Emetics and antiemetics

Emesis (vomiting)

• Act of forceful expulsion of gastric contents through the mouth• Often preceded by nausea

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

Neurotransmitters Involved

• Histamine via H1 receptors

• Serotonin via 5HT3 receptors

• Acetylcholine via M receptors

• Dopamine via D2 receptors

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Emetic Centre

CTZHormonesAzotaemiaDiabetes

VestibularSightsSmellTaste

Vomiting Gut

OpioidsChemotherapyAnaesthetics

BBB

HypotensionHypoxaemia

Vomiting Centre (medulla)

Cerebral cortex

Anticipatory emesisSmellSight

Thought

Vestibular nucleiMotion

sickness

Pharynx & GIT

Chemo & radio therapy Gastroenteritis

Chemoreceptor Trigger Zone

(CTZ)(Outside BBB)

Cancer chemotherapyOpioids

Muscarinic, 5 HT3 & Histaminic H1

5 HT3 receptors

Dopamine D2

5 HT3,,

Opioid Receptors

Muscarinic Histaminic H1

Pathophysiology of Emesis

Emetics

They are required when an undesirable substance has been ingested

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

Emetic Drugs - Contraindications

• Hernias• Aneurysm• Severe heart diseases• Peptic ulcer• Pulmonary TB• Prolapse of rectum or uterus• Threatened abortion• Weak / debilitated persons

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

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

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 emesisSmellSight

Thought

Vestibular nucleiMotion

sickness

Pharynx & GIT

Chemo & radio therapy Gastroenteritis

Chemoreceptor Trigger Zone

(CTZ)(Outside BBB)

Cancer chemotherapyOpioids

Muscarinic, 5 HT3 & Histaminic H1

5 HT3 receptors

Dopamine D2

5 HT3,

Opioid Receptors

Muscarinic Histaminic H1

Pathophysiology of Emesis

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Classification - Antiemetic drugs

1. H1antihistamines Meclizine, Cinnarizine, Cyclizine,

Dimenhydrinate & Diphenhydramine.

2. Muscarinic Antagonist

Hyoscine (Scopolamine).

3. Selective 5-HT3 Antagonists

Ondansetron, Granisetron, Palonosetron & Dolasetron.

4. D2 Antagonists a. Substituted Benzamides

Metoclopramide, Trimethobenzamide b. Butyrophenones

Domperidone , Droperidol c. Phenothiazines

Prochlorperazine, Promethazine & Thiethylperazine.5. Cannabinoids

Dronabinol , Nabilone6. Glucocorticoids

Dexamethasone, Methylprednisolone7. Benzodiazepines

Diazepam , Lorazepam8. Neurokinin-I Antagonist

Aprepitant (oral formulation), Fosaprepitant (IV formulation)

D2 Antagonists

a. Substituted Benzamides Metoclopramide, Trimethobenzamide

b. Butyrophenones Domperidone , Droperidol

c. Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine.

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

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

DroperidolCentral 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.

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) & chemotherapyPalonosetron: 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 & vomitingEffective 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.

MuscarinicAntagonistHyoscine (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

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

• 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

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

Neurokinin-1 (NK1 )Antagonists Aprepitant, Fosaprepitant

Given orally BA = 65% , Crosses BBB.t ½ : 11 hrs, Metabolized by hepatic CYP3A4.

MOAAct 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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