antiemetics

AntiemeticsAntiemetics

DefinitionsDefinitions

NauseaNausea• Unpleasant feeling that often precedes vomitingUnpleasant feeling that often precedes vomiting

Emesis (vomiting)Emesis (vomiting)• Forcible emptying of gastric, and occasionally, Forcible emptying of gastric, and occasionally,

intestinal contentsintestinal contents Antiemetic agentsAntiemetic agents

• Used to relieve nausea and vomitingUsed to relieve nausea and vomiting

VC and CTZVC and CTZ

Vomiting center (VC)Vomiting center (VC) Chemoreceptor trigger zone (CTZ)Chemoreceptor trigger zone (CTZ)

• Both located in the brainBoth located in the brain• Once stimulated, cause the vomiting reflexOnce stimulated, cause the vomiting reflex

Mechanism of ActionMechanism of Action

Many different mechanisms of actionMany different mechanisms of action Most work by blocking one of the vomiting Most work by blocking one of the vomiting

pathways, thus blocking the stimulus that pathways, thus blocking the stimulus that induces vomitinginduces vomiting

Mechanism of Action and IndicationsMechanism of Action and Indications

Anticholinergic agents (ACh blockers)Anticholinergic agents (ACh blockers)• scopolaminescopolamine• Also used for motion sicknessAlso used for motion sickness

Mechanism of ActionMechanism of Action

Antihistamine agents (HAntihistamine agents (H11 receptor blockers) receptor blockers)• dimenhydrinate, dimenhydrinate, diphenhydramine, meclizine, diphenhydramine, meclizine,

promethazinepromethazine• Also used for nonproductive cough, allergy Also used for nonproductive cough, allergy

symptoms, sedationsymptoms, sedation

Mechanism of Action (cont'd)Mechanism of Action (cont'd)

Neuroleptic agentsNeuroleptic agents• Block dopamine receptors on the CTZBlock dopamine receptors on the CTZ• chlorpromazine,chlorpromazine, perphenazine, triflupromazine perphenazine, triflupromazine• Also used for psychotic disorders, intractable Also used for psychotic disorders, intractable

hiccupshiccups


Prokinetic agentsProkinetic agents• Block dopamine in the CTZBlock dopamine in the CTZ• Cause CTZ to be desensitized to impulses it Cause CTZ to be desensitized to impulses it

receives from the GI tractreceives from the GI tract• Also stimulate peristalsis in GI tract, enhancing Also stimulate peristalsis in GI tract, enhancing

emptying of stomach contentsemptying of stomach contents• metoclopramidemetoclopramide, cisapride, cisapride• Also used for GERD, delayed gastric emptyingAlso used for GERD, delayed gastric emptying


Serotonin blockersSerotonin blockers• Block serotonin receptors in the GI tract, CTZ, and Block serotonin receptors in the GI tract, CTZ, and

VCVC• dolasetron, granisetron, dolasetron, granisetron, ondansetronondansetron• Used for N&V for patients receiving Used for N&V for patients receiving

chemotherapy and postoperative nausea and chemotherapy and postoperative nausea and vomitingvomiting


TetrahydrocannabinoidsTetrahydrocannabinoids• Major psychoactive substance in marijuanaMajor psychoactive substance in marijuana• Inhibitory effects on reticular formation, thalamus, Inhibitory effects on reticular formation, thalamus,

cerebral cortexcerebral cortex• Alter mood and body’s perception of its Alter mood and body’s perception of its

surroundingssurroundings


Tetrahydrocannabinoids (cont'd)Tetrahydrocannabinoids (cont'd)• dronabinol (Marinol)dronabinol (Marinol)• Used for N&V associated with chemotherapy, and Used for N&V associated with chemotherapy, and

anorexia associated with weight loss in AIDS anorexia associated with weight loss in AIDS patientspatients

IndicationsIndications

Vary per class of antiemeticsVary per class of antiemetics General use: prevention and reduction of General use: prevention and reduction of

nausea and vomitingnausea and vomiting

Now answer this question

Which group of drugs can be used as antiemetics ?

Serotonin 5 HT3 Antagonists

Dopamine D2 Antagonist

Anticholinergics

H1 Antihistaminics

Cannabinoids

CLASSIFICATIONCLASSIFICATION1.1. Anti histamines (HAnti histamines (H11 antagonist) antagonist)

CyclizineCyclizine MeclozineMeclozine DimenhydrinateDimenhydrinate HdroxyzineHdroxyzine DiphenhydramineDiphenhydramine

2.2. Anticholinergic drugsAnticholinergic drugs HyoscineHyoscine

3.3. Selective 5-HTSelective 5-HT33 receptor antagonist. receptor antagonist. OndansetronOndansetron GranisetronGranisetron TropisetronTropisetron DolasetronDolasetron

4.4. PhenothiazinesPhenothiazines ProchlorperazineProchlorperazine ThiethylperazineThiethylperazine PromethazinePromethazine

5.5. DD2 2 receptor Antagonistreceptor Antagonist MetoclopramideMetoclopramide Domperidone:- does not cross BBB and thus has no CNS Domperidone:- does not cross BBB and thus has no CNS

side effects.side effects.

6.6. CannabinoidsCannabinoids NabiloneNabilone DronabinolDronabinol

7.7. GlucocorticoidsGlucocorticoids DexamethasoneDexamethasone MethylprednisoloneMethylprednisolone

8.8. BenzodiazepinesBenzodiazepines DiazepamDiazepam LorazipamLorazipam

9.9. Neurokinin-1 receptor AntagonistNeurokinin-1 receptor Antagonist AprepitantAprepitant FosaprepitantFosaprepitant

Serotonin 5 HT3 Antagonist

Potent antiemetics

Even though 5 HT3 receptors are present in vomiting centre & CTZ, the antiemetic action is restricted to emesis caused by vagal stimulation.

High first pass metabolism

Excreted by liver & kidney

No dose reduction in renal insufficiency but needed in hepatic insufficiency

Given once or twice daily – orally or intravenously.

Drugs AvailableOndansetron 32 mg / day

Granisetron 10 mg / kg / day

Dolasetron 1.8 mg / kg / day

IndicationsChemotherapy induced nausea & vomiting – given 30

min. before chemotherapy.

Postoperative & postradiation nausea & vomiting

Adverse EffectsExcellent safety profile

Headache & constipation

All three drugs cause prolongation of QT interval, but more pronounced with dolasetron.

Dopamine D2 Antagonist

Antagonise D2 receptors in CTZ.

Drugs available

Metoclopramide 2.5 mg b.d

Domperidone 10 mg b.d

Both drugs are also prokinetic agents due to their 5 HT4 agonist activity.

Domperidone – oral ; Metoclopramide – oral & i.v

Metoclopramide crosses BBB but domperidone cannot.


Which is a better antiemetic – Metoclopramide or Domperidone ?

As CTZ is outside BBB both have antiemetic effects.

But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side effects..

Domperidone is well tolerated.

Phenothiazines & Butyrophenones

Phenothiazines

Prochlorperazine

Promethazine

Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism.

Butyrophenone

Droperidol

Droperidol used for postop. nausea & vomiting, but cause QT prolongation.

H1 Antihistaminics

Most effective drugs for motion sickness

Drugs available

Meclizine

Cyclizine

Dimenhydrinate

Diphenydramine

Promethazine – Used in pregnancy, used by

NASA for space motion sickness

Anticholinergics

Scopolamine (hyoscine) – used as transdermal patch for motion sickness

Cannabinoids

Dronabinol – used as adjuvant in chemotherapy induced vomiting.It is a psychoactive substance

Nabilone


A physician prescribed Tab.Ondansetron for prophylaxis of motion sickness. Even though ondansetron is a potent antiemetic it didn’t produce any effect in this patient. Can you explain why ?

Explanation :

Vestibular nuclei has only muscarinic and H1 histaminic receptors.

Points to Ponder

Even though both atropine and scopolamine are antimuscarinic, only scopolamine is used in the treatment of motion sickness. Why ?

Generally transdermal patches are applied over the arm or chest. But scopolamine transdermal patch is applied behind the ear. Why?

AreaArea Type of receptors Type of receptors StimulusStimulus

Chemoreceptor Chemoreceptor trigger zone (CTZ)trigger zone (CTZ)

a)a) Dopamine DDopamine D22b)b) 5HT5HT33c)c) OpioidOpioid

1)1) Cancer Cancer chemotherapychemotherapy2)2) OpioidsOpioids

Vestibular nucleiVestibular nuclei a)a) MscarinicMscarinicb)b) Histamine HHistamine H11

1)1) Motion sicknessMotion sickness

Pharynx and GITPharynx and GIT a)a) 5HT5HT33 1)1) Cancer Cancer chemotherapychemotherapy

2)2) Radio therapyRadio therapy3)3) GastroenteritisGastroenteritis

Cerebral cortexCerebral cortex 1)1) SmellSmell2)2) SightSight3)3) ThoughtThought4)4) Anticipatory Anticipatory

emesisemesis

Serotonin 5HT3 receptor Serotonin 5HT3 receptor antagonistsantagonists

5HT3 receptor 5HT3 receptor

PhenothiazinesPhenothiazines Dopamine DDopamine D22 receptors receptorsAntihistaminicAntihistaminicAnticholinergicAnticholinergic

Substituted benzamidesSubstituted benzamides Dopamine DDopamine D22 receptors receptors

Anticholinergic drugsAnticholinergic drugs Muscarinic receptorsMuscarinic receptors

Antihistaminic drugsAntihistaminic drugs Histamine HHistamine H11 receptors receptors

Diphenhydramine Diphenhydramine dimenhydrinatedimenhydrinate

First generation H1 receptor First generation H1 receptor blockers that have blockers that have anticholinergic and sedating anticholinergic and sedating propertiesproperties

MeclizineMeclizine First generation H1 receptor First generation H1 receptor blockers that have lesser blockers that have lesser anticholinergic and sedating anticholinergic and sedating propertiesproperties

HyoscineHyoscine Muscarinic receptor blockerMuscarinic receptor blocker

Drugs to Know AboutDrugs to Know About

OndansetronOndansetron Scopolamine Scopolamine MetoclopramideMetoclopramide ChlorpromazineChlorpromazine DiphenhydramineDiphenhydramine MeclizineMeclizine PromethazinePromethazine

Vomiting Centre (medulla)

Cerebral cortex

Anticipatory emesisSmellSight

Thought

Vestibular nucleiMotion

sickness

Pharynx & GIT

Chemo & radio therapy Gastroenteritis

Chemoreceptor Trigger Zone

(CTZ)(Outside BBB)

Cancer chemotherapyOpioids

Muscarinic, 5 HT3 & Histaminic H1

5 HT3 receptors

Dopamine D2

5 HT3,,Opioid Receptors

Muscarinic Histaminic H1

Pathophysiology of Emesis

antiemetics

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