Lecture 3 Nausea and Vomiting Cairns

DEFINITIONS:

Nausea Prodromal symptom of emesis, but both can occur separately; often described as “feeling queasy or sick to stomach” = unpleasant sensation

Vomiting Expulsion of stomach (or as deep as ileum) contents through the oral (and nasal) cavity

Emesis To vomit; function is to rid GIT of toxins

Retching Contraction of GI system without oral ejection

Vomiting can be effectively blocked by antiemetics, but nausea much more difficult to treat with these drugs

PHYSIOLOGY OF NAUSEA: nausea may increase sweating, salivation, cutaneous vasoconstriction & HR, which are mediated through activation of sympathetic ANS

BRAIN AREAS INVOLVED IN NAUSEA:

VOMITING CENTER (dorsal vagal complex): found in medullary reticular formation (brain stem)

AREA POSTREMA (AP):

• A chemo-sensitive organ (chemoreceptor trigger zone = CRTZ)

o Not isolated from peripheral circulation by BBB

o Contains receptors for dopamine, neurokinins,

serotonin, neuropeptides, and hormones

• Regulates GI, CV and immune functions

• Projects to nucleus tractus solitarius (NTS)

• Brainstem blood supply changes (ex// hemorrhage, migraine)

causes activation induce nausea

NUCLEUS TRACTUS SOLITARIUS (NTS):

• Receives input from vagal afferents in GIT, vestibular system & CRTZ

• Projects to the central pattern generator that coordinates emesis, which

may be in the reticular formation

o Thought vomiting reflux initiated from this center

• Coordination of emesis includes swallowing, salivation, respiration,

cardiovascular, and GI contractions (retching)

DORSAL MOTOR NUCLEUS OF THE VAGUS:

• Contains the pre-ganglionic effector neurons of

the vagus nerve

• Is normally inhibited, but its activity can be

modulated by: opioids, serotonin, cannabinoids,

tachykinins, dopamine

HIGHER BRAIN CENTERS:

ASCENDING PATHWAY:

1. Parabrachial nucleus (PBN) in brainstem receives input from NTS (GI function)

and cerebellum (motion)

2. Information from PBN is relayed to the:

a. Hypothalamus: coordinates autonomic response

b. Limbic system: affective response (feelings of stress & discomfort) ► Hypothalamus, amygdala, hippocampus, thalamus, basal ganglia, cingulate gyrus

CORTICAL AREAS: ► Prefrontal cortex, anterior cingulate, insula, nucleus accumbens, amygdala

► Areas similar to those involved in pain processing appear

involved in nausea

VOMITING REFLEXES (NTS):

1. Relaxation of the gastric muscles, reverse peristalsis in duodenum

2. Normal respiration rhythm stops

3. Coordinated contraction of diaphragm & abdominal muscles

a. Accompanied by contraction of the external (inspiratory) intercostal

muscles and relaxation of the internal (expiratory) intercostal muscles

b. Increased thoracic and abdominal pressures = vomiting

4. Lower esophageal sphincter (LES) and the area of the diaphragm surrounding

the esophagus relaxes to assist in expulsion of gastric contents

5. Protective movements including raising the soft palate and closure of the

pharynx/larynx to protect the airway

VESTIBULAR SYSTEM & MOTION INDUCED NAUSEA:

• Labyrinthine input to vestibular neurons that project to the NTS

and activate neurons in this nucleus

o Vestibular apparatus: detects head motion

o Vestibular nuclei: maintain body position in space

• Input for vestibular & visceral afferents also goes to the

posterior cerebellum (vestibulo-cerebellum) which may be

critical in detecting deviations in sensory input from expectancy

VAGUS NERVE: cranial nerve X

• Vagal afferent fibers (nodose ganglion) project to the dorsal vagal complex

• Abnormal activation of vagal afferents input nausea & vomiting reflex

o Vago-vagal reflex = vagal afferent input motor output via vagal nerve

PLASMA ARGININE VASOPRESSIN (AVP):

• Increased by emetic stimuli

o Positive correlation between plasma AVP increase &

nausea induced by motion sickness

o Infusion of AVP induces nausea in humans

• Role in induction of nausea or is released because of nausea

ABNORMAL AFFERENT INPUTS:

• Abnormal mechanical stimulation = GI dysrhythmia, dysmotility, abnormal

distension of stomach, intestine, or biliary tract

o Normal: 3 contractions/minute = gastric slow wave rhythm

o Dysrhythmia: increase to 4-9 contractions/min precedes nausea

o Triggers: motion, pregnancy, drugs & delayed gastric emptying

• Painful stimulation from GIT (irritation of stomach lining)

o Vagal afferents are normally excited by serotonin released from

enterochromaffin cells in response to nutrients

o Injury of the GIT also can lead to release of serotonin

EMETIC AGENTS = drugs used to induce vomiting

APOMORPHINE:

• Activates DA, 5-HT and

α -adrenergic receptors

• Vomiting thought due to

activation of DA & µ-

opioid receptors in CRTZ

• Used to induce vomiting

in dogs

SYRUP OF IPECAC:

• Proposed to cause 5-HT

release

• Once used to promote

vomiting after ingestion of

poisons

► Not recommended

for this anymore

Lecture 3 Nausea and Vomiting Cairns

ANTIEMETICS: drugs that suppress nausea & prevent vomiting (central action) vs. agents that modulate GI motility many drugs have both these actions

SEROTONIN RECEPTOR ANTAGONISTS:

• 5-HT3 antagonists reduce signals from CRTZ & activation of vagal afferents

ONDASETRON:

• Prototypical 5-HT3 antagonist = causes a non-competitive channel block

• Usual starting dose is 4 mg – max 16 mg (PO or injection)

o Half-life 4 hours, extensively metabolized

• Adverse effects:

o Constipation in some pts, diarrhea in others

o Headache, dizziness

o QT prolongation (cardiac arrhythmia/arrest risk)

PALONOSETRON:

• 2nd generation = greater affinity for 5-HT3 receptor

o May bind to additional sites of the receptor to induce an allosteric

modulation that promotes receptor internalization

• Single IV dose of 0.075 (post-op nausea) to 0.25 mg (chemo)

o Longer half-life (40 hours), 50% excreted in urine unchanged

o One dose lasts 72 hours

NEUROKININ RECEPTOR ANTAGONISTS: block NK1 receptor

• Tachykinins (substance P) are found in the ENS and released (along

with 5-HT) from ECL excite vagal afferent activity

• Neurokinin receptors are also in the dorsal vagal complex

APREPITANT: (netupitant, rolapitant = longer half-lives)

• 40 mg PO dose, 3 hours before procedure

o Metabolized by CYP3A4 (and 1A2, 2C19)

• Adverse effects:

o Fatigue, dizziness, disorientation, loss of touch sensitivity

o Constipation or diarrhea, dyspepsia

CANNABINOIDS (nabilone, tetrahydrocannabinol)

• THC and nabilone inhibit gut motility through activation of CB1

receptors, which inhibits release of ACh

o Centrally, activation of CB1 receptors in NTS may contribute

• Mild anxiolytic activity

• Some cannabinoids (ex// cannabidiol & cannabigerol) can produce

a hyperemesis syndrome (problem with chronic marijuana use)

NABILONE:

• 1-2 mg bid-tid po only

• Extensively metabolized (CYP1A2, 2A6, 2C19, 2D6, 3A4)

• AEs: sedation, dizziness, psychotropic (altered behavior)

ANTIHISTAMINES: diphenhydramine, dimenhydrinate, doxylamine, hydroxyzine

• H1 antagonist = diminishes vestibular stimulation & blocks CRTZ

DIMENHYDRINATE: salt of diphenhydramine

• 50 mg IV q4h (usual max 100 mg q4h); oral 25-50 mg q 6-8h

• Adverse effects: dry mouth, blurred vision, tachycardia, drowsiness

o Anticholinergic = all; antihistaminergic = drowsiness

DICLECTIN: doxylamine and pyridoxine (vit B6)

• Delayed release, 20 mg doxylamine (max dose 80 mg doxylamine)

o Half-life 10-12 hours, metabolized

• No dose adjustment in renal or hepatic failure

MUSCARINIC ANTAGONISTS: scopolamine/hyoscine, atropine

SCOPOLAMINE (hyoscine):

• Non-selective muscarinic antagonist (peripheral & central)

o Has both antinausea & antiemetic properties

• Patch applied near ear (6-8 hours for onset)

o Half-life = 4 hours; duration up to 72 hours (5 µg/h)

• Can be affected by grapefruit juice (CYP3A inhibitor)

• Adverse effects (anticholinergic): dry mouth, increased thirst,

dry skin, constipation, urinary retention, drowsiness, blurred

vision, dilated pupils (increase light sensitivity)

ERYTHROMYCIN:

• Purely prokinetic; activates motilin receptors to modulate activity

of vagal afferent fibers

• Low doses before meals (50-100 mg) may help pts with sx related

to gastric emptying

o Antibiotic doses (250-500 mg) can cause N/V/D

D2 RECEPTOR ANTAGONISTS:

• Mechanism as antinauseants uncertain, but thought to involve central D2

receptor antagonism in the CRTZ

HALOPERIDOL: D2 receptor antagonist

• 0.5 – 1 mg tid-qid (up to max of 4 mg/day)

o Metabolized by CYP3A4 and CYP2D6

• Usually only used for severe nausea and vomiting

• Adverse effects: mild sedation, EPS, hypotension

PROCHLORPERAZINE: D2 receptor antagonist with anti-ACh & anti-H1 activity

• 5-10 mg PO or IV, tid-qid (up to a max of 40 mg/day)

• Adverse effects: drowsiness, hypotension, EPS, dry mouth,

urinary retention, constipation

OLANZAPINE: 5HT2 & H1 inverse receptor agonist; antagonist at 5HT2A,

5HT2C, 5HT3, 5HT6, M1, M3, D1,2,3,4 and α1

• 5-10 mg/day common dose

• Adverse effects: sleepiness (common), dizziness, postural hypotension,

dyspepsia, weight gain

METOCLOPRAMIDE: central (CRTZ) D2 & weak 5-HT3 antagonist, peripheral

(GIT) 5HT4 agonist activity

• Prokinetic = increasing peristalsis speeds clearance of food from

stomach to duodenum

• 10 mg usual dose (drop dose by 50% if CrCl < 40 mL/min)

o 5-6 hour half-life, eliminated via renal excretion

• EPS (dystonia) in younger patients with increasing dose

DOMPERIDONE: D2 receptor antagonist that doesn’t cross the BBB = no EPS

(still acts on CRTZ, and peripherally)

• 10-20 mg q 4-8h prn

• Adverse effects: dry mouth, less common = abd. cramps & diarrhea

CISAPRIDE: 5-HT4 agonist & 5-HT3 antagonist (chemically related to

metoclopramide)

• Increases ACh release = motility enhancing or prokinetic effect to

speed stomach emptying

• Usual 5-10 mg po q6h 15 min PC

• Pro-arrhythmic properties (blocks K channels) caused it to be

removed from market, but available through Health Canada’s

Special Access Program (APO-Cisapride tabs 10 mg)

CORTICOSTEROIDS: dexamethasone, prednisone

• Antiemetic mechanism unknown

o May interact with glucocorticoid receptors in AP & NTS

o Prostaglandin inhibition (+ other anti-inflammatory effects)

may be responsible (ex: nausea related to injury of GI lining)

o Dexamethasone decreases expression of 5-HT3 receptors

and decreases release of serotonin

• Usual dose 4-5 mg (no dose adjustment in renal or hepatic failure)

o Appears synergistic with ondansetron

• AEs: rounded, plethoric (moon) face, trunk obesity; muscle

wasting; thinning, purple striae & easy bruising of skin; poor

wound healing; osteoporosis; mental disorders (depression); HTN,

diabetes; may increase intracranial pressure; associated with

peptic ulcers; increase number of platelets & RBCs

Lecture 3 Nausea and Vomiting Cairns

MOTION SICKNESS:

• Results from mismatch of sensory input from vestibular, visual & visceral

systems (including those based on experience) conflicting information

about body position

o Triggers: sea sickness, car sickness (made worse by reading), virtual

reality, loss of gravity, looking at screen (phone) while walking

• Affects almost everyone, but 5-10% of people very susceptible

o More common in 2-12 yo, then declines (rare by age ≥ 50 years)

• Symptoms: nausea & vomiting (vomiting gives period of symptom relief)

o Cold sweat, headache, drowsiness, salivation, pallor, anxiety

o Sopite syndrome = tiredness, boredom, apathy, irritability and

personality changes that can persist long after nausea has ended

• Why does motion sickness occur?

o Neurotoxin detector hypothesis: response is to detect brain altering

toxins and allow them to be eliminated by vomiting

o Ancestral hypothesis: hominids in swaying trees would be protected

by getting sick and thus hanging on instead of looking for food

MOTION SICKNESS TREATMENT:

• Habituation: allows people to become used to mismatched motion

• Control: pilots & drivers = much less motion sickness than passengers

• Controlled regular breathing: increases tolerance (perhaps by inhibiting

vomiting reflex, since breathing needs to stop to allow emesis)

• Drug treatment: vestibular neurons have M, D2, 5-HT2, H1 & H2

receptors, and emetic centers have H1 & M receptors

o H1 antihistamines (dimenhydrinate): inhibits vestibular

input to the NTS in part by decreasing the firing of afferent

fibers from the semicircular canals

o Antimuscarinics (scopolamine): vestibular afferent fibers

express M1, M2, and M5 receptors

NOTE: DA & 5-HT3 antagonists NOT EFFECTIVE for motion sickness

MENIERE’S DISEASE:

• Disorder of inner ear that results in recurrent attacks of dizziness from

several minutes to days

o Associated with tinnitus (ringing), hearing loss, & aura fullness

o Nausea is common & vomiting may occur during attack

• Swelling of membranous labyrinth of inner ear (endolymphatic hydrops)

leads to excess endolymph leaks out at cessation of each attack

• Prevalence: 1-2 per 1000 individuals

MENIERE’S DISEASE TREATMENT:

• Prophylaxis of dizziness: betahistine (partial H1 agonist & H3 antagonist)

o Analog of histidine = precursor of histamine

o 8-16 mg po tid

o Few SEs other than headache

• For acute attacks: prochlorperazine, meclizine (anti-H1) or domperidone

MIGRAINE-RELATED NAUSEA:

• Symptoms: severe headache (often unilateral, pulsating, behind eye) and

aggravated by physical activity; prodrome including aura (20%),

photophobia, phonophobia and osmophobia, NVD, nasal sinus congestion,

rhinorrhea, lacrimation, ptsosis, yawning, frequent urination, muscle

tenderness & cutaneous allodynia

• > 50% of migraineurs suffer from nausea during attacks

o 2/3rds of migraine sufferers are prone to motion sickness

• Pain is thought to be mediated by activation of meningeal vascular

nociceptors (trigeminal) activates brainstem trigeminal neurons which

make connections with NTS and parabrachial nucleus = may explain nausea

TREATMENT OF MIGRAINE-RELATED NAUSEA:

• Triptans that alleviate headache also seem to decrease nausea

(suggested that they act in NTS)

o Vomiting can temporarily relieve headache pain

• Metoclopramide (10 mg) can relieve both the headache and nausea

• Ondansetron (8 mg)

POST-OPERATIVE NAUSEA:

• 20-40% of surgical patients suffer postoperative nausea & vomiting

o Abdominal or gynecological surgical procedures may cause

release of 5-HT and neurokinins

o Head/neck surgery may activate NTS through trigeminal nerve

• Causes/risk factors:

o All gas anesthetics carry risk; longer exposures increase risk

o Use of opioid analgesics may be a cause

o Younger (< 50 yo) = more likely to suffer (decreases with age)

o Increased risk in women (2.6 x), non-smokers and those

suffering from motion sickness (genetic)

TREATMENT OF POST-OPERATIVE NAUSEA:

• Use non-volatile anesthetic = decreased nausea

• Aprepitant: 40 mg po 1-2 h before anesthesia induction

• Ondansetron: 4-8 mg IV end of surgery

• Metoclopramide: 10-25 mg IV 30 min prior to end of surgery

• Dexamethasone: 4-8 mg IV after induction of anesthesia

o Can combine with ondansetron

• Scopolamine patch: evening prior to anesthesia

► Can combine antiemetics with different mechanisms

► Non-pharm: acupuncture, isopropyl alcohol inhalation,

aromatherapy

TREATMENT OF LATE OR DELAYED POST-OPERATIVE NAUSEA:

• Occurs 5 or more hours after anesthesia ends

o Repeat prophylactic use

o Low-dose ondansetron (1-2 mg)

o Any other agent with rapid action

• Scopolamine patches & dexamethasone = too slow to be useful

OPIOID ANALGESICS:

• Nausea and vomiting (and retching) are common (20-50%) after

administration of opioid analgesics

o Particularly to naïve individuals started on them, but also in

chronic pain patients given a higher dose

o Dose-related phenomenon (higher doses suppress vomiting)

TREATMENT OF NAUSEA BY OPIOID ANALGESICS:

• 5HT3 antagonist: ondansetron 8-16 mg, palonosetron (0.075mg)

• D2 antagonists: haloperidol or prochlorperazine

o Metoclopramide only at doses > 10 mg

o Olanzapine 5 mg per day

o Risperidone for refractory opioid-induced N & V

• Alternatives:

o Switch opioid analgesic (tapentadol may have less effects)

o Add low dose naloxone or methylnaloxone (= peripherally

restricted antagonist)

CENTRAL MECHANISMS:

• Opioids directly stimulate CRTZ (activation of mu and delta

receptors) and vestibular apparatus (mu receptor)

• Signalling of nausea through D2 & 5-HT3 receptor activation

• Ambulatory patients are more susceptible to vomiting

PERIPHERAL MECHANISMS:

• Activation of peripheral mu (and kappa) receptors

• Inhibits gut motility by inhibiting ACh release by vagal afferents

distension, delayed gastric emptying & constipation

activate vagal afferents

• May also induce spasm in the esophagus

Lecture 3 Nausea and Vomiting Cairns

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING:

• Common, and influences decision about further therapy with these agents

o Risk increased with type of chemotherapy used

• Increased risk in women, < 50 years old, history of motion sickness and

history of previous emesis during treatment

TYPES OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING:

• Acute: occurs during first 24 hours after chemotherapy

o Development related to chemotherapeutic used, dosage, patient

susceptibility and environment

• Delayed: occurs > 24 hours after chemo

o Cisplatin, doxorubicin or cyclophosphamide major causes

o For cisplatin, nausea & vomiting peaks 2-3 days post chemo and

lasts up to one week

• Breakthrough: occurs despite prophylaxis

• Anticipatory: occurs prior to chemo treatment (up to 10-45% of pts)

o Adverse memory of chemo

• Refractory: recurs and is not responsive to prophylaxis or treatment

PATHOPHYSIOLOGY:

Acute • Agents create free radicals that promote the release of serotonin (and substance P) from ECL cells excite vagal afferents through 5HT3 (and NK1) receptors act on area postrema

Delayed • Agents or metabolites directly activate the central pattern generator for vomiting, partly through increases in substance P levels

Anticipation • Pavlovian conditioning = aversive response (nausea and vomiting) to a stimulus (chemotherapy) is learned

Stress • Mediated through activation of HPA axis

• Circulating hormones may act on hypothalamus to induce autonomic response that initiate N & V o Ex: VIP increases when motion sickness is

induced (relaxes smooth muscle of stomach) o Ex: vasopressin (ADH) levels increase before

emesis & corelated with nausea intensity

TREATMENT OF CHEMOTHERAPY-INDUCED NAUSEA & VOMITING:

Acute • Prophylaxis is usually a combination of corticosteroid (dexamethasone) and 5-HT3 antagonist (ondansetron 8 mg or palonosetron 0.25 mg) o +/- aprepitant (single dose of 125 mg) for

highly emetic-causing chemo

• Dopamine antagonists used once nausea & emesis are established (metoclopramide 20 mg tid)

Delayed • Dexamethasone, aprepitant, palonosetron

• NOT 1st gen 5-HT3 antagonists (i.e. not ondansetron)

• Olanzapine may be effective when added to a 5-HT3 antagonist and dexamethasone o Nausea may be particularly reduced o Refractory nausea & vomiting may respond

• Cannabinoids do not seem to provide additional benefit, and ginger does not appear effective

Refractory • Anxiety = major component, so anxiolytic (lorazepam)

• Olanzapine

Anticipatory • Council on effectiveness of prophylactic agents (this works in 70-75% of patients!)

• Use most effective prophylactic therapy

• Anxiolytics if anxiety is a factor (lorazepam)

• Behavioral therapy

RADIATION-INDUCED NAUSEA AND VOMITING:

• > 80% of patients receiving total body, half body and abdominal

radiotherapy have nausea and vomiting

o < 30% suffer from nausea when extremities are irradiated

• Emesis tends to occur in early phase of treatment

o Thought that tissue damage and release of 5-HT & substance P

lead to nausea and vomiting (but exact cause unknown)

• Risk factors similar to chemotherapy

o Increased risk in women, < 50 years old, history of motion

sickness and history of previous emesis during treatment

TREATMENT OF RADIATION-INDUCED NAUSEA AND VOMITING:

• 5-HT3 antagonists (ondansetron) are best choice for patients

receiving upper abdominal irradiation who have acute nausea

• Evidence for prophylaxis is lacking

• Other agents have not shown great efficacy in treating nausea

induced by irradiation

GASTROPARESIS:

• Delayed emptying without evidence of mechanical obstruction

o Nausea and vomiting are most common symptoms

o Poor correlation between sx severity & degree of gastric stasis

• Proposed causes:

o Injury to nerve or muscles of stomach (vagus nerve regulates

fundic accommodation, antral contraction & pyloric relaxation)

o Injury to interstitial cells of Cajal (which regulate gastric

pacemaker activity)

• Types: diabetic, postsurgical, and idiopathic

• Roughly 3x more common in young women than in men

TREATMENT:

• Prokinetics: domperidone, metoclopramide (but ↑ SE), cisapride

• Opioid analgesics contraindicated (slow gastric emptying)

HANGOVER:

• Tiredness, headache & nausea/vomiting from alcohol consumption

• Alcohol is metabolized to acetaldehyde by alcohol dehydrogenase, and

then to acetate by acetaldehyde dehydrogenase

o Acetaldehyde is thought to cause some of the hangover sx

o Acetaldehyde dehydrogenase mutations can predispose to

severe hangover

• Nothing works particularly well – other than responsible consumption

NAUSEA AND VOMITING DURING PREGNANCY (MORNING SICKNESS):

• 50-80% of women, usually 2-4 weeks after fertilization (peaks at 4 m)

o In most women, nausea persists throughout the day

o Tends to resolve by week 22 in most women, but 5% suffer

throughout pregnancy

• Hyperemesis gravidarum: condition of persistent nausea, weight loss,

electrolyte imbalance (hypokalemia), dehydration

PATHOGENESIS:

• Genetics – tendency appears inherited

• Elevated beta HCG, estrogen & progesterone = alter GI motility and

slow gastric emptying

• Estrogen increases NO levels (by stimulation of NO synthase) which

relaxes gastric smooth muscle

• Nausea correlated with increased prostaglandin E2 (from placenta)

TREATMENT:

• Concern is over potential harm to fetus

• H1 antagonists: diphenhydramine, dimenhydrinate, meclizine,

doxylamine, diclectin (pyridoxine + doxylamine, or as single entities)

o Metoclopramide is safe, but increased SE profile