Fig. 32.1 Neuronal pathways and receptors involved in the control of nausea and vomiting.
The pathways and neurotransmitter receptors involved in nausea and vomiting are complex and only those underpinning the mechanisms of action of the anti-emetic drugs are shown. The chemoreceptor trigger zone (CTZ) has neuronal connections to the vomiting centre (VC), which is a collection of nuclei including the dorsal motor nucleus of the vagus and the nucleus tractus solitarius. 5HT3, 5-Hydroxytryptamine type 3 receptor; DA, dopamine receptor; ENK receptor, enkephalin (opioid) receptor; H1, histamine type 1 receptor; M, muscarinic receptor (possibly M2); NK1, neurokinin 1 receptor; VN, vestibular nuclei. Other mediators such as glutamate may also be involved.
Abdominal and cardiac vagal afferents are activated by mechano- or chemosensory receptors. Chemosensory receptors respond to several agonists such as acetylcholine, dopamine, serotonin, histamine and neurokinins. Some drugs induce vomiting by an effect on gastric chemosensory receptors.
The area postrema in the floor of the fourth ventricle is the location of the chemoreceptor trigger zone (CTZ). This lies outside the blood–brain barrier and responds to stimuli from the cerebrospinal fluid and the systemic circulation. The CTZ has many receptors for neurotransmitters (such as dopamine, serotonin and substance P) and hormones and it has numerous afferent and efferent connections with the underlying nucleus tractus solitarius.Other sources include:
Several neurotransmitter receptors are involved in direct activation of the vomiting centre including those for dopamine (D2), serotonin, acetylcholine (muscarinic), histamine (H1) and substance P (neurokinin 1, NK1) (Fig. 32.1).
The roles of these multiple receptors in the triggering of nausea and vomiting are complex. For example, 5-HT3 receptor antagonists will provide protection against nausea and vomiting induced by cytotoxic drugs and radiation but not by motion or by apomorphine. Vomiting can result from the summation of several sub-emetic stimuli, for example in the genesis of postoperative nausea and vomiting.
Efferent connections from the vomiting centre include the vagus and phrenic nerves. When stimulated these nerves relax the fundus and body of the stomach and the lower oesophageal sphincter, and retrograde giant contractions occur in the small intestine. Diaphragmatic and abdominal muscle contractions compress the stomach, and together these factors produce vomiting.
Many drugs produce vomiting by stimulating the CTZ and they do not have to cross the blood–brain barrier for this action (Box 32.1).
Box 32.1 Drugs associated with a high incidence of nausea and vomiting
Cytotoxic agents (especially cisplatin, cyclophosphamide, doxorubicin, nitrosoureas)
Non-steroidal anti-inflammatory drugs
Anti-emetic agents
Mechanism of action and clinical use: Antihistamines prevent and treat vomiting by their antagonist action at histamine H1 receptors (Ch. 39), and many also have antimuscarinic effects. Promethazine also blocks some 5-HT receptor subtypes. Antihistamines are effective against most causes of vomiting but, apart from the use of cyclizine for drug-induced vomiting, they are rarely treatments of choice. Promethazine is used to treat vomiting in pregnancy since it appears to be free from teratogenic effects.
Pharmacokinetics: These drugs are well absorbed orally; both promethazine and cyclizine can also be given by intramuscular or intravenous injection. After oral dosing, promethazine undergoes extensive first-pass metabolism.
Antimuscarinic agent
Mechanism of action and clinical use: Muscarinic receptors are involved in the visceral afferent input from the gut to the vomiting centre and in the tract that the eighth cranial nerve takes from the labyrinth to the CTZ via the vestibular nucleus. Hyoscine (known as scopolamine in the USA) is used for the treatment of motion sickness and postoperative vomiting. Some antihistamines such as promethazine and cyclizine (see above), and dopamine receptor antagonists such as prochlorperazine (see below), also have antimuscarinic activity.
Pharmacokinetics: Hyoscine is available for oral, parenteral or transdermal use. Oral absorption is good. The adhesive patch for transdermal delivery can be placed behind the ear and delivers a therapeutic dose for 72 h.
Dopamine receptor antagonists
Mechanism of action and clinical use: Domperidone, metoclopramide and the antipsychotic drugs are antagonists at dopamine D2 receptors and inhibit dopaminergic stimulation of the CTZ (Fig. 32.1).
Anti-emetic doses of antipsychotic drugs are generally less than one-third of those used to treat psychoses. The pharmacology of the antipsychotic drugs is discussed in Chapter 21.
Domperidone acts solely by dopamine receptor blockade. Metoclopramide is a dopamine antagonist at usual oral doses, but it also acts as a 5-HT3 receptor antagonist at higher doses. This enhanced efficacy is utilised by intravenous administration of high doses of metoclopramide to treat the vomiting induced by cytotoxic agents such as cisplatin.
Metoclopramide also has prokinetic actions on the gut including increased tone of the gastro-oesophageal sphincter and enhanced gastric emptying and small intestinal motility. These effects arise from agonist activity at the 5-HT4 receptor subtype in the enteric nervous system, which leads indirectly to cholinergic stimulation.
Dopamine receptor antagonists are mainly used to reduce vomiting induced by drugs and surgery. Pure dopamine receptor antagonists are ineffective in motion sickness. Antipsychotic drugs such as prochlorperazine are effective for vestibular disorders and motion sickness as a result of their antimuscarinic activity.
Pharmacokinetics: Metoclopramide and domperidone are well absorbed orally, but have limited bioavailability due to extensive first-pass metabolism in the liver. Metoclopramide is also available for intravenous or intramuscular use, while domperidone can be given rectally by suppository. Metoclopramide has a shorter half-life (3–5 h) than domperidone (12–16 h).
Unwanted effects: Central nervous system (CNS) unwanted effects are produced by metoclopramide and the antipsychotics, but to a lesser extent by domperidone as a result of its lower CNS penetration.
Acute and chronic extrapyramidal effects from dopamine receptor blockade in the basal ganglia can lead to acute dystonias (especially in children and young adults), akathisia and a parkinsonian-like syndrome. Tardive dyskinesias can develop with prolonged use (see also Ch. 24).
5-HT3 receptor antagonists
Mechanism of action and clinical use: The 5-HT3 receptor antagonists block the 5-HT3 receptors in the CTZ and in the gut (Fig. 32.1). They are particularly effective against the acute vomiting induced by highly emetogenic chemotherapeutic agents used for treating cancer (e.g. cisplatin; Ch. 52) and for postoperative vomiting that is resistant to other agents. They are also used for prophylaxis when the consequences of retching and vomiting could be particularly deleterious, for example after eye surgery.
Pharmacokinetics: Oral absorption of ondansetron is rapid, and it can also be given by intravenous or intramuscular injection or by rectal suppository. Granisetron has a similar profile and is available for oral or intravenous use. Palonosetron has a long half-life and is given intravenously.
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