Antiemetic Agents

By: Luthfi M Ramdhani

Pathophysiology
Cancer chemotherapy Opioids

Cerebral cortex
Smell Sight Thought Anticipatory emesis

Chemoreceptor Trigger Zone (CTZ)

(Outside BBB)
Dopamine D2 5 HT3,,Opioid Receptors

Vomiting Centre

(medulla)
Muscarinic, 5 HT3 & Histaminic H1

Motion sickness

Vestibular nuclei
Muscarinic Histaminic H1

Chemo & radio therapy Gastroenteritis

Pharynx & GIT

5 HT3 receptors

VC input
1- CTZ (rich in D2, 5-HT3, opoid, neurokinin1) 2- Vestibular system 3- Irritation of pharynx (gag reflex, vagus nerve) 4- Vagal and spinal afferent Ns. Supplying GIT 5- Psychiatrically, stress Pre-treatment is recommended to control vomiting

Serotonin receptors antagonists (5-HT3 antagonists)

MOA: hambat muntah ec stimulasi Vagal Nerve

Stimulasi (anestesi,chemo,radiotherapy) blocks serotonin receptors (5-HT3) in VC, CTZ and peripheral 5HT receptors Example: Ondansetron (T1/2: 6 Hr) and Palonoseyron (T1/2: 40Hr) Side effects:

Well tolerated Prolong QT interval Arrhythmia

Corticosteroids
MOA: tidak jelas, tp dapat meningkatkan 5-HT3 antagonists. digunakan utk mencegah muntah ec cytotoxic drug Example: dexamethasone, methylprednisolone

Side effects: Many

Neurokinin Receptors Antagonists (NK1 antagonists)

MOA: selective inhibitors of neurokinin 1

(substance P system) Example: Aprepitant,

kombinasi + Cortiko recommended Inhibiting P450 Decrease prothrombin time in Warfarin treated patients

Side effects:

Dopamine Antagonists
MOA: It inhibits D2, M1 and H1 receptors It has a sedative effect (histamine blocker) Example: Phenothiazines group: chloropromazine Butyrophenones group: haloperidole

Used neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anesthetics

Metoclopramide Bekerja pada GI Tract sebagai Pro-Kinetic utk GI Disease Kurang bagus pada penggunaan postop/cytotoxic Vomiting
Side effects Dopamine antagonist: Extrapyramidal syndrome (restless, dystonia, parkinsonism), prolong QT wave

Anti Histaminic
MOA: blocks H1 receptors, anticholinergic

effect

Antiemetik lemah, digunakan untuk motion sickness

Example: Diphenhydramine Side effect: Anticholinergic side effects: dryness of mouth, blurring of vision, sedation, dizziness, urinary retention

Anticholinergic
MOA: blocks M1 receptors minimal M1 blocker, minimal sedation Example: Meclizine and hyoscine Meclizine: mencegah motion sickness + untuk vertigo ec labrynthine dysfunction Hyoscine: sama, tp lebih baik Side effects: Anticholinergic effects

Benzodiazepine
MOA: antiemetik, menurunkan anxiety

dengan berikatan pd GABA Receptor # Clion channel Example: Lorazepam and Midazolam

Kobinasi + 5-HT3 antagonists sangat efektif utk post op vomiting Tolerance, addiction, CNS dysfunction, respiratory depression,

Side effects:

Cannabinoids
MOA:

zat aktif nya THC (tetrahydrocannabinol), psikoaktif di Marijuana dan bersifat antiemetic.
Mechanism is unknown Jarang digunakan, jika perlu bisa diberikan pada cachexia cytotoxic nausea, dan vomiting, atau pada orang yang tidak respon thd pengobatan lain

Example: Cannabis and Dronabinol Side effects: Euphoria, sedation, hallucination, dry mouth and increase appetite

Other

Trimethobenzamide; bekerja pada CTZ Ginger Emetrol also diklaim sebagai effective antiemetic. Syrup form (5mL) contains 1.87g of glucose, 1.87g of

fructose and 21.5mg of phosphoric acid.

Propofol diberikan IV, rescue therapy for emesis. Peppermint diklaim dpt mencegah nausea or stomach pain Muscimol selective agonist of the GABAA receptor.

Control of GIT Motility

Neurogenic control of GIT motility: the ENS
Enteric nervous system (ENS) myenteric (Auerbach's) plexus antara circular and longitudinal muscle layers (responsible for motor control) submucosal (Meissner's) plexus, dibawah epithelium (regulates secretion, fluid transport, and vascular flow)

Autonomic nervous system: Parasympathetic : Menghasilkan acetylcholine at nerve terminals. Menyebabkan kontraction otot di dinding intestine relaksasi sphincters meningkatkan sekresi kelenjar Sympathetic: releasing norepinephrine pd nerve terminals relaxation of muscles in the wall of the intestine contraction of the sphincters

Prokinetik Agent
Stimulasi Fungsi GI Motor Neuron

MOA: Smooth muscle dikontrol oleh para + Simpatis Serotonin (5HT) stimulates 5HT3, 5HT1, calcitonin gene-related peptide (CGRP), motilin menginduksi vomiting and nyeri perut 5HT4 stimulasi untuk menghaasilkan Ach dan CGRP utk mengontrol motiliti Dopamine inhibits gastric and intestinal contraction

Jenis Obat
Cholinomimmetics

Dopamine antagonists
Stimulation of motilin Chloride channel activator

Cholinomimmetics
MOA: Parasympathetic stimulating M3

receptors. Increasing motility. Relax sphincters and stimulates secretions Examples:

Bethacoline better drugs are available

Longer duration, Ach.esterase resistant

Neostigmine (cholinesterase inhibitors)

Duration 0.5-2 h

 Side effects: Cholinergic effects: salivation, nausea, vomiting diarrhea, bradycardia

Dopamine Receptor Antagonists

MOA: Inhibiting D2 receptors

Example:

Metoclopramide Domperidone Does not cross BBB

It has an antiemetic effect as well and

stimulates Side effects of Metoclopramide

CNS effect and extrapyramidal syndrome Elevation of prolactin???? infertility

Metoclopramide
Mechanisms of action (on GIT): Dopamine receptor antagonism 5-HT4-receptor agonist Vagal and central 5-HT3-antagonist Sensitization of muscarinic receptors on smooth muscle Stimulates Prolactin secretion to induce lactation 2- Antiemetic action: Mechanism of action: Antagonize dopamine receptors in the CTZ

Therapeutic Use Metoclopramide

1- Nausea and vomiting that often accompany GI dysmotility syndromes. 2- Gastroesophageal reflux disease (symptomatic relief but not healing of esophagitis). 3- Gastroparesis where it improves gastric emptying. 4- Diagnostic procedures such as intestinal intubation or contrast radiography of the GI tract. 5- Postoperative ileus

Adverse Effects:

Metoclopramide

1- Extrapyramidal effects (more commonly in children and young adults and at higher doses). Tardive dyskinesia Akathisia parkinsonian-like symptoms
2- Galactorrhea by blocking the inhibitory effect of dopamine on prolactin release (infrequent)

Domperidone
Pharmacological actions: Mechanism of action: dopamine D2 receptor antagonist

Antiemetic action Mechanism of action: dopamine D2 receptor antagonist (of D2 receptors in CTZ which is outside BBB)

Domperidone
Adverse effects:
Galactorrhea

No extrapyramidal side effects (can not cross

the blood-brain barrier)

Macrolides
MOA: stimulates motilin receptors used for

treatment of gastropariesis

Tolerance develop rapidly

Example: Erythromycin (an antibiotics)

Side effects:

Liver toxicity Its metabolites inhibits P450

Chloride channel activator

MOA:

stimulate opening of Cl channel (Activator) as Parasympathetic stimulants, to increase fluid secretion in small intestine to help with the passage of stool Example: Lubiprostone (prostanoic acid derivative) Side effect:

Delay gastric emptying Nausea, diarrhea and abdominal pain.