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Space Pharmacology: How Space Affects Pharmacology

  • Virginia WotringEmail author
Living reference work entry

Abstract

The spaceflight environment is at best, very different from Earth, and at worst (without the protection offered by the systems of a space suit or a spacecraft) deadly. Candidates for NASA’s astronaut program must meet many requirements to be selected, but even the healthiest people in the best circumstances use medications from time to time. During their spaceflight missions, astronauts are exposed to perhaps the most extreme of all extreme environments, and there are features of the spaceflight environment that drive uses of particular medications. This chapter will provide an overview of these mission-related medication needs and will discuss the special considerations that must be given to stocking the medication supplies for use on spaceflight missions.

The spaceflight environment is at best very different from Earth and at worst (without the protection offered by the systems of a space suit or a spacecraft) deadly. The Earth and its magnetic field offer us some protection from galactic cosmic rays, but this protection is reduced at higher altitudes. At the International Space Station in low orbit around the Earth, crew are exposed to ~ 50 times the radiation that we are on Earth, and the impacts of this exposure are not yet fully understood. In contrast, some effects of reduced gravity are more readily observable (Fig. 1). Deleterious effects of the spaceflight environment on bone and muscle first became apparent during Skylab missions, and others, like spaceflight-associated neuro-ocular syndrome, came to light recently and are still under study. The spaceflight food system is designed to withstand long-duration ambient storage and meet nutritional requirements on space flight missions, but in recent years, we’ve learned the importance of the microbiome for human health. It now seems possible that the preserved diet prepared for space missions coupled with the absence of items containing healthy microorganisms (like yogurt) could have negative impacts on crew health. And psychologically, the demanding workload, distance from friends and family, reduction in privacy, and potential for danger could each become stress points and may be additive (Table 1).
Fig. 1

Astronaut Peggy Whitson demonstrates some effects of microgravity. (Image: NASA)

Table 1

Features of the space flight environment that can have physiological or psychological impacts on crew

Microgravity

Loss of bone mineral density, muscle atrophy (including heart), vestibular dysfunction

Elevated exposure to space radiation

Oxidative stress, DNA damage, possibly others

Closed environment

Preserved diet (little fresh food), elevated CO2, little social variety, unvarying sensory input

Isolation

Removed from family, friends, natural surroundings on earth

Workload

Demanding, high visibility

Candidates for NASA’s astronaut program must meet many requirements to be selected, and this includes medical and psychological evaluation. Even so, the healthiest of people in the best circumstances use medications from time to time. Even for adults who are fit and healthy, it is typical to use pain relievers to treat occasional joint or muscle pain, hypnotics to treat occasional insomnia, or remedies for periodic minor gastrointestinal disturbances like heartburn (Kaufman et al. 2002). During their spaceflight missions, astronauts are exposed to perhaps the most extreme of all extreme environments (Table 1), and there are features of the spaceflight environment that drive uses of particular medications. This chapter will provide an overview of these mission-related medication needs (over the counter (OTC) and prescription) and will discuss the special considerations that must be given to stocking the medication supplies for use on spaceflight missions.

Medication Usage on Space Flights

On the first space flights, no one really knew what being in microgravity would feel like or what physiological disturbances would be experienced. In order to prepare, flight surgeons and pilots drew inferences from the experiences of airplane pilots, especially those who flew the highest and fastest planes, military test pilots. Flight surgeons provided early astronauts with medications for motion sickness and for pain (Fig. 2), but we have little information about when or if these were used.
Fig. 2

Gordon Cooper carried these pre-loaded injectors for motion sickness and pain relief on his Mercury 9 flight. (Image: NASA)

Space shuttle missions were 7–16 days and packed with activities. Crew reported using every available spare minute to observe and photograph Earth and to perform their own experiments with being in microgravity (Fig. 3).
Fig. 3

Gerald Carr and William Pogue on Skylab 4 in 1974. (Image: NASA)

After shuttle missions, astronauts were asked to complete questionnaires about the use of any medications during their mission as part of a voluntary research study. These data highlight the needs of people (even healthy ones) in the spaceflight environment. Trouble sleeping Sleep difficulty was the main driver of medication use, followed by headache, congestion, and space motion sickness (Table 2) (Putcha et al. 1999). These missions were short and intense, with a heavy workload for each crewmember. It was assumed that these medication uses could be explained mostly by the intense nature of these missions. However, a similar study conducted from medical records of International Space Station (ISS) crewmembers showed that medication usage was very similar (Table 2), even though the missions were much longer, with schedules planned to be more like a typical workdays on Earth. Taken together, these findings highlight medication needs induced by the spaceflight environment itself. This environment includes not just microgravity but elevated exposure to radiation, living in a closed environmental system where all air and water are recycled, preserved food supplies, unvarying social variety, little privacy, confinement inside the spacecraft, constant exposure to noise (fans to circulate air and other machinery required to operate ISS systems), isolation from friends and family, and demanding duties in a highly visible situation.
Table 2

Indications for medication use on spaceflight missions

Space shuttle (<16 d)

ISS (> 30 d)

Sleep

Sleep

Headache

Body pain

Congestion/allergy

Congestion/allergy

Space adaptation syndrome (SAS)

Skin rash

Body pain

Space adaptation syndrome (SAS)

Gastrointestinal

Extravehicular activity (EVA)

Extravehicular activity (EVA)

Headache

 

Alertness

 

Gastrointestinal

 

Eye

 

Infection

Spaceflight Effects on Pharmacokinetics

Even after >50 years of medication use on spaceflight missions, it is not known if pharmacokinetics (how the body absorbs, distributes, metabolizes, and excretes medications) is altered by the spaceflight environment. Many astronauts have taken many medications on their missions and reported no adverse events. However, crewmembers have reported lack of desired efficacy, particularly associated with treatments for rash and space motion sickness (Fig. 4) (Wotring 2015b; Armaghani et al. 2014; Crucian et al. 2016; Putcha 2009). The use of multiple doses of sleep aids in a single night would also seem to indicate less than desired efficacy (Barger et al. 2014). Small in-flight research studies have had varying conclusions, with some showing delayed absorption or reduced peak concentrations of administered acetaminophen (Fig. 5) (Cintrón et al. 1987; Kovachevich et al. 2009), but the same findings could be explained by the use of other medications, like those for nausea that can alter gastrointestinal motility. Clear evidence regarding effects (or lack thereof) of the spaceflight environment on pharmacokinetics is required for confidence in dosing strategies.
Fig. 4

Self-report relief with different nausea treatments varied considerably, with promethazine (alone, or with dexedrine (PhenDex) providing the best relief. Crewmembers reported less relief from scopolamine with dexedrin (ScopDex). (Image: NASA)

Fig. 5

Salivary concentration over time after acetaminophen dose in three different individuals (Panels A–C). (Image: NASA)

Mission-Related Needs for Medication Use

Sleep

The conditions onboard spacecraft have been less-than-ideal for sleeping. Crewmembers have noted a variety of impediments to their sleep, including noise, ambient light, and activity by nearby crewmembers (Stuster 1996). While these are certainly contributing factors, the lack of circadian cues and subsequent circadian misalignment may be an overarching cause. Humans evolved in an environment with a roughly 12 h day and a 12 h night. The hallmarks of night include darkness, cooler temperatures, and often quietness, while day usually has bright light, warmer temperatures, and sounds from diurnal animals and their activities. Space shuttles and the ISS have had constant temperatures, constant equipment noise, and relatively dim lighting. These engineering-driven features of the environment put crewmembers into a living situation almost entirely lacking the circadian cues required to set their circadian rhythms (Dijk et al. 2001; Flynn-Evans et al. 2016; Lockley et al. 2003). Recent research on light has even shown that for humans on Earth, morning light is slightly shifted toward blue wavelengths, while evening light is red-shifted. This research has led to the adoption of variable-wavelength lighting on the ISS to provide bluer light in the mornings and redder in the evenings (Fucci et al. 2005). It is expected that this will reduce the need for sleep aids on future spaceflight missions.

Currently both zaleplon and zolpidem are available for crew to use to help them fall asleep and/or stay asleep all night (Stingl et al. 2015; Barger et al. 2014). Reliance on these medications is much higher (about tenfold) than it is for healthy adults on Earth, and sometimes crewmembers have used multiple doses over the course of a night (Barger et al. 2014). Use of hypnotics with long half-lives (like the sustained release zolpidem formulation) or repeated dosing during a single night could prove dangerous in the event of a mission emergency that requires crew to awaken and perform important tasks. Because of this NASA began a study to measure the effects of these different sleep aids on individual crewmembers before their flights. The clever experimental design allowed each crewmember to observe their reactions to the common sleep aids, from which they could make informed choices regarding use of medications in the future (Johnston 2010). There may also be a future increased reliance on administered melatonin to help set circadian rhythms, but determination of an optimal formulation, dose, and dose timing have proven difficult, possibly related to variable quality and dose in US melatonin products due to its status as a supplement rather than a medication (Arendt et al. 2008).

Bone

Loss of body weight was one of the first significant physiological findings associated with spaceflight (Zwart et al. 2014; Carpentier et al. 2018). NASA studies have determined that bones demineralized during spaceflight and muscles atrophied, both likely associated with lack of use and loading. These findings were coupled with the fact that crews tended to eat less than their bodies required (Smith and Zwart 2008). NASA has provided crew with effective countermeasures in the form of adequate calories, calcium, and vitamin D along with exercise equipment and protocols designed to prevent muscle atrophy and bone demineralization, and these countermeasures have proven effective in many crewmembers (Smith et al. 2012). As a potential alternative or supplemental treatment, a bisphosphonate osteoporosis drug has also been tested and found efficacious in maintenance of bone mineral density during spaceflight missions, particularly when combined with exercise (LeBlanc et al. 2013) (Fig. 6).
Fig. 6

Change in bone mineral density after long-duration space flight. 1 p < 0.05, pre versus post; 2 p < 0.05 (bisphosphonate group significantly different from pre-ARED); 3 p < 0.05 (bisphosphonate group significantly different from ARED). Pre-ARED (n = 18); ARED (n = 11); bisphosphonate (n = 7) (LeBlanc et al. 2013)

Space Adaptation Syndrome

Almost 70% of astronauts report feeling of nausea, disorientation, malaise, and headache during the first 1–3 days of a mission and again the first few days after landing. This has been described in the literature as space motion sickness (SMS) or space adaptation syndrome (SAS) (Homick 1979). The underlying cause is thought to be a mismatch between sensory input from the visual system (unaffected by microgravity) and the vestibular and proprioceptive systems, which are greatly affected by microgravity (Oman 1998). A variety of medications have been used to treat or prevent nausea and vomiting including various antihistamines and anticholinergics, proven treatments for motion-induced illnesses on Earth (Davis et al. 1988). Scopolamine and promethazine have been the most commonly used antinausea treatments on space mission, sometimes accompanied by dextroamphetamine to reduce lethargy (Jennings 1998). Modafinil, with its improved safety, has now replaced dextroamphetamine as the stimulant of choice in many situations (Estrada et al. 2012).

Antinausea therapy was recently revolutionized by the development of 5HT3 receptor antagonists like ondansetron, but even though these drugs are remarkably effective at relief of chemically induced nausea and vomiting, the 5HT3 receptor antagonists have proven ineffective in the treatment of motion-induced nausea (Hershkovitz et al. 2009). Evidently, the mechanisms underlying the nausea and vomiting induced by motion and that induced by chemicals (cancer chemotherapy or pregnancy) are sufficiently different that different classes of drugs are best for treatment. Numerous studies have also attempted to identify characteristics of crew who are most susceptible, but no useful correlations have been identified (Davis et al. 1988; Thornton 2011). Currently promethazine is the most commonly used treatment on ISS missions, and its use is generally limited to the first few days of a mission.

Pain

Crewmembers report several reasons for using pain relievers, including headaches, muscle pain, and joint pain (Wotring 2015b). Headaches may be associated with headward fluid shifts, especially during the microgravity adaptation period or with elevated carbon dioxide levels on the ISS (Law et al. 2014). Muscle and joint pain are sometimes reported after strenuous workouts (Fig. 7) or after extravehicular activity (EVA) in a pressurized suit (Wotring 2015b).
Fig. 7

Sunita WIlliams on the ISS treadmill. Aerobic exercise is used to maintain aerobic fitness and muscle. A harness must be used with the treadmill when in microgravity. (Image: NASA)

Ibuprofen is the most commonly chosen pain reliever among crewmembers, but aspirin, acetaminophen, and prescription pain relievers are also available. (Stingl et al. 2015).

Developing Needs for Longer Duration Missions

As spaceflight missions change in purpose, destination, or equipment, new needs are identified. Several physiological effects of spaceflight are linked to duration of exposure. Several physiological systems seem to adapt to normal or possibly a new “space normal” in the early part of a mission; these include sensorimotor and renal (fluid shifts). Other needs are emerging.

Spaceflight-associated neuro-ocular syndrome (SANS) was identified fairly recently, as crewmembers routinely stayed on the ISS for 6 months or more (Mader et al. 2011). Its etiology is not yet understood, but it may include alterations in intraocular or cerebrospinal fluid pressures. The syndrome shares some features with benign intracranial hypertension, for which acetazolamide is a treatment (Lawley et al. 2017; Lee et al. 2018; Zhang and Hargens 2018). However, since acetazolamide use increases the risk of renal stone by 3% (Ahlstrand and Tiselius 1987), the use of this medication in persons at risk of renal stones (due to bone remodeling) is not recommended. This syndrome therefore needs to be better defined before safe and sensible treatments can be suggested. Regular eye exams are now part of ISS missions (Fig. 8).
Fig. 8

Karen Nyberg performs a self-examination of the eye during her ISS mission. Additional data regarding the health and function of the eye is required since spaceflight-associated neuro-ocular syndrome has been reported. (Image: NASA)

Crewmembers on ISS missions are exposed to radiation 0.3 mGy/day (Wilson 2000; Hu et al. 2009), and it is expected that those on a mission to Mars will be exposed to about three times as much or 0.5–1 Gy total on a 2.5 year mission (Wilson 2000) (Zeitlin et al. 2013). Radiation can cause physiological damage, although the body has mechanisms to repair some damage (Zeitlin et al. 2013). Currently, NASA limits crew exposure to radiation to safeguard astronaut health (Cucinotta et al. 2010), but studies to optimize the body’s repair mechanisms or to provide pharmacological support are underway. It is anticipated that pharmacological countermeasures to protect the body from damage or to repair radiation-induced damage will be available by the time long-distance missions into deep space begin (Wotring 2012).

Astronauts train on Earth before their missions for the duties that are planned for them to perform during their missions. For long-duration missions, there could be a time delay of years in between training and eventual in-flight need for that training. It might be optimal to maximize crewmembers’ ability to recall learned material or otherwise enhance their cognitive abilities. There are drugs in development and testing for the treatment of memory impairment in dementia patients or others suffering from a loss of cognitive ability (Fond et al. 2015). Cognition enhancers, nootropics, and other agents that act on the central nervous system are in testing for dementia patients, although the use of these drugs in healthy individuals has not been tested. It is not yet known if any of these agents would improve memory or cognitive function in healthy, high-performing individuals.

Mission-Related Requirements of the Formulary

There are multiple factors that need to be considered when selecting medications for a space mission formulary, and sometimes they are conflict with one another or with other mission needs. Availability of storage (mass and volume) is of concern on nearly every space mission but will likely be even more constrained on missions with more crew, longer duration, or significant equipment to carry. Missions may have different anticipated medical needs, mostly based on the tasks planned for the mission. For example, missions that involve landing on a planetary body with partial gravity carries added risks of falls and bone fractures, while missions where crew stay onboard a space craft have very low risk of falls or fractures. For each mission, the anticipated needs must be evaluated, and the desired drugs chosen to fit the mass and volume allotted for medication storage.

Selection of Medications for Missions

Ideal medications for space missions are well-tolerated by most people, have few, minor untoward effects, have multiple therapeutic indications, and have shelf lives that exceed the mission duration in the storage conditions available on the mission. Drug selections for the first spaceflight missions were based on knowledge from military flight surgeons and included items feasible for self-administration by persons without medical training. Now, many crew requirements are assessed based on knowledge from earlier space missions; in some cases, this has included pre- and post-mission inventories that showed the actual numbers of unit doses consumed. Going forward, accurate provisioning may be aided by two new in-flight activities: real-time inventory tracking of medical consumables (Zoldak 2016) and crew self-reports of medication use (Wotring 2015a).

The World Health Organization’s Model List of Essential Medicines is an expertly vetted list of medications meant to supply every possible medical need and is updated regularly to reflect newly developed drugs (WHO 2017). This can serve as an excellent model upon which to base formulary development for provisioning any clinic. Crewmembers don’t require medications to treat tropical diseases or serious conditions like AIDS, and current mission durations obviate the need for cancer treatments. Therefore, entire sections of WHO Essential Medicines List are unnecessary for spaceflight crew. For indications like pain or infection, the list identifies a selection of useful drugs while categorizing those drugs that are members of a related class. This permits selection of a single member of most medication classes for use in a small spaceflight formulary. Multiple anti-infectives are carried on spaceflight missions, each with a different mechanism of action, and multiple drugs are carried to treat the most common indications, like pain relief and sleep aids. Small supplies of medications to treat unpredictable emergencies are also included.

Predicted Medical Needs

NASA has employed modeling methods to predict which medical conditions might occur on space missions and at what frequency. The models use known medical events from past space missions and those from scenarios that are considered to be reasonable analogs, like Antarctic exploration missions and submarine or other military missions. This Integrated Medical Model (IMM) can be run for different types of spaceflight missions, varying the duration, crew composition and numbers, and activities like planetary landing or EVA (Minard et al. 2011). The output of the IMM can then be used to generate a list of medical conditions anticipated for a specific mission (Watkins et al. 2011). The mission-specific medical condition list can, in turn, be used to guide selections of medications and other medical supplies for the mission.

Stability of Medications in the Unusual Environment of Spaceflight Missions

Medications can become ineffective as they degrade over time, which reduces their efficacy. Additionally, a few medications have been shown to accumulate toxic compounds as they degrade. On Earth, expiration dates can drive replacement of old stock and limit negative outcomes associated with aging medications, but on spaceflight missions to distant destinations, resupply of consumables may not be feasible. NASA estimates that a journey to Mars would require 30–36 months, which is longer than the shelf life of most FDA-approved medications (Wotring 2012) (Fig. 9).
Fig. 9

NASA pharmacists prepare streamlined medication kits based on intended use, separating commonly used medications from medications that are part of research studies, as well as from specialized packs for emergencies. The outer fabric offers good protection from light, but not from oxygen or moisture. (Image: NASA)

Environmental factors like humidity, light, and oxygen drive most of the chemical reactions that degrade medications. Medication manufacturers use packaging to limit exposure of their products to the environmental factors to which each product is sensitive. Given the limitations on medical kit mass and volume, sometimes medications in solid dosage forms are repackaged from stock bottles into zip-top polyethylene bags, which offer little protection from the environment but significantly reduce volume (Putcha et al. 2016).

Currently, it is not known if space radiation alters medication degradation. Preliminary efforts to evaluate this possibility have each been limited, and it is not possible to make a firm conclusion with the current data. In a survey of ~ 20% of the medications in the ISS medical kit, NASA researchers reported that six exhibited significant degradation of active ingredient during storage on the ISS for up to 28 months, and others showed changes in physical appearance indicating degradation. It important to note, however, that only a single sample of each medication was analyzed (albeit in triplicate); therefore, definitive conclusions cannot be drawn (Du et al. 2011). A later study took advantage of 550-day-old medical supplies onboard the ISS that were expired and scheduled for destruction. Samples were instead returned to Earth for analysis. Nine medications were chemically analyzed, and three failed to meet current standards for purity. Unfortunately, this opportunistic study suffers from the absence of lot-matched controls, aged for the same time period on Earth (Wotring 2016). Given the lack of clear evidence, no conclusions can yet be drawn regarding the possible effects of the spaceflight environment on medication degradation. Additional research is required before long-duration spaceflight missions commence.

Possibilities for In Situ Drug Analysis and Production

NASA has sponsored development of Raman spectroscopy-based analysis of finished drug products, so that astronauts may one day test unit doses immediately before use on long-duration space missions (Shende et al. 2014). The device relies on a library of stored spectra from safe medications and from those that have degraded. It compares the spectrum it measures to this library to evaluate safety and active ingredient content.

It may be hard to imagine producing a unit dose of a medication (possibly containing only milligrams of active ingredient) in an environment where a balance can’t be used to weigh ingredients. Multiple research and development groups are actively pursuing the possibility of medication production in situ; on our planet, this could alleviate global drug shortages and help provide adequate medication supplies in places where distribution or storage is problematic. With the advent of the first 3D-printed medication (FDA 2017), the possibility of manufacturing medication doses during missions seems more practical than it once did (Alhnan et al. 2016). Genetic engineering techniques may also permit the use of microorganisms as manufacturing plants for active ingredients (Keasling 2010). These new innovations may one day permit crew to manufacture fresh medications as needed during their missions, addressing any issues with medication stability over time as well as ensuring that medication supply meets medical needs.

Personalized Medicine for Astronauts

Personalized or precision medicine has made great improvements in efficiently matching patients with optimal treatment regimens for them, particularly in the treatment of many different cancers. As more is learned regarding genetic sequences and corresponding responses to particular medications, we expect that many more treatment regimens can be personalized based on genetic testing. On Earth, cancer treatments have driven pharmacogenomics, and astronauts have not needed these types of medications on missions. However, it is expected that genetic tests will be soon be developed to optimize treatment plans for many other indications; some of these are likely to include indications of interest to spaceflight crew (Chancellor et al. 2014; Goel and Dinges 2012).

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for Space Medicine and Department of Pharmacology and Chemical BiologyBaylor College of MedicineHoustonUSA

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