Pharmacology of Antiemetics

This section takes a comprehensive look at the pharmacology of antiemetics; looking at the aetiological factors that give rise to nausea and vomiting, before looking at the categories of drugs themselves.

Introduction

Girl Vomiting

Vomiting is a ubiquitous and necessary process in the body that becomes enacted whenever the body feels the need to defend itself against a potential or actual pathogen. Unfortunately, this reflex becomes much more accentuated and clinically relevant given that many patients who have to go through the ordeals of chemotherapy, the vast majority (~80%) of which will experience nausea and vomiting. Thus, developing drugs in this area is an extremely worthwhile endeavour and this section aims to provide a convenient overview of the various classifications of drugs currently used in nausea and vomiting.

Before we take a look at the pharmacology of antiemetics, it's important to have some degree of familiarity with the mechanisms that cause vomiting in the first place. It must therefore be conceded at the beginning of this discussion that many specific mechanisms are currently unknown but that a general physiology of causation has been identified. It's upon this general physiological disturbance that antiemetic drugs are developed to act within the mechanism and disrupt it to prevent the vomiting reflex.

What causes Nausea & Vomiting?

The chief location of emesis (vomiting) is currently unknown but the generalised '"vomiting centre' (VC) is located in the medulla oblongata of the brainstem. This vomiting centre if composed of a series of important nuclei, all of which play a role in inducing vomiting. They include:

  • Dorsal motor nucleus of the Vagus nerve
  • Nucleus tractus solitarius

Vomiting

Afferent nerves, that is, nerves directed toward these centres, will induce emesis. Efferent nerves from the vomiting centre initiate the motor reflexes that cause the reflex in the first place. These efferents include the vagus nerve and the phrenic nerves. Thus, when these efferent connections are stimulated they relax the fundus of the stomach and lower the esophageal sphincter itself. This is then combined with retrograde contractions from the small intestine coupled with contractions from the diaphragm and abdominal muscles which squeeze the stomach contents upward in the reflex motion.

Returning however to the afferent connections. As we have seen, these afferent connections, when stimulated, induce emesis. The vomiting reflex, as we're all too familiar, can be initiated from many factors. These include:

  • The presence of toxins in our stomach. This will stimulate abdominal and cardiac vagal afferents. Many drugs act on this mechanism.
  • Vertigo or motion difficulties can induce emesis. These factors will stimulate H1 and M receptors as well as triggering the CTZ (Chemoreceptor Trigger Zone), a zone particularly linked with the induction of vomiting.
  • The vestibular nuclei also have afferent connections to the vomiting centre in response to motion.
  • Higher brain centres, such as the cerebral cortex, and those involved with smells also have afferent connections to the vomiting centre.

All of these causative afferent connections play a key role in the pathogenesis of emesis. It's tackling these key roles the underpins the pharmacology of antiemetics, something we'll discover below time and time again.

Thus, so far we've discovered two main centres of emesis: the VC and the CTZ. It's the afferents and efferents of these connections, particularly the neurotransmitters which act on them, which play the central role in any study of this area. Table 1.1 shows the main neurotransmitters at work and the receptors they act upon in the pharmacology of emesis. 

Table 1.1 Neurotransmitters & Receptors of Emesis
Dopamine D2
Serotonin 5HT3 and 5HT4
Acetylcholine Muscarinic
Histamine H1
Substance P Neurokinin 1 (NK1)

The difficulty with having many possible afferents married to many different neurotransmitters is that is reduces the specificity of one particular drug to one particular form of nausea. Take the serotonin receptor antagonists (that we'll look at in more detail below), these drugs will ameliorate nausea induced by chemotherapy but not that of motion sickness. Hence, it would be totally wrong to assume universality in function when it comes to nausea. This specificity must be bore in mind.

Before we conclude this section, you must not forget the importance of induction nausea i.e. nausea induced by drugs. Many drugs have a high incidence of inducing nausea and these include: cytotoxic drugs, NSAID's, allopurinol, sulfasalazine, theophylline, oestrogens, bromocriptine, levodopa, opioid analgesics and digoxin. This is by no means an exhaustive list but supplies some of the main types and classes of drugs that are well known to correlate with a high incidence of nausea. This vomiting can also become an important diagnostic indicator. The colour of the vomit can tell us a lot about where the blood has come from, how long it has resided in the stomach and how serious the symptom is likely to be. Table 1.2 highlights this relationship. 

Table 1.2. Relationship between Colour of Blood & Severity
Yellow Suggests pyloric valve in the stomach is open with bile flowing from the duodenum into the stomach.
Bright Red Esophageal rupture of some description is most common. Considered more of an emergency than other colours.
Dark Red Suggests liver-like clots. It may be due to a perforated ulcer in the stomach for example.
Coffee Due to the oxidation of iron in the blood; less severe with the stomach having time to cause oxidation.

Pharmacology of Antiemetic Drugs

Now that we've taken a look over some of the most important aetiological factors in the pharmacology of antiemetics, it's now time to take a look at the main classes of drugs involved therein. This involves taking a look at eight key categories.

  • Antihistamines
  • Antimuscarinic Drugs
  • Antidopaminergics
  • 5HT3-receptor Antagonists
  • Neurokinin-1 (NK1) Receptor Antagonists
  • Cannabinoids
  • Corticosteroids
  • Benzodiazepines

Antihistamines

Examples: Cyclizine; Promethazine

If we remember back to the causative factors in the production of vomiting you'll recall how histamine receptors, particularly H1 receptors, induced emesis by triggering the chemoreceptor trigger zone (CTZ), hence it should come with little surprise how antihistamines at this receptor are acutely involved in the prevention and treatment of vomiting. We're going to take a look at the pharmacology of two particularly important antihistamine drugs, that of cyclizine and promethazine.

  • Cyclizine (Marezine; Valoid) is a piperazine derived drug that primarily acts antagonistically on H1 receptors but also has notable antimuscarinic activity as well. As a consequence of this latter antagonism, anticholingeric symptoms such as xerostomia (dry mouth), urinary retention and blurred vision are quite common however the most common side-effect by far is the experience of drowsiness. However, antihistamines are not considered the most ideal treatment of choice for vomiting except in two notable cases. First, cyclizine is widely employed in drug-induced vomiting. Second, promethazine is free of teratogenic potential and hence can be given to treat vomiting in pregnancy. Many other forms of vomiting are usually treated with other drugs.
  • Unlike the piperazine cyclizine, Promethazine is derived from the phenothiazine family. Similarly with cyclizine, it has notable antimuscarinic activity as well as antagonism of several serotonergic receptors as well (5-HT2A; 5-HT-2C). Both drugs, cyclizine and promethazine, are well absorbed orally and can also be given by IM or IV administration. Promethazine, however, is vulnerable to a considerable first-pass effect. The half-life of promethazine is about 10 hours while cyclizine is approximately double that. Both of these drugs are eliminated by hepatic metabolism. 

Antimuscarinic Drugs

Examples: Hyoscine (Scopolamine in the US)

Muscarinic receptors are inextricably linked with the process of vomiting as they're heavily involved as afferents to the vomiting centre of the brain. Hyoscine is used in the treatment of motion sickness and postoperative vomiting. It primarily acts as a competitive inhibitor at M1 receptors However, as we have seen with the antihistamines and as we'll see with the dopamine receptor antagonists, these too carry intrinsic antimuscarinic activity, just not to the same degree that hyoscine does. 

Hyoscine can be administered in many different forms including parenteral, transdermal and oral routes, where the latter has reasonably good absorption. The transdermal patch can be put behind the ear where it will deliver a therapeutic effect for about 3 days. It is metabolised via hepatic routes and has a half-life of approximately 8 hours. As an antimuscarinic drug, it carries with it the typical side-effects of dry mouth, urinary retention and blurred vision.

Dopamine Receptor Antagonists

Examples: Prochlorperazine; Metoclopramide; Domperidone

These drugs act as antagonists at D2 receptors. Thus, they're involved in the inhibition of dopaminergic stimulation on the CTZ. Prochlorperazine (Compazine) is also classified as an antipsychotic drug but the dose at which it's administered for its antiemetic effect is approximately a third of that than its dose for psychosis.

Metoclopramide (Reglan) acts as a dopamine receptor antagonist at regular doses but higher doses also have the effect of acting as a 5-HT3 receptor antagonist. This double efficacy can come into play when trying to treat cytotoxic-induced vomiting such as that which occurs with anticancer agents. In addition to this, Metoclopramide also has significant prokinetic effects which increase the rate of gastric emptying while also increasing the tone of the gastroesophageal sphincter. These prokinetic effects may be due to an inducement in 5-HT4 receptors in the enteric nervous system.

Dopamine receptor antagonists are chiefly used in vomiting that occurs due to drugs or operations. Pure dopamine receptor antagonists, such as Domperidone (Motilium), lack any antimuscarinic effect and thereby become ineffective when trying to treat motion sickness. Prochlorperazine, on the other hand, can be used to treat various vestibular disorders and motion sickness primarily due to this additional antimuscarinic effect. 

Metoclopramide and Domperidone undergo extensive first-pass metabolism and thereby have very limited oral bioavailability. Metoclopramide can be given IV or IM while Domperidone can be administered rectally through the use of suppositories. Both drugs are primarily eliminated through hepatic means with Metoclopramide having a half-life of about 4 hours compared to 14 hours experienced with Domperidone. 

CNS effects are typical with Metoclopramide and Prochlorperazine due to the ability to cross the blood brain barrier to some extent - this crossing is much less appreciable with Domperidone. Due to the inhibition of dopamine receptors, dystonias, extrapyramidal effects and parkinsonian-like symptoms are potential. 

5HT3 Receptor Antagonists

Examples: Granisetron; Ondansetron

These drugs act as antagonists at 5HT3 receptors located at the level of the gut but also at the level of the CTZ. Emetogenic drugs, such as that used in cancer treatment, which induce vomiting quite easily will find refuge in 5HT3 receptor antagonists as these agents tackle this type of nausea best. However, Granisetron (Kytril) and Ondansetron (Zofran) have also proven useful in postoperative nausea and vomiting.

There is rapid oral absorption for Ondansetron but it can also be given via alternative routes such as IV and IM, or even via the rectal route. It goes through a very partial first-pass effect and is also primarily eliminated by metabolism in the liver and has a relatively brief half-life of only just 3 hours. 

Ondansetron and Granisetron commonly cause headache as well as constipation.

Neurokinin Receptor Antagonists

Examples: Aprepitant

The mechanism of action of aprepitant (Emend) involves blocking NK1 receptors at the level of the CNS. In addition to this primary effect, Aprepitant also enhances the effects of 5HT3 receptor antagonists as well as corticosteroid drugs in the prevention of acute or delayed emesis due to chemotherapeutic drugs. Aprepitant has very good absorption from the gut and is extensively metabolised via CYP 3A4 in the liver with a long-half life of about 10 hours.

CNS unwanted effects are common such as dizziness, headache and tiredness. In addition, it's not uncommon to see GI effects such as abdominal pain and diarrhoea. 

In terms of interactions, Aprepitant is an inhibitor of the isoenzyme CYP 3A4 and an inducer of CYP 2C9. Due to these effects, it would decrease the effect of Warfarin should the two be taken together. 

Cannabinoids

Antiemetic Drugs

Example: Nabilone

Nabilone (Cesamet) is a derivative of the active ingredient of Cannabis; Tetrahydrocannabinol. The exact mechanism of effect of this drug is not widely understood but it's thought to involve an inhibition of cortical activity. Nabilone also has the effect of inhibiting 5HT3 receptors.

Nabilone is principally absorbed from the gut and is extensively metabolised through the liver with a brief half-life of approximately 2 hours. However, the metabolism of Nabilone is such that its metabolites have longer half-lives and hence have a more prolonged effect. CNS effects are relatively common such as sedation and sleep disturbances. In addition, it's not uncommon to see dry mouth and ataxia experienced post-administration of Nabilone.

Corticosteroids

Examples: Dexamethasone; Methylprednisolone

These are intrinsically weak antiemetic drugs. However, if they're co-administered with a high dose of Metoclopramide (or with a 5HT3 receptor antagonist) then this will produce an addictive effect, particularly prior to chemotherapy treatment. The mechanism of action is currently unknown.

Benzodiazepines

Examples: Lorazepam (Ativan)

These drugs have no intrinsic antiemetic activity however they help with anticipatory nausea, particularly when a patient has experienced nausea in a prior session of chemotherapy. In this sense, they act as a sedative and amnesiac-inducing agent; helping with the psychological slant of nausea and vomiting. 

Conclusion

This section has taken a look at some of the principal areas in the pharmacology of antiemetics. At the beginning of this article, we looked at the aetiological physiological factors involved in nausea and vomiting. With this in mind, we then moved on to look at the pharmacology of antiemetic drugs, specifically looking at eight main categories of such drugs. Evidently, some of these antiemetic drugs are used more often than others, but for the sake of being comprehensive, they were included.

By | 2016-12-07T18:59:34+00:00 December 4th, 2014|Pharmacology Guides|1 Comment

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One Comment

  1. ally November 21, 2016 at 21:06

    Excellent overview, thanks!

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