Anti-Emetics

Question 1

Emesis

Answer 1

Emetic – agent which causes vomiting
Anti-emetic – agent which prevents vomiting
forceful evacuation of gastric contents through mouth; A protective physiological mechanism in response to something harmful being ingested
Stages:
Feeling of nausea
Retching
Vomiting

Question 2

Integrated Physiology of Emesis

Answer 2

The Vomiting Reflex is regulated by the CNS (medulla)
The mechanism of emesis is a complex process dependent on multiple biological, chemical, and neural pathways.
Emesis is controlled and centralized within the brainstem in a neural network on the dorsal surface of the medulla oblongata.
This region is referred to as the “brainstem emetic (vomiting) control center” or dorsal vagal complex.

Question 3

There are three major inputs to the dorsal vagal complex which cause nausea and vomiting:

Answer 3

The Chemoreceptor Trigger Zone (located in the dorsal vagal complex),

The Vagal Pathway

The Vestibular Pathway.

Question 4

Signal Integration and Drugs

Answer 4

Endogenous mediators of emesis
Serotonin Ach Dopamine Substance P Histamine Enkephalin

Anatagonist i.e. anti emetics
5HT3, M, D2, NK1, H1, Omega

Question 5

General Antiemetic Drugs

Answer 5

Choice of drug will be based upon the stimulus causing nausea and vomiting which determines which receptors are activated

Several classes of drugs are effective and available

Used for specific conditions, but there is overlap

Many histamine, muscarinic & serotonin receptor antagonists exhibit clinically useful activity

Different classes of anti-emetics have different side effect profiles

Question 6

Targets for Anti-Emetics - Chemoreceptor trigger zone

Answer 6

Dopamine: D2
Substance P/Neurokinin: NK1
Serotonin or 5HT3 Receptors: 5HT3

Question 7

Targets for Anti-Emetics - Vagal pathway

Answer 7

Serotonin or 5HT3 Receptors: 5HT3

Question 8

Targets for Anti-Emetics - Vestibular pathway

Answer 8

Histamine: H1
Muscarinic: M

Question 9

Targets for Anti-Emetics - Vomiting Centre

Answer 9

Histamine: H1
Muscarinic: M
Substance P/Neurokinin: NK1
Serotonin or 5HT3 Receptors: 5HT3

Question 10

H1 Antagonists / Antihistamines

Answer 10

Cyclizine - motion sickness
Cinnarizine - motion sickness, vestibular disorders (e.g. Meniére´s disease, vertigo)
Promethazine - severe morning sickness of pregnancy

Of limited use against substances that act directly on CTZ

Side effects: Drowsiness and sedation; but these do contribute to efficacy

Question 11

H3 Agonists

Answer 11

Betahistine hydrochloride / anti-vertigo drug Serc®.

Mode of action:
Activates H-receptors on blood vessels in the inner ear
→ local vasodilation
→ increased permeability
→ reverses the underlying problem of endolymphatic hydrops

Side-effects: gastro-intestinal disturbances; headache, rashes, pruritus

Question 12

Good “general purpose” antiemetics -

Hyoscine, Scopolaimine

Answer 12

• non-selective antagonists
• motion sickness (drug of choice)
• oral and / or transdermal patch application

Side-effects:

• dry mouth, blurred vision,
• less sedative actions than antihistamines

Question 13

Anti-Emetic Dopamine Receptor Antagonists

Answer 13

D2 receptors have a strong representation in the in chemoreceptor trigger zone
D2 Antagonists have a powerful anti-emetic action, and will antagonise muscarinic and histamine receptors too

Question 14

Phenothiazines

Answer 14

D2 receptor antagonist
Severe morning sickness of pregnancy 
Administered orally, i.v. or suppository
Inexpensive
Side-effects:  sedative, hypotension, 
dystonia (especially children), dyskinesia

Question 15

dystonia

Answer 15

a state of abnormal muscle tone resulting in muscular spasm and abnormal posture, typically due to neurological disease or a side effect of drug therapy

Question 16

Metoclopramide

Answer 16

D2 receptor antagonist
Penetrates blood brain barrier
Acts on GIT; increasing GI motility
Oral administration/injection (i.m./i/v.)

Side-effects: movement disorders (esp. children), fatigue, motor restlessness, spasmodic torticollis, occulogyric crises, menstruation disorders (via effect on prolactin release), Rare Reactions; QT prolongation

Question 17

Domperidone (Motilium, Motillium)

Answer 17

D2 receptor antagonist
Does not penetrate BBB; has reduced central effectiveness, but fewer side effects

Used for migraine & cytotoxic therapy-induce emesis; emesis due to emergency hormonal contraception

Oral administration/i.v./suppositories

Question 18

BBB

Answer 18

BLOOD BRAIN BARRIER

Question 19

Ondansetron

Answer 19

Drug of choice for CINV (chemotherapy) and PONV (anesthetics)
Oral, suppositories, i.v. or intramuscular administration

Side-effects: gastro-intestinal disturbances; headache (not common)
Granisetron (Oral, i.v.), palonosetron (i.v.), tropisetron (Oral, i.v.)

Question 20

Aprepitant

Answer 20

Neurokinin-1 antagonist
Active in late phase emesis with cytotoxic drugs
Substance P antagonist
Used for CINV and PONV
Oral / i.v. admin
Side Effects: fatigue, listlessness, constipation / diarrhea, loss of appetite, hiccups Rare Side Effects: dizziness, ringing in the ears, hiccups, dyspepsia, diarrhoea, constipation, anorexia; asthenia, headache..

Question 21

CINV

Answer 21

Chemotherapy-induced nausea and vomiting

Question 22

PONV

Answer 22

Postoperative nausea and vomiting

Question 23

Anti-Emetic Action of Cannabinoids

Answer 23

Mode of action:
Acts as an agonist of the CB receptors, but mechanism of action an an entiemetic is unknown.
CB1 found in the brainstem, but may act thought to act via opioid receptors in CTZ

Question 24

Nabilone (Cesamet)

Answer 24

Mimetic of the main chemical component of cannabis (HTC)
Valuable in the treatment of CINV ; FDA approval in 1985, marketed 11 years later
Adjunct therapy for chronic pain management
Thought to act via opioid receptors in CTZ
Oral Administration
Side effects: drowsiness, dizziness, dry mouth, mood changes, postural hypotension Rare Side Effects:, hallucinations, psychotic reactions

Question 25

Corticosteriods - Dexamethasone

Answer 25

‡ vomiting caused by cytotoxics (chemotherapy)
‡ mechanism of action not fully understood
‡ used in combination with D2 or 5HT3 antagonists → improved actions