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Pharmacology
Pharmacology SJ Enna, University of Kansas Medical Center, Kansas, KS, USA DB Bylund, University of Nebraska Medical Center, Omaha, NE, USA ã 2014 Elsevier Inc. All rights reserved.
Introduction Pharmacodynamics Pharmacokinetics Issues in Modern Pharmacology References
1 1 2 2 2
Introduction Pharmacology, the science of drugs, was established as an independent scientific discipline in the nineteenth century. This came about primarily because of developments in chemistry which made possible the isolation and chemical characterization of individual constituents from plants and plant extracts that had for centuries been used as treatments for a variety of disorders (Enna and Norton, 2012). The identification by Fredrich Serturner in 1804 of morphine as an active constituent of opium, an exudate of the opium poppy, is one of the first examples of systematic, pharmacological research. Another is the extraction and purification of salicin from the bark of the willow tree by Johann Buchner, Henri Leroux and others in the late 1820s. A powder made from willow bark had for thousands of years been used for treating fever and pain. The early pharmacological experiments with salicin revealed that it is converted in the body to salicylic acid, which is largely responsible for the therapeutic effects. Once the chemical structures of morphine and salicin were determined it was possible to synthesize and test chemical analogs in an effort to improve safety and efficacy. This resulted in the development of many useful drugs, such as the morphine analog pentazocine, and acetylsalicylic acid, or aspirin, a chemical relative of salicin. By 1846 the main two branches of pharmacology were establish by Rudolf Buchheim (Starke, 1998). Buchheim was the first to conduct research aimed at determining both how, and to what extent, drugs alter physiological function (pharmacodynamics), and how, and to what extent, they are altered by the body (pharmacokinetics). The science of pharmacology evolved rapidly as advances in the chemical and biological sciences led to the development of new techniques that became essential for drug discovery and development. Pharmacology includes what is known about the chemical properties of drugs, their beneficial and harmful biological effects, and their therapeutic uses. The word drug encompasses any agent used for therapeutic purposes, including gene therapy. Today, pharmacologists study not only the mechanisms responsible for the action of established therapeutics, but also define the sites of action of drug candidates and identify potential therapeutic targets for new drug development.
Pharmacodynamics Pharmacodynamics is the subdiscipline of pharmacology concerned with the way a drug affects the body, with pharmacodynamic studies aimed primarily at defining the mechanisms responsible for the therapeutic and toxic effects of therapeutic agents. Such information is critical for understanding the clinical response to drugs and for designing safer and more effective medications. Pharmacodynamic studies indicate that most drugs act by attaching to specific cellular components to activate or inhibit biochemical functions (Yamamura et al., 1985). Typically, the drug binding site is a neurotransmitter or hormone receptor, a transporter, structural protein or enzyme in either the patient or an invading organism. Commonly, drug attachment to its binding site results in activation or inhibition of the receptor, transporter or enzyme, thereby augmenting or reducing physiological processes. Activators are referred to as agonists and inhibitors as antagonists for the target site. Data supporting the selectivity of the drug receptor concept includes the finding that chemical isomers evoke different pharmacological responses. Isomers are compounds with the same molecular formula, but a slightly different configuration. That is, while the atoms in chemical isomers are identical and are linked in the same way, the spatial orientation of one or more of them differs between the two forms. In the early twentieth century John Langley noted that most of the pharmacological responses to hyoscyamine are mediated by the l-isomer, with the d-isomer being virtually inactive. From this he concluded that only a cellular component with a high degree of selectivity for chemical structures, such as a specific binding, or receptor, site could make such a subtle distinction between two otherwise identical compounds. In 1933 A.J. Clark summarized the evidence supporting receptors as the site of drug action (Clark, 1933). Among the pharmacological principles he delineated is the importance of dose-response studies in defining drug actions, thereby providing a mathematical framework for quantifying pharmacodynamic data.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.07821-1
1
2
Pharmacology
Pharmacokinetics Pharmacokinetics is the subdiscipline of pharmacology concerned with the way the body affects the drug. This includes studies of the absorption, metabolism and excretion of the chemical agent. Such work is vital for determining whether the drug reaches the desired site of action and remains there for a sufficient period of time, and at the necessary concentration, to induce the intended effect. Drug access to, and residency at, the target site are not easy to attain as humans have evolved multiple ways to prevent foreign substances from gaining entry to the body and to dispose of such agents once they reach the blood. Once a drug reaches its target, a sufficient quantity must accumulate to activate or inhibit the site. This is a function of the dose administered, the extent to which the compound is absorbed and excreted, and its affinity, or attraction, for the target. Thus, while an agent may be capable of reaching the systemic circulation and penetrating into the target organ and tissue, to obtain the desired response it may be necessary to administer large quantities if its absorption is limited, its metabolism and excretion are rapid, or its affinity for the receptor is low. To be useful clinically, most drugs must be active for several hours following administration. The duration of drug action is directly related to the amount of time the agent is located at the target in the necessary quantity. The cytochrome P450 family is one of the major classes of enzymes responsible for the metabolism of many drugs and endogenous substances. Drugs and their metabolites are most often excreted by the kidneys and gastrointestinal tract. Pharmacokinetic data are crucial for determining drug dosages and regimens. If a drug is absorbed primarily by active transport there is a potential for adverse drug interactions if it is administered with another compound that attaches to the same transporter. In this case the two substances will compete for the limited number of transporter proteins, resulting in a decline in the absorption of one or the other, or both. Similarly, a drug that is metabolized by a particular cytochrome P450 enzyme may, if present in sufficient concentrations, slow or enhance the metabolism of other drugs and endogenous substances. Such effects on drug metabolizing enzymes can lead to a dramatic change in the blood levels of other substances, resulting in side effects, toxicities, or a decrease in effectiveness. Given these possibilities, pharmacokinetic data are crucial for maximizing drug safety and efficacy.
Issues in Modern Pharmacology Pharmacology is an integrative discipline, encompassing all of the topics covered in this reference module, including physiology, cell biology, genetics, microbiology, toxicology, immunobiology, pathophysiology, medicinal chemistry and virology. Pharmacology research is continuously driven by technical advances in the chemical and biological sciences. With the exception of analytical techniques, the methods employed for pharmacokinetic studies have changed little over the years. In contrast, pharmacodynamic investigations, particularly in the early stages of the drug discovery process, have become increasingly more focused on drug actions at the molecular level, with less attention paid initially to the overall biochemical and physiological effects of test agents. It is now believed that this overemphasis on molecular targeting is responsible, in part, for the decline in the discovery of new drugs even though research expenditures have continued to increase. For this reason, efforts are underway to establish greater balance in the drug discovery process, incorporating more whole animal and physiological testing to compliment the molecular screens to increase the possibility of serendipitous discoveries, which have historically been the hallmark of drug discovery. Pharmacological data obtained from whole animal, isolated organ, and molecular studies are presented and discussed in this module. Regardless of the techniques employed, or the order of their use, pharmacological research has been, and will remain, a key element of the biomedical research enterprise as long as there is a need for the discovery and development of new medications.
References Clark AJ (1933) The mode of action of drugs on cells. Baltimore, MD: Williams and Wilkins. Enna SJ and Norton S (2012) Herbal supplements and the brain: Understanding their health benefits and hazards. Upper Saddle River, NJ: FT Press. Starke K (1998) A history of Naunyn-Schmiedeberg’s Archives of Pharmacology. Naunyn-Schmiedeberg’s Archives of Pharmacology 358: 1–109. Yamamura HI, Enna SJ, and Kuhar MJ (1985) Neurotransmitter receptor binding, 2nd edn. New York, NY: Raven Press.
Introduction Pharmacodynamics Pharmacokinetics Issues in Modern Pharmacology References
1 1 2 2 2
Introduction Pharmacology, the science of drugs, was established as an independent scientific discipline in the nineteenth century. This came about primarily because of developments in chemistry which made possible the isolation and chemical characterization of individual constituents from plants and plant extracts that had for centuries been used as treatments for a variety of disorders (Enna and Norton, 2012). The identification by Fredrich Serturner in 1804 of morphine as an active constituent of opium, an exudate of the opium poppy, is one of the first examples of systematic, pharmacological research. Another is the extraction and purification of salicin from the bark of the willow tree by Johann Buchner, Henri Leroux and others in the late 1820s. A powder made from willow bark had for thousands of years been used for treating fever and pain. The early pharmacological experiments with salicin revealed that it is converted in the body to salicylic acid, which is largely responsible for the therapeutic effects. Once the chemical structures of morphine and salicin were determined it was possible to synthesize and test chemical analogs in an effort to improve safety and efficacy. This resulted in the development of many useful drugs, such as the morphine analog pentazocine, and acetylsalicylic acid, or aspirin, a chemical relative of salicin. By 1846 the main two branches of pharmacology were establish by Rudolf Buchheim (Starke, 1998). Buchheim was the first to conduct research aimed at determining both how, and to what extent, drugs alter physiological function (pharmacodynamics), and how, and to what extent, they are altered by the body (pharmacokinetics). The science of pharmacology evolved rapidly as advances in the chemical and biological sciences led to the development of new techniques that became essential for drug discovery and development. Pharmacology includes what is known about the chemical properties of drugs, their beneficial and harmful biological effects, and their therapeutic uses. The word drug encompasses any agent used for therapeutic purposes, including gene therapy. Today, pharmacologists study not only the mechanisms responsible for the action of established therapeutics, but also define the sites of action of drug candidates and identify potential therapeutic targets for new drug development.
Pharmacodynamics Pharmacodynamics is the subdiscipline of pharmacology concerned with the way a drug affects the body, with pharmacodynamic studies aimed primarily at defining the mechanisms responsible for the therapeutic and toxic effects of therapeutic agents. Such information is critical for understanding the clinical response to drugs and for designing safer and more effective medications. Pharmacodynamic studies indicate that most drugs act by attaching to specific cellular components to activate or inhibit biochemical functions (Yamamura et al., 1985). Typically, the drug binding site is a neurotransmitter or hormone receptor, a transporter, structural protein or enzyme in either the patient or an invading organism. Commonly, drug attachment to its binding site results in activation or inhibition of the receptor, transporter or enzyme, thereby augmenting or reducing physiological processes. Activators are referred to as agonists and inhibitors as antagonists for the target site. Data supporting the selectivity of the drug receptor concept includes the finding that chemical isomers evoke different pharmacological responses. Isomers are compounds with the same molecular formula, but a slightly different configuration. That is, while the atoms in chemical isomers are identical and are linked in the same way, the spatial orientation of one or more of them differs between the two forms. In the early twentieth century John Langley noted that most of the pharmacological responses to hyoscyamine are mediated by the l-isomer, with the d-isomer being virtually inactive. From this he concluded that only a cellular component with a high degree of selectivity for chemical structures, such as a specific binding, or receptor, site could make such a subtle distinction between two otherwise identical compounds. In 1933 A.J. Clark summarized the evidence supporting receptors as the site of drug action (Clark, 1933). Among the pharmacological principles he delineated is the importance of dose-response studies in defining drug actions, thereby providing a mathematical framework for quantifying pharmacodynamic data.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.07821-1
1
2
Pharmacology
Pharmacokinetics Pharmacokinetics is the subdiscipline of pharmacology concerned with the way the body affects the drug. This includes studies of the absorption, metabolism and excretion of the chemical agent. Such work is vital for determining whether the drug reaches the desired site of action and remains there for a sufficient period of time, and at the necessary concentration, to induce the intended effect. Drug access to, and residency at, the target site are not easy to attain as humans have evolved multiple ways to prevent foreign substances from gaining entry to the body and to dispose of such agents once they reach the blood. Once a drug reaches its target, a sufficient quantity must accumulate to activate or inhibit the site. This is a function of the dose administered, the extent to which the compound is absorbed and excreted, and its affinity, or attraction, for the target. Thus, while an agent may be capable of reaching the systemic circulation and penetrating into the target organ and tissue, to obtain the desired response it may be necessary to administer large quantities if its absorption is limited, its metabolism and excretion are rapid, or its affinity for the receptor is low. To be useful clinically, most drugs must be active for several hours following administration. The duration of drug action is directly related to the amount of time the agent is located at the target in the necessary quantity. The cytochrome P450 family is one of the major classes of enzymes responsible for the metabolism of many drugs and endogenous substances. Drugs and their metabolites are most often excreted by the kidneys and gastrointestinal tract. Pharmacokinetic data are crucial for determining drug dosages and regimens. If a drug is absorbed primarily by active transport there is a potential for adverse drug interactions if it is administered with another compound that attaches to the same transporter. In this case the two substances will compete for the limited number of transporter proteins, resulting in a decline in the absorption of one or the other, or both. Similarly, a drug that is metabolized by a particular cytochrome P450 enzyme may, if present in sufficient concentrations, slow or enhance the metabolism of other drugs and endogenous substances. Such effects on drug metabolizing enzymes can lead to a dramatic change in the blood levels of other substances, resulting in side effects, toxicities, or a decrease in effectiveness. Given these possibilities, pharmacokinetic data are crucial for maximizing drug safety and efficacy.
Issues in Modern Pharmacology Pharmacology is an integrative discipline, encompassing all of the topics covered in this reference module, including physiology, cell biology, genetics, microbiology, toxicology, immunobiology, pathophysiology, medicinal chemistry and virology. Pharmacology research is continuously driven by technical advances in the chemical and biological sciences. With the exception of analytical techniques, the methods employed for pharmacokinetic studies have changed little over the years. In contrast, pharmacodynamic investigations, particularly in the early stages of the drug discovery process, have become increasingly more focused on drug actions at the molecular level, with less attention paid initially to the overall biochemical and physiological effects of test agents. It is now believed that this overemphasis on molecular targeting is responsible, in part, for the decline in the discovery of new drugs even though research expenditures have continued to increase. For this reason, efforts are underway to establish greater balance in the drug discovery process, incorporating more whole animal and physiological testing to compliment the molecular screens to increase the possibility of serendipitous discoveries, which have historically been the hallmark of drug discovery. Pharmacological data obtained from whole animal, isolated organ, and molecular studies are presented and discussed in this module. Regardless of the techniques employed, or the order of their use, pharmacological research has been, and will remain, a key element of the biomedical research enterprise as long as there is a need for the discovery and development of new medications.
References Clark AJ (1933) The mode of action of drugs on cells. Baltimore, MD: Williams and Wilkins. Enna SJ and Norton S (2012) Herbal supplements and the brain: Understanding their health benefits and hazards. Upper Saddle River, NJ: FT Press. Starke K (1998) A history of Naunyn-Schmiedeberg’s Archives of Pharmacology. Naunyn-Schmiedeberg’s Archives of Pharmacology 358: 1–109. Yamamura HI, Enna SJ, and Kuhar MJ (1985) Neurotransmitter receptor binding, 2nd edn. New York, NY: Raven Press.