ANTI-EMETICS AND PROKINETICS

Question 1

How’s the general individual susceptibility to vomiting?

Answer 1

*Infants < older children and adults
*Women < men and the aged < young adults to postanaesthetic vomiting.

Estrogens lower the threshold of the CTZ, thus vomiting of pregnancy and nausea during combination OC therapy

Question 2

Describe the relevant pathphysiology of vomiting

Answer 2

①Vomiting is mediated by two separate brainstem centres: the chemoreceptor trigger zone (CTZ) and the vomiting centre. It is rich in dopaminergic receptors.
⊛Activation of trigger zone stimulates the vomiting centre. The act of vomiting is controlled by the vomiting centre, mainly through vagal action.
⊛The vomiting centre has afferent input from the gut, higher cortical centres and vestibular apparatus
⊛Muscarinic and histamine H1-receptors are highly concentrated around the area of the vomiting centre.
⊛It is important to consider the underlying cause when choosing the most appropriate drug aiming for symptomatic relief

Question 3

How do we manage vomiting?

Answer 3

①Treatment of the cause, e.g., relief of pain, intestinal obstruction and colic, reduction in the intracranial tension or correction of metabolic acidosis.

⓶Symptomatic treatment with antiemetics.

③Supportive therapy, e.g., correction of dehydration and electrolyte disturbances

Question 4

What are antiemetics？

Answer 4

Antiemetics are drugs which specifically prevent or relieve nausea and vomiting.

Question 5

List the 6 classes of Antiemetics

Answer 5

①ANTIDOPAMINERGIC (D 2 receptors) e.g., Chlorpromazine (Largactil) and related drugs; Metoclopramide, Domperidone

⓶ANTIHISTAMINIC, e.g., Cyclizine, Meclizine, Promethazine (Phenergan)

③ANTI-5HT 3 e.g., Ondansetron, Dolasetron and Palonosetron and Ginger

④ANTIMUSCARINIC, e.g., Scopolamine

⑤ANTAGONIST of the NK 1 receptors for substance P: Aprepitant

⑥MISCELLANEOUS such as Nabilone (a cannabinoid), Trimethobenzamide, Benzquinamide

Question 6

Some antiemetic drugs promote forward propulsion of the contents of the upper GI tract, particularly the stomach . What are these called?

Answer 6

Prokinetics
*Acceleration of gastric emptying is a prokinetic action. May be indicated before induction of general anaesthesia for emergency surgery;

Question 7

Clinically, how are the antiemetics are grouped according to their potency?

Answer 7

①Most potent: Ondansetron, Granisetron and high dose Metoclopramide

⓶Moderately potent: Low dose Metoclopramide, Phenothiazines (Prochlorperazine), Butyrophenones (Droperidol), and Cannabinoids.

③Weak: Anticholinergics, Antihistaminics and Benzodiazepines (Lorazepam)

④Glucocorticoids such as dexamethasone given parenterally in large doses, are used as adjuncts in the management of resistant nausea and vomiting induced by cancer chemotherapeutic agents

Question 8

What do you use manage vomiting due to GI irritation?

Answer 8

Anticholinergics: in severe cases, a Phenothiazine

Question 9

What do you use manage vomiting due to Motion Sickness?

Answer 9

Scopolamine, Dimenhydrinate, Cyclizine, Meclizine

Question 10

What do you use manage vomiting due to Preganancy ?

Answer 10

Doxylamine, Pyridoxamine, Dimenhydrinate

Question 11

What do you use manage vomiting due to Uremia, Cancer, Irradiation Sickness, Anti-Cancer Chemotherapy?

Answer 11

Phenothiazine and Butyrophenone, Antipsychotics; Metoclopramide; Ondansetron; Nabilone; Dexamethasone( adjunctive in cancer chemotherapy)

Question 12

What do you use manage vomiting due to Gastroperesis?

Answer 12

Prokinetic drugs

Question 13

What do you use manage vomiting Postoperative ?

Answer 13

Prokinetic drugs and Anti-histaminic drugs

Question 14

Dopamine antagonists —phenothiazines: Chlorpromazine

Answer 14

*Mechanism of action: They act mainly on the chemoreceptor trigger zone with dopamine receptor antagonist properties as well as anticholinergic and other actions.

Indications:
Phenothiazines are effective in a variety of situations, including the vomiting of chronic renal failure, neoplastic disease, and drug-induced vomiting.

Adverse effects
Prolonged use may produce Parkinsonian-type tremor or other dyskinesias

Question 15

Dopamine antagonist: Metoclopramide

Answer 15

Mechanism:
Metoclopramide is a central dopamine receptor antagonist, effective at blocking stimuli to the chemoreceptor trigger zone. Has effects on upper gastrointestinal tract motility (prokinetic).

Indications:
It is effective in most causes of vomiting, apart from motion sickness.

Adverse effects:
Acute extrapyramidal reactions, such as opisthotonous, oculogyric crisis or other dystonias. Especially in the treatment of children and young adults. They can be treated with an intravenous anticholinergic agent, such as benzotropine. Raises serum prolactin levels and causes gynaecomastia through antidopaminergic effects.

Drug interactions:
Metoclopramide potentiates extrapyramidal side effects of phenothiazines

Question 16

Dopamine antagonist: domperidone

Answer 16

Mechanism:
effective at the chemoreceptor trigger zone.

Indications:
Effective in most situations, especially nausea and vomiting related to cytotoxic drug therapy. It can be administered rectally via suppository.

Adverse effects:
Raises prolactin levels
May produce cardiac dysrhythmias following rapid intravenous injection.
Less likely to cause extrapyramidal reactions than metoclopramide

Question 17

Antihistamines: promethazine

Answer 17

Mechanism:
Antihistamines are competitive antagonists of histamine at H1-receptors, acting mainly on the vomiting center rather than the chemoreceptor trigger zone. They also have weak anticholinergic effects.

Indications:
Motion sickness or vestibular disorders
Allergic rhinitis and other allergic reactions

Adverse effects :
Drowsiness, insomnia and euphoria
Central effects accentuated by alcohol

Question 18

Serotonin antagonists: ondansetron

Answer 18

Mechanism:
Ondansetron is a selective antagonist of serotonin at 5-HT3-receptors. The mode of action in controlling nausea and vomiting is unclear but it has both CNS and peripheral actions.

Indications:
Ondansetron is indicated for the treatment of nausea and vomiting associated with cytotoxic therapy or radiotherapy.
The dose and rate of administration depends on the severity of the problem and on the chemotherapy used.

Adverse effects:
Constipation and headache; flushing may occur

Question 19

Anticholinergic drugs: hyoscine

Answer 19

Mechanism:
Anticholinergic drugs compete with acetylcholine at muscarinic receptors in the gut and CNS and have antispasmodic action in the gut wall.

Indication:
Successful in motion sickness because of their central action.
Usually adequate prophylaxis for motion sickness.

Adverse effects:
Drowsiness, dry mouth, blurred vision and difficulty in micturition

Question 20

Cannabinoids: nabilone

Answer 20

Mechanism:
Tetrahydrocannabinol is one of the active constituents of marijuana. Nabilone is a synthetic cannabinoid

Indications:
- Used in the treatment of nausea and vomiting during cytotoxic therapy. Its mode of action is unclear.
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Adverse effects:
causes drowsiness, dizziness and dryness of the mouth.
Euphoria and hallucinations are rare.
Prolonged use may produce toxic effects on the CNS

Question 21

PROKINETIC AGENTS AND OTHER STIMULANTS OF GI CONTRACTILITY

Answer 21

*Prokinetic agents enhance coordinated GI motility and transit of material in the GI tract.
*Ach released from primary motor neurons in the myenteric plexus, is the principal immediate mediator of muscle contractility.
*However most clinically useful prokinetic agents act “upstream” of ACh, at receptor sites on the motor neuron itself, or indirectly, on neurons one or two orders removed.
*The agents enhance the release of excitatory neurotransmitter at the nerve-muscle junction without interfering with the normal physiological pattern and rhythm of motility.
*Coordination of activity among the segments of the gut, is necessary for propulsion of luminal contents, therefore is maintained

Question 22

ACETYLCHOLINESTERASE INHIBITORS

Answer 22

*These drugs inhibit the degradation of ACh by its esterase, allowing ACh to accumulate at sites of release.
*Unlike muscarinic receptor agonists, the parasympathomimetic drugs do not stimulate muscle directly, but accelerate GI transit times by enhancing the contractile effects of ACh
released at synaptic and neuromuscular junctions.
*Among the cholinergic muscle stimulants, neostigmine methylsulfate has been used off-label for some GI disorders, associated with acute colonic pseudo-obstruction (Ogilvie’s syndrome) and paralytic ileus.
*Atropine should be available in case of severe bradycardia

Question 23

Dopamine Receptor Antagonists : metoclopramide and domperidone

Answer 23

*Dopamine is present in significant amounts in the GI tract and has several inhibitory effects on motility including reduction of lower esophageal sphincter and intragastric pressures.
*These effects result from suppression of ACh release from myenteric motor neurons, mediated by D2 receptors.
*This class of drugs antagonize the inhibitory effect of dopamine on myenteric motor neurons, excitatory motor neuron and aboral relaxation via the inhibitory motor neuron .
*Dopamine receptor antagonists are effective as prokinetic agents they have the additional advantage of relieving nausea and vomiting by antagonism of dopamine receptors in the chemoreceptor trigger zone