Antiemetics, Their Function, and Their Role in Controlling Chemotherapy-Induced Nausea and Vomiting
Â Â Â Because chemotherapyterm is such a harsh treatment on the body, the body reacts to these poisonous chemicals and tries to rid the body of them. One way the body responds is through a vomiting action preceded by a nausea feeling. Because the continuation of treatment is critical in chemotherapy and since nausea and vomiting is a common side effect, antiemetics are used to prevent or lessen the nausea and vomiting mechanisms. Antiemetics are compounds that prevent emesis, otherwise known as vomiting. Antiemetics function through various molecular pathways and are classified into categories by their target. A key aspect to understanding the function of antiemetics is the structure of the nervous system signaling pathway as it relates to nausea and vomiting.
Â Â Â The body has a vomiting center called the area postrema in the lateral medullary recticular formation in the pons, which is located at the base of the brain in the brain stem. This center contains numerous receptors which can ascertain signals carried in the blood to induce a nausea or vomiting response. This center also takes in nervous system input from throughout the body, specifically from tasting and in the gastrointestinal tract, which can produce nausea or vomiting response as well. A brief overview of vomiting and its mechanism can be found at Wikipedia.
Â Â Â Many types of chemotherapy are known to produce chemotherapy-induced nausea and vomiting (CINV). The Multinational Association of Supportive Care in Cancer established definitions and guidelines for CINV. The drugs are grouped by risk of CINV, with high risk being 90% of patients will have CINV, moderate is 30-90%, low is 10-30%, and minimal is less than 10%.
Â Â Â Drugs in the high risk group for CINV are cisplatin, mechlorethamine, streptozocin, cyclophosphamide at doses abover 1,500 mg/m2, carmustine, and dacarbazine.
Â Â Â Moderate-risk drugs are oxaliplatintermterm, cytarabine at doses above 1 gm/m2, carboplatin, ifosfamide, cyclophosphamide at doses less than 1,500 mg/m2, doxorubicin, daunorubicin, epirubicin, idarubicin, and irinotecantermterm.
Â Â Â Low-risk drugs are paclitaxel, docetaxel, mitoxantrone, topotecan, etoposide, pemetrexed, methotrexate, doxorubicin HCL liposome injection, mitomycin, gemcitabine, cytarabine up to 100 mg/m2, fluorouraciltermterm, bortezomib, cetuximabtermterm, and trastuzumab.
Â Â Â Minimal-risk drugs are bleomycin, busulfan, 2-chlorodoxy-adenosine, fludarabine, vinblastine, vincristine, vinorelbine, and bevacizumabtermterm.
Â Â Â As mentioned before, antiemetics are grouped based on their function. The major groups are 5-hydroxy-tryptamine 3 (5-HT3) receptor antagonists, NK-1 receptor antagonist, corticosteroids, dopamine receptor antagonists, and cannabinoids.
Â Â Â The 5-HT3 receptor is a serotonin receptor, part of a family of receptors known as the Cys-loop family of receptors. This family of receptors is important for many aspects in neuronal signaling. The 5-HT3 antagonists commonly used are dolasetron (commercially Anzemet), granisetron (Kytril), ondansetron (Zofran), tropisetron (Navoban), and palonosetron (Aloxi). These compounds effectively block the normal signaling through the 5-HT3 receptor, inhibiting the signal that would normally reach the vomiting center. A free detailed mechanistic review on 5-HT3 antagonists can be found here.
Â Â Â Neurokinin type 1 (NK-1) receptor is found in the vomiting center and in the abdominal vagus (a nerve running along the esophagus and the stomach) and binds the neuro-peptide called substance P. Binding of substance P elicits a neuronal signal that ultimately leads to vomiting and nausea. The antagonists of NK-1 are approved for acute as well as delayed CINV. Aprepitant (commercially Emend) is the only approved NK-1 antagonists so far. A free detailed review on the mechanism of NK-1 antagonists can be found here.
Â Â Â Corticosteroids are hormones in the steroid class meaning they have the base structure of cholesterol. The corticosteroids have a range of function in the body and Wikipedia gives a good overview corticosteriods here. Dexamethasone is a synthetic corticosteroid of the glucocorticoid class and is the most commonly prescribed corticosteroid. It is given in conjunction with 5-HT3 antagonists to augment their effects.
Â Â Â Dopamine receptor antagonists inhibit the class of receptors that binds dopamine, a hormone and neurotransmitter. Dopamine is an emetic and can induce nausea, hence blocking dopamine receptors is another treatment of CINV. Domperidone (commercially Motilium) and metoclopramide (Reglan) are the two main dopamine receptor antagonists used for antiemetic treatment. Here is an excellent review on the pharmacokenetics of dopamine receptor antagonists.
Â Â Â Cannabinoids are drugs that bind to cannabinoid receptors (CB) found throughout the central (CB1) and peripheral (CB1 and CB2) nervous systems. There are endogenous cannabinoids produced in humans that bind weakly to these receptors. The synthetic cannabinoids nabilone (commercially Cesamet) and dronabinol (Marinol) bind more strongly to the CBs. Cannabinoids are antiemetic in that they are agonists to the CBs and partially block the release of other neurotransmitters. A good review can be found here on cannabinoids in the treatment of chemotherapy-induced nausea and vomiting, although it is not free.
While no one antiemetic is 100% effective, combinations of antiemetics are in trial producing synergistic effects between certain classes.
Here is an overview of antiemetic drugs.
Here is a great overview of chemotherapy drugs and their associated side effects. Â
Another good article on CINV can be found in Oncology Times 29;17: September 10, 2007 Treatment-Induced Nausea and Vomiting: Research Roundup