Pharmacology

Emetic and anti-emetics

Emetic and anti-emetics

  • Nausea and vomiting are basic human protective reflexes against the absorption of toxic, as well as responses to certain stimuli.
  • Nausea: coming from two Greek words “Nautia” means sickness and “Vomere” means discharge.
  • Nausea is define as a subjectively discomfort or unpleasant wavy like sensation in the back of the throat or epigastrium.
  • Effect may shows flushing, tachycardia, sweating, excess salivation and sensation of being cold or hot may occur.
  • Vomiting or emesis is characterized by contraction of the abdominal muscle, descent of diaphragm and opening of gastric cardia, resulting in forceful expulsion of stomach contents from the mouth.

Pathophysiology

  • Complex interaction between central and peripheral pathway:

Peripheral areas:

  • Gastric mucosa
  • Smooth muscle
  • Afferent pathway of vagus and sympathetic nerve.

Central areas:

  • Area postrema
  • Chemoreceptor trigger zone (CTZ)
  • Nucleus tractus solitarus (NTS)
  • Vomiting centre

CTZ

  • The area postrema in the floor of 4th ventricle contains CTZ.
  • Sensory organ containing dopaminergic (D5), serotonergic (5HT3), Histamine (H1) and muscarinic (M1) receptors.
  • Located outside BBB.

Vomiting centre

  • Situated in the dorsolateral reticular formation close to respiratory centre.
  • Vomiting centre contains many brain stem nuclei.

Act of vomiting

Emetics

  • Emetics are the drugs which promote vomiting. These drugs are used for evacuation of toxic substance from stomach.
  • Example: Powdered mustard suspension / strong salt solution used in emergency.
  • Act on CTZ: Apomorphine
  • Act reflexly and on CTZ: Ipecacuanha

Apomorphine

  • It is a semisynthetic derivatives of Morphine.
  • Acts on a dopaminergic agonist on CTZ.
  • Administered on i.m. / s.c. (slowly act on oral route and required high dose).
  • Dose: 6mg i.m / s.c.
  • Apomorphine has therapeutic effect in Parkinsonism, but it not used due to side effect.

Ipecacuanha

  • It is obtain from dried root extract of Cephalis ipecacuanha (emetine)
  • Act by irritating gastric mucosa as well as through CTZ.
  • Syrup ipecac:  15-30 ml in adults, 10-15 ml in children, 5 ml in infants.

Contraindication

  • Acid or alkali poisoning: perforating and esophagus injury.
  • CNS stimulant poisoning: Convulsion.
  • Kerosene (Petroleum) poisoning: Aspiration pneumonia.
  • Morphine and phenothiazine poisoning: infection.

Anti-emetics

  • The drugs used to suppress vomiting.

Classification

1) Anticholinergics

e.g. Hyoscine, Dicyclomine

2) Anti-histaminic

e.g. Promethazine, Diphenhydramine, Dimenhydrinate,  Doxylamine, Cyclizine, Meclozine, Cinnarizine

3) Neuroleptics

e.g. Chlorpromazine, Prochlorpromazine, Triflupromazine, Haloperidol 

4) Prokinetic agents

e.g. Domperidone, Metoclopramide, Cisapride, Mosapride.

5) 5HT3 receptor antagonist

e.g. Ondansetron, Grarisetron, Topisetron, Palonosetron, Ramosetron.

6) NK1 receptor antagonist

e.g. Aprepitant, Fosaprepitant

7) Adjuvant anti-emetics

e.g. Dexamethasone, Benzodiazepine, Dronabinol, Nabilone.

Anti-cholinergic (Hyoscine, Dicyclomine)

  • It blocks the cholinergic transmission from vestibular nucei to higher centres with in the cerebral cortex.

Side effects

  • Drowsiness.
  • Dry mouth.
  • Dilated pupil and blurred vision.
  • Decreased sweating.
  • Decreased gastrointestinal motility.
  • Decreased gastrointestinal secretions and difficultly with micturition.
  • May precipitate closed angle glaucoma.

Hyoscine

  • Dose: 0.2-0.4 mg
  • Oral/i.m.
  • Short duration of action
  • Adverse effect: Sedation
  • Used in motion sickness.
  • Transdermal patches (Applied behind pinna with mild side effect)

Dicyclomine

  • Dose 10-20mg
  • Oral absorption is slow
  • Dicyclomine + Pyridoxine used as morning sickness (Prophylaxis).

Antihistaminic

Promethazine

  • Used on motion sickness for 4-6 hours.
  • Side effect: sedation, dryness of mouth

Doxylamine

  • H1 antihistamine (Sedative).
  • Doxylamine with Vitamin B6 used for Morning sickness.
  • Slow absorption on oral route.
  • Side effect: drowsiness, dry mouth, vertigo, abdominal upset.
  • Dose: 10-20 mg.

Cyclizine / Meclizine

  • It show less sedative and anti-cholinergic action.
  • Long acting antihistamine
  • Protects against sea sickness for 24 hours.

Cinnarizine

  • Used for motion sickness.
  • Inhibit influx of Ca2+ from endolymph into the vestibular sensory cells which medicates labyrinth reflexes.

Neuroleptics

  • It is a broad spectrum antiemetics, which act by blocking the D2 receptor in CTZ.
  • Useful for drug induce, disease induce, malignancy associated and radiation induced vomiting.
  • Side effects: sedation, acute muscle dystonia, extrapyramidal effect.

Prochlorpenarizine

  • D2 blocking phenothiazine.
  • Labyrinth suppressant, selective anti vertigo and anti-emetic action.
  • Side effect: Acute dystonia (Dystonia – involuntary and repetitive muscle contraction can affect one muscle, group of muscle or entire body), tardive dyskinesia (inventory and abnormal movement of face like movement of jaw, tongue, and lips), Parkinsonism.

Prokinetic drugs

  • Increase gastric peristalsis.
  • Relax pylorus and 1st part of duodenum.
  • Hasters gastric emptying.
  • Lower esophageal sphincter tone is increased.
  • Gastric esophageal reflexes is opposed.

Metoclopramide

  • Act through D2 receptor, 5HT4 and 5HT3 receptors.
  • D2 antagonism leads to increase gastric emptying, enhance LES tone.
  • Central D2 antagonism leads to extrapyramidal effects, hyperprolactinemia.
  • 5HT3 antagonism leads to minor increase in Ach release (central action appears only in large doses).
  • 5HT4 antagonism increase release of Ach leading to Gastric effect, LES tonic effect.
  • Pharmacokinetic: rapidly absorbed from oral route, enter brain, crosses placenta, secrete in milk.
  • Side effects: sedation, dizziness, Parkinsonism, galactorrhea, gynecomastia, loose motions, dystonia, and myoclonus in sucking infant.
  • Uses: anti-emetic, gastrokinetic in emergency, post vagotomy or diabetes associated gastric stasis, dyspepsia, GERD.

Domperidone

  • D2 antagonist with low anti-emetic and Prokinetic actions.
  • Poorly cross BBB
  • Hyperprolactinemia
  • Pharmacokinetics: absorbed orally, low bioavailability due to fast pass metabolism.
  • t ½ : 7.5 hours.
  • Dose: 10-40 mg
  • Side effect: dry mouth, loose stools, headache, rashes, galactorrhea, cardiac arrhythmia.
  • Uses: chemotherapy induce nausea and vomiting and drug induce. 

5HT3 antagonist

  • Blocks the depolarizing action of serotonin through 5HT3 receptors on vagal afferents in GIT as well as NTS and CTZ.
  • Useful for: cytotoxic drug induced, radiation induce, inflammation induced vomiting.
  • Side effect: well tolerated with minor side effect like; headache, constipation or Diarrhoea, abdominal discomfort and rash in i.v. injection.

Ondansetron

  • Oral bioavailability is 60-70%.
  • Eliminated through urine.
  • t ½ : 3-5 times.
  • Duration of action 4-12 hours.
  • Weak 5 HT4 blockade.
  • First choice of antihistaminic.

Adjuvant antiemetics

Corticosteroid

  • May act on steroid receptors in area postrema.
  • Dexamethasone (8-20mg).
  • Augment Meta chlopramide and ondansetron for cisplastin induced delayed emesis.

Benzodiazepine

  • Weak antiemetics shows sedation property.
  • Adjuvant to metoclopramide and ondansetron.
  • Diazepam/lorazepam (oral/i.v.).

Newer antiemetics therapy

Neurokinin antagonist

  • NK1 receptor in area postrema and NTS.
  • Adjuvant to dexamethasone and 5HT3 antagonist.
  • Metabolized by CYP3A4 and may inhibit the metabolism of other drugs.

Hello! My name is Smrutiranjan Dash, a pharmacy professional. belonging from, Bargarh, Odisha. I have acquired Master degree in Pharmacy (Pharmacology) form B.P.U.T, Rourkela, Odisha. Presently I am working as an Assistant Professor at The pharmaceutical college, Barpali.

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