LECTURE 5 - Pathophysiology and Pharmacotherapy of Nausea & Vomiting

non-specific symptom

Drug-induced nausea/vomiting (n/v)

Anticipatory n/v

cock graft equation

3 consecutive phases of N/V

Nausea

Retching

Emesis

Simple N/V

Symptoms: self-limiting, resolves on its own

Signs: complaint of queasiness or discomfort

Laboratory tests: none

Complex N/V

Symptoms: not relieved after administration of antiemetics

Signs: weight loss, fever, abdominal pain

Laboratory tests: serum electrolyte

Upper/lower GI evaluation

Nonpharmacologic Interventions N/V

Dietary management

Acupressure, hypnosis, psychotherapy

For motion sickness: minimize exposure and magnitude of movement, restrict visual activity, ensure adequate ventilation

Pharmacologic Interventions for N/V

Treatment of simple n/v → OTC products

Treatment of complex n/v usually requires combination therapy with different pharmacologic mechanisms

Antacids

Place in therapy

(GERD)

heartburn

simple n/v

neutralizes gastric acid

Antacids

Use with caution

in patients with kidney dysfunction

Antacids

Adverse effects

diarrhea (magnesium)

constipation (aluminum and calcium)

H2-Receptor Antagonists (H2RA)

Famotidine (Pepcid®, Zantac 360®)

cimetidine (Tagamet®)

nizatidine (Axid®)

H2RA

Place in therapy

simple n/v associated with heartburn or GERD

H2RA

DDI

cimetidine

H2RA

adverse effects

Few adverse effects associated with this class of drugs

Motion Sickness and Vestibular Disturbances

Disturbances in the inner ear

Dizziness / vertigo

what does the vestibular system contain?

cholinergic and H1 receptors

what are anticholinergic and antihistamines are most commonly used to prevent and treat?

motion sickness

First line for motion sickness

Scopolamine patch prior to motion exposure

Anticholinergic and antihistamines

Adverse effects

drowsiness, reduced mental acuity, visual disturbance, dry mouth, urinary retention

Anticholinergics

Place in therapy

prevention and treatment of motion sickness

Some efficacy in preventing PONV

Scopolamine patch

dosage

1 mg/72 hours- apply 1 patch every 3 days

Anticholinergics

Adverse effects:

sedation, visual disturbance, dry mouth, dizziness

kidney dysfunction

Antihistamine-Anticholinergics

Diphenhydramine (Benadryl®, ZzzQuil®)

Dimenhydrinate (Dramamine® Original)

Meclizine (Bonine®, Dramamine® Less Drowsy)

Hydroxyzine (Atarax®)

Antihistamine-Anticholinergics

Place in therapy

motion sickness

vertigo

migraine headache

Antihistamine-Anticholinergics

Adverse effects

drowsiness, blurred vision, urinary retention, dry mouth seen mostly with first-generation antihistamines (diphenhydramine, dimenhydrinate, meclizine)

Second-generation antihistamines

cetirizine and fexofenadine

why are cetirizine and fexofenadine are ineffective?

it doesn't affect CNS

Postoperative Nausea & Vomiting

Common complication of surgery

Occurs within 24 hours of undergoing anesthesia

Patient risk factors for PONV

Female sex

Nonsmoking status

History of PONV

History of motion sickness

Anesthetic and surgical risk factors for PONV

Volatile anesthetics

Nitrous oxide

Intraoperative or postoperative opioids

Duration and type of surgery

High risk for PONV

2-3 prophylactic antiemetics (MEDS)

Moderate risk for PONV

1-2 prophylactic antiemetics (MEDS)

when are NK1 antagonists administered?

during induction of anesthesia

Postoperative Nausea & Vomiting

what do you give At the end of surgery?

Droperidol or haloperidol

5-HT3 receptor antagonist (ondansetron)

Steroids

Antihistamines

Anticholinergics

what medication has the best prevention for PONV ?

ondansetron

5-Hydroxytryptamine-3 Receptor Antagonists

Ondansetron (Zofran®)

Granisetron (Kytril®)

Dolasetron (Anzemet®)

Palonosetron (Aloxi®)

are all antacids Rx or OTC?

OTC

are H2-Receptor Antagonists (H2RA) Rx or OTC?

OTC

are anticholinergics Rx or OTC ?

Rx

are Antihistamine-Anticholinergics Rx or OTC

Rx: hydroxyzine and trimethobenzamide

the rest are OTC

are 5-Hydroxytryptamine-3 Receptor Antagonists Rx or OTC?

Rx

5-HT3 Receptor Antagonists

Place in therapy

complex n/v

prevention / treatment of PONV and CINV

5-Hydroxytryptamine-3 Receptor Antagonists

Adverse effects

headache

somnolence

diarrhea

constipation

QT prolongation

what medication should be used for acute and delayed CINV?

Palonosetron

what is the only 5-HT3-RA that doesn’t affect QT interval?

Palonosetron

is Dopamine Antagonist- Phenothiazines Rx or OTC?

Rx

Dopamine Antagonist- Phenothiazines

Promethazine (Phenergan®)

Prochlorperazine (Compazine®)

Chlorpromazine (Thorazine®)

Dopamine Antagonist- Phenothiazines

formulations

oral solids

liquids

rectal suppositories

parenteral

Dopamine Antagonist- Phenothiazines

Place in therapy

simple and complex n/v related to

motion sickness, vertigo, gastritis or gastroenteritis, NVP, PONV, CINV

Dopamine Antagonist- Phenothiazines

Adverse effects

sedation, orthostatic hypotension

EPS - can be seen in single-dose users as well as chronic users!

QT prolongation with prochlorperazine and chlorpromazine

Dopamine Antagonists- Butyrophenones

Droperidol (Inapsine®)

Haloperidol (Haldol®)

is Dopamine Antagonists- Butyrophenones Rx or OTC ?

Rx

Dopamine Antagonists- Butyrophenones

Place in therapy

limited use due to risk of adverse effects; preventing PONV

why is haloperidol used in palliative care ?

to reduce N/V

why is haloperidol used 2nd line?

for patients intolerant to first-line agents

Dopamine Antagonists- Butyrophenones

Adverse effects

sedation

agitation

restlessness

EPS

QT prolongation

Dopamine Antagonists- Butyrophenones

black box warning

QT prolongation

cardiac arrhythmias

are Dopamine Antagonists Rx or OTC?

Rx

Dopamine Antagonists

Metoclopramide (Reglan®)

Dopamine Antagonists

Place in therapy

complex n/v; PONV, CINV, NVP, diabetic gastroparesis, GERD

Increases lower esophageal sphincter tone

Promotes gastric motility (prokinetic)

Dopamine Antagonists

formulations

oral solid, oral liquid, and injectable

Dopamine Antagonists

Adverse effects

somnolence, reduced mental acuity, anxiety, depression, EPS, asthenia

apply one patch in hairless area behind EACH ear and remove patch after 72 hrs

are corticosteroids Rx or OTC ?

Rx

Corticosteroids

Dexamethasone (Decadron®)

also used in combination with other antiemetics

Corticosteroids

Place in therapy

complex n/v; prevention and treatment of PONV, CINV, radiation-induced n/v

Dexamethasone is effective in preventing acute/delayed CINV when used alone or with 5-HT3 receptor antagonists

Dexamethasone (Decadron®)

adverse effects

GI upset, anxiety, insomnia, hyperglycemia, fluid retention, psychosis (high doses), bone mineral density loss (chronic use)

are Cannabinoids Rx or OTC ?

Rx

Cannabinoids

Dronabinol (Marinol®)

nabilone (Casamet®)

C-III

Dronabinol

C-II

Nabilone

Cannabinoids

Place in therapy

Antiemetic and appetite stimulant activity - for cancer related pain

not first-line agents; prevention and treatment of refractory CINV

can Cannabinoids be used alone or with others ?

can be Used alone or in combination with other antiemetics

Cannabinoids

Adverse effects

sedation, euphoria, xerostomia, hypotension, ataxia, dizziness, vision difficulties

Cannabinoids

Route of administration

PO

Slow onset of action

types of Benzodiazepines

Lorazepam (Ativan®)

alprazolam (Xanax®)

BOTH ARE CIV

are Benzodiazepines Rx or OTC?

Rx

Benzodiazepines

Place in therapy

prevention and treatment of psychological n/v

are Benzodiazepines Weak antiemetic agents?

yes, usually used with combo

Benzodiazepines

Adverse effects

sedation and amnesia

respiratory depression occurs in high doses

osteoporosis

are Neurokinin-1 Receptor Antagonists Rx or OTC?

Rx

Neurokinin-1 Receptor Antagonists

Aprepitant (Emend®)

Fosaprepitant (Emend®)

Rolapitant (Varubi®)

Netupitant/palonosetron or NEPA for oral (Akynzeo®)

Fosnetupitant/palonosetron for injection (Akynzeo®)

Neurokinin-1 Receptor Antagonists

Place in therapy

preventing acute / delayed CINV

combined with 5-HT3 antagonist

Aprepitant

CYP3A4

an inhibitor and substrate of CYP3A4 → DDI

Rolapitant

CYP3A4

has no effect

is Dopamine Antagonist - Amisulpride Rx or OTC?

Rx

Dopamine Antagonist - Amisulpride

brand name

Barhemsys

Dopamine Antagonist - Amisulpride

Place in therapy

rescue PONV

pt failed other prophylactic antiemetic drugs

Dopamine Antagonist - Amisulpride

dosage form

IV

Doses differ between prevention and treatment

Dopamine Antagonist - Amisulpride

Adverse drug reactions

procedural hypotension, hypokalemia, increase serum prolactin, abdominal distension, pain at infusion site, chills

Nausea & Vomiting in Pregnancy

Affects majority of women

Must consider teratogenic potential of drug

Nausea & Vomiting in Pregnancy

Initial therapy

always nonpharmacologic (diet modification)

Nausea & Vomiting in Pregnancy

Pyridoxine (vit B6 )

Pyridoxine (vit B6 ) 10-25 mg 4x daily alone or + antihistamine

Hyperemesis gravidarum

mother may require IV fluid replacement with thiamine if weight loss occurred; reserve corticosteroids as last resort and avoid during the first 10 weeks

Hyperemesis gravidarum treatment

Ondansetron, metoclopramide, promethazine, corticosteroids

what happens when Corticosteroid use in the first trimester?

can cause oral clefts in the fetus

Nausea & Vomiting in Pregnancy

Monitoring

Severity of n/v

Change in patient weight

Number of vomiting episodes per day

Acid-base balance

Daily urine volume

Skin turgor (the skin’s elasticity)

Acid-base balance

electrolytes

BUN and creatinine