Evidence Report: Risk of Therapeutic Failure Due to Ineffectiveness of Medication Virginia E. Wotring Ph. D. Universities Space Research Association, Houston, TX Human Research Program Human Health Countermeasures Element Approved for Public Release: August 02, 2011 National Aeronautics and Space Administration Lyndon B. Johnson Space Center Houston, Texas 2 TABLE OF CONTENTS I. PRD RISK TITLE: RISK OF THERAPEUTIC FAILURE DUE TO INEFFECTIVENESS OF MEDICATION ..................................................................... 6 II. EXECUTIVE SUMMARY .............................................................................................. 6 III. INTRODUCTION ............................................................................................................ 7 IV. PHARMACOK INETICS ............................................................................................... 11 A. Absorption ...................................................................................................................... 11 1. Evidence ................................................................................................................................ 16 2. Risk ........................................................................................................................................ 20 3. Gaps ....................................................................................................................................... 21 B. Distribution ..................................................................................................................... 21 1. Evidence ................................................................................................................................ 26 2. Risk ........................................................................................................................................ 27 3. Gaps ....................................................................................................................................... 28 C. Metabolism ..................................................................................................................... 28 1. Evidence ................................................................................................................................ 30 2. Risk ........................................................................................................................................ 32 3. Gaps ....................................................................................................................................... 32 D. Excretion ......................................................................................................................... 33 1. Evidence ................................................................................................................................ 34 2. Risk ........................................................................................................................................ 34 3. Gaps ....................................................................................................................................... 35 V. PHARMACODYNAMICS............................................................................................. 35 E. Central Nervous System ................................................................................................... 35 1. Evidence ................................................................................................................................ 38 2. Risk ........................................................................................................................................ 43 Evidence Report: Risk of Therapeutic Failure Due to Ineffectiveness of Medication 3. Gaps ....................................................................................................................................... 43 B. Cardiovascular System ..................................................................................................... 44 1. Evidence ................................................................................................................................ 46 2. Risk ........................................................................................................................................ 49 3. Gaps ....................................................................................................................................... 49 C. Gastrointestinal System ................................................................................................... 50 1. Evidence ................................................................................................................................ 55 2. Risk ........................................................................................................................................ 62 3. Gaps ....................................................................................................................................... 62 D. Skeletal System................................................................................................................ 63 1. Evidence ................................................................................................................................ 64 2. Risk ........................................................................................................................................ 67 3. Gaps ....................................................................................................................................... 67 E. Muscular System ............................................................................................................. 68 1. Evidence ................................................................................................................................ 68 2. Risk ........................................................................................................................................ 70 3. Gaps ....................................................................................................................................... 70 F. Immunological System ..................................................................................................... 71 1. Evidence ................................................................................................................................ 72 2. Risk ........................................................................................................................................ 74 3. Gaps ....................................................................................................................................... 74 G. Multisystem Radiation Effects .......................................................................................... 75 1. Evidence ................................................................................................................................ 75 2. Risk ........................................................................................................................................ 80 4 Evidence Report: Risk of Therapeutic Failure Due to Ineffectiveness of Medication 3. Gaps ....................................................................................................................................... 80 VI. RISK IN CONTEXT OF EXPLORATION MISSION OPERATIONAL SCENARIOS ................................................................................................................... 81 VII. COMPUTER-BASED SIMUL ATION INFORMATION ........................................... 82 VIII. GAPS ................................................................................................................................ 83 IX. CONCLUSION ............................................................................................................... 83 X. REFERENCES ................................................................................................................ 83 XI. APPENDIX OF ABBREVIATIONS ........................................................................... 111 5 Evidence Report: Risk of Therapeutic Failure Due to Ineffectiveness of Medication I. PRD Risk Title: Risk of Therapeutic Failure Due to Ineffectiveness of Medication Description: Given that terrestrial medical practices, including therapeutic medications, must be used as the basis for therapeutic use on missions, there is a possibility that medications used will be less than ideal for the actual circumstances encountered on missions. II. Executive Summary It is possible that the actions of administered drugs on crewmembers during spaceflight are different from their actions on Earth, but even after more than 40 years of spaceflight experience, most questions about medication use during missions remain unanswered. Use of medications with insufficient knowledge about their actual activities may result in inadequate treatment and may even reduce performance and well-being in some circumstances. There is evidence that this has already occurred during and immediately after spaceflights. The spaceflight pharmaceutical activity knowledge base must be improved to enable flight surgeons and crewmembers to make better-informed decisions about using pharmaceuticals during flight. The spaceflight environment induces changes in human physiology, and these changes have been the subject of much study over the past few decades. These