Space Pharmacology by Virginia E. Wotring

Author:Virginia E. Wotring
Language: eng
Format: epub
Publisher: Springer US, Boston, MA

Motion Sickness Treatments

Terrestrial motion sickness and nausea treatment have guided attempts at treating SMS. Tremendous improvements have been made in recent years in the treatment of nausea caused by cancer chemotherapy. The 5HT3 antagonists, ondansetron in particular, effectively reduce the chemically induced activation of the chemoreceptive trigger zone (CTZ) and/or act directly on the 5HT3 receptors of the enteric nervous system to reduce activity of the gut itself. Unfortunately, ondansetron does not seem to be effective in the treatment of nausea induced by motion (Stott et al. 1989; Levine et al. 2000; Reid et al. 2000; Muth 2006; Hershkovitz et al. 2009). In fact, a 5HT3 receptor antagonist was indistinguishable from a placebo in prevention of motion-induced nausea (Stott et al. 1989).

Agents that target the vestibular inputs to the vomiting center via muscarinic and histamine receptors have proven to be more efficacious in alleviating motion-induced symptoms (Reid et al. 2000). These include the antihistamines (promethazine) and the anticholinergics (scopolamine) that have been found effective for SMS (Davis et al. 1993a; Putcha et al. 1999).

antihistamines. Histamine antagonists (via the H1 receptor subtype) are effective for reducing motion-induced illness, but several second-generation non-sedating antihistamines from the 1990s were removed from the market because of QT interval prolongation and ventricular arrhythmia, probably via interaction with a potassium channel (Kohl et al. 1991). These risky antihistamines include terfenadine (Seldane®) and astemizole (Hismanal®).

Of the less-sedating current-generation antihistamines, chlorpheniramine significantly lengthens the time tolerated in a rotating chair, with side effects of dry mouth and sleepiness. Chlorpheniramine delays reaction time on behavioral performance tests, but no other performance impairments have been noted (Buckey et al. 2004).

Promethazine has activity at D2 dopamine receptors, H1 histamine receptors, muscarinic acetylcholine receptors (Connolly et al. 1992), and inward rectifier potassium channels (Jo et al. 2009), and there is some evidence for activity at the benzodiazepine site of GABAA receptors (Plant and MacLeod 1994). Promethazine (PMZ) does not affect autonomic functions such as arterial pressure, carotid baroreflex, and catecholamine concentrations (Brown and Eckberg 1997). It is perceived as effective for prevention and treatment of SMS by flight surgeons and crewmembers (Davis et al. 1993a; Putcha et al. 1999).

Metoclopramide is a D2 antagonist and 5-HT3/4 antagonist, but it has proven ineffective on motion-induced nausea, at least in the rotating chair model (Kohl 1987). Taken together, the motion sickness efficacy of various antihistamines suggest that properties required for relief of motion sickness include both H1 antagonism and D2 dopamine antagonism.

Antihistamines in general are associated with sedation, reduced reaction times, and other performance impairments (Parrott and Wesnes 1987; Hindmarch and Johnson 2001a; Ridout and Hindmarch 2003). In the rotating chair model of motion sickness, operationally used doses of PMZ improved N&V symptoms but caused impairments on a variety of behavioral tests involving cognition and reaction time (Fig. 7.3). Impairments were similar to those caused by moderate doses of alcohol (Cowings et al. 2000). Interestingly, stimulation of H1 receptors has been shown to increase their expression level (Kitamura et al. 2004). It is not yet

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