patient-related risk factors for PONV?

Age less than 50, female, nonsmoker, history of PONV or motion sickness, hydration status

What are risk factors for PONV that are related to anesthesia?

Use of general anesthesia, use of volatile anesthetics, nitrous oxide use for > 1 hr, use of opioids

What are risk factors for PONV that are related to surgery?

Type of surgical procedure (laparoscopic, gynecological, cholecystectomy), duration of surgery

Describe risk mitigation for adult PONV

Minimize use of NO, volatile anesthetics, high-dose neostigmine

Consider regional anesthesia

Opioid sparing/multimodal anesthesia (enhanced recovery pathway)

How many agents should be given for PONV based on the number of risk factors present?

1-2 risk factors = give 2 agents

> 2 risk factors = give 3-4 agents

What N/V medications can be used for prophylaxis?

5HT3RAs, antihistamines, propofol anesthesia, acupuncture, corticosteroids, dopamine antagonists, NK1RAs, anticholinergics

Describe rescue treatments for PONV

Use anti-emetic from different class than prophylactic drug

What four predictors is the Apfel simplified risk score based on?

Female, non-smoker, history of motion sickness/PONV, postoperative opioids

Each factor = +1 to score

How are the results of the Apfel simplified risk score interpreted?

0-1 risk factors = low risk

2 risk factors = medium risk

3+ risk factors = high risk

How are the results of the Apfel simplified risk score interpreted in terms of percent incidence of PONV?

0 risk factors = 0%

1 risk factor = 20%

2 risk factors = 40%

3 risk factors = 60%

4 risk factors = 80%

How can the risk of PONV be minimized?

Hydration, local (regional) anesthetic instead of systemic, avoid NO and volatile anesthetics, avoid opioids and consider other analgesics

Describe PONV prophylaxis for children and those with no risk factors

No antiemetic OR either a 5HT3 RA or dexamethasone

Describe PONV prophylaxis for patients with 1-2 risk factors

Multi-modal prophylaxis recommended = 2-drug regimen

What is the cornerstone of therapy when considering a 2-drug regimen for PONV?

Combination of 5HT3 RA plus dexamethasone (4-8 mg)

Also strong evidence to support the use of aprepitant + dexamethasone

Describe PONV prophylaxis for patients with > 2 risk factors

Multi-modal prophylaxis recommended = 3-4 drug regimen from different drug classes

What antiemetics should be administered at the introduction of anesthesia?

Aprepitant, palonosetron, dexamethasone

What antiemetics should be administered at the end of surgery?

Droperidol, 5HT3 RAs

What antiemetic should be administered the evening prior to surgery or 2-4 hours prior to anesthesia?

Scopolamine

Describe rescue therapy for PONV

When using the cornerstone of therapy, patients should be given rescue therapy from a different drug class such as dopamine antagonists = a phenothiazine, metoclopramide, droperidol

Describe repeating agents for PONV following surgery

Repeating the agent given for PONV prophylaxis within 6 hours of surgery offers no additional benefit

If an emetic episode occurs > 6 hours post-op, a repeat dose of 5-HT3 RA can be considered

What PONV medications is it NOT recommended to repeat doses of?

Dexamethasone or transdermal scopolamine

What is the recommended treatment of PONV when no prophylaxis was given?

Low dose 5HT3 RA

Ex: ondansetron 4 mg PO or IV

What is the role in therapy of 5HT3 RAs?

Considered standard of care in management of CINV and PONV

What is considered the "gold-standard" 5HT3 RA?

Ondansetron

What is the maximum IV dose of ondansetron and why?

16 mg

High bioavailability = risk of QT prolongation and at 16 mg, the risks outweigh the benefits

What dose-related effect can occur with any 5HT3 RA?

Dose-related QTc prolongation

Monitor ECG if high risk

What is notable about palonosetron compared to other 5HT3 RAs?

Longer half-life (~40 h)

This means that it can prevent both acute AND delayed CINV

What is notable about granisetron compared to other 5HT3 RAs?

Longer acting

This means that it is effective in preventing emesis beyond 24 h

What is the role in therapy of corticosteroids?

Prevention of CINV or PONV, as a single agent or in combination with other antiemetics

Low cost

What are adverse events of corticosteroids?

Minimal with one-time dosing

Additional dosing could cause hyperglycemia, fluid retention, insomnia, psychosis, mood changes, or infection risk

What is the role in therapy of NK1RAs?

In combination with other antiemetics in CINV and PONV

Which NK1RA is a substrate and moderate inhibitor of CYP3A4 and a weak inducer of CYP2C9?

Aprepitant

T 1/2 = ~40h

What DDIs can occur with aprepitant?

May increase concentration of chemotherapy medications

Risk for decreased effectiveness of estrogen-containing contraceptives

Can increase INR when given with warfarin therapy

What are some DDIs with rolapitant?

Some antineoplastic meds

What is an FDA warning of rolapitant?

Reports of severe hypersensitivity reactions shortly following IV administration

What should patients be screened for prior to rolapitant administration?

Cross-reactive allergens to components of rolapitant (soybeans, legumes)

What is the role in therapy of antihistamines and antimuscarinics?

Primary use = prevention of N/V associated with vertigo and motion sickness

Frequently employed as self-care therapies

What is the dosing of scopolamine patches?

Apply 1 patch behind the ear at least 2-4 hours prior to time of intended effect

Lasts 72 h

What are adverse effects of antihistamines and antimuscarinics?

Anticholinergic-related = sedation/drowsiness/confusion, dry mouth, blurry vision, urinary retention

Due to the adverse effects, in which patient populations should antihistamines/antimuscarinics be avoided?

Geriatrics due to sedation, drowsiness, confusion

Narrow angle glaucoma due to blurry vision

BPH due to urinary retention

What is the role in therapy or dopamine antagonists?

NOT first-line for N/V

Used primarily as rescue antiemetics for PONV

Why are dopamine antagonists NOT first-line agents for N/V?

Due to their side effects of sedation, orthostatic hypotension, and extrapyramidal symptoms

What is the role in therapy of butyrophenones?

If used, is mainly for anticipatory and acute CINV and PONV

What is the role in therapy of metoclopramide?

Pro-kinetic = accelerates transit through small bowel

Useful in gastroparesis but limited by CNS effects

What are general AEs of dopamine antagonists?

Extrapyramidal symptoms (EPS) = AVOID chronic use (> 12 weeks)

QTc prolongation = TdP

Sedation, hypotension, hyperprolactinemia

What are examples of extrapyramidal symptoms?

Pseudoparkinsonism, acute dystonia, akathisia, tardive dyskinesia

What are examples of pseudoparkinsonism?

Stooped posture, shuffling gait, rigidity, bradykinesia, tremors at rest, pill-rolling motion of the hand

What are examples of acute dystonia?

Facial grimacing, involuntary upward eye movement, muscle spasms of the tongue, face, neck, and back, laryngeal spasms

What are examples of akathisia?

Restless, trouble standing still, paces the floor, feet in constant motion (rocking back and forth)

What are examples of tardive dyskinesia?

Protrusion and rolling of the tongue, sucking and smacking movements of the lips, chewing motion, facial dyskinesia, involuntary movements of the body and extremities

Which dopamine antagonists have the highest risk of QTc prolongation?

Butyrophenones > phenothiazines > metoclopramide

Which dopamine antagonist has a BBW and what it is?

Droperidol

BBW = risk of sudden cardiac death

How should a patient be monitored prior to droperidol administration?

12-lead ECG recommended prior to administration

Cardiac monitoring for 2-3 hours following administration

What can occur if promethazine IV is administered in an undiluted bolus?

Tissue necrosis

What is the MOA of BZDs?

GABA receptor antagonist = relaxation

What is the role in therapy of BZDs?

Relatively weak antiemetics, generally used as an adjunct to other antiemetics

Used to prevent anxiety or anticipatory N/V, some role in PONV

What are AEs of BZDs?

Dizziness, sedation

Avoid in older adult population due to fall risk

Development of tolerance = dependence = withdrawal

What is the role in therapy of cannabinoids?

Not indicated as first-line agents

Used for CINV for breakthrough N/V, symptomatic treatment in combination with other antiemetics, or when CINV is refractory to other antiemetics

What are adverse effects of cannabinoids?

CNS depression = avoid in older adults!

Hypotension, xerostomia, euphoria

What is the first-line treatment for N/V in pregnancy?

Dietary prevention

Avoid spicy, fatty, or large meals and eat smaller, more frequent meals (every 1-2 hrs)

Avoid triggers, use ginger, pre-natal vitamins 1 month before pregnancy may prevent N/V

What is the first-line therapy for refractory/persistent N/V in pregnancy?

Pyridoxine (vitamin B6) +/- doxylamine

If no relief, can try other agents, like dimenhydrinate, diphenhydramine, prochlorperazine, or promethazine

IV fluids may be needed in those with dehydration

How should N/V be treated in pediatrics?

Usually self-limiting and improves with correction of dehydration

Which antiemetic is contraindicated in patients under 2 and why?

Promethazine

Potential risk of respiratory depression