Antiemetics

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Antiemetics
Vomiting The act of vomiting and the sensation
of nausea that accompanies it are protective
reflexes that serve to rid the stomach and
intestine of toxic substances and prevent their
further ingestion
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Pathophysiology of Emesis
Cerebral cortex
Cancer chemotherapy Opioids
Smell Sight Thought
Anticipatory emesis
Chemoreceptor Trigger Zone (CTZ)
Vestibular nuclei
Vomiting Centre (medulla)
Motion sickness
Muscarinic Histaminic H1
Muscarinic, 5 HT3 Histaminic H1
(Outside BBB)
Dopamine D2 5 HT3,,Opioid Receptors
Chemo radio therapy Gastroenteritis (vagus)
Pharynx GIT
5 HT3 receptors
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Area Type of receptors Stimulus
Chemoreceptor trigger zone (CTZ) Dopamine D2 5HT3 Opioid Cancer chemotherapy Opioids
Vestibular nuclei Mscarinic Histamine H1 Motion sickness
Pharynx and GIT 5HT3 Cancer chemotherapy Radio therapy Gastroenteritis
Cerebral cortex Smell Sight Thought Anticipatory emesis
Serotonin 5HT3 receptor antagonists 5HT3 receptor
Phenothiazines Dopamine D2 receptors Antihistaminic Anticholinergic
Substituted benzamides Dopamine D2 receptors
Anticholinergic drugs Muscarinic receptors
Antihistaminic drugs Histamine H1 receptors
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Indications of antiemetics

• 1- Chemotherapy-induced vomiting
• 2- Post irradiation vomiting
• 3- Postoperative vomiting
• 4- Vomiting of pregnancy
• 5- Motion sickness

Group of drugs used as antiemetics
Serotonin 5 HT3 Antagonists Dopamine D2
Antagonist Anticholinergics H1 Antihistaminics
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• Serotonin 5 HT3 Antagonist
• Potent antiemetics

Mechanism of action 1- Peripheral 5-HT3 receptor
blockade on intestinal vagal afferents. 2-
Central 5-HT3 receptor blockade in the vomiting
center and chemoreceptor trigger zone
Antiemetic action is mainly against Emesis
mediated by vagal stimulation (e.g. postoperative
and chemotherapy) High first pass
metabolism Excreted by liver kidney No dose
reduction in renal insufficiency but needed in
hepatic insufficiency
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Drugs Available

1. Ondansetron
2. Granisetron
3. Dolasetron
4. Palonosteron

Adverse Effects
The most common adverse effects are 1- Headache
and dizziness 2- Constipation or diarrhoea
Indications

1. Chemotherapy induced nausea and vomiting
2. postradiation nausea vomiting
3. Vomiting of pregnancy
4. Postoperative vomiting

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Corticosteroids

• Corticosteroids have antiemetic properties
• Mechanism of action possibly by suppressing
  peritumoral inflammation and prostaglandin
  production.
• Use to enhance efficacy of 5HT3 receptor
  antagonists in the treatment of
  chemotherapy-induced vomiting.

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Phenothiazines

• Phenothiazines as promethazine are antipsychotic
  agents
• Use
• Chemotherapy-induced vomiting
• Radiotherapy-induced vomiting
• postoperative nausea and vomiting
• Mechanism of the antiemetic action inhibition of
  central dopamine, muscarinic and H1 histamine
  receptors receptors

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Butyrophenones

• Butyrophenones as droperidole are antipsychotic
  agents
• Mechanism of the antiemetic action inhibition of
  central dopamine receptors
• Use
• Chemotherapy-induced vomiting
• Radiotherapy-induced vomiting
• postoperative nausea and vomiting
• Adverse effects droperidol may prolong the QT
  inter, therefore, it should not be used in
  patients with QT prolongation (should only be
  used in patients who have not responded
  adequately to alternative agents).

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Substituted Benzamides

• 1- Metoclopramide
• 2- Trimethobenzamide
• Mechanism of antiemetic action Central
  dopamine-receptor blockade
• Side effects (mainly extrapyramidal)
• Restlessness
• Dystonias
• Parkinsonian symptoms

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H1 receptor antagonists and Anticholinergics

• Use
• prevention or treatment of motion sickness.
• Adverse effects sedation, dizziness,confusion,
  dry mouth, cycloplegia, and urinary retention.
• .

Diphenhydramine dimenhydrinate First generation H1 receptor blockers that have anticholinergic and sedating properties
Meclizine First generation H1 receptor blockers that have lesser anticholinergic and sedating properties
Hyoscine Muscarinic receptor blocker
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Benzodiazepines

• Uses
• Benzodiazepines such as diazepam are used prior
  to the initiation of chemotherapy to reduce
  anticipatory vomiting or vomiting caused by
  anxiety

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Cannabinoids(Dronabinol)

• The mechanisms for the antiemetic effects is not
  known.
• Pharmacokinetics.
• readily absorbed after oral administration
• It undergoes extensive first-pass metabolism
  with limited systemic bioavailability after
  single doses Mmetabolites are excreted primarily
  via the biliary-fecal route
• Adverse effects include
• Euphoria or dysphoria, sedation and
  hallucinations
• Abrupt withdrawal leads o withdrawal syndrome
  (restless, insomnia and irritability)
• Autonomic effects (sympathetic) in the form of
  tachycardia, palpitation, conjunctival injection,
  and orthostatic hypotension.
• Use
• For the prevention of chemotherapy-induced nausea
  and vomiting

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Control of GIT motility

• Neurogenic control of GIT moyility the ENS
• Enteric nervous system (ENS) is a collection of
  nerves within the wall of the GI tract
  responsible for the autonomous gastrointestinal
  activity. It consists of connected networks of
  neurons
• myenteric (Auerbach's) plexus, found between the
  circular and longitudinal muscle layers
  (responsible for motor control)
• submucosal (Meissner's) plexus, found below the
  epithelium (regulates secretion, fluid
  transport, and vascular flow).
• Neurons in both plexuses release
  acetylcholine at their terminals.
• Autonomic nervous system
• Parasympathetic act by releasing
  acetylcholine at nerve terminals. It causes
  contraction of muscles in the wall of the
  intestine and relaxation of the sphincters and
  increases gland secretion
• Sympathetic act by releasing
  norepinephrine at nerve terminals. It causes
  relaxation of muscles in the wall of the
  intestine and contraction of the sphincters
• Types of cholinergic receptors are M2 and M3
  (present in the GIT in a 41 ratio). M3 receptor
  is more important in muscle contraction.

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Agents that increase GIT motility

• 1- Cholinergic agents
• Stimulate cholinergic receptors. Enhance
  contractions in an uncoordinated manner that
  produces no net propulsive activity. Not useful
  for treating motility disorders
• 2- Prokinetic agents
• enhance coordinated GIT propulsive motility.
  Prokinetic agents act at receptor sites on the
  motor neuron itself increasing the release of
  acetylcholine at the motor nerve terminal without
  interfering with the normal physiological pattern
  and rhythm of motility. Useful for treating
  motility disorders

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Cholinergic Agents

• Direct cholinergic agents
• Stimulate cholinergic receptors in the wall of
  the GIT.
• 1- ACh is not used pharmacologically because
• it affects both nicotinic and muscarinic
  receptors
• It is degraded rapidly by acetylcholinesterase.
• 2- Bethanechol
• Muscarinic receptor agonist
• Resists enzymatic hydrolysis.
• In addition, it lacks real prokinetic
  efficacy,

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• Indirect cholinergic agents
• Acetylcholinesterase Inhibitors. These drugs
  inhibit the degradation of ACh , allowing ACh to
  accumulate at sites of release.
• Neostigmine has been used to treat paralytic
  ileus.

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Decreased motility of GIT

• Decreased motility of the GIT results from
  suppression of ACh release from myenteric motor
  neurons mediated by stimulation of D2
  dopaminergic receptors.

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Prokinetic agents

• Enhance coordinated GI T propulsive motility.
• Mechanism of action
• 1- Antagonize the inhibitory effect of
  dopamine on myenteric motor neurons,
• 2- Relieve nausea and vomiting by
  antagonism of dopamine receptors in the
  chemoreceptor trigger zone
• Metoclopramide
• Domperidone.

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Substituted benzamides1- Metoclopramide (1)

• Pharmacological action
• 1- Enhance coordinated GIT propulsive motility of
  the upper digestive tract where it increases
  lower esophageal sphincter tone and stimulates
  antral and small intestinal contractions.
  Metoclopramide has no clinically significant
  effects on motility of the colon.
• 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
• 2- Antiemetic action
• Mechanism of action
• Antagonize dopamine receptors in the CTZ

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1- Metoclopramide (2)

• Therapeutic Use
• Nausea and vomiting that often accompany GI
  dysmotility syndromes.
• Gastroesophageal reflux disease (symptomatic
  relief but not healing of esophagitis).
• Gastroparesis where it improves gastric
  emptying.
• Diagnostic procedures such as intestinal
  intubation or contrast radiography of the GI
  tract.
• Postoperative ileus
• Persistent hiccups

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1- Metoclopramide (3)

• Administration
• 1- Oral (rapid absorption)
• 2- I.m. in cases of nausea and vomiting
• 3- I.v. infusion in chemotherapy-induced vomiting

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1- Metoclopramide (4)

• Adverse Effects
• 1- Extrapyramidal effects (more commonly in
  children and young adults and at higher doses).
• Tardive dyskinesiarepetitive,
  involuntary, purposeless movements (usually
  involve the face) like tongue protrusion, lip
  smacking, pursing of the lips and rapid eye
  blinking. It occurs with chronic treatment
  (months to years) and may be irreversible
• Akathisia restlessness and inability to
  sit still or remain motionless
• Dystonias muscular spasms of neck
  usually occurring acutely after intravenous
  administration
• parkinsonian-like symptoms that may occur
  several weeks after initiation of therapy
  generally respond to treatment with
  anticholinergic or antihistaminic drugs and are
  reversible upon discontinuation of
  metoclopramide.
• 2- Galactorrhea by blocking the inhibitory
  effect of dopamine on prolactin release
  (infrequent)

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2- Domperidone

• Pharmacological actions
• 1- Enhance coordinated GIT propulsive motility of
  the upper digestive tract where it increases
  lower esophageal sphincter tone and stimulates
  antral and small intestinal contractions. It
  has no clinically significant effects on motility
  of the colon.
• Mechanism of action
• dopamine D2 receptor antagonist
• 2- Antiemetic action
• Mechanism of action
• dopamine D2 receptor antagonist (of D2 receptors
  in CTZ which is outside BBB)

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• Adverse effects
• No extrapyramidal side effects (can not cross the
  blood-brain barrier)
• Galactorrhea (by inhibiting dopamine-mediated
  inhibition of the release of prolactin as the
  pituitary lacks blood-brain barrier)