The document discusses emetics and antiemetics. It describes the physiology of vomiting and pathophysiology of cytotoxic drug-induced vomiting. It discusses various emetics like apomorphine, ipecacuanha, and their mechanisms of action. It also discusses various classes of antiemetics like dopamine D2 antagonists, 5-HT3 antagonists, antimuscarinics, neuroleptics, neurokinin receptor antagonists and others. It provides details about specific drugs from these classes like ondansetron, metoclopramide, domperidone. It also discusses prokinetic agents that enhance gastrointestinal motility like metoclopramide, domperidone,
2. PHYSIOLOGY OF VOMITING
Stimulation of the vomiting center in the medulla
oblongata results in vomiting.
The vomiting center receives afferents from the
chemoreceptor trigger zone (CTZ), vestibular
apparatus, GI tract and centers in the brain .
CTZ is not protected by the blood- brain barrier
and is stimulated by various drugs , chemicals and
radiation .
3. Pathophysiology of cytotoxic drug
induced vomiting
Cytotoxic drugs/radiation
↓
Damage cells, irritate the gut mucosa
↓
Release mediators from gut mucosa
↓
Activation of vagal afferents in the gut
↓
Emetogenic impulses to NTS, CTZ
↓
Stimulate emetic center
↓
Vomiting
*NTS:nucleus tractus solitarius
4. EMETICS
Emetics are drugs that produce vomiting,
When a noxious substance is ingested, the
vomiting has to be induced.
Emetics may act directly by stimulating the
CTZ or reflexly by irritating the stomach
mucosa.
Mustard powder (1 teaspoon) with water or
hypertonic salt solution can evoke vomiting
reflexly.
5. Apomorphine is a derivative of morphine.
Given SC/IM, it produces vomiting in 5-10
minutes.
It acts by stimulating the dopaminergic
receptors in the CTZ.
Apomorphine can depress respiration and
should, therefore, be avoided in presence of
respiratory depression.
6. Ipecacuanha obtained from the dried root of
Cephalis ipecacuanha contains an alkaloid
emetine.
Given as a syrup (Ipecac syrup, dose: 15-20
ml), it produces vomiting in 15 minutes. It acts
both directly on the CTZ and reflexly irritating
the gastric mucosa.
It is safe in children.
7. Some drugs that commonly
produce emesis
Most anticancer drugs-cisplatin, methotrexate,
Levodopa, bromocriptine and other dopamine
agonists
Morphine and other opioids
Cholinomimetic drugs
Metronidazole
Ergot alkaloids
Chloroquine, emetine
8. ANTIEMETICS
Antiemetics are drugs used in the prevention and
treatment of vomiting.
Vomiting is a protective mechanism aimed at
eliminating the unwanted harmful material from
stomach. But in some situations, vomiting may
not serve any useful purpose and may only be
troublesome.
It can cause dehydration, weakness and
electrolyte imbalance.
10. Dopamine D₂ Antagonists
Metoclopramide and domperidone act
centrally by blocking dopamine D2 receptors
in the CTZ and thereby prevent vomiting.
They enhance the tone of the lower
esophageal sphincter and increase gastric
peristalsis-they are prokinetics .
Trimethobenzamide has antihistaminic activity
in addition to dopamine blockade.
11. 5-HT3 Antagonists
Ondansetron:
5-Hydroxytryptamine released in the gut is an important
inducer of emesis and the nerve endings including vagal
afferents in the gut are rich in 5-HT3 receptors.
It is believed that anticancer drugs, radiation therapy and
infection of the gastrointestinal mucosa induce the release of
5-HT3 in the gut which initiates emetic reflex through 5-HT3
receptors present in the gut, nucleus tractus solitarius (NTS)
and area postrema in the brain.
Ondansetron blocks 5-HT3 receptors in the GI tract, CTZ and
nucleus tractus solitarius and prevent vomiting.
It's powerful antiemetic and can be given orally(4-8mg)or IV
Granisetron is more potent
Dose: Granisetron 1-2 mg daily Graniset 1,2 mg tablet.
12. Uses
5-HT3 antagonists are used to control vomiting induced by
anticancer drugs or radiotherapy.
They should be given intravenously 30 min before
(ondensetron 8 mg infusion over 15 min) or orally 1 hr
before starting chemotherapy. From second day,
ondansetron may be given orally 8 mg twice daily for 3-7
days.
They are also useful in postoperative vomiting and other
drug-induced vomiting (but not in motion sickness).
To prevent postoperative vomiting, a 5-HT3, blocker is given
IV (4-8 mg ondansetron) before induction and the dose may
be repeated after 8 hr or as required
13. Antimuscarinics
Hyoscine is a labyrinthine sedative very effective in
motion sickness.
Motion sickness or travelling sickness is due to over
stimulation of the vestibular apparatus along with
psychological and environmental factors.
Hyoscine also relaxes the gastrointestinal smooth
muscle.
Taken 30 minutes before journey, hyoscine (0.4-0.6 mg
oral) acts for 6 hours .
A transdermal patch delivers hyoscine constantly
over 3 days and is to be applied behind the ear.
Sedation and dry mouth are common side effects.
Dicyclomine is used to control vomitting in morning
sickness and motion sickness- orally in the dose of 10-
20 mg.
14. H1, antihistamines as promethazine, diphenhydramine,
doxylamine, cyclizine and cinnarizine have anticholinergic
properties.
Antihistamines block H1 receptors in the area postrema as
well as muscarinic receptors in the CNS. They probably
also act on the GI tract. Some of them are useful in motion
sickness and postoperative vomiting.
Doxylamine is available in combination with pyridoxine for
'morning sickness' in some countries. Though some studies
have shown it to be free of teratogenic potential, its safety
is not proved and, therefore, not used for the purpose in
countries like USA and England.
Dose: Doxylamine 10 mg + Pyridoxine 10 mg tab.
GRAVIDOX, DOXINATE 10 mg tab
15. Neuroleptics
Neuroleptics also block D₂- receptors in the CTZ and
are useful in vomiting due to most causes except
motion sickness.
common side effects: Sedation
Prochlorperazine is mainly used as an antiemetic in
vomiting and is also effective in vertigo associated with
vomiting.
Prochlorperazine
Dose: 5-25 mg STEMETIL 5. 25 mg tab, 12.5 mg/ml inj).
16. Neurokinin Receptor Antagonists
These drugs bind to neurokinin (NK1) receptor in the area
postrema and act as antiemetics.
Aprepitant has recently completed clinical trials and is
available for oral use and
fosaprepitant is given IV and gets converted to aprepitant
in the body.
NK1 antagonists may be used for the prevention of
chemotherapy induced vomiting in combination with a 5-
HT3 antagonist and a glucocorticoid.
Dose: APREPITANT 125 mg 1 hr before chemotherapy
followed by 80 mg daily for next two days.
17. Other Antiemetics
1. Glucocorticoids are used in combination with other
antiemetics like ondansetron or metoclopramide.
Glucocorticoids control delayed vomiting following
anticancer drug therapy. They may act by activating the
glucocorticoid receptors in the NTS.
2. Pyridoxine (vitamin B6) is used in the prevention of
vomiting in pregnancy without any known
pharmacological basis.
The proposed rationale is that pyridoxine serves
as a cofactor in GABA synthesis and GABA
acting as the inhibitory neurotransmitter at CTZ
may suppress vomiting. Dose: 20-60 mg.
3. Cannabinoids: Dronabinol, a cannabinoid is A9
tetrahydrocannabinol.
It may act by the stimulation of the
cannabinoid receptors (CB1) in the vomiting
center. It also increases appetite.
18. Dose 5 mg/ m², 2 hr before chemotherapy and the dose may be
repeated every 4 hr to complete 4-6 hr.
Dronabinol can cause hallucinations, euphoria,
dysphoria, behavioural abnormalities ,dependence,
increased appetite ,dryness of mouth and hypotension
4. Sedative hypnotics: Barbiturates and benzodiazepines
may raise the threshold for vomiting by depressing the
CNS.
Sedative hypnotics are used as adjuvants to other
antiemetics in treating anticancer drug- induced vomiting.
5. Propofol: The general anesthetic propofol has useful
antiemetic properties
19. PROKINETIC AGENTS
Drugs that enhance gastroduodenal motility and hasten
gastric emptying are called pro- kinetic agents. The
following are prokinetic agents.
Prokinetics
1. D₂ antagonists
Metoclopramide, domperidone
2. Others
• Cisapride, mosapride, itopride
• Cholinomimetics-bethanechol
• Anticholinesterases-neostigmine
3. Motilin receptor agonists-erythromycin
20. Metoclopramide
Introduced in 1970s, structurally related to
procainamide but is not a local anesthetic.
GIT: Metoclopramide promotes forward movement of
contents of the upper GI tract- increases oesophageal
and gastric peristalsis. It raises lower oesophageal
sphincter pressure, speeds up gastric emptying and
prevents the reflux of stomach contents into the
oesophagus.
It thus prevents reflux oesophagitis.
21. CNS: Metoclopramide acts as an antiemetic by
blocking the D2, dopamine receptors on the CTZ. The
effect on the gut, i.e. speeding up gastric emptying
also contributes.
Mechanism of action
1)D2 blockade : stimulation of dopamine receptors in gut
particularly upper git, inhibits cholinergic stimulation of GIT
smooth muscle, relaxes the stomach and delays gastric
emptying
Serotonergic receptors:.
2)a) 5HT4 agonist :Metoclopramide stimulates 5 HT4
receptors on excitatory neurons of gut which enhances
release of ACh
b) 5HT3 antagonist: in high doses metoclopramide blocks
5 HT3 receptors. Blockade of 5HT3 receptors in NTS and
CTZ adds to antiemetic effects.
22. Uses
1. Gastro-oesophageal reflux disease: (GERD) heart burn due to
reflux of acid into the oesophagus is benefited by prokinetic
agents. They may be used as adjuvants to drugs that reduce
acid secretion because the latter are safer drugs. Prokinetics
also help some patients with non-ulcer dyspepsia.
2. As antiemetics in postoperative period and in vomiting due to
anticancer drugs (along with ondensetron) and radiotherapy, in
nausea and vomiting due to gastro- intestinal disorders and
migraine- metoclopramide is an effective antiemetic.
3. As preanaesthetic medication to promote gastric emptying
before emergency induction of general anaesthesia.
4. In endoscopy to assist passage of tubes into the duodenum.
5. Delayed gastric emptying: In patients under- going surgeries
like vagotomy and in diabetic gastroparesis, gastric emptying
may be delayed. Prokinetics are useful in such patients.
23. Domperidone
Domperidone is a D₂ dopamine receptor blocker like
metoclopramide.
It blocks the dopamine receptors in the CTZ and
thereby acts as an antiemetic.
Advantages over metoclopramide are domperidone
does not cross the blood-brain barrier and hence
extrapyramidal and neuropsychiatric side effects are
rare.
Because CTZ is outside the BBB, domperidone can
produce its antiemetic effects.
Domperidone can be used in place of metoclopramide
and is preferred over it by many clinicians.
24. Uses
Cisapride enhances gastric motility by promoting the
release of acetylcholine in the gut wall. However, it is
now banned because it can cause cardiac
arrhythmias.
Mosapride and renzapride are similar to cisapride but
do not produce cardiac arrhythmias and do not prolong
QT interval- hence preferred.
Itopride blocks dopamine D₂ receptors like
metoclopramide and also enhances ACh levels in the
gut (cholinesterase inhibitor). It promotes gastric
motility and also has antiemetic effects.
It is given in the dose of 50 mg TDS.
25. Adverse effects include headache, dizziness
and gastrointestinal disturbances. Itopride can
be used in the treatment of gastroparesis,
GERD and dyspepsia.
Tegaserod, a 5-HT, partial agonist which me
promotes gastric emptying, also has
cardiotoxicity and has been withdrawn from
the market
26. Cholinomimetic Drugs
Cholinergic agonists, like bethanechol,
enhance gastrointestinal motility by activating
M1, muscarinic receptors in the gut.
They were earlier used in gastroparesis but
are not preferred due to cholinergic side
effects.
Anti- cholinesterase drug neostigmine also
enhances gastrointestinal motility and
promotes colonic evacuation.
It is used in the dose of 2 mg IV in acute
colonic pseudo-obstruction (Ogilvie's
syndrome) to empty the colon
27. Motilin Receptor Agonists
Motilin is a peptide hormone which promotes
motility in the upper gastrointestinal tract’
Erythromycin is a motilin receptor agonist
and promotes gastric and intestinal motility. It
has been tried in diabetic gastroparesis and in
decreased small bowel motility.
28. Drugs for vomiting due to various
causes
Motion sickness Hyoscine, cyclizine, promethazine,
cinnerzine
Vomiting due to cytotoxic
drugs
1)Ondansetron,+ dexamethasone+ aprepitant
2)Metoclopramide+ dexamethasone+
diphenhydramine+ lorazepam
Vomiting due to other
drugs
Chlorpromazine, metoclopramide
Postoperative vomiting Ondansetron, metoclopramide
Vomiting in pregnancy Doxylamine, dicyclomine, pyridoxine, cyclizine,
meclizine, metoclopramide
