The document discusses various causes, pathophysiology, and treatment of emesis and nausea. It covers the following topics:
- Emetics that induce vomiting and their mechanisms of action.
- Various classes of anti-emetics including antihistamines, neuroleptics, 5-HT3 antagonists, NK1 antagonists, cannabinoids, glucocorticoids, benzodiazepines and their mechanisms and uses.
- Prokinetic drugs like metoclopramide and domperidone that enhance gastrointestinal motility.
- Specific conditions like motion sickness, nausea during pregnancy, chemotherapy-induced nausea and vomiting, post-operative nausea and specific
2. Emesis and its causes
Pathophysiology of Emesis
Emetics
Anti emetics
Therapeutic uses of Anti-emetics
Special topics
Motion sickness
Emesis in pregnancy
Chemotherapy induced vomiting
Post operative nausea and vomiting
3. Vomiting (Emesis) is the forceful expulsion of
contents of the stomach and often, the proximal
small intestine
Vomiting is a complex reflex involving both
autonomic and somatic neural pathways.
4. Vomiting is a complex process that consists of
(gastric relaxation and
retroperistalsis),
(rhythmic action of respiratory muscles
preceding vomiting and consisting of contraction of
abdominal and intercostal muscles and diaphragm against
a closed glottis),
(intense contraction of the abdominal
muscles and relaxation of the upper esophageal
sphincter).
Pre-ejection Phase
Retching
Ejection
5.
6. The “chemoreceptor trigger zone” or area
postrema is located at the caudal end of the
fourth ventricle.
This is outside the blood-brain barrier but is
accessible to emetogenic stimuli in the blood or
cerebrospinal fluid.
The chemoreceptor trigger zone is rich in
dopamine D 2 receptors and opioid receptors,
and possibly serotonin 5-HT 3 receptors and NK 1
receptors.
7.
8. These are drugs used to evoke
vomiting.
Act on CTZ : Apomorphine
Act reflexly and on CTZ : Ipecacuanha
EMETICS
9. Poisoning
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
Indications
10. Apomorphine
Semi synthetic derivative of morphine
• Given IM or SC, act centrally;
• Dose is 6 mg (2-8mg)
• Induces vomiting in 5 -10 min
• Respiratory and CNS depressant
Contraindicated
Respiratory depression
11. Ipecacuanha
Dried root of Cephaelis ipecacuanha
Contains alkaloid - emetine
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
16. Hyoscine (0.2–0.4 mg oral, i.m.) is the most effective drug
for motion sickness.
It has a brief duration of action;
Mechanism of Action Acts by blocking conduction of nerve
impulses across a cholinergic link in the pathway leading from
the vestibular apparatus to the vomiting centre.
Side effects sedation, dry mouth and other anticholinergic side
effects; suitable only for short brisk journies.
17. Dicyclomine (10–20 mg oral) has been used
for prophylaxis of motion sickness and for
morning sickness.
18. H1 ANTIHISTAMINICS
Useful mainly in motion sickness and to a
lesser extent in morning sickness,
postoperative and some other forms of
vomiting.
Their antiemetic effect appears to be based
on anticholinergic, antihistaminic, weak
antidopaminergic and sedative properties
19. Promethazine, diphenhydramine,
dimenhydrinate
These drugs afford protection of motion
sickness for 4–6 hours, but produce sedation
and dryness of mouth.
By their central anticholinergic action they
block the extrapyramidal side effects of
metoclopramide while supplementing its
antiemetic action.
20. Doxylamine- It is a sedative H1 antihistaminic
with prominent anticholinergic activity.
Pharmacokinetics- Oral absorption of
doxylamine is slow, and its t½ is 10 hr.
Side effects -drowsiness, dry mouth, vertigo and
abdominal upset.
Dose: 10–20 mg at bed time.
21. Cinnarizine It is an antivertigo drug having
antimotion sickness property.
Mechanism of Action- acts by inhibiting influx of
Ca2+ from endolymph into the vestibular
sensory cells which mediates labyrinthine
reflexes.
22. 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
Vestibular disorders ( Meniere’s disease)
Meclizine 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
24. Therapeutic Uses:
Broad spectrum antiemetic action effective in:
Drug induced and postoperative nausea
andvomiting (PONV).
Disease induced vomiting: gastroenteritis,
Uraemia, liver disease, migraine, etc.
Malignancy associated and cancer
chemotherapy (mildly emetogenic) induced
vomiting.
Radiation sickness vomiting (less effective).
25. Prokinetic Drugs
Drugs that promote gastrointestinal transit
and speed gastric emptying by enhancing
coordinated propulsive motility.
Effective antiemetic agents
Two clinically important drugs:
Metoclopramide
Domperidone
26. Metoclopramide
Mechanism ofAction: acts through dopaminergic and
serotonergic receptors
D2 antagonism: Central antidopaminergic (D2) action of
metoclopramide on CTZ is responsible for its anti emetic
activity
5-HT4 agonism: It acts in the GIT to enhance Ach release
from the myenteric motor neurons and thereby enhance the
contractile activity.
5HT3 antagonism: At higher concentrations it blocks 5HT3
receptors in the inhibitory myentric interneurons and in the
CTZ
27. D2 antagonism:
Central
antidopaminergic
(D2) action of
metoclopramide on
CTZ
5-HT4 agonism: It
acts in the GIT to
enhance Ach
release from the
myenteric motor
neurons
5HT3 antagonism:
At higher
concentrations it
blocks 5HT3
receptors in the
inhibitory myentric
interneurons and in
the CTZ
28. Pharmacokinetics
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: 10-20mg orally or IV every 6 hrs.
29. As Antiemetic
effective in postoperative, drug induced, disease
associated (especially migraine), radiation sickness,
etc,
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.
30. Therapeutic Uses:
Used in emesis due to
Uremia
Radiation
Viral gastro enteritis, hepatic-biliary disease
Anticancer drugs
Migraine
Post operatively & pre-operatively
Used as a gastro kinetic agent
GERD
Dyspepsia
31. Adverse Effects -
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.
Diarrhea
Drowsiness and fatigue, dizziness, restlessness and
anxiety.
Galactorrhoea, Gynecomastia, impotence and
menstrual disorders – due to increased prolactin
levels (blocks the action of PIH)
32. Domperidone- It is a D2 receptor antagonist.
It crosses blood-brain barrier poorly.
Extrapyramidal side effects are rare, but
hyperprolactinaemia can occur.
Pharmacokinetics- absorbed orally, but
bioavailability is only ~15% due to first pass
metabolism.
It is completely biotransformed and metabolites
are excreted in urine.
Plasma t½ is 7.5 hr.
Dose- 10-40mg
34. Cisapride
Mechanism of Action
The prokinetic action is exerted mainly through
5-HT4 agonism which promotes ACh release
from myenteric neurones, aided by
weak 5-HT3 antagonism which suppresses
inhibitory transmission in myenteric plexus.
Enteric neuronal activation via 5-HT4 receptor
also promotes cAMP-dependent Cl– secretion in
the colon, increasing water content of stools.
35. Safety of cisapride was challenged by reports of
serious ventricular arrhythmias and death.
At high concentrations, cisapride blocks delayed
rectifying K+ channels in heart—prolongs Q-Tc interval
and predisposes to ventricular fibrillation.
Following such reports, cisapride was suspended from
marketing in most countries several years back, but
was available in India till it was banned in March 2011.
36. 5-HT4 agonist
The drug functions as a motility stimulant,
achieving its desired therapeutic effects through
activation of the 5-HT4 receptors of the enteric
nervous system in the gastrointestinal tract.
It also stimulates gastrointestinal motility and
the peristaltic reflex, and allegedly reduces
abdominal pain.
Approved by the FDA in 2002, it was
subsequently removed from the market in 2007
due to FDA concerns about possible adverse
cardiovascular effects.
TEGASEROD
38. Mechanism of Action:
Blocks-the depolarization action of 5-HT exerted
through blockage of 5-HT3 receptors in the vagal
afferents of the GIT as well as in the NTS and
CTZ
It has weak 5-HT4 antagonist activity
39. Pharmacokinetics:
Oral bioavailability is 60-70%
t1/2 is 3-5hrs
No significant drug interactions have been noted.
Adverse effects:
Excellent safety profile
Headache, Dizziness & constipation
All three drugs cause prolongation of QT interval, but
more pronounced with dolasetron.
40. Therapeutic Uses:
Chemotherapy and Radiation therapy induced nausea and
vomiting
Post operative nausea and vomiting
Advisable to administer Ondansetron(4-8 mg IV) 4 hours
before surgery is advisable.
Drug induced vomiting
Vomiting due to GI disorders
Uraemia and neurological injuries induced vomiting
Hyperemesis Gravidarum
41. Granisetron: 10 times more potent than
ondansetron and effective in repeated cycles of
chemotherapy.
Polonosetron: Longest acting (t1/2 is 40 hrs)
Approved by the FDA in delayed cancer induced
nausea and vomiting-occurring between 2nd to
5th day
Romosetron: Similar to ondansetron and is
marketed only in few countries
43. Uses
Used in combination with 5HT3 antagonists &
Corticosteroids for prevention of acute & chronic
nausea and vomiting from Cancer chemotherapy
44. Tetrahydrocannabinol (THC) main psychoactive chemical
in marijuana
It probably acts through the CB1 subtype of
cannabinoid receptors located on neurones in the
CTZ and/ or the vomiting centre itself.
Pharmacokinetics: complete absorption on oral
administration, significant 1st pass effect, metabolites
excreted slowly over days to weeks in faeces & urine
Cannabinoids
Dronabinol
Nabilone
46. Benzodiazepines
Diazepam
Lorazepam
The weak antiemetic property of BZDs is primarily
based on the sedative action, relieving psychogenic
component.
Used as adjuvant to metoclopramide/ondansetron,
Used prior to Cancer chemotherapy to reduce
anticipatory vomiting
Vomiting caused by anxiety
47. TYPES OF EMESIS
MOTION SICKNESS
MORNING SICKNESS (VOMITING
DURING PREGNANCY)
CHEMOTHERAPY/ RADIATION
INDUCED NAUSEA AND EMESIS
(CIE)
POST OPERATIVE EMESIS
48. Emesis and Pregnancy
Nausea and vomiting of pregnancy (NVP) is the most common
medical condition of pregnancy, affecting up to 80% of all
pregnant women to some degree
Etiology:
Exact pathogenesis is unclear
Elevated levels of human chorionic gonadotropin (hCG)
Chronic infection with Helicobacter pylori may play a role in
hyperemesis gravidarum.
Delayed gastric motility caused by progesterone may be
responsible for the condition
Psychologic factors
49. Doxylamine/pyridoxine:
• The only FDA-approved drug for treating nausea and vomiting in
pregnancy
• A greater form of reduction in Hyperemesis gravidarum
• No teratogenic potential
Ondansetron :
• Class B safety in pregnancy
• Most common parenteral and oral antiemetic used due to its
efficacy
Anticholinergics may be used as supportive drugs.
Ginger capsules: 250 mg taken 4 times a day have been
demonstrated to be effective against nausea and vomiting of
pregnancy
50. Contraindicated Drugs
Domperidone (X)
The combination of pyridoxine 10 mg and
doxylamine 10 mg was withdrawn from the
market due to increased risk of birth defects
with the combination.
51. MOTION SICKNESS
Result during space flights, taking off and
landing of an aeroplane etc.
It is a labyrinthine vomiting via stimulation of
vestibular nuclei.
Drugs used:
H1 ANTAGONIST/CENTRAL
ACTING
ANTICHOLINERGIC.
Hyoscine.
Side effects of hyoscine: anticholinergic
Blurred vision, dryness of mouth,
cyclopelgia, sedation and sleepiness.
DIPHENHYDRAMINE, CYCLIZINE,
MECLIZINE – prevents motion sickness and
treatment of vertigo due to labyrinth
dysfunction.
CINNARAZINE-Anti vertigo
drug.
Used in prevention of motion
sickness.
Acts as antihistaminic,
anticholinergic, antiserotonin &
Ca2+ channel blocker.
Inhibits influx of Ca2+ from
endolymph into vestibular
apparatus.
52. Chemothrapy Induced Emesis
• Anti-cancer drugs induce emesis by direct
activation of 5HT3 receptors in CTZ / may activate
vagal and splanchnic 5HT3 receptors to send
emetogenic signals to vomiting center through
neurotransmitters.
ONDANSETRON
GRANISETRON
DOLASETRON
TROPISETRON
PALONOSETRON
RAMOSETRON
55. POST OPERATIVEVOMITING
• Complications in patients receiving general
anaesthesia.
• 5HT3 ANTAGONIST- preferred
• PROCHLORAZINE- blocks Dopamine 2 and
muscarinic receptors.
• PROMETHAZINE- potent anticholinergic and
antihistaminic.
56.
57. Elevated cholecystokinin levels slow gastric emptying and
motility and are associated with feed intolerance in critically
ill patients
☆Dexloxiglumide
Selective and highly potent CCK-1 receptor antagonist
Inhibits gall bladder contraction
Improves lower oesophageal sphincter function
Hastens colonic transit
58. ☆Alvimopan
High affinity for μ receptors
Does not cross the blood–brain barrier
No effect on gastric emptying
hastened gut recovery and shortened time to
hospital discharge in patients after bowel
resection or hysterectomy
μ-opioid antagonist
60. References
Hasketh PJ: Chemotherapy-induced nausea and
vomiting. N Engl J Med 2008;358:2482.
LeTP et al: Update on the management of
postoperative nausea and vomiting and
postdischarge nausea vomiting in ambulatory
surgery.Anesthesiol Clin 2010;28:225.
Roila F et al; Guideline update for MASCC and
ESMO in the prevention of chemotherapy- and
radiotherapy-induced nausea and vomiting:
Results of the Perugia consensus conference.Ann
Oncol 2010;21(Suppl 5):v232.
61. DeMaeyer JH et al: 5-HT 4 receptor agonists: Similar
but not the same. Neurogastroenterol Motil
2008;20:99.
Patrick A et al: Review article: Gastroparesis.
Aliment PharmacolTher 2008;27:724.
Reddymasu SC et al: Severe gastroparesis: medical
therapy or gastric electrical stimulation. Clin
Gastroenterol Hepatol 2010;8:117.
Borison H L et al. 1981 J Clin Pharmacol 21: 235-295.)
Goodman and Gillman
Davidson
Guyton physiology
KDTripathi pharmacology
Katzung
Editor's Notes
In astudy, 61.8 percent of pregnant women with hyper-emesis were found to be positive for the H. pylori genome,