ANTI-EMETICS

SUBJECT: SYSTEMIC PHARMACOLGY23-10-2014

MERIN BABUM.Pharm 1st Semester

Department of PharmacologyAmrita School Of Pharmacy, Kochi

NAUSEA & VOMITING

ACT OF EMESIS: To get rid the stomach and intestine toxic substances and prevent further ingestion.

VOMITING: Expulsion of gastric contents through mouth due to mass antiperistalsis.

NAUSEA: Uneasy feeling of vomiting.

RETCHING: Series of weaker and unproductive vomiting movements.

VOMITING

• Vomiting is a complex process that consists of :

• PRE-EJECTION PHASE: Gastric relaxation and retro peristalsis.

• RETCHING:Rhythmic action of respiratory muscles preceding vomiting and

consist of abdominal & intercoastal muscles and diaphragm against a closed glottis.

• EJECTION:Intense contraction of abdominal muscles and relaxation of upper

oesophageal sphincter.

• Followed by multiple autonomic phenomena:Salivation, Shivering, Vasomotor changes

ANTI-EMETIC MECHANISM

ANTI-EMETIC MECHANISM

• Anti-emesis process is coordinated by a central emesis center in lateral reticular formation of midbrain adjacent to both chemoreceptor trigger zone (CTZ) in the area postrema (AP) at the bottom of 4th ventricle and solitary tract nucleus (STN).

• Lack of blood-brain barrier (BBB) allows CTZ to monitor the blood and CSF for toxic substances and to relay information to emesis center to trigger nausea and vomiting.

ANTI-EMETIC MECHANISM

Vestibular apparatus generates impulses during motion sickness which reach vomiting center via cerebellum. Vestibular apparatus is rich in M1, H1

receptors.

Emesis also receives information from gut through vagus nerve (via STN) and splanchnic afferent nerves via spinal cord. They are rich in 5HT3

receptors.

Irritants of GIT mucosa ( irritants, chemotherapeutic drugs, radiation, endogenous toxins and poisons ) --- release mucosal serotonin from entero-chromaffin like cells (ECL cells) which activate 5HT3 receptors.

Inputs to emesis center also come from cerebral cortex ( particularly in anticipatory nausea & vomiting.

M1, H1,5HT3 and neurokinin-1 (NK1) receptors are present in vomiting center.

CLASSIFICATION OF ANTI-EMETIC DRUGS

• 5HT3 ANTAGONISTS:Ondansetron, Granisetron, Dolansetron, Palonosetron, Ramosetron, Tropisetron.

• CENTRALLY ACTING DOPAMINE RECEPTOR ANTAGONIST:Metoclopramide, Domperidone, Chlorpromazine, Prochlorperazine

• HISTAMINE (H1) RECEPTOR ANTAGONIST:Cyclizine, Promethazine, Diphenhydramine, Hydroxyzine

• ANTICHOLINERGIC ( MUSCARINIC RECEPTOR ANTAGONIST):Hyoscine (Scopolamine)

• NEUROKININE RECEPTOR ANTAGONIST:Aprepitant

• CANABINOID RECEPTOR AGONIST:Dronabinol, Nabilone

OTHER ANTI-EMETIC DRUGS

• CORTICOSTEROIDS:Betamethasone, Dexamethasone

• VITAMIN B6 (PYRIDOXINE):

• PHOSPHATED CARBOHYDRATE SOLUTION:

5HT-3 ANTAGONISTSDRUG MOA PK USE ADVERSE

EFFECTS

ONDANSETRON-prototype drug

5-HT is releasedfrom

enterochromaffincells (ECL) of

small intestine in response to

chemotherapy agents.

These stimulate vagal afferents

initiating vomiting reflex.

Antagonism of 5HT-3 receptors suppress nausea

& vomiting

Anti-emetic effect persists for

long time even after they

disappear from circulation.

A: well absorbed from GIT.

M: metabolised by CY1A2,

CYP2D6, CYP3A4 followed by

glucouridination

Chemotherapy induced

emesis

Constipation/DiarrhoeaHeadache

Lightheadness

5HT-3 ANTAGONISTS

DRUG MOA PK USE ADVERSE EFFECTS

GRANISETRON M: liver - Chemotherapy induced nausea- Nausea secondary to upper abdominal irradiation- Hyperemesisof pregnancy

Constipation/DiarrhoeaHeadache

DOLANSETRON

PALONOSETRON M: CYP2D6E: urine

Delayed emesis-due to long half

life

DOPAMINE RECPTOR ANTAGONISTS

METOCLOPRAMIDE:

• Acts centrally blocking D2 receptors in CTZ.

• Used in nausea and vomiting due to GI disorders, in postoperative period and vomiting due to cytotoxic drugs and radiotherapy.

DOMPERIDONE:

• Blocks D2 receptors in CTZ and acts as antiemetic.

• Advantage: doesn’t cross BBB – rare extrapyramidal effects

• SE: headache, dryness of mouth, diarrhoea, rashes

ANTI-HISTAMINERGIC DRUGS

• H1 antagonists --- useful for motion sickness and post-operative emesis.• Act on vestibular afferents and within brainstem.

CYCLIZINE, HYDROXYCYZINE, PROMETHAZINE, DIPHENHYDRAMINE.

PROMETHAZINE:

• Most potent and effective.• Drug must be taken 1 hr before the motion.• Useful for chemotherapy/ radiation therapy for malignancies.

ANTI-CHOLINERGIC DRUGS

HYOSCINE (SCOPOLAMINE):

• Labyrinthine sedative.

Very effective in motion sickness.• Motion sickness is due to over stimulation of vestibular

apparatus along with psychological and environmental factors.

Given as transdermal patch.

Useful for post-operative nausea & vomiting.

SUBSTANCE P ANTAGONISTS

Nausea and vomiting associated with Cisplatin have 2 components:

Acute Phase: within 24hrs after chemotherapy

Delayed Phase: affects only some patients ( only days 2-5)

Antagonists for NK1 receptors for substance P -- APREPITANTHave anti-emetic effects in delayed nausea and improve the efficiency of standard anti-emetic regimen.

Aprepitant given along with highly emetogenicchemotherapy in combination with 5HT3 ANTAGONIST + CORTICOSTEROID.

CANNABINOIDS

DRONABINOL- naturally occurring cannabinoid.

Stimulates CB1 subtype of cannabinoid receptors on neuron in and around vomiting center in brain stem.

PHARMACOKINETICS:Highly lipid soluble drug.Onset of action within 1 hr. Peak levels within 2-4hrs.E: urine.

USE:Useful prophylactic agent in chemo patients when others are not effective.

ADVERSE EFFECTS:Complex effects on CNS-central sympathomimetic effect.

Palpitation, tachycardia, vasodilation, hypotension.Abrupt withdrawal --- abstinence syndrome.

OTHER ANTI-EMETICS

GLUCOCORTICOIDS:

DEXAMETHASONE:

• Useful for treatment in nausea in patients with widespread cancer.

• Suppress peritumoural inflammation & PG production.

PHOSPHATED CARBOHYDRATE SOLUTION:

• Aqueous solution of glucose, fructose and phosphoric acid- relieve nausea.

• It is taken for a short period of time.

TYPES OF EMESIS

MOTION SICKNESS

MORNING SICKNESS (VOMITING DURING PREGNANCY)

CHEMOTHERAPY/ RADIATION INDUCED NAUSEA AND EMESIS (CIE)

POST OPERATIVE EMESIS

VOMITING OF VARIED ORIGIN & ADJUVANT ANTI-EMETIC

TYPES OF EMESIS-MOTION SICKNESS

Result during space flights, taking off and landing of an aeroplane etc.

It is a labyrinthine vomiting via stimulation of vestibular nuclei.

Drugs used:H1 ANTAGONIST/ CENTRAL ACTING

ANTICHOLINERGIC.Hyoscine.Side effects of hyoscine: anticholinergic

Blurred vision, dryness of mouth, cyclopelgia, sedation and sleepiness.

DIPHENHYDRAMINE, CYCLIZINE, MECLIZINE – prevents motion sickness and treatment of vertigo due to labyrinth dysfunction.

CINNARAZINE-Anti vertigo drug. Used in prevention of motion sickness.

Acts as antihistaminic, anticholinergic, antiserotonin & Ca2+ channel blocker.

Inhibits influx of Ca2+ from endolymph into vestibular apparatus.

TYPES OF EMESIS-MORNING SICKNESS

• Morning sickness ( Vomiting during pregnancy).

• During 1st trimester of pregnancy due to effect of increased oestrogen levels on CTZ.

• DOXYLAMINE- safest drug.CYCLIZINE, MECLIZINE

• VITAMIN B6 (PYRIDOXINE):High doses (60mg/d) acts as

cofactor for enzyme glutamate decarboxylase and increases GABA.

• Inhibits neurotransmitter at CTZ.

TYPES OF EMESIS- CIE

• Anti-cancer drugs induce emesis by direct activation of 5HT3 receptors in CTZ / may activate vagal and splanchnic 5HT3 receptors to send emetogenic signals to vomiting center through neurotransmitters.

ONDANSETRON GRANISETRON DOLASETRON TROPISETRON PALONOSETRON RAMOSETRON

TYPES OF EMESIS-POST OPERATIVE VOMITING

• Complications in patients receiving general anaesthesia.

• 5HT3 ANTAGONIST- preferred

• PROCHLORAZINE- blocks Dopamine 2 and muscarinic receptors.

• PROMETHAZINE- potent anticholinergic and antihistaminic.

TYPES OF EMESIS-VOMITING OF VARIED ORIGIN

Drug induced vomiting.

Increased intra-cranial pressure induces emesis.

Vomiting in patients due to brain injury, cerebral tumour, hydrocephalous- increases CSF pressure.

- Activates receptors on CTZ.

NABILONE, DRONABINOL.

i. Laurence L.B, Bruce A C, Bjorn C K. Goodman and Gilman’s The Pharmacological Basis of Therapeutics.2011. 12th edition. China: Mc Graw Hill books; pp: 1341-6.

ii. Padmaja Udayakumar. Textbook of medical pharmacology.2nd edition. New Delhi: CBS Publishers and distributors; pp: 326-9.

iii. Sharma HL , Sharma KK. Principles of pharmacology.2nd edition. Hyderabad: Paras publisher; pp: 395-9.

REFERENCE