antiemetics

1. Emetics and antiemetics

2. Emesis (vomiting)
• Act of forceful expulsion of gastric
contents through the mouth
• Often preceded by nausea

3. Emesis
• Rational (valuable) reflex
• prevention of ingestion of noxious substances (sight, smell,
taste, texture)
• local gut reflexes stimulate vomiting e.g. toxins
• Irrational reflexes
• labyrinth
• pregnancy

5. Neurotransmitters Involved
• Histamine via H1 receptors
• Serotonin via 5HT3 receptors
• Acetylcholine via M receptors
• Dopamine via D2 receptors

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Emetic Centre
CTZ
Hormones
Azotaemia
Diabetes
Vestibular
Sights
Smell
Taste
Vomiting Gut
Opioids
Chemotherapy
Anaesthetics
BBB
Hypotension
Hypoxaemia

7. Vomiting Centre
(medulla)
Cerebral cortex
Anticipatory emesis
Smell
Sight
Thought
Vestibular
nucleiMotion
sickness
Pharynx & GIT
Chemo & radio therapy
Gastroenteritis
Chemoreceptor
Trigger Zone
(CTZ)
(Outside BBB)
Cancer chemotherapy
Opioids
Muscarinic, 5 HT3 &
Histaminic H1
5 HT3 receptors
Dopamine D2
5 HT3,,
Opioid Receptors
Muscarinic
Histaminic H1
Pathophysiology of Emesis

8. Emetics
They are required when an undesirable substance
has been ingested

9. Emetic Drugs - Uses
• Acute cases of poisoning (except in corrosive substances
poisoning or if patient is not fully conscious)
• Alcoholic intoxication
• Removal of foreign bodies from the oesophagus
• Certain cases of paroxysmal tachycardia

10. Emetic Drugs -
Contraindications
• Hernias
• Aneurysm
• Severe heart diseases
• Peptic ulcer
• Pulmonary TB
• Prolapse of rectum or uterus
• Threatened abortion
• Weak / debilitated persons

11. Emetic Drugs
• Centrally acting: Apomorphine
• directly stimulate the CTZ or VC
• Reflexly acting: Ipecacuanha
• stimulate the VC by irritating gastric & duodenal mucosa which
stimulate afferent fibres of vagus nerve
• Locally acting: Aluminum, Sodium Chloride
(Concentrated Solution)
• Other Drugs as Adverse Effect: Morphine,
Digitalis, Emetine, Aspirin, Quinine & Anticancer
drugs

12. Emetic drugs
• Apomorphine
• Ipecacuanha

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Apomorphine
• Semi synthetic derivative of morphine
• Given IM or SC, act centrally; local effect on GIT not required.
• Dose is 6 mg (2-8mg)
• Induces vomiting in 5 -10 min
• CNS depressant contraindicated in respiratory depression
•

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Ipecacuanha
• Contains two alkaloids- emetine & cephaeline
• Used as syrup ipecac.
• Produces effect in 15 min.
• Acts by irritating gastric mucosa & through CTZ centre.
• Dose = 5ml in infants
= 10-15ml in children
= 15-20ml in adults

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Contraindications
• Corrosive poisoning
• Kerosene poisoning
• Unconscious patients
• Morphine poisoning

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Anti-emetics

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Introduction - Anti-emetics
• Two centres: vomiting centre (VC) and chemoreceptor
trigger zone (CTZ)
• Both near the floor of the fourth ventricle, close to the
vital centres
• VC is within the blood brain barrier (BBB)
• CTZ outside in the area postrema
• They are connected together

18. ANTIEMETIC
DRUGS
A group of drugs which are used to control
nausea and vomiting
Provide symptomatic relief
Removal of causative factor to have ultimate relief

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Vomiting Centre
(medulla)
Cerebral cortex
Anticipatory emesis
Smell
Sight
Thought
Vestibular
nucleiMotion
sickness
Pharynx & GIT
Chemo & radio therapy
Gastroenteritis
Chemoreceptor
Trigger Zone
(CTZ)
(Outside BBB)
Cancer chemotherapy
Opioids
Muscarinic, 5 HT3
& Histaminic H1
5 HT3
receptors
Dopamine D2
5 HT3,
Opioid Receptors
Muscarinic
Histaminic H1
Pathophysiology of Emesis

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21. Classification - Antiemetic drugs
1. H1antihistamines
Meclizine, Cinnarizine, Cyclizine,
Dimenhydrinate & Diphenhydramine.
2. Muscarinic Antagonist
Hyoscine (Scopolamine).
3. Selective 5-HT3 Antagonists
Ondansetron, Granisetron,
Palonosetron & Dolasetron.

22. 4. D2 Antagonists
a. Substituted Benzamides
Metoclopramide, Trimethobenzamide
b. Butyrophenones
Domperidone , Droperidol
c. Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine.
5. Cannabinoids
Dronabinol , Nabilone
6. Glucocorticoids
Dexamethasone, Methylprednisolone
7. Benzodiazepines
Diazepam , Lorazepam
8. Neurokinin-I Antagonist
Aprepitant (oral formulation), Fosaprepitant (IV formulation)

23. D2 Antagonists
a. Substituted Benzamides
Metoclopramide, Trimethobenzamide
b. Butyrophenones
Domperidone , Droperidol
c. Phenothiazines
Prochlorperazine, Promethazine &
Thiethylperazine.

24. Metoclopramide
Chemistry: Substituted Benzamide
MOA: Dopamine D2 receptors antagonist
It is potent Antiemetic & Prokinetic agent
As Antiemetic
• It has potent Antiemetic & antinausea effect.
• Blocks D2 receptors in CTZ of the medulla (area postrema)
As Prokinetic agent
• It can selectively stimulate gut motor function.
• Blocks D2 receptor in GIT & blocks the normal inhibitory
effect of Dopamine on cholinergic smooth muscle
stimulation--- ↑ motility.

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The Uses - Metroclopramide
Potent antiemetic controls / reduces vomiting due to
• Uremia
• Radiation
• Viral gastro enteritis, hepatic-biliary disease
• Anticancer drugs
• Migraine
• Post operatively & pre-operatively

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Metroclopramide…
Pharmacokinetics
• Rapidly absorbed from GIT after oral administration.
• Undergoes a high degree first pass metabolism.
• It is excreted in the urine as free and as metabolites.
• It is also excreted in the breast milk.
• DOSE: 10-20mg orally or IV every 6 hrs

27. Adverse Effects - Metroclopramide
• Extrapyramidal reactions with facial and skeletal muscle
spasms- Restlessness, Dystonias , Parkinsonian symptoms.
-----More common in young and very old. Usually occur shortly
after staring treatment and subside with in 24 hours of stopping
the drug.
• Bowel upsets, Diarrhea
• Drowsiness and fatigue, dizziness, restlessness and anxiety.
• Galactorrhoea, Gynecomastia, impotence and menstrual
disorders – due to increased prolactin levels

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Trimethobenzamide
Substituted Benzamide
Antiemetic like Metoclopramide.
D2 Antagonist & mild anti- histaminic activity
DOSE: 250mg orally, 200mg rectally, 200mg IM

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Phenothiazines
Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine
Phenothiazines are antipsychotics with potent antiemetic
property due to D2 antagonism and anti-maucarinic
properties
Sedative property due to anti-histaminic property
Mainly used as anti-emetic in severe N& V
Main A/E: EPS , sedation , postural hypotension

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Butyrophenones
Antipsychotic drugs , D2 antagonists
Droperidol
Central D2 antagonist
Main A/E: EPS , postural hypotension
QT prolongation may occur
Domperidone
• Does not cross BBB. Only blocks D2 in CTZ where BBB is leaky.
• May be used in N&V due to Levodopa, without affecting its
efficacy.
• No EPS.
• Used as antiemetic , prokinetic agent & for post partum lactation
stimulation.

31. Selective 5-HT3 Antagonists
Ondansetron, Granisetron , Dolasetron & Palonosetron
MOA
Act as anti-emetic by Selectively blocking central 5HT3 receptors in
Vomiting center & CTZ & Mainly by blocking Periphery 5HT3
receptors on intestinal vagal and spinal afferent fibers
Antiemetic action is restricted to emesis caused by vagal stimulation
(e..g post operative) & chemotherapy
Palonosetron: newer with greater affinity for 5-HT3 receptor &
comparatively longer half life
No effect on Dopamine / muscarinic receptors

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Ph. K - Selective 5-HT3 Antagonists
• High first pass metabolism
• t1/2 : 4-9 hrs (Ondansetron, Granisetron & Dolasetron)
40 hrs (Palonosetron)
• Given once or twice daily – orally or intravenously
• Excreted by liver & kidney
• No dose reduction in renal insufficiency but needed in
hepatic insufficiency (Ondansetron)

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The Uses - Selective 5-HT3 Antagonists
• Chemotherapy- Induced Nausea & vomiting
• Primary Agents - prevention of acute chemotherapy induced
Nausea & vomiting
Effective alone in most of the cases. Efficacy is enhanced in
combination. Can be given I/V 1/2 hr before chemotherapy
• To prevent Delayed Nausea & vomiting occurring after 24 hrs
of Cancer chemotherapy
in combination with Dexamethasone & NK1 receptor
antagonist.
• To prevent & treat post operative & post radiation
Nausea & vomiting

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A/Es - Selective 5-HT3 Antagonists
• Excellent safety profile
• Headache, Dizziness & constipation
• All three drugs cause prolongation of QT interval, but
more pronounced with dolasetron.
DIs
Hepatic clearance may decrease by enzyme inhibitors

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H1antihistamines & Muscarinic Antagonists
H1antihistamines
Meclizine, Cinnarizine, Cyclizine & Diphenhydramine &
its salt Dimenhydrinate.
• They have anticholinergic & H1 antagonist sedating properties
(1st generation).
• They produce specific depression of conduction in
vestibulocerebellar pathway.
MuscarinicAntagonist
Hyoscine (Scopolamine).

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H1antihistamines & Muscarinic Antagonists…
Theraputic Uses
• Vestibular system is important in motion sickness
via cranial nerve VIII - rich in Cholinergic M1 &
Histamine H1receptors
• Most effective drugs for motion sickness
• Effective for nausea & vomiting associated with motion
sickness.
• Vestibular disorders ( Meniere’s disease)
• (hyoscine) – used as transdermal patch for motion sickness
• Meclozine is long acting so useful in sea sickness
• Cinnarizine also has antivertigo effect. Act by inhibiting
influx of calcium to vestibular sensory cells from
endolymph

37. Cannabinoids
(Dronabinol , Nabilone)
Dronabinol
Tetrahydrocannabinol (THC) main psychoactive
chemical in marijuana
Pharmacokinetics: complete absorption on oral
administration, significant 1st pass effect, metabolites
excreted slowly over days to weeks in faeces & urine

38. • MOA: Act as antiemetic & appetite stimulant in addition
to psychoactive action. MOA not clear.
• Cancer chemotherapy induced Nausea & vomiting
with Phenothiazines – synergistic effect but AEs
are added – not used as better drugs are available
• Nabilone
• closely related THC analog

39. Glucocorticoids
Dexamethasone , Methylprednisolone
Antiemetic MOA not clear
Enhance action of 5HT3 antagonists in Cancer
chemotherapy induced Nausea & vomiting

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Benzodiazepines
Diazepam, Lorazepam
• Used prior to Cancer chemotherapy to reduce
anticipatory vomiting
• Vomiting caused by anxiety

41. Neurokinin-1 (NK1 )Antagonists
Aprepitant, Fosaprepitant
Given orally BA = 65% , Crosses BBB.
t ½ : 11 hrs, Metabolized by hepatic CYP3A4.
MOA
Act as Antiemetic: Selectively block NK1 receptor in area
postrema.
No effect on Serotonin , Dopamine or Corticoid receptors

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Aprepitant
• Non peptide, selective, Neurokinin type 1 (NK 1)
receptors antagonist
• Block substance P from binding to NK1 receptor
• Broader spectrum and activity in delayed emesis (In
Preclinical studies)
• Augment the antiemetic activity of 5HT3 receptor
antagonists and dexamethasone
• Inhibit both acute and delayed CINV

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Neurokinin-1 (NK1 )Antagonists
Uses
Used in combination with 5HT3 antagonists &
Corticosteroids for prevention of acute & chronic
nausea and vomiting from Cancer chemotherapy

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Neurokinin-1 (NK1 )Antagonists
A/Es
• Fatigue, dizziness & diarrhoea.
• Enzyme inhibition
• Metabolized by CYP3A4 & may inhibit metabolism of many anticancer drugs
(Docetaxel, Paclitaxel, Etoposide, Vinblastine, Imatinib) ---- ↑ levels ---
toxicity.
• Metabolism of Aprepitant may be inhibited by Ketoconazole, Ciprofloxacin,
Clarithromycin, Nafazodone, Ritonavir, Nelfinavir, Verapamil & Quinidine)
• Aprepitant ↓ INR in patients taking warfarin.

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Therapeutic Uses of Anti-emetics
• Motion sickness: Hyoscine
• Vestibular disorders( Menieres, disease): Cinnerazine
• Vomiting due to Uremia, Radiation, Viral gastro enteritis,
Liver disease, Migraine, Prochlorperazine ,
Metroclopramide
• Vomiting due to pregnancy ( hyperemesis gravidarum),
Meclizine with vit. B6 (Navidoxine)

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• Vomiting due to Cytotoxic Anticancer drugs: 5HT3
Antagonists Metroclopramide, Cannabinoids,
corticosteroids , Aprepitant
• Anticipatory Vomiting due to Cytotoxic Anticancer
drugs. Benzodiazepines (Diazepam)
• Post Operative Vomiting: Metoclopramide ,
Prochlorperazine , Dimenhydrinate, 5HT3 Antagonists
(Ondensetron)

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Thank You

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