Antiemetics

Prof. Hanan HagarPharmacology Department

College of Medicine

Learning objectives Classify the main different classes of antiemetic drugs Classify the main different classes of antiemetic drugs

according to their mechanism of action.according to their mechanism of action. Know the characteristic pharmacokinetics & dynamics of Know the characteristic pharmacokinetics & dynamics of

different classes of antiemetic drugs.different classes of antiemetic drugs. Identify the selective drugs that can be used according to Identify the selective drugs that can be used according to

the cause of vomiting.the cause of vomiting. Learn the Adjuvant antiemetics.Learn the Adjuvant antiemetics. Describe the major side effects for the different classes of Describe the major side effects for the different classes of

antiemetics.antiemetics.

Causes of VomitingCauses of VomitingNausea and vomiting may be manifestations Nausea and vomiting may be manifestations of many conditions and may occur due to of many conditions and may occur due to stimulation of stimulation of vomiting center that respond to vomiting center that respond to inputs from:inputs from:

Chemoreceptor trigger zone Chemoreceptor trigger zone (CTZ)(CTZ) stimulation stimulation Disturbance of Disturbance of vestibular systemvestibular system Higher cortical centers stimulation Higher cortical centers stimulation (CNS)(CNS) The The periphery (Pharynx, GIT)periphery (Pharynx, GIT) via sensory nerves via sensory nerves

1. 1. Chemoreceptor trigger zone stimulationChemoreceptor trigger zone stimulation CTZ is an area of medulla that communicate CTZ is an area of medulla that communicate

with vomiting center to initiate vomiting.with vomiting center to initiate vomiting. CTZ is physiologically outside BBB.CTZ is physiologically outside BBB. CTZ Contains CTZ Contains opioid receptors, D2 opioid receptors, D2

receptors & 5 HT3 receptors, Substance Preceptors & 5 HT3 receptors, Substance P stimulated by:stimulated by:

Drugs (opioids, general anesthetics),Drugs (opioids, general anesthetics), Chemicals and toxins Chemicals and toxins in blood, CSFin blood, CSF.. Radiation. Radiation.

2. The periphery via sensory nerves2. The periphery via sensory nerves

GIT irritation, myocardial infarction, renal orGIT irritation, myocardial infarction, renal or

biliay stones.biliay stones.

3. Disturbance of vestibular system 3. Disturbance of vestibular system

by motion sicknessby motion sickness

4. Higher cortical centers stimulation4. Higher cortical centers stimulation: :

emotional factors, nauseating smells or sights.emotional factors, nauseating smells or sights.

Receptors Associated with Nausea and VomitingReceptors Associated with Nausea and Vomiting

Vomiting Centre (medulla)

Cerebral cortex

Anticipatory emesisSmellSight

Thought

Vestibular nuclei

Motion sickness

Pharynx & GIT

Chemo & radio therapy Gastroenteritis

ChemoreceptorTrigger Zone

(CTZ)

(Outside BBB)

chemotherapyOpioids

Anesthetics

Muscarinic, 5 HT3 & Histaminic H1

5 HT3 receptors

5 HT3

Dopamine D2

Opioid receptors

Substance p

Muscarinic Histaminic H1

Pathophysiology of Emesis

Chemical transmitters & receptors Chemical transmitters & receptors involved in vomiting include:involved in vomiting include:

Ach Ach (Muscarinic receptors)(Muscarinic receptors) Dopamine Dopamine (D2)(D2) Histamine Histamine (Histaminergic receptors H(Histaminergic receptors H11))

Serotonin Serotonin (5 -HT(5 -HT33) ) Substance P Substance P (Neurokinin receptors, NK1)(Neurokinin receptors, NK1) Opioid Opioid (Opioid receptors)(Opioid receptors)

Classification of Antiemetic DrugsClassification of Antiemetic Drugs

1.1. 5-HT3 antagonists5-HT3 antagonists

2.2. DD2 2 receptor antagonistsreceptor antagonists

3.3. NKNK1 1 antagonistsantagonists

4.4. HH11-receptor antagonists-receptor antagonists

5.5. Muscarinic receptor antagonistsMuscarinic receptor antagonists

6.6. Cannabinoids Cannabinoids

7.7. Glucocorticoids Glucocorticoids

5-HT3 antagonists5-HT3 antagonists

Drugs as Drugs as Ondansetron, Granisetron Ondansetron, Granisetron Orally or parenterallyOrally or parenterally Potent antiemetic effectsPotent antiemetic effects Block Block 5-HT3 receptor in vomiting center, CTZ 5-HT3 receptor in vomiting center, CTZ

and 5HT3 receptors on intestinal vagal and 5HT3 receptors on intestinal vagal

afferents. afferents.

Uses of 5-HT3 antagonistsUses of 5-HT3 antagonists First choice for prevention of:First choice for prevention of:

– Chemotherapy-induced nausea and vomiting Chemotherapy-induced nausea and vomiting (CINV) (CINV) especially cisplatin.especially cisplatin.

– Post-radiation NV& Post-operative NVPost-radiation NV& Post-operative NV– Their effects is increased by combination Their effects is increased by combination

with corticosteroids and NK1 antagonists.with corticosteroids and NK1 antagonists.Side effectsSide effectsoWell toleratedWell toleratedomild headache, dizziness and constipationmild headache, dizziness and constipationominor ECG abnormalities (QT prolongation) minor ECG abnormalities (QT prolongation)

D2 receptor antagonistsD2 receptor antagonists block D2 dopamine receptors in the CTZblock D2 dopamine receptors in the CTZ Two types exist: Two types exist:

1)1) Prokinetics drugs Prokinetics drugs 2)2) Neuroleptics (antipsychotics)Neuroleptics (antipsychotics)

Uses of D2 receptor antagonistsUses of D2 receptor antagonists are among the most commonly used drug for are among the most commonly used drug for

nausea and vomiting of non-specific causes.nausea and vomiting of non-specific causes. Effective against vomiting due to drugs,Effective against vomiting due to drugs, gastroenteritis, post-operative, toxins, gastroenteritis, post-operative, toxins,

uremia, radiation.uremia, radiation.

D2 receptor antagonists D2 receptor antagonists

1) Prokinetics drugs1) Prokinetics drugs Drugs as metoclopramide, domperidoneDrugs as metoclopramide, domperidone Both are prokinetic agents due to their Both are prokinetic agents due to their 5 HT4 5 HT4

agonistic activity. agonistic activity. used in GERD (gastroesophageal reflux used in GERD (gastroesophageal reflux

disease), gastroparesis.disease), gastroparesis. Used as antiemetics Used as antiemetics (blocking D2 receptors)(blocking D2 receptors) Metoclopramide crosses BBB but Metoclopramide crosses BBB but

domperidone cannot domperidone cannot (both have antiemetic (both have antiemetic effects as CTZ is outside BBB).effects as CTZ is outside BBB).

Side effectsSide effects (only for metoclopramide):(only for metoclopramide): Dyskinesia (Dyskinesia (extra-pyramidal side effects)extra-pyramidal side effects),, Galactorrhea, menstrual disorders, Galactorrhea, menstrual disorders,

impotence.impotence. Sedation, postural hypotension.Sedation, postural hypotension.

D2 receptor antagonistsD2 receptor antagonists

Neuroleptics (Antipsychotics)Neuroleptics (Antipsychotics) Chlorpromazine (CPZ), droperidol Chlorpromazine (CPZ), droperidol used for used for postoperative vomiting and postoperative vomiting and

chemotherapy-induced nausea & vomiting.chemotherapy-induced nausea & vomiting.

Side effectsSide effects: extrapyramidal symptoms : extrapyramidal symptoms

sedation, postural hypotensionsedation, postural hypotension

Neurokinin1 (NK1) receptor antagonistsNeurokinin1 (NK1) receptor antagonistsAprepitant Aprepitant

Is a substance P antagonists that acts by Is a substance P antagonists that acts by blocking neurokinin 1 receptors. blocking neurokinin 1 receptors.

OrallyOrally Used in prevention of acute and delayed Used in prevention of acute and delayed

chemotherapy-induced nausea and vomiting chemotherapy-induced nausea and vomiting and for prevention of postoperative nausea and for prevention of postoperative nausea and vomiting.and vomiting.

Usually combined with 5-HTUsually combined with 5-HT33 antagonists antagonists and corticosteroids.and corticosteroids.

H1-receptor antagonistsH1-receptor antagonists Effective for motion sickness, morning Effective for motion sickness, morning

sickness in pregnancysickness in pregnancy Drugs as Drugs as

– DiphenhydramineDiphenhydramine– Meclizine - CyclizineMeclizine - Cyclizine– Promethazine: severe morning sickness of Promethazine: severe morning sickness of

pregnancy pregnancy (if only essential).(if only essential).Side effects: Side effects: – prominent sedation, hypotension, prominent sedation, hypotension,

anticholinergic effects (dry mouth, dilated anticholinergic effects (dry mouth, dilated pupils, urinary retention, constipation. pupils, urinary retention, constipation.

Muscarinic receptor antagonistsMuscarinic receptor antagonists

Hyoscine (scopolamine)Hyoscine (scopolamine) Orally, injection, patchesOrally, injection, patches Used as transdermal patches in motion Used as transdermal patches in motion

sickness sickness (applied behind the external ear)(applied behind the external ear). . Not in chemotherapy-induced vomitingNot in chemotherapy-induced vomiting Side effects:Side effects: tachycardia, blurred vision, tachycardia, blurred vision,

dry mouth, constipation, urinary retention dry mouth, constipation, urinary retention

(atropine-like actions).(atropine-like actions).

CannabinoidsCannabinoids

Nabilone, dronabinol Nabilone, dronabinol mechanism of action not understood.mechanism of action not understood. act at central cannabinoid receptors.act at central cannabinoid receptors. Used in vomiting due to cytotoxic Used in vomiting due to cytotoxic

anticancer drugs anticancer drugs (adjuvant therapy).(adjuvant therapy). Not commonly used.Not commonly used.Side effects: Side effects: euphoria, dysphoria, sedation,euphoria, dysphoria, sedation,hallucination.hallucination.

GlucocorticoidsGlucocorticoids Dexamethasone - Dexamethasone - methylprednisolone methylprednisolone

Used in chemotherapy-induced vomitingUsed in chemotherapy-induced vomiting

combined with combined with 5-HT5-HT33 antagonists or NK1 antagonists or NK1

receptor antagonists. receptor antagonists.

GlucocorticoidsGlucocorticoids

Side effects:Side effects:– HyperglycemiaHyperglycemia– Hypertension– Cataract– Osteoporosis– Increased intraocular pressure– Increased susceptibility to infection– Increased appetite & obesity

SummarySummary The choice of antiemetic depends on the etiologyThe choice of antiemetic depends on the etiology

Motion sicknessMotion sickness Muscarinic antagonistsMuscarinic antagonistsAntihistaminicsAntihistaminics

Vomiting with pregnancy (morning sickness)Vomiting with pregnancy (morning sickness) avoid all drugs in the first trimesteravoid all drugs in the first trimester

Pyridoxine (B6)Pyridoxine (B6)Promethazine ( late pregnancy)Promethazine ( late pregnancy)..

Drug- induced vomiting (CTZ)Drug- induced vomiting (CTZ)Dopamine antagonistsDopamine antagonists

Post operative nausea & vomitingPost operative nausea & vomitingDopamine antagonistsDopamine antagonists

55--HTHT33 antagonists antagonists

NK1 antagonistsNK1 antagonists

Vomiting due to cytotoxic drugsVomiting due to cytotoxic drugs..

55--HTHT33 antagonists antagonists

NK1 antagonistsNK1 antagonists

D2- antagonistsD2- antagonists

GlucocorticoidsGlucocorticoids

CannabinoidsCannabinoids

Thank you

Questions?