Download antiemetics

Emetics and antiemetics
• Act of forceful expulsion of gastric
contents through the mouth
•
Often preceded by nausea
Emesis (vomiting)
Emesis
• Rational (valuable) reflex
• prevention of ingestion of noxious substances (sight, smell,
taste, texture)
• local gut reflexes stimulate vomiting e.g. toxins
• Irrational reflexes
• labyrinth
• pregnancy
Control of Vomiting Reflex
 2 centers play imp. role in the vomiting
reflex
The chemoreceptor trigger zone (CTZ) is
outside BBB respond directly to chemical stimuli
in blood and cerebrospinal fluid
 The vomiting center (VC) in the medulla –
receives inputs from several sources (?)and
coordinates the motor mechanisms of vomiting
Both near the floor of the fourth ventricle, close
to the vital centres
 VC is within the blood brain barrier (BBB)
 CTZ outside in the area postrema
 They are connected together
Control of Vomiting Reflex
 Cancer
chemotherapy
 Opioids
 Anesthetics
CTZ
(Outside BBB)
Dopamine D2
5 HT3,, Opioid
receptors
Cerebral cortex
Smell
Sight
Thought
Vomiting Center
(medulla)
Vestibular
Motion sickness nuclei
Muscarinic ,
Muscarinic, 5 HT3 &
H1
H1
Chemo
& radiotherapy
Gastroenteritis
Pharynx & GIT
5 HT3 receptors
Hormones
Azotaemia
Diabetes
CTZ
Opioids
Chemotherapy
Anaesthetics
BBB
Vestibular
Sights
Smell
Taste
Hypotension
Hypoxaemia
Emetic Centre
Vomiting
Gut
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Neurotransmitters Involved
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Histamine via H1 receptors
Serotonin via 5HT3 receptors
Acetylcholine via M receptors
Dopamine via D2 receptors
ANTIEMETIC
DRUGS
A group of drugs which are used to control
nausea and vomiting
Provide symptomatic relief
Removal of causative factor to have ultimate relief
Classification - Antiemetic drugs
1. H1antihistamines
Meclizine, Cinnarizine, Cyclizine,
Dimenhydrinate & Diphenhydramine.
2. Muscarinic Antagonist
Hyoscine (Scopolamine).
3. Selective 5-HT3 Antagonists
Ondansetron, Granisetron,
Palonosetron & Dolasetron.
4. D2 Antagonists
a. Substituted Benzamides
Metoclopramide, Trimethobenzamide
b. Butyrophenones
Domperidone , Droperidol
c. Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine.
5. Cannabinoids
Dronabinol , Nabilone
6. Glucocorticoids
Dexamethasone, Methylprednisolone
7. Benzodiazepines
Diazepam , Lorazepam
8. Neurokinin-I Antagonist
Aprepitant (oral formulation), Fosaprepitant (IV formulation)
D2 Antagonists
a. Substituted Benzamides
Metoclopramide, Trimethobenzamide
b. Butyrophenones
Domperidone , Droperidol
c. Phenothiazines
Prochlorperazine, Promethazine &
Thiethylperazine.
Metoclopramide
Chemistry: Substituted Benzamide
MOA: Dopamine D2 receptors antagonist
It is potent Antiemetic & Prokinetic agent
As Antiemetic
• It has potent Antiemetic & antinausea effect.
• Blocks D2 receptors in CTZ of the medulla (area postrema)
As Prokinetic agent
• It can selectively stimulate gut motor function.
• Blocks D2 receptor in GIT & blocks the normal inhibitory
effect of Dopamine on cholinergic smooth muscle
stimulation--- ↑ motility.
The Uses - Metroclopramide
Potent antiemetic controls / reduces vomiting due to
• Uremia
• Radiation
• Viral gastro enteritis, hepatic-biliary disease
• Anticancer drugs
• Migraine
• Post operatively & pre-operatively
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Metroclopramide…
Pharmacokinetics
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Rapidly absorbed from GIT after oral administration.
Undergoes a high degree first pass metabolism.
It is excreted in the urine as free and as metabolites.
It is also excreted in the breast milk.
• DOSE: 10-20 mg orally or IV every 6 hrs
Adverse Effects - Metroclopramide
• Extrapyramidal reactions with facial and skeletal muscle
spasms- Restlessness, Dystonias , Parkinsonian symptoms.
-----More common in young and very old. Usually occur shortly
after staring treatment and subside with in 24 hours of stopping
the drug.
• Bowel upsets, Diarrhea
• Drowsiness and fatigue, dizziness, restlessness and anxiety.
• Galactorrhoea, Gynecomastia, impotence and menstrual
disorders – due to increased prolactin levels
Trimethobenzamide
Substituted Benzamide
Antiemetic like Metoclopramide.
D2 Antagonist & mild anti- histaminic activity
DOSE: 250mg orally, 200mg rectally, 200mg IM
Phenothiazines
Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine
Phenothiazines are antipsychotics with potent antiemetic
property due to D2 antagonism and anti-maucarinic
properties
Sedative property due to anti-histaminic property
Mainly used as anti-emetic in severe N& V
Main A/E: EPS , sedation , postural hypotension
Butyrophenones
Antipsychotic drugs , D2 antagonists
Droperidol
Central D2 antagonist
Main A/E: EPS , postural hypotension
QT prolongation may occur
Domperidone
• Does not cross BBB. Only blocks D2 in CTZ.
• May be used in N&V due to Levodopa, without affecting its
efficacy.
• No EPS.
• Used as antiemetic , prokinetic agent & for post-partum lactation
stimulation.
Selective 5-HT3 Antagonists
Ondansetron, Granisetron , Dolasetron &
Palonosetron
MOA
Act as anti-emetic by Selectively blocking central 5HT3 receptors in
Vomiting center & CTZ & Mainly by blocking Periphery 5HT3
receptors on intestinal vagal and spinal afferent fibers
Antiemetic action is restricted to emesis caused by vagal stimulation
(e..g post operative) & chemotherapy
Palonosetron: newer with greater affinity for 5-HT3 receptor &
comparatively longer half life
No effect on Dopamine / muscarinic receptors
Ph. K - Selective 5-HT3 Antagonists
• High first pass metabolism
• t1/2 : 4-9 hrs (Ondansetron, Granisetron & Dolasetron)
40 hrs (Palonosetron)
• Given once or twice daily – orally or intravenously
• Excreted by liver & kidney
• No dose reduction in renal insufficiency but needed in
hepatic insufficiency (Ondansetron)
The Uses - Selective 5-HT3 Antagonists
• Chemotherapy- Induced Nausea & vomiting
• Primary Agents - prevention of acute chemotherapy- induced
Nausea & vomiting
Effective alone in most of the cases. Efficacy is enhanced in
combination. Can be given I/V 1/2 hr before chemotherapy
• To prevent Delayed Nausea & vomiting occurring after 24 hrs
of Cancer chemotherapy
in combination with Dexamethasone & NK1 receptor
antagonist.
• To prevent & treat post operative & post radiation
Nausea & vomiting
Side effects- Selective 5-HT3 Antagonists
• Excellent safety profile
• Headache, Dizziness & constipation
• All three drugs cause prolongation of QT interval, but
more pronounced with dolasetron.
DIs
Hepatic clearance may decrease by enzyme inhibitors
H1antihistamines & Muscarinic Antagonists
H1antihistamines
Meclizine, Cinnarizine, Cyclizine & Diphenhydramine &
its salt Dimenhydrinate.
• They have anticholinergic & H1 antagonist sedating properties
(1st generation).
• They produce specific depression of conduction in
vestibulocerebellar pathway.
MuscarinicAntagonist
Hyoscine (Scopolamine).
H1antihistamines & Muscarinic Antagonists…
Theraputic Uses
• Vestibular system is important in motion sickness
via cranial nerve VIII - rich in Cholinergic M1 &
Histamine H1receptors
• Most effective drugs for motion sickness
• Effective for nausea & vomiting associated with motion
sickness.
• Vestibular disorders ( Meniere’s disease)
• (hyoscine) – used as transdermal patch for motion sickness
• Meclezine is long acting so useful in sea sickness
• Cinnarizine also has antivertigo effect. Act by inhibiting
influx of calcium to vestibular sensory cells from
endolymph
Therapeutic uses of H1receptor antagonists
Chemotherapyinduced vomiting
Motion Sickness
Vertigo
Routes of
administration of
Scopolamine
Transdermal patch
Oral
Cannabinoids
(Dronabinol , Nabilone)
Dronabinol
Tetrahydrocannabinol (THC) main psychoactive
chemical in marijuana
Pharmacokinetics: complete absorption on oral
administration, significant 1st pass effect, metabolites
excreted slowly over days to weeks in faeces & urine
• MOA: Act as antiemetic & appetite
stimulant in addition to psychoactive
action.
• MOA not clear.
• Cancer chemotherapy induced Nausea &
vomiting with Phenothiazines – synergistic
effect but AEs are added – not used as better
drugs are available
• Nabilone
• Closely related THC analog
Glucocorticoids
Dexamethasone , Methylprednisolone
Antiemetic
MOA: not clear
 Enhance action of 5HT3 antagonists in
Cancer chemotherapy induced Nausea &
vomiting
Diazepam, Lorazepam
• Used prior to Cancer chemotherapy to
reduce anticipatory vomiting ‫المتوقع‬
• Vomiting caused by anxiety
Benzodiazepines
Neurokinin-1 (NK1 )Antagonists
Aprepitant, Fosaprepitant
Given orally BA = 65% , Crosses BBB.
t ½ : 11 hrs, Metabolized by hepatic CYP3A4.
MOA
Act as Antiemetic: Selectively block NK1 receptor in area
postrema.
No effect on Serotonin , Dopamine or Corticoid
receptors
.
• Non-peptide, selective, Neurokinin type 1 (NK 1)
receptors antagonist
• Block substance P from binding to NK1 receptor
• Broader spectrum and activity in delayed emesis (In
Preclinical studies)
• Augment the antiemetic activity of 5HT3 receptor
antagonists and dexamethasone
• Inhibit both acute and delayed Chemotherapyinduced N&V
Aprepitant
Uses
Used in combination with 5HT3 antagonists &
Corticosteroids for prevention of acute & chronic
nausea and vomiting from Cancer chemotherapy
Neurokinin-1 (NK1 )Antagonists
Adverse effeccts
• Fatigue, dizziness & diarrhoea.
• Enzyme inhibition
• Metabolized by CYP3A4 & may inhibit metabolism of many
anticancer drugs (Docetaxel, Paclitaxel, Etoposide, Vinblastine,
Imatinib) ---- ↑ levels --- toxicity.
• Metabolism of Aprepitant may be inhibited by Ketoconazole,
Ciprofloxacin, Clarithromycin, Nafazodone, Ritonavir, Nelfinavir,
Verapamil & Quinidine)
• Aprepitant ↓ International Normalized Ratio (INR) in
patients taking warfarin.
Neurokinin-1 (NK1 )Antagonists
Therapeutic Uses of Anti-emetics
• Motion sickness: Hyoscine
• Vestibular disorders( Menieres, disease): Cinnerazine
• Vomiting due to pregnancy ( hyperemesis gravidarum),
Meclizine with vit. B6 (Navidoxine)
• Vomiting due to Uremia, Radiation, Viral gastro enteritis,
Liver
disease,
Migraine,
Prochlorperazine
,
Metroclopramide
• Vomiting due to Cytotoxic Anticancer drugs: 5HT3
Antagonists
Metroclopramide,
Cannabinoids,
corticosteroids, Aprepitant
• Anticipatory Vomiting due to Cytotoxic Anticancer
drugs. Benzodiazepines (Diazepam)
• Post Operative Vomiting: Metoclopramide ,
Prochlorperazine , Dimenhydrinate, 5HT3 Antagonists
(Ondensetron)
Manikandan 37
Emetic drugs
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They are required when an undesirable
substance has been ingested
Uses: Acute cases of poisoning (except in
corrosive substances poisoning or if patient is
not fully conscious)
Alcoholic intoxication
Removal of foreign bodies from the oesophagus
Certain cases of paroxysmal tachycardia
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Hernias
Aneurysm
Severe heart diseases
Peptic ulcer
Pulmonary TB
Prolapse of rectum or uterus
Threatened abortion
Weak / debilitated persons
Emetic Drugs - Contraindications
• Centrally acting: Apomorphine
• directly stimulate the CTZ or VC
• Reflexly acting: Ipecacuanha
• stimulate the VC by irritating gastric & duodenal
mucosa which stimulate afferent fibres of vagus nerve
• Locally acting: Aluminum, Sodium Chloride
(Concentrated Solution)
• Other Drugs as adverse Effect: Morphine,
Digitalis, Emetine, Aspirin, Quinine &
Anticancer drugs
Emetic Drugs
Emetic drugs
• Apomorphine
• Ipecacuanha
• Semi
synthetic derivative of morphine
• Given IM or SC, act centrally; local effect
on GIT not required.
• Dose is 6 mg (2-8mg)
• Induces vomiting in 5 -10 min
• CNS depressant effect contraindicated in
respiratory depression
Apomorphine
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Contains two alkaloids- emetine & cephaeline
Used as syrup ipecac.
Produces effect in 15 min.
Acts by irritating gastric mucosa & through CTZ
centre.
• Dose = 5ml in infants
= 10-15ml in children
= 15-20ml in adults
Ipecacuanha
Contraindications
• Corrosive poisoning
• Kerosene poisoning
• Unconscious patients
• Morphine poisoning
Thank You
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