Clinical Pharmacology of Spaceflight

Eleanor A. O'Rangers, PharmD

Disclosures

January 03, 2011

In This Article

Efficacy of Medications Used During Space Missions

Of note, during flight surgeon medical debriefings, some orally administered medications taken during flight were reported to be less effective than expected. Evidence of reduced efficacy of some drugs during spaceflight, however, is limited.[18,19] Additional anecdotes of drug inefficacy come from flight surgeon and astronaut verbal report, postflight medical debriefings, and results from various research protocols conducting during flights. According to National Aeronautics and Space Administration (NASA) pharmacologist Lakshmi Putcha, 20% of astronauts have reported that when they take medications during spaceflight, the anticipated effects of the drugs were less than anticipated, or the medications did not work at all (Putcha L. Personal communication, March 1998). This means that a typical dose of a medication used to treat a headache, for example, did not relieve the headache completely (or at all) when taken during spaceflight. These anecdotal observations, if validated, could have important implications for the selection, dosing, and potential side effects of medications used during spaceflight. It is unfortunate that systematic data collection of drug experiences remain a significant gap in the US space program.

Surprisingly, very limited research has been conducted to determine whether the expected earth-based pharmacokinetics and pharmacodynamics of a drug are altered in a microgravity environment. However, we know that in such an environment, multiple physiologic processes undergo changes to compensate for the loss of a gravity vector; these adaptations follow variable time courses (Figure 1).

Some of these physiologic changes may contribute to differences in pharmacokinetics, which could in turn have profound implications for dosing of, therapeutic response to, and toxic effects of medications.

Figure 1. Physiologic changes associated with microgravity exposure.
From the Physiology Slide Set of the American Society of Gravitational and Space Biology (http://asgsb.org/slidesets/slidesets.html).

Bioavailability

With regard to oral bioavailability of medications during spaceflight, several factors, including alterations in drug dissolution rate in gastric juices, gastric emptying, gastric or intestinal absorption, hepatic first-pass metabolism, and intestinal blood flow, could all be influenced by microgravity. Other conditions related to early microgravity exposure could also influence bioavailability, including space motion sickness or changes in gut microflora and gut enzymatic release and distribution.[16,20,21,22] The observation of vitamin D deficiency in astronauts returning from long-duration missions on the international space station could suggest a reduction in absorption of orally administered vitamin D, although the effect of reduced exposure to sunlight while on board the international space station could also be a confounding factor.[23] Finally, transient reductions in appetite and bowel sounds have been documented upon initially reaching space.[24]

As indicated in Figure 2, increases in gastrointestinal transit time were documented in 2 astronauts who underwent a lactulose hydrogen breath test 38 days before launch and during extended-duration spaceflight. Gastrointestinal transit time increased during flight days 30, 54, and 88 and remained elevated 6 days after landing and recovery.[10]

Figure 2. Gastrointestinal transit time during long duration spaceflight.
From Health Human Countermeasures Element, Human Research Program, National Aeronautics and Space Administration (NASA). Evidence Book. Risk of Therapeutic Failure Due to Ineffectiveness of Medication. Houston, Tx: NASA; 2008. Available at: http://humanresearch.jsc.nasa.gov/elements/smo/docs/EB_2008/HRP_EviBook08_Ch21_Pharmacology_Report.pdf

In a small study involving 5 astronauts from 3 shuttle missions, acetaminophen was administered (650 mg as two 325-mg tablets orally). Salivary samples rather than blood sample were analyzed to determine the pharmacokinetics of the drug during ground-based testing and during flight. A decrement in absorption of acetaminophen was observed in space compared with ground based testing, as noted by a consistently lower maximum salivary concentration (Cmax)and greater time to reach peak concentration (Tmax) in the test group[25] (Table 4).Moreover, salivary concentrations of acetaminophen varied greatly among individual astronauts when measured over several flight days; the reasons for this are unclear, but factors may include changes in gut motility, gut absorption, and space motion sickness.

Table 4. Absorption Parameters of Acetaminophen[26]

Participant Cmax: Peak Concentration (mg/mL) Tmax: Time to Reach Peak (h)
  Control In-flight Control In-flight
1 9.6 6.4 0.5 1.1 (MD 4)
2 8.9 6.1 0.5 1.0 (MD 4)
3 9.8 14.1 0.5 1.0 (MD 3)
4 12.6 14.8 0.5 ≤0.25 (MD 2)
5 13.0 15.6 0.5 ≤0.25 (MD 2)
MD = mission day


In a series of similar experiments involving 12 astronauts evaluated over 7 shuttle flights, salivary acetaminophen Tmax was similarly extended. during flight, along with a concomitant reduction in the Cmax. However, Cmax seemed to increase on flight days 2 and 3, again reflecting interindividual variability in drug pharmacokinetics during flight. Overall, these preliminary data on oral acetaminophen pharmacokinetics suggested that drug absorption may be affected to varying degrees during short-term exposure to microgravity.[26] Whether pharmacokinetic disposition would return to normal after acclimatization to microgravity is unknown; the effects of prolonged microgravity exposure on drug pharmacokinetics are even more speculative at this time.

The data presented also do not address another important aspect of drug therapy: how the human body responds to a drug (pharmacodynamics). In the case of acetaminophen, would an astronaut achieve the same degree of headache relief or fever reduction in microgravity as when he or she is on earth? Also, is the threshold for drug toxicity the same in microgravity, which would also guide drug dosage? Again, no data current exist to provide a basis for clinical recommendations.

The pharmacokinetics of the combination of oral scopolamine and dextroamphetamine (0.4 mg/5mg) was used by astronauts to combat space motion sickness before being replaced by intramuscular promethazine injections during a space shuttle mission in 1989.[27] The pharmacokinetics of the earlier combinationwere examined in a small sample of astronauts.[28] Participants ingested a single capsule containing 0.4 mg scopolamine and 5 mg dextroamphetamine orally twice during ground-based pharmacokinetic studies and once during spaceflight. Salivary concentrations of both drugs were obtained to determine pharmacokinetics. The preflight differences in pharmacokinetics for scopolamine were minimal, but large interindividual variability was observed during flight. Owing to the limited number of participants when the initial report was filed, firm conclusions cannot be made regarding the pharmacokinetic disposition of scopolamine in space. However, like acetaminophen, clear differences were observed between the in-flight and ground-based experiments. This may be due in part to the fact that oral scopolamine has a poor absorption profile even in the absence of microgravity; however, other physiologic factors that are altered during spaceflight may also influence the disposition of scopolamine in space as also may have been the case for acetaminophen.

In a more recent ground-based animal study, the pharmacokinetics of oral procainamide were studied in mice who underwent hindlimb suspension. This model is accepted as producing many of the physiologic effects of microgravity on whole-body physiology in rodents.[29,30] After 24 hours of hindlimb suspension, procainamide 150-250 mg/kg was administered via oral gavage to suspended and control mice; pharmacokinetics were determined at 1, 2, 3 and 6 hours after administration. The serum concentration of procainamide at 1 hour after administration was nearly 40% lower in suspended mice than in control mice; this difference was maintained at 2 and 3 hours but was no different at 6 hours. The half-life of procainamide was nearly 55% longer in suspended mice, suggesting a possible effect of hindlimb suspension on drug elimination. No meaningful differences in the primary metabolite of procainamide, N-acetylprocainamide (NAPA), were observed.[31]

Taken together, the human and rodent data on oral dosage forms of medication and differences in their pharmacokinetics during spaceflight suggest that the oral route may not be the ideal mode of drug administration in space. However, substantially more data need to be collected on a series of medications to definitively determine whether the oral route should be avoided for drug administration.

Volume of Distribution

Cephalad fluid shifts, redistribution of fluid out of the central compartment, and fluid decreases due to prelaunch intake restrictions, along with losses due to space motion sickness and diuresis, produce total body water and plasma volume losses upon entry into space. (Figure 3).[32,33,34]

Figure 3. Cephalad fluid shifts due to microgravity exposure.
From the Physiology Slide Set of the American Society of Gravitational and Space Biology (http://asgsb.org/slidesets/slidesets.html).

Tissue binding of medications can be altered because of protein loss secondary to muscle and tissue atrophy,[3,4] redistribution of plasma proteins out of the central compartment,[33] alterations in blood lipid levels,[35] or reduced erythrocyte production.[36,37] Thus, volume losses coupled with reduced tissue binding could alter the distribution of a medication throughout the body, which could influence therapeutic and toxic effects. In-flight data documenting altered pharmacokinetics due to 1 or more of these factors are not available.

However, the possibility that fluid redistribution contributes to altered pharmacokinetics has been suggested by a ground-based simulation of microgravity utilizing head-down tilt bed rest, a technique that can produce many of the physiologic effects of exposure to microgravity in humans.[30] In a study of 4 healthy volunteers, 0.5 mg/kg of indocyanine green (ICG), whose metabolism depends on hepatic blood flow, was administered on 5 occasions: twice during ambulatory control periods and 3 times during a 10-day antiorthostatic bed rest period (days 2, 5, and 8). Clearance of ICG was reduced during bed rest (432.01 mL/min on day 8) compared with during ambulation (803.68 mL/min).[38]

In a similar study, the pharmacokinetics of lidocaine -- which, like ICG, is dependent on hepatic blood flow for metabolism -- were determined in 8 healthy men during ambulatory (days 1 and 7) and an antiorthostatic bed rest period of 4 days (days 2 through 5). Lidocaine, 1 mg/kg body weight, was administered at 8 am on days 1 to 5 and day 7 for determination of pharmacokinetics. In contrast to the ICG study, however, the clearance of lidocaine seemed to be increased during bed rest, from 8.24 ± 3.22 mL/kg/min to 11.63 ± 3.00 mL/kg/min.[39] The disparate findings of these ground-based studies only suggest that the microgravity model of antiorthostatic bed rest produces changes in drug metabolism. A specific mechanism cannot be ascertained from these data, nor can the actual microgravity effect be predicted. However, the fact that the pharmacokinetics of even a low-therapeutic-index drug may be altered during spaceflight is of some concern.

Clearance

Microgravity could affect drug elimination via the kidneys, the skin, or the pulmonary route. As suggested by antiorthostatic bed rest studies, it could also affect liver metabolism of drugs owing to changes in perfusion secondary to the cephalad redistribution of blood. No data on human hepatic drug metabolism in space are available. However, several metabolic changes have been observed during human spaceflight, and they may imply that enzymatic activity in space is altered owing to the influence of such factors as changes in plasma adrenocorticotropic hormone, thyrotropin, plasma renin activity, and antidiuretic hormone levels.[40] Some data in rats sent into space also suggest that hepatic metabolism changes in microgravity. For example, liver lipids; glycogen; hepatic enzymes involved in cholesterol, glycerolipid, and sphingolipid biosynthesis; and other enzymatic processes were measured in rats on Spacelab 3 for 7 days. Various differences in these parameters compared with ground-based control animals were documented. Of particular note, a 50% reduction in hepatic cytochrome P450 content was observed in animals on Spacelab, as was an elevation in hepatic glycogen content and alterations in lipid metabolism at several enzymatic steps.[41] A similar rat experiment involving 14 days of spaceflight yielded analogous results, but another 14-day rodent flight showed conflicting results. Thus, a definitive conclusion regarding hepatic metabolism alterations by microgravity has yet to be reached.

Nevertheless, a few ground-based animal studies have also suggested that microgravity might influence certain hepatic metabolic pathways -- specifically, oxidative metabolism. In one of these studies, antipyrine, a drug used as a probe for hepatic oxidative function (specifically CYP1A2) and total body water, was administered to hindlimb-suspended rats and controls over 7 days. Antipyrine, 20 mg/kg, administered as a single oral or intravenous dose, was evaluated at baseline (day -1) and on study days 1, 3, and 7 days after the initiation of suspension. Total-body clearance of antipyrine was significantly elevated in the suspended rats for both the oral and intravenous dosing groups on study days 3 and 7; clearance was elevated in the oral antipyrine group after day 1 as well. This study suggested that even short periods of microgravity exposure can affect this oxidative metabolic pathway in the liver.[42] In another study involving hindlimb-suspended rats, isolated perfused livers excised from suspended animals showed a 50% decrease in CYP2E1 activity compared with nonsuspended controls, which suggested a similar observation in rats sent into space and suspended animals: That is, microgravity exposure alters hepatic metabolism, which could in turn affect drug metabolism.[43]

The effect of microgravity on oxidative metabolic pathways may differ from phase 2 metabolic pathways, however. In another series of hindlimb suspension experiments, no differences were observed in the pharmacokinetics of acetaminophen compared with control animals after 7 days of suspension.[44] Although these observations seem to contradict the human data on acetaminophen pharmacokinetics in microgravity, acetaminophen was administered intravenously in this rat experiment; thus, any effect of microgravity-like conditions on gastric absorption, which may be a major contributor to altered pharmacokinetic disposition of acetaminophen in space, were avoided.

Other Synergistic Factors Influencing Drug Efficacy in Microgravity

Inhaled drug delivery. Microgravity may also influence the efficiency of aerosol drug delivery. Anecdotal reports from Apollo astronauts suggested that standard spray bottles did not work well in microgravity, although the reasons were not officially documented. In a series of parabolic flights in 1990, several aerosol formulations were evaluated for spray dispersion and total drug quantity dispensed in transient microgravity conditions compared with ground-based control experiments.[45] The medications evaluated included benzocaine 20%, an albuterol inhaler, phenylephrine 0.25% pump nasal spray, and oxymetazoline 0.05% nasal spray with a standard spray (squeeze) bottle. High-speed photography was used to capture the spray data under experimental and control conditions. Compared with ground-based controls, parabolically flown benzocaine spray and albuterol inhalers seemed to function normally. The phenylephrine spray functioned as expected when the container was full, but as the container emptied, spray consistency was substantially affected, including the delivery of larger droplets. The standard spray bottle, which contained oxymetazoline, functioned well when full, but like the pump spray bottle, it performed progressively worse as it became empty. Indeed, the standard spray bottle performed the worst of all the aerosol delivery methods during flight. The pump spray and standard spray bottles probably began to fail as they emptied owing to the shift of fluid toward the top of the bottles during microgravity conditions. The results of this limited experiment suggested that containers that deliver an aerosol under pressurization may be preferred for aerosol drug delivery in space, but the issue of container volume and its effect on spray efficiency in microgravity for non-pressurized aerosol drug delivery should be further explored.(The spray formulation -- suspension or solution -- was not specifically addressed as another potential variable affected by microgravity in this experiment.)

Whether differences in spray dispersion could lead to therapeutic failure has not been documented, or evaluated. Consider, for example, whether nitroglycerin spray would work in a microgravity environment to deliver a dose sufficient to ameliorate anginal chest pain (that is, if preload reduction is even possible in the presence of cephalad fluid shifts during microgravity exposure!)

Drug formulation (dosage form) stability. In the past several years, the effect of microgravity and the general space environment on medication stability has begun to be questioned. Many factors can affect the stability of a medication, including humidity, temperature, pH, and radiation exposure (eg, electromagnetic radiation, such as visible light, and ionizing radiation, such as galactic cosmic radiation or solar particle events).[10] When medications are exposed to any or all of these factors, they are prone to degradation. Medications carried on the space shuttle traditionally have been recycled for use on future missions or are replaced only if used or if their expiration date has been reached. However, in a series of studies in which the stability of antibiotics, motion sickness medications and other selected dosage forms (tablets, suppositories, creams, ointments, and patches) were evaluated after spaceflight (space shuttle and 6-month sojourns on the International Space Station) and compared with ground-based controls, significant degradation was observed -- including discoloration or a decrease in the proportion of labeled active ingredients to amounts less than US Food and Drug Administration standards for shelf-life assurance, This was of particular concern for certain antibiotics, lidocaine, and promethazine.This reduced shelf life of medications after relatively short exposures to the space environment have important implications for mission planning, stowage, and medication stock turnover requirements -- not to mention concerns about drug efficacy and safety owing to altered drug potency and the accumulation of breakdown products in the formulation.

Pharmacodynamics. The majority of this review has focused on the potential for pharmacokinetic changes as a consequence of microgravity exposure. Whether pharmacodynamics -- the relationship of drug concentration to the intensity of its effect on the body -- are affected by microgravity is even less certain. However, ground-based animal studies suggest the potential for altered pharmacodynamics in space. In rats subjected to dehydration, the central nervous system depressant effects of desmethyldiazepam and phenobarbital were more pronounced.[46,47] These effects were not due to higher drug concentrations in the central nervous system or to obvious changes in receptor number or affinity. These observations could suggest that astronauts exposed to microgravity, who are relatively volume-contracted owing to fluid losses, could also experience altered drug pharmacodynamics. During crew medical debriefings, shuttle astronauts observed that promethazine was less likely to produce sedation in flight than when used on the ground,[27] suggesting that altered bioavailability, pharmacodynamics, or drug potency was at play during spaceflight. In addition, both physicians and astronauts have reported use of higher and more frequent doses of sleep or motion sickness medications on several space shuttle flights compared with what would be expected on the ground.[10]

Another pharmacodynamic issue in space may relate to microgravity-induced changes in microorganism growth, as opposed to physiologic changes to the body that influence drug response. For example, Salmonella grown on the space shuttle exhibited altered gene expression and enhanced virulence compared with ground-based control cultures.[48] Similar observations of altered growth or virulence and a shift in minimum inhibitory concentrations for antibiotic susceptibility have been documented for both Staphylococcus aureus and Escherichia coli cultures grown on the space shuttle and in the Russian Salyut program.[49,50,51,52] The results suggest microbial changes induced by microgravity exposure may change the pharmacodynamics of antibiotics. Would an infection occurring during spaceflight respond to a typical course of antibiotics?

Microgravity Environmental Variables

Pressurization. Suit, vehicle, and habitat pressurization are necessary prerequisites for survival in the extreme space environment and while exploring celestial bodies (eg, planets, moons, and asteroids) Pressurization conditions among these various "containment fields" will differ, especially relative to ambient sea-level pressure on earth. In studies conducted at high altitude on earth, where there is reduced barometric pressure and a lower partial pressure of oxygen (analogous to current spacesuit pressurization), changes in drug pharmacokinetics have been documented for meperidine, acetazolamide, prednisolone, furosemide, caffeine, and ICG. Many of the pharmacokinetic differences may be due to hypoxia-induced alterations in erythrocyte production and subsequent effects on drug binding to these cells.[53,54,55,56,57]

Circadian rhythm. Some spaceflight missions have required astronauts to undergo circadian shifting to permit 24-hour flight operations; however, the microgravity environment itself has also been shown to induce circadian rhythm disturbances in astronauts, including more wakefulness episodes and reduced slow-wave sleep during the final one third of a sleep episode. Moreover, sleep loss, decrements in performance and post-flight changes in rapid eye movement sleep have been documented as well.[58]

Chronopharmacokinetic studies have been reported for many drugs and have shown that the timing of drug administration over 24 hours can influence drug pharmacokinetics and pharmacodynamics. This is probably because multiple physiologic processes demonstrate chronoregulation.[59] Disruptions in the normal circadian rhythm, therefore, may change drug pharmacokinetics and represent another microgravity variable that requires further investigation to ascertain the importance of its effect on drug disposition in space.

Crew medical knowledge. There are very few physicians (or other healthcare providers) who are also astronauts. Therefore, the likelihood that a space mission crew will not having a healthcare provider flying with them during a mission is high. Limited medical training is provided to astronauts designated as crew medical officers during mission preparation,[60] but the general lack of medical background among crew members may contribute to polypharmacy or potentially inappropriate prescribing of medications if ground flight surgeons are not consulted about medical issues. Thus, the potential for drug misadventure in an environment that may influence drug disposition is compounded by the lack of medical expertise among astronauts.

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