This chapter covers the quantitative aspect of agonist activation: how the blood, and by extension the interstitial fluid, presents a pharmaceutical agent to the cell; quantification of drug concentration and tissue response; diffusion and elimination of an intracellular agent; statistical analysis of the tissue response; and the difficult problems associated with drug development. Because of the necessary role played by agonist receptors in this process, the background of some of the major receptor types is also included.

Membrane receptor proteins

Agonists initiate a cell response by binding to a receptor. Without trying to give a complete list of every kind of receptor, three of the major categories of receptors are the G-protein coupled receptors (GPCRs), the tyrosine kinase receptors, and nuclear receptors. GPCRs dominate cell activation using the temporally limited G-protein system. There are more than 800 GPCR proteins, and the complexity of their activation scheme is daunting. Tyrosine kinase receptors are activated by insulin and a variety of growth factors, and activate processes associated with the structural growth of cells and tissues. Nuclear receptors bind to hydrophobic hormones, steroids, thyroid hormones, etc., that do their work by initiating gene transcription. This section gives a brief overview of these receptor types, with the understanding that all of them have far more complexity than can be covered here. Recognizing the pivotal role these molecules play in linking the quantitative aspects of cell activation, pharmacokinetics, dose–response relations, intracellular diffusion, and data analysis of biological responses, it is appropriate that a general discussion of their functions is included.

Nothing happens without the expenditure of energy. Humans use the energy in ATP to drive all of the reactions in the body, either directly by using the energy of the phosphate bond between the second and third phosphates of ATP, or by siphoning energy from chemical and electrical gradients produced by ATP hydrolysis. Before ATP can be utilized it has to be produced. ATP is made anaerobically through glycolysis, and aerobically using oxidative phosphorylation in mitochondria. Once made, its concentration can be buffered in many cells through the creatine kinase reaction, with phosphocreatine contributing its phosphate to ADP to maintain the ATP concentration during periods of high energy expenditure. Energy expenditure is not solely dependent on the supply of ATP, however. The removal of the products of energy use, especially inorganic phosphate, are as important to function as the supply of ATP. The different components of ATP production and buffering, and inorganic phosphate removal, directly influence human athletic performance. The different phases that phosphocreatine, glycolysis, and oxidative phosphorylation control are graphically demonstrated in the rate of running in world track records as a function of the log of the distance run.

Energetics of human performance

The most interesting races on the track take place when someone goes out fast, takes an early lead, and then is run down by the field. Will the leader hang on, or will someone catch up with a strong finishing kick? The factors involved in human performance include ability, training and motivation. For most people, psychological limitations play a major role in reducing performance. Training and experience produce the confidence needed to reach the fastest time possible. World class runners are “world class” precisely because they have overcome the psychological limitations on performance, and their racing is only limited by physiological factors. Physiological factors include some elements that can be controlled, like rest and diet, and others that cannot, like leg length. The variable elements ultimately involve energy. How much energy is available to drive the myosin ATPase reactions that move muscle? At what rate are the energy supplies used? Can the energy supplies be increased to prolong top flight performance? The starting point for answers to these questions is to look at the relation of the rate of running of world track records as a function of the race distances in Figure 4.1.

One of the hallmarks of physiological systems is homeostasis. Homeostatic systems maintain a steady-state set point over time using negative feedback. Negative feedback activates recovery processes when there is deviation from the set point. While some states are always tightly maintained, some changes can occur during the lifetime of the individual. These changes take two forms: adjustment of the homeostatic set point, or a step change to a new set point by a positive feedback mechanism. Positive feedback systems do not use a recovery process to return to the original set point. New negative feedback processes now keep the organism at the new set point. A set point must have an energy minimum, such that small variations from the minimum create a driving force returning the system to the set point. Energy minima occur at multiple levels, from atoms to organisms. For systems in transition the energy profile may exhibit metastable states between two large minima. Metastable states offer temporal buffering of state changes. In enzymes and ion channels the energy barriers between the external states and internal metastable states and the depth of the metastable state control the rate of the metabolic reaction or ionic current. Complex analytical methods such as catastrophe theory provide insight into state transitions. Catastrophe theory models changes in space, not time, with state transitions occurring whenever the state variable reaches particular values in parameter space. The feedback systems that maintain homeostasis are deterministic far from equilibrium, but become chaotic when transitions are near equilibrium. Not all catastrophic transitions are fatal, but for living systems catastrophes can lead to death in two ways, homeostatic instability or global thermal equilibrium. These two modes of death correspond to having too much ambient energy or too little ambient energy. This leads to the Goldilocks problem, in which ambient energy will be too high, too low or just right. Since life must be a continuum, a system cannot leave the viable energy range without extinction, leading to restrictions in modeling evolution. All living systems will have feedback systems, both negative and positive, that keep them away from either of the life–death transitions. Fractal systems regularly transition between deterministic and chaotic states. Conditions with multiple fractal inputs can have significant variability around a set point using allometric regulation. Narrowing of the fractal distribution has been associated with pathological states and increased risk of death.

Thank you for the time and effort you have made to read this book. I hope you have found it profitable. Like every science textbook, it reflects the work of thousands, as every idea in this book was discovered by somebody. Discovering something new, even if it is just new to you, is very satisfying. When I am working on a new idea, I see it as a many-sided physical object in my mind, changing in shape, color and texture, rotating in all directions, until I can see the edges are parallel. When they are, I have the answer. I don’t know why my mind works like this, but it does. Sometimes the problem percolates for days or weeks, but sometimes it can take on-and-off thinking for years. Looking for confirmation of an idea means thinking up original experiments and making them work. When you do a novel experiment, you have to have so much trust in and understanding of your equipment that if you get an unusual result, you can believe the result is correct because you know the equipment is working properly, and therefore the hypothesis is true. This moment of discovery of something really original is thrilling: you know that you know something new, you know that it is important, and you know that no one else in the whole world knows it. It is a great gift to have that flash of insight when an experiment confirms an original idea. In over 35 years in science, I have been lucky enough to have this happen exactly four times. Each time, it is a golden moment, a glimpse of nature never seen before. In the spirit of discovery, I have climbed a hill to the west, away from a settled valley, and seen the dawn illuminate a new, unknown valley before me. Many scientists make that same climb, find a new valley and settle there, plowing the fields, building the towns, and leading others to the benefits of their discovery. Others, and I count myself lucky to be one of them, go into that new valley, stay for a while, and whether others come behind or not, set their restless mind on the new, undiscovered land over that next hill.