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 including travel by car, air or boat, 2) Food poisoning. Which caused by bacteria, 3) Viral in ection !hich is sometimes associated !ith diarrhea. ") medication can cause nausea and even vomiting. #) $ostoperative nausea and vomiting. %ausea a ects an estimated 3&' o patient !ithin 2" hr a ter surgery. () $regnancy may induce vomiting. )) gastroenteritis.

I.3. Physiologic mechanisms that result in nausea and vomiting1 Etiology of "ausea and #omiting
Visceral 2timuli +hemoreceptor ,rigger 0one Vestibular input

1opamine and 2erotonin released

1opamine and serotonin released

3istamine and acetylcholine released

Medullary vomiting +enter stimulated

%ausea and vomiting

II. Classification of Antiemetic Agents

II.1. Dopamine antagonists *lock dopamine receptor in +,-. E . !etoclopramide and Domperidone II.2. Antihistamines $rovide relie rom motion sickness through an action on the vestibular apparatus. ./. +ycli0ine, 1imenhydrinate and 1iphenhydramine

II.3. $%&'3 receptor antagonists ()erotonin antagonists* *lock both peripheral and central #43,3 5 receptors and are especially e ective against the emetogenic e ects o chemotherapy. ./. 6ndansetron II.+. antipsychotic 7ct at the chemoreceptor trigger 0one 8+,-) to block dopaminergic emetic receptors. .9. phenothia0ines II.$. Canna,inoids 7re especially use ul in the emesis rom cancer chemotherapy. .9. ,etrahydrocannabinol II.-. Anticholinergic agent :n combination !ith d4amphetamine and scopolamine are most e ective against motion sickness. ./. 2copolamine 8,ransderm 2cop) II... /ther agents 7re especially use ul in the post operative nausea and vomiting. .9. 1e/amethasone and 1ia0epam

II.1. Dopamine antagonists2

Action and Clinical pharmacology:

1omperidone is a peripheral dopamine antagonist structurally related to the butyrophenones !ith antiemetic and gastroprokinetic properties. E0.1 Domperidone:%
+l 3 % 6 % 3 % % 6 % 3

'he mechanism of action of domperidone:

is related to its peripheral dopamine receptor blocking properties. .mesis induced by apomorphine, morphine or levodopa through stimulation o the chemoreceptor trigger 0one 8situated outside the blood4brain barrier) can be blocked by domperidone. ,here is indirect evidence that emesis is also inhibited at the gastric level, since domperidone also inhibits emesis induced by oral levodopa, and local gastric !all concentrations ollo!ing oral domperidone are much greater than those o the plasma and other organs. 1omperidone does not readily cross the blood4brain barrier and there ore is not e/pected to have central e ects. 1omperidone elevates serum prolactin levels but has no e ect on circulating aldosterone levels.

Pharmaco1inetics:
:n man, peak plasma levels o domperidone occur !ithin 1& to 3& minutes ollo!ing :.M. in;ection and 3& minutes a ter oral 8 asted) administration. $lasma concentrations 2 hours a ter
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oral administration are lo!er than ollo!ing :.M. in;ection, and this is likely the result o hepatic irst4pass and gut !all metabolism. $eak plasma concentrations are "& ng<m= ollo!ing an :.M. in;ection o 1&mg, 2& g<m= a ter a single 1& mg tablet, and )& to 1&& g<m= a ter oral doses o (& mg 8tablets or oral drops). ,he hal 4li e !as calculated as appro/imately ).& hours in each case. ,he degree o human plasma protein binding !as calculated rom tritiated domperidone concentrations o 1& and 1&& g<m= as >1.) and >3.&', respectively. ,he ma;or metabolic path!ays or domperidone in man are hydro/ylation and o/idative %4dealkylation, the products or !hich are hydro/ydomperidone and 2,3 5 dihydro 524 o/o 514 3 5 ben0imida0ol414propionic acid, respectively. 7 ter oral administration o "& mg "4domperidone to healthy volunteers, 31' o the radioactivity is e/creted in the urine and ((' in the eces over a period o " days.

Indications and clinical uses:

:n the symptomatic management o upper gastrointestinal motility disorders associated !ith chronic and subacute gastritis and diabetic gastroparesis. 1omperidone may also be used to prevent gastrointestinal symptoms associated !ith the use o dopamine agonist antiparkinsonian agents.

Contra%Indications:
:n patients !ith kno!n sensitivity or intolerance to the drug. 1omperidone should not be used !henever gastrointestinal stimulation might be dangerous, i.e., gastrointestinal hemorrhage, mechanical obstruction or per oration. 7lso contraindicated in patients !ith a prolactin4releasing pituitary tumor 8prolactinoma).

Assay: (Eur P 2222*

%on a?ueous titration as !eak base using perchloric acid as titratant and naphtholben0ein solution as indicator.

Adverse 3eactions:
C"): dry mouth, headache<migraine, insomnia, nervousness, di00iness, thirst, lethargy, irritability. 4astrointestinal: abdominal cramps, diarrhea, regurgitation, changes in appetite, nausea, heartburn, constipation. Endocrinological: hot lushes, mastalgia, galactorrhea, gynecomastia, menstrual :rregularities. !ucocutaneous: rash, pruritus, urticaria, stomatitis, con;unctivitis. 5rinary:
@rinary re?uency, dysuria. +ardiovascular edema, palpitations. Musculoskeletal leg cramps, asthenia. Miscellaneous, drug intolerance.

)ymptoms and 'reatment of /verdose:

)ymptoms: *ased on the pharmacological properties o domperidone, symptoms o overdosage may include +%2 e ects 8such as dro!siness, disorientation and e/trapyramidal reactions, especially in children) and cardiovascular e ects 8arrhythmia, hypotension) might possibly occur.

'reatment:
7nticholinergic, anti4parkinsonian drugs or antihistamines !ith anticholinergic properties may be help ul in controlling the e/trapyramidal reactions. ,here is no speci ic. 7ntidote to domperidone but in the event o overdosage, gastric lavage as !ell as the administration o activated charcoal may be use ul. +lose observation and supportive therapy are recommended. 2ymptoms are sel 4limiting and usually disappear !ithin 2" hours. ./.2 Metoclopramide 3+: 4eneric "ame: Metoclopramide 3+:
6 +l % 6 % %

"47mino4#4chloro4%4A248diethylamino)ethylB424 metho/yben0amide, monohydrochloride, monohydrate.

)ynthesis:
6 6 +l 32% 63 6+33 8+33+6)26 6 "4 7cetamido4#4chloro4 24metho/yben0oic acid
6 +l +l 6+33 %324+324+324%8+23#)2 2. 3+l

+l

63 6+33 26+l2

%3

"4 7mino4#4chloro424 metho/yben0oic acid

%3 6

Metoclopramic

!echanism of action
1opaminergic blocking agents 5 ./act mechanism o action is unko!n, ho!ever, it is believed that inhibits gastric smooth muscle rela/ation produced by dopamine, thus enhancing cholinergic responses o the gastrointestinal smooth muscle. 7 ccelerates intestinal transit and gastric emptying by preventing rela/ation o gastric body and increasing the phasic activity o antrum. ,his action is accompanied by rela/ation o the upper small intestine, resulting in an improved coordination bet!een the body and antrum o the stomach and the upper small intestine. 1ecreases re lu/ into the esophagus by increasing the resting pressure o the lo!er esophageal sphincter and improves acid clearance rom the esophagus by increasing amplitude o esophageal peristaltic contractions. 7ntiemetic 5 1opamine antagonist action raises the threshold o activity in the chemoreceptor trigger 0one and decreases the input rom a erent visceral nerves. 5ses of !etoclopramide: Metoclopramide is used to relieve nausea and vomitingC heartburn, stomach pain, and bloatingC and a persistent eeling o ullness a ter meals.

Assay: (5)P 00I# and Eur P 2222*

%on a?ueous titration as abase using glacial acetic acid as a solvent and perchloric acid as a titrant.

)ide effects from metoclopramide such as:

1ro!siness Destlessness Fatigue +onstipation 1iarrhea

II.2 Antihistamincs3
1. 1imenhydrinate structure
+33 % 3 6 +33 % +l % % +33 6 +33 % 6

Chemical nomenclature E 5 +hlorotheophyllin, compound !ith. 2 5 8diphenylmetho/y) 5 %,% 5 dimethylethylamine.

Assay (5)P 00I# and Eur pharm. 2222*

1* 6or diphenhydramine: a) %on a?ueons titeration as !eak base using percholeric acid as titerant, the end point is determined potentiometrically. 2* 6or 7 8 chlorotheophyllin: Volhard titerationF For determination o chloride content. +l4 G /ss 7g%63 7g+l

G %634

9ss 7g%o3 is back titerated against 7mmonium thioglycolate using erric alum as indicator

)ide effect
1ro!siness o di00inessC

>

 Destlessness, e/citation, nervousness, or insomniaC *lurred or double visionC 1ry mouth, nose, or throat. 2* Cycli9ine
3 + % % +33

Chemical nomenclature 14 8diphenylmethyl) 5 " 5 methylpipera0ine. II.3. $%&'3% receptor antagonists ()erotonin antagonist* ./.1 ondansetron structure
6 % % 33+ % 33+

1,2,3,>4 ,etrahydro4>4methyl434A824methyl4134 imida0olB4"34+arba0ol4"4one, monohydrochloride, dihydrateC !ode of action 6ndansetron is a highly selective antagonist at # 5 3,3 receptorsC it has an a inity 2#& 5 1&&& times greater or the # 5 3,3 receptor than or any other receptor. ,he drug antagoni0es #43,3 receptors both centrally and peripherally and peripherally. Assay (5)P 00I#*: &P:C method.
1&

!eta,olism 3ydro/ylation<%4demethylation o the indole nucleus, then con;ugation !ith glucuronic acid or sulphate.Metabolites are inactive. 5ses: @sed in the prevention and treatment o postoperative nausea and vomiting. Widely used in the management o nausea and vomiting induced by chemotherapy and radiotherapy.

II.+. Antipsychotic +
A* Phenothia9ines ./.1 chlorproma0ine 2tructure
2 +l %

% Me

Me

!ode of action: 7ntiemetic e ects are due to central dopaminergic blockade. Desults in an increased threshold or vomiting at the chemoreceptor trigger 0one. !eta,olism: 3epatic metabolism. @ndergoes o/idation, dealkylation, demethylation, sul o/idation, %4o/idation and hydro/ylation. Many active metabolites. Assay:

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%on a?ueous titeration as !eak base 5ses: :n the prevention and treatment o nausea and vomiting associated !ith terminal illness, schi0ophrenia and intractable hiccup. ./.2 prochlorpera0ine 2tructure
2 % 8+32)3 % +l % +33

24 chloro 5 1& 5 A3 5 8"4methyl 5 1 5 pipera0inyl) 5 propylB 5 1& 34 pheno4thia0ine.

II.$. Canna,inoids $
./. ,etrahydrocannbinol 8,3+).
63 +663

+#311

;hat can canna,is treat< ,he strongest evidence relates to the e ectiveness o ,3+ and the synthetic derivative nabilone, in relieving nausea and vomiting !hich is caused by cancer chemotherapy. )ide effects of canna,is +ommon side e ects include sedation, mood alterations, and physical symptoms such as dry mouth, H:, disturbance, blurred vision, !eakness and lack o coordination.
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II.-. Anticholinergics ./. 2copolamine

6 6 % +33 6 + + 3 +3263

II... /ther agents . :ora9epam

3 % +l % +l 6 63

=ora0epam is classi ied as a sedative4hypnotic o the ben0odia0epine class. Indications

2upportive therapy o nausea < emesis re?uently associated !ith cancer 5 chemotherapy together !ith accepted irst line antiemetics

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Postoperative "ausea and vomiting (P/"#* 7

Figure 2ites o action o drugs that in luence $6%V IIIIIIIIIIIIIIIIIIIIIIIII nausea a ect an estimated 3&' o patient !ithin 1"hr a ter surgery.

!echanism of nausea:
81) 82) intestinal irritation and postoperative stasis stimulate the vomiting center via vesicular iber rich in serotonin. Heneral anesthetics directly activate the chemoreceptor trigger 0one !hich, in turn, stimulates the vomiting center via dopamine and serotonin.

1opamine antagonists such as domperidone and prometha0ine have been used to treat patients !ith postoperative nausea and vomiting. Metoclopramide, dopamine antagonist commonly is used in patients !ith nausea caused by intestinal stasis.

1"

2erotonin antagonists also minimi0e postoperative nausea, and the 7H7 recommends using them as irst4line agents or preventing and treating postoperative nausea and vomiting. 1e/amethasone has been sho!n to be a use ul ad;unct to serotonin antagonists in the prevention and treatment o postoperative nausea and vomiting. $ropo ol given in lo! doses has been suggested to reduce postoperative nausea and vomiting. 3o!ever, studies have been unable to sho! an e ect. 2tructure o propo ol

Antiemetic com,inations
%o!adays, none o the available antiemetics is entirely e ective in all the patients that. 7 combination o drugs currently used in the treatment o nausea and vomiting in patients receiving chemotherapy. +ould be e ective !hen there is sever re?uent $6%V. 1e/amethasone has antiemetic activities, and the synergistic action !ith ondansetron and granisetron has been sho!n a ter surgery, in the prevention o $6%V, in similar patient groups as combinations !ith droperidol. ,here has been sho!n also a synergistic action o de/amethasone !ith per ena0ine.

1#

)election of Antiemetics ,y clinical situation=

)ituation Migraine 3eadache Associated "eurotransmitters 1opamine 8probably a primary mediator) 3istamine, 7cetylcholine 3ecommended Antiemetic For headache and nauseaF metoclopramide 8Deglan) or prochlorpera0ine 8+ompa0ine) For nauseaF oral antiemetics, metoclopramide, $rochlorpera0ine, 2erotonin antagonists 7ntihistamines and anticholinergics 8e?ually e ective) For nauseaF ginger, vitamin *(. For hyperemesis gravidarumF $rometha0ine 8phenergan, irst 5line agent)C serotonin antagonists and corticosteroids 8second4line agents First 5 line agentsF 1opamine antagonists 2econd4line agentsF 2erotonin antagonists @se in children is controversial. $reventionF serotonin 7ntagonists, droperidol 8inapsine), de/amethasone ,reatmentF dopamine 7ntagonists, serotonin 7ntagonists, 1e/amethasone

Vestibular %ausea

$regnancy induced %ausea

@nkno!n

Hatroenteritis

1opamine, 2erotonin

$ostoperative %ausea and vomiting

1opamine, 2erotonin

1(