Antiemetic drugs

Dr. Jatin Dhanani

Causes of vomiting Food intolerance, Viral & Bacterial infection, Motion sickness Post operative Pain Shock Drug induced Radiation Disturbances of the equilibrium or middle ear

affection

Pathophysiology of vomiting

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Emetics Substances which produce vomiting

Required when an undesirable substance (poison) has been ingested

Home based ?????

Emetic drugs Apomorphine Ipecacuanha

Apomorphine Semi synthetic derivative

of morphine directly stimulate CTZ or

VC Given IM or SC (not

orally) 6 mg Induces vomiting in 5 -

10min CNS & Respiratory

depressant

Ipecacuanha Irritate gastric & duodenal

mucosa → stimulate afferent fibers of vagus nerve → Stimulate the VC

Contains two alkaloids- emetine & cephaeline

Used as syrup ipecac Produces effect in 15 min Dose

Infants = 5 ml

Children = 10-15ml

Adults = 15-20ml

Contraindications of emetics Corrosive poisoning CNS stimulant drug poisoning Kerosene poisoning Unconscious patients Morphine poisoning

Classification – Antiemetic drugs H1antihistamines

Promethazine, Dimenhydrinate & Diphenhydramine, cyclizine, Meclizine, Cinnarizine

Muscarinic AntagonistHyoscine (Scopolamine), dicyclomine

Selective 5-HT3 Antagonists Ondansetron, Granisetron, Palonosetron & Dolasetron

Prokinetic agents Metoclopramide, domperidone, cisapride, mosapride, tagaserod

D2 Antagonists (neuroleptics) Haloperidol, chlorpromazine, prochlorperazine

CannabinoidsDronabinol, Nabilone

Neurokinin-I AntagonistAprepitant (oral formulation), Fosaprepitant (IV formulation)

Adjuvant antiemetics Glucocorticoids

(Dexamethasone, Methylprednisolone)

Benzodiazepines (Diazepam, Lorazepam)

Prokinetic agents

Drugs which promote gastrointestinal transit and speed gastric emptying

MetoclopramideDomperidoneCisapride, Mosepridetegaserod

Metoclopramide

Chemistry: Substituted Benzamide

MOA: Dopamine D2 receptors antagonist

It is potent Antiemetic & Prokinetic agent

As Antiemetic Blocks D2 receptors in CTZ of the medulla (area postrema) Blocks 5-HT3 receptors in CTZ (at high dose)

As Prokinetic agent 5-HT4 agonistic action in gut in excitatory ENS of intrinsic

PAN (main mech.) Others

1. Blocks D2 receptor in GIT → increase Ach release,

2. Blockade of 5-HT3 receptor in inhibitory ENS of intrinsic PAN, and also

3. Directly sensitize muscarinic receptor of smooth muscle of GIT --- ↑ motility

Pharmacokinetics Rapidly absorbed from GIT after oral administration Undergoes a high degree first pass metabolism Approx. onset of action is 30 – 60 min, 10 min and

2 min after oral, IM, and IV administration – So, route selected according to severity

Excreted in the urine as free and as metabolites. Also excreted in the breast milk. DOSE: 10-20 mg orally or IV every 6 hrs

Uses – metoclopramide

As Antiemetic: in various type of vomitingpostoperative, drug induced, disease associated & radiation sickness As prokinetic:

During emergency general anesthesia (food taken less than 4 hr before)

To relieve postvegotomy or diabetic gastric stasis To facilitate duodenal intubation GERD: adjuvant to acid suppressant therapy

Dyspepsia and other functional GI disorders Hiccups

Adverse Effects Extrapyramidal reactions

facial and skeletal muscle spasms- Restlessness, Dystonias, Parkinsonian symptoms (Occulogyric crises)

More common in young and very old Occurs shortly after staring treatment & subside with in 24

hours of stopping the drug Bowel upsets, Diarrhoea Drowsiness, fatigue, dizziness, restlessness, anxiety Galactorrhoea, Gynecomastia, impotence and

menstrual disorders – due to increased prolactin levels

Trimethobenzamide

Substituted Benzamide

Antiemetic like Metoclopramide.D2 Antagonist & mild anti- histaminic activity

DOSE: 250mg orally,

200mg rectally,

200mg IM

Domperidone Only blocks D2 in CTZ Does not cross BBB

Used along with Levodopa and bromocriptine (prevent peripheral side effect, without affecting its efficacy)

No EPS Use: as antiemetic, prokinetic agent & for post

partum lactation stimulation A/E: less than metoclopramide

Dry mouth, loose stools, headache, rashes, galactorrhoea

cardiac arrhythmia on rapid iv injection

Cisapride MOA: 5-HT4 agonist (main) and weak 5-HT3

antagonist, while no affinity on D2 receptor Actions

Restore and facilitates motility throughout the GIT including colon

LES tone improved Promote cAMP-dependent Cl- secretion in colon →

increase water content of stool Indication

GERD Nonulcer dyspepsia, impaired gastric emptying,

chronic constipation

A/E Abdominal cramp and diarrhoea Dizziness Rise in serum transaminase level Torsades de pointes and ventricular arrhythmia (at

high conc./ with CYP 3A4 inhibitors)

Mosapride Not caused ventricular arrhythmia

Tegaserod No 5-HT3 action Less efect on LES tone & mainly increase colonic

motility, gastric emptying and intestinal transit Indication: constipation predominant irritable

bowel syndrome

5-HT3 antagonists Mechanism of action

Blocks Peripheral 5HT3 receptors on intestinal vagal and spinal afferent fibers (main)

Also block central 5HT3 receptors in Vomiting center & CTZ

Antiemetic action restricted to emesis caused by vagal stimulation (eg

post op) & chemotherapy/ radiotherapy Also effective in vomiting with drug overdose,

uremia and certain neurological injuries

OndensetronGranisetronDolasetronPalnosetron

Pharmacokinetics – 5-HT3 blockers

High first pass metabolism t1/2 : 4-9 hrs (Ondansetron, Granisetron & Dolasetron)

40 hrs (Palonosetron) Given once or twice daily – orally or intravenously No dose reduction in renal insufficiency but needed

in hepatic insufficiency (Ondansetron)

Dose: (ondansetron)

Chemotherapy: 8 mg IV 15min – ½ hr b/f therapy – f/b 2 dose 4 hr apart – f/b 8 mg bid for 3-5 days

Post operative: 4-8 mg IV b/f induction – f/b 8 hrly

Adverse Effects

Excellent safety profile Headache & Dizziness Mild constipation or diarrhea and abdominal

discomfort Rashes and allergic reaction Prolongation of QT interval (dolasetron)

H1antihistamines & Muscarinic Antagonists Most effective drugs for motion sickness MOA

Anticholinergic, H1 antagonist & sedative properties

Produce specific depression of conduction in vestibulocerebellar pathway via cranial nerve VIII - rich in Cholinergic M1 & Histamine H1receptors

H1 antihistaminicsPromethazineDiphenhydramineDimenhydrinateDoxylamineCyclizine, meclizine Cinnarizine

Muscarinic antagonistsHyoscine & Dicyclomine

Hyoscine Most effective drug for motion sickness Dose: 0.2 – 0.4 mg oral or IM 1.5 mg Transdermal patch – for 3 days

Dicyclomine (10-20 mg) For motion and morning sickness

Promethazine, diphenhydramine, dimenhydrinate

Antihistaminics with anticholinergic properties Added with metoclopramide

Doxylamine Widely used in morning sickness: along with

pyridoxine

Cyclizine & meclizine Less sedative and less anticholinergic Meclizine – long acting (use in seasickness)

Cinnarizine Antivertigo drug also useful in motion sickness Inhibits the influx of Ca ++ ion from endolymph to

vestibular sensory cells

Neuroleptics

Mechanism of Action Acts by blocking D2 receptor in the CTZ Additional antimuscarinic and antihistaminic

property

ChlorpromazineProchlorperazineHaloperidol

Potent and broad spectrum antiemetic agents Drug induced and post anesthetic N & V Disease induced: uremia, liver diseases,

migraine, gastroenteritis Malignancy and cancer chemotherapy induced

vomiting Radiation sickness (less effective) Hyperemesis gravidarum Not use in motion sickness

Problems High potential of side effects like muscle dystonia,

sedation Not use widely

Cannabinoids semisynthetics MOA:

activate CB1 receptors at vomiting center or higher center

Ph.K: complete absorption on oral adm, significant 1st pass

effect, metabolites excreted slowly over days to weeks in faeces & urine

Use: Cancer chemotherapy induced N & V with

Phenothiazines – synergistic Appetite stimulant in cachectic/AIDS patients

DronabinolNabilone

Neurokinin-1 (NK1 )Antagonists

MAO: Non peptide, selective, NK 1 receptors antagonist Block substance P from binding to NK1 receptor

Augment the antiemetic activity of 5HT3 receptor antagonists and dexamethasone

Broader spectrum and activity in delayed emesis Inhibit both acute and delayed Chemotherapy

induced N & V

Aprepitant,Fosaprepitant

Adjuvant antiemetics Glucocorticoids

As an adjuvant to the other antiemetic drugs during cancer chemotherapy

Acts by ↓ing inflammation and PG production at peritumor areas

Use in refractory cases only Benzodiazepines

Action is based on sedative property Weak antiemetics Use as an adjuvant to other antiemetic

DexomethasoneMethylprednisolone

DiazepamLorazepam

Thank You