Anti Emetic

7/28/2019 Anti Emetic

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I. Introduction

I.1. Definition: Medicines that prevent and control nausea and

vomiting.I.2. Cause of nausea and vomiting:

1) motion sickness.

Motion sickness may occur in many settings includingtravel by car, air or boat,

2) Food poisoning. Which caused by bacteria,

3) Viral infection which is sometimes associated with diarrhea.

4) medication can cause nausea and even vomiting.

5) Postoperative nausea and vomiting.

Nausea affects an estimated 30% of patient within 24 hr after surgery.

6) Pregnancy may induce vomiting.

7) gastroenteritis.

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I.3. Physiologic mechanisms that result in nausea andvomiting 1

II. Classification of Antiemetic Agents

II.1. Dopamine antagonists

Block dopamine receptor in CTZ.

Ex. Metoclopramide and Domperidone

II.2. Antihistamines

Provide relief from motion sickness through an action on thevestibular apparatus.

Ex. Cyclizine, Dimenhydrinate and Diphenhydramine

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Etiology of Nausea and Vomiting

Visceral Chemoreceptor Vestibular Stimuli Trigger zone input

Dopamine and Dopamine and Histamine andSerotonin serotonin acetylcholinereleased released released

Medullary vomitingCenter stimulated

Nausea and vomiting


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II.3. 5-HT 3 receptor antagonists (Serotonin antagonists)

Block both peripheral and central 5-HT 3 receptors and areespecially effective against the emetogenic effects of

chemotherapy.

Ex. Ondansetron

II.4. antipsychotic

Act at the chemoreceptor trigger zone (CTZ) to block dopaminergic emetic receptors.

EX. phenothiazinesII.5. Cannabinoids

Are especially useful in the emesis from cancer chemotherapy.

EX. Tetrahydrocannabinol

II.6. Anticholinergic agent

In combination with d-amphetamine and scopolamine are mosteffective against motion sickness.

Ex. Scopolamine (Transderm Scop)

II.7. Other agents

Are especially useful in the post operative nausea and vomiting.

EX. Dexamethasone and Diazepam

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II.1. Dopamine antagonists 2

Action and Clinical pharmacology:

Domperidone is a peripheral dopamine antagoniststructurally related to the butyrophenones with antiemetic andgastroprokinetic properties.

EX.1 Domperidone:-

N

N

O NH

N N

O

H

Cl

The mechanism of action of domperidone:

is related to its peripheral dopamine receptor blocking properties. Emesis induced by apomorphine, morphine or levodopa through stimulation of the chemoreceptor trigger zone(situated outside the blood-brain barrier) can be blocked bydomperidone. There is indirect evidence that emesis is alsoinhibited at the gastric level, since domperidone also inhibitsemesis induced by oral levodopa, and local gastric wallconcentrations following oral domperidone are much greater than those of the plasma and other organs. Domperidone doesnot readily cross the blood-brain barrier and therefore is notexpected to have central effects.

Domperidone elevates serum prolactin levels but has noeffect on circulating aldosterone levels.

Pharmacokinetics:

In man, peak plasma levels of domperidone occur within10 to 30 minutes following I.M. injection and 30 minutes after oral (fasted) administration. Plasma concentrations 2 hours after

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oral administration are lower than following I.M. injection, andthis is likely the result of hepatic first-pass and gut wallmetabolism. Peak plasma concentrations are 40 ng/mLfollowing an I.M. injection of 10mg, 20 g/mL after a single 10mg tablet, and 70 to 100 g/mL after oral doses of 60 mg(tablets or oral drops). The half-life was calculated asapproximately 7.0 hours in each case. The degree of human

plasma protein binding was calculated from tritiateddomperidone concentrations of 10 and 100 g/mL as 91.7 and93.0%, respectively.

The major metabolic pathways for domperidone in man

are hydroxylation and oxidative N-dealkylation, the products or which are hydroxydomperidone and 2,3 dihydro 2- oxo 1- H

benzimidazol-1-propionic acid, respectively. After oraladministration of 40 mg 4-domperidone to healthy volunteers,31% of the radioactivity is excreted in the urine and 66% in thefeces over a period of 4 days.

Indications and clinical uses:

In the symptomatic management of upper gastrointestinalmotility disorders associated with chronic and subacute gastritisand diabetic gastroparesis. Domperidone may also be used to

prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents.

Contra-Indications:

In patients with known sensitivity or intolerance to thedrug.

Domperidone should not be used whenever gastrointestinal stimulation might be dangerous, i.e.,gastrointestinal hemorrhage, mechanical obstruction or

perforation.

Also contraindicated in patients with a prolactin-releasing

pituitary tumor (prolactinoma).

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Assay: (Eur P 2000)

Non aqueous titration as weak base using perchloric acid

as titratant and naphtholbenzein solution as indicator.

Adverse Reactions:

CNS:

dry mouth, headache/migraine, insomnia, nervousness,dizziness, thirst, lethargy, irritability.

Gastrointestinal: abdominal cramps, diarrhea, regurgitation, changes in

appetite, nausea, heartburn, constipation.

Endocrinological:

hot flushes, mastalgia, galactorrhea, gynecomastia,menstrual Irregularities.

Mucocutaneous:

rash, pruritus, urticaria, stomatitis, conjunctivitis.

Urinary:

Urinary frequency, dysuria. Cardiovascular edema, palpitations. Musculoskeletal leg cramps, asthenia. Miscellaneous,drug intolerance.

Symptoms and Treatment of Overdose:

Symptoms:

Based on the pharmacological properties of domperidone,symptoms of overdosage may include CNS effects (such asdrowsiness, disorientation and extrapyramidal reactions,especially in children) and cardiovascular effects (arrhythmia,

hypotension) might possibly occur.

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Treatment:

Anticholinergic, anti-parkinsonian drugs or antihistamineswith anticholinergic properties may be helpful in controlling theextrapyramidal reactions. There is no specific.

Antidote to domperidone but in the event of overdosage, gastriclavage as well as the administration of activated charcoal may

be useful. Close observation and supportive therapy arerecommended. Symptoms are self-limiting and usuallydisappear within 24 hours.

Ex.2 Metoclopramide HCI

Generic Name: Metoclopramide HCI

N N

O

O

N

Cl

4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide, monohydrochloride, monohydrate.

Synthesis:

Cl

H2 N OCH 3

OH

O

(CH 3CO) 2O

O

NH

Cl

OCH 3

O

OH

SOCl 2

4- Amino-5-chloro-2-methoxybenzoic acid

4- Acetamido-5-chloro-2-methoxybenzoic acid

O

NH

Cl

OCH 3

O

Cl NH 2 -CH 2 -CH 2 -N(C 2 H 5 ) 2

2. HClMetocloprami

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Mechanism of action

Dopaminergic blocking agents Exact mechanism of

action is unkown, however, it is believed that inhibits gastricsmooth muscle relaxation produced by dopamine, thusenhancing cholinergic responses of the gastrointestinal smoothmuscle. A ccelerates intestinal transit and gastric emptying by

preventing relaxation of gastric body and increasing the phasicactivity of antrum. This action is accompanied by relaxation of the upper small intestine, resulting in an improved coordination

between the body and antrum of the stomach and the upper

small intestine. Decreases reflux into the esophagus byincreasing the resting pressure of the lower esophageal sphincter and improves acid clearance from the esophagus by increasingamplitude of esophageal peristaltic contractions.

Antiemetic Dopamine antagonist action raises thethreshold of activity in the chemoreceptor trigger zone anddecreases the input from afferent visceral nerves.

Uses of Metoclopramide:

Metoclopramide is used to relieve nausea and vomiting;heartburn, stomach pain, and bloating; and a persistent feeling of fullness after meals.

Assay: (USP XXIV and Eur P 2000)

Non aqueous titration as abase using glacial acetic acid as

a solvent and perchloric acid as a titrant.

Side effects from metoclopramide such as: Drowsiness Restlessness Fatigue Constipation Diarrhea

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II.2 Antihistamincs 3

1. Dimenhydrinate

structure

O

NH

CH 3

CH 3 N

NCl

N

N

O

O

CH 3

CH 3

Chemical nomenclature

8 Chlorotheophyllin, compound with.

2 (diphenylmethoxy) N,N dimethylethylamine.

Assay (USP XXIV and Eur pharm. 2000)

1) For diphenhydramine:

a) Non aqueons titeration as weak base using percholeric acid astiterant, the end point is determined potentiometrically.

2) For 8 chlorotheophyllin:

Volhard titeration: For determination of chloride content.

Cl - + xss AgNO 3 AgCl + NO 3-

Xss AgNo 3 is back titerated against

Ammonium thioglycolate using ferric alum as indicator

Side effect

Drowsiness of dizziness;

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Restlessness, excitation, nervousness, or insomnia;

Blurred or double vision;

Dry mouth, nose, or throat.

2) Cyclizine

C

H

N N CH 3

Chemical nomenclature

1- (diphenylmethyl) 4 methylpiperazine.

II.3. 5-HT 3- receptor antagonists (Serotonin antagonist)

Ex.1 ondansetron

structure

N

H3C

O

N

NH3C

1,2,3,9- Tetrahydro-9-methyl-3-[(2-methyl-1H-

imidazol]-4H-Carbazol-4-one, monohydrochloride, dihydrate;Mode of action

Ondansetron is a highly selective antagonist at 5 HT3receptors; it has an affinity 250 1000 times greater for the 5 HT3 receptor than for any other receptor. The drug antagonizes5-HT3 receptors both centrally and peripherally and

peripherally.

Assay (USP XXIV): HPLC method.

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Metabolism

Hydroxylation/N-demethylation of the indole nucleus, thenconjugation with glucuronic acid or sulphate.Metabolites are

inactive.

Uses:

Used in the prevention and treatment of postoperativenausea and vomiting. Widely used in the management of nauseaand vomiting induced by chemotherapy and radiotherapy.

II.4. Antipsychotic 4

A) Phenothiazines

Ex.1 chlorpromazine

Structure

S

NCl

N

Me

Me

Mode of action:

Antiemetic effects are due to central dopaminergic blockade. Results in an increased threshold for vomiting at thechemoreceptor trigger zone.

Metabolism:

Hepatic metabolism. Undergoes oxidation, dealkylation,demethylation, sulfoxidation, N-oxidation and hydroxylation.Many active metabolites.

Assay:

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Non aqueous titeration as weak base

Uses:

In the prevention and treatment of nausea and vomitingassociated with terminal illness, schizophrenia and intractablehiccup.

Ex.2 prochlorperazine

Structure

S

N

(CH 2)3

Cl

N N CH 3

2- chloro 10 [3 (4-methyl 1 piperazinyl) propyl] 10H- pheno-thiazine.

II.5. Cannabinoids 5

Ex. Tetrahydrocannbinol (THC).

O

OHCOOH

C5H11

What can cannabis treat?The strongest evidence relates to the effectiveness of THC

and the synthetic derivative nabilone, in relieving nausea andvomiting which is caused by cancer chemotherapy.

Side effects of cannabis

Common side effects include sedation, mood alterations,

and physical symptoms such as dry mouth, GIT disturbance, blurred vision, weakness and lack of coordination.

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II.6. Anticholinergics 6

Ex. Scopolamine

CC

H

CH 2OH

OO

N CH 3O

II.7. Other agents 7

Lorazepam

N

H N

O

OH

Cl

Cl

Lorazepam is classified as a sedative-hypnotic of the benzodiazepine class.

Indications

Supportive therapy of nausea / emesis frequently associatedwith cancer chemotherapy together with accepted first lineantiemetics

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Postoperative Nausea and vomiting (PONV) 8

Figure Sites of action of drugs that influence PONV

*************************

nausea affect an estimated 30% of patient within 14hr after surgery.

Mechanism of nausea:

(1) intestinal irritation and postoperative stasis stimulate thevomiting center via vesicular fiber rich in serotonin.

(2) General anesthetics directly activate the chemoreceptor trigger zone which, in turn, stimulates the vomitingcenter via dopamine and serotonin.

Dopamine antagonists such as domperidone and promethazinehave been used to treat patients with postoperative nausea andvomiting. Metoclopramide, dopamine antagonist commonly is usedin patients with nausea caused by intestinal stasis.

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Serotonin antagonists also minimize postoperative nausea,and the AGA recommends using them as first-line agents for

preventing and treating postoperative nausea and vomiting.

Dexamethasone has been shown to be a useful adjunct toserotonin antagonists in the prevention and treatment of

postoperative nausea and vomiting.

Propofol given in low doses has been suggested to reduce postoperative nausea and vomiting. However, studies have beenunable to show an effect.

Structure of propofol

Antiemetic combinations

Nowadays, none of the available antiemetics is entirelyeffective in all the patients that.

A combination of drugs currently used in the treatment of nausea and vomiting in patients receiving chemotherapy. Could

be effective when there is sever frequent PONV.

Dexamethasone has antiemetic activities, and the

synergistic action with ondansetron and granisetron has beenshown after surgery, in the prevention of PONV, in similar patient groups as combinations with droperidol. There has beenshown also a synergistic action of dexamethasone with

perfenazine.

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Selection of Antiemetics by clinical situation 9

Situation Associated

Neurotransmitters

Recommended

AntiemeticMigraineHeadache

Dopamine(probablya primarymediator)

For headache and nausea:metoclopramide (Reglan) or

prochlorperazine (Compazine)For nausea: oral antiemetics,metoclopramide,

Vestibular Nausea

Histamine,Acetylcholine

Prochlorperazine,Serotonin antagonistsAntihistamines and anticholinergics(equally effective)

Pregnancy induced Nausea

Unknown For nausea: ginger, vitamin B 6.For hyperemesis gravidarum:Promethazine(phenergan, first lineagent); serotoninantagonists andcorticosteroids (second-line agents

Gatroenteritis Dopamine,Serotonin

First line agents:Dopamine antagonistsSecond-line agents:Serotonin antagonistsUse in children is controversial.

Postoperative Nausea andvomiting

Dopamine,Serotonin

Prevention: serotoninAntagonists, droperidol(inapsine),dexamethasoneTreatment: dopamineAntagonists, serotoninAntagonists,Dexamethasone

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