Pharmacokinetics and Pharmacodynamics of Abused Drugs (Edited by Steven B. Karch, MD, FFFLM)

This volume discusses pharmacokinetics and pharmacodynamics. Chapters 1 through 4 discuss aspects of pharmacokinetics. Chapters 5 through 8 discuss aspects of pharmacodynamics.

Pharmacokinetics is defined as the study of the quantitative relationship between administered doses of a drug and the observed plasma/blood or tissue concentrations. The field of pharmacokinetics is concerned with drug absorption, distribution, biotransformation, and excretion or elimination. These processes, in addition to the dose, determine the concentration of drug at the effector or active site and, therefore, the intensity and duration of drug effect.

The practice of pharmacokinetics has been used in clinical medicine for many years in order to optimize the efficacy of medications administered to treat disease. Through a consideration of pharmacokinetics, physicians are able to determine the drug of choice, dose, route, frequency of administration, and duration of therapy in order to achieve a specific therapeutic objective. In the same manner, study of the pharmacokinetics of abused drugs aids investigators in addiction medicine, forensic toxicology, and clinical pharmacology in understanding why particular drugs are abused, factors that affect their potential for abuse, how their use can be detected and monitored over time, and also provides a rational, scientific basis for treatment therapies.

Pharmacodynamics is the study of the physiological and behavioral mechanisms by which a drug exerts its effects in living organisms. An effect is initiated by the drug binding to receptor sites in a cell’s membrane, setting in motion a series of molecular and cellular reactions culminating in some physiological (e.g., opioid-induced analgesia) or behavioral (e.g., alcohol-induced impairment) effect. Drugs typically have multiple effects. For example, a benzodiazepine will produce its primary anxiolytic effect, but may also cause side effects of sedation and impaired performance.

The question of the behavioral effects of abused drugs has been the focus of research by behavioral pharmacologists for many decades. Because of the widespread use of psychoactive drugs throughout society, employers have become increasingly concerned about drugs in the workplace and the potential for impaired job performance and onsite drug-related accidents. There are now computerized tests that employers can use to aid in the detection of impaired employees. Some drugs of abuse also produce characteristic effects on the visual system, and for this reason, devices that detect eye movement and function are also being tested for their ability to predict drug ingestion and potential impairment in the workplace.

Knowledge of both pharmacokinetics and pharmacodynamics is central to an understanding of drug abuse and its treatment.

 

INTRODUCTION

Pharmacokinetics is defined as the study of the quantitative relationship between administered doses of a drug and the observed plasma/blood or tissue concentrations.1 The pharmacokinetic model is a mathematical description of this relationship. Models provide estimates of certain parameters, such as elimination half-life, which provide information about basic drug properties. The models may be used to predict concentration vs. time profiles for different dosing patterns.

The field of pharmacokinetics is concerned with drug absorption, distribution, biotransformation, and excretion or elimination. These processes, in addition to the dose, determine the concentration of drug at the effector or active site and, therefore, the intensity and duration of drug effect. The practice of pharmacokinetics has been used in clinical medicine for many years in order to optimize the efficacy of medications administered to treat disease. Through a consideration of pharmacokinetics, physicians are able to determine the drug of choice, dose, route, frequency of administration, and duration of therapy in order to achieve a specific therapeutic objective. In the same manner, study of the pharmacokinetics of abused drugs aids investigators in addiction medicine, forensic toxicology, and clinical pharmacology in understanding why particular drugs are abused, factors that affect their potential for abuse, and how their use can be detected and monitored over time, and also provides a rational, scientific basis for treatment therapies.

TRANSFER ACROSS BIOLOGICAL MEMBRANES

The processes of absorption, distribution, biotransformation, and elimination of a particular substance involve the transfer or movement of a drug across biological membranes. Therefore, it is important to understand those properties of cell membranes and the intrinsic properties of drugs that affect movement. Although drugs may gain entry into the body by passage through a single layer of cells, such as the intestinal epithelium, or through multiple layers of cells, such as the skin, the blood cell membrane is a common barrier to all drug entry and therefore is the most appropriate membrane for general discussion of cellular membrane structure. The cellular blood membrane consists of a phospholipid bilayer of 7- to 9-nm thickness with hydrocarbon chains oriented inward and polar head groups oriented outward. Interspersed between the lipid bilayer are proteins, which may span the entire width of the membrane permitting the formation of aqueous pores.2 These proteins act as receptors in chemical and electrical signaling pathways and also as specific targets for drug actions.3 The lipids in the cell membrane may move laterally, conferring fluidity at physiological temperatures and relative impermeability to highly polar molecules. The fluidity of plasma membranes is largely determined by the relative abundance of unsaturated fatty acids. Between cell membranes are pores that may permit bulk flow of sub-stances. This is considered to be the main mechanism by which drugs cross the capillary endo-thelial membranes, except in the central nervous system (CNS), which possesses tight junctions that limit intercellular diffusion.3

Physicochemical properties of a drug also affect its movement across cell membranes. These include its molecular size and shape, solubility, degree of ionization, and relative lipid solubility of its ionized and non-ionized forms. Another factor to consider is the extent of protein binding to plasma and tissue components. Although such binding is reversible and usually rapid, only the free unbound form is considered capable of passing through biological membranes.

Drugs cross cell membranes through passive and active or specialized processes. Passive movement across biological membranes is the dominant process in the absorption and distribution of drugs. In passive transfer, hydrophobic molecules cross the cell membrane by simple diffusion along a concentration gradient. In this process there is no expenditure of cellular energy. The magnitude of drug transfer in this manner is dependent on the magnitude of the concentration gradient across the membrane and the lipid water partition coefficient. Once steady state has been reached, the concentration of free (unbound) drug will be the same on both sides of the membrane. The exception to this situation is if the drug is capable of ionization under physiological conditions. In this case, concentrations on either side of the cell membrane will be influenced by pH differences across the membrane. Small hydrophilic molecules are thought to cross cell membranes through the aqueous pores.4 Generally, only unionized forms of a drug cross biological membranes due to their relatively high lipid solubility. The movement of ionized forms is dependent on the pKa of the drug and the pH gradient. The partitioning of weak acids and bases across pH gradients may be predicted by the Henderson Hasselbalch equation. For example, an orally ingested weakly acidic drug may be largely unionized in the acidic environs of the stomach but ionized to some degree at the neutral pH of the plasma. The pH gradient and difference in the proportions of ionized/non-ionized forms of the drug promote the diffusion of the weak acid through the lipid barrier of the stomach into the plasma.

Water moves across cell membranes either by the simple diffusion described above or as the result of osmotic differences across membranes. In the latter case, when water moves in bulk through aqueous pores in cellular membranes due to osmotic forces, any molecule that is small enough to pass through the pores will also be transferred. This movement of solutes is called filtration. Cell membranes throughout the body possess pores of different sizes; for example, the pores in the kidney glomerulus are typically 70 nm, but the channels in most cells are <4 nm.2

The movement of some compounds across membranes cannot be explained by simple diffusion or filtration. These are usually high-molecular-weight or very lipid soluble substances. Therefore, specialized processes have been postulated to account for the movement. Active processes typically involve the expenditure of cellular energy to move molecules across biological membranes. Characteristics of active transport include selectivity, competitive inhibition, storability, and movement across an electrochemical or concentration gradient. The drug complexes with a macromolecular carrier on one side of the membrane, traverses the membrane, and is released on the other side. The carrier then returns to the original surface. Active transport processes are important in the elimination of xenobiotic. They are involved in the movement of drugs in hepatocytes, renal tubular cells, and neuronal membranes. For example, the liver has four known active transport systems, two for organic acids, one for organic bases, and one for neutral organic compounds.2 A different specialized transport process is termed “facilitated diffusion.” This transport is similar to the carrier-mediated transport described above except that no active processes are involved. The drug is not moved against an electrochemical or concentration gradient and there is no expenditure of energy. A biochemical example of such transport is the movement of glucose from the gastrointestinal tract through the intestinal epithelium.

Absorption

In order for a drug to exert its pharmacological effect, it must first gain entry into the body, be absorbed into the bloodstream, and transported or distributed to its site of action. This is true except in the case of drugs that exert their effect locally or at the absorption site. The absorption site, or port of entry, is determined by the route of drug administration.

Routes of administration are either enteral or parenteral. The former term denotes all routes pertaining to the alimentary canal. Therefore, sublingual, oral, and rectal are enteral routes of administration. All other routes, such as intravenous, intramuscular, subcutaneous, dermal, vaginal, and intraperitoneal, are parenteral routes.

Absorption describes the rate and extent to which a drug leaves its site of administration and enters the general circulation. Factors that, therefore, affect absorption include the physicochemical properties of the drug that determine transfer across cell membranes as described earlier; formulation or physical state of the drug; site of absorption; concentration of drug; circulation at absorption site; and area of absorbing surface.




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