Brody's Human Pharmacology: With STUDENT CONSULT
Both physicians and patients acknowledge the fundamental importance of drug treatment as one of the primary means used for the prevention and alleviation of disease. Billions of prescriptions are written each year in the United States for nearly 2000 active ingredients available in 50,000 different preparations or forms of delivery. In addition, during the past 10 years, more than 100,000 over-the-counter (OTC) preparations and thousands of herbal and dietary supplements have become available. The use of both prescription and nonprescription compounds is part of daily life, and the quality of life is often influenced by the choices made.
Pharmacology and Related Terminology
In its broadest sense, Pharmacology encompasses the study of all compounds that interact with the body, and includes knowledge of the interactions between these compounds and body constituents at any level of organization.
Pharmacodynamics is defined as what a drug does to the body, including the molecular mechanism(s) by which a drug acts. Most drugs interact with proteins, such as receptors or enzymes, to effect changes in the physiological or biochemical function of particular organs, thus altering pathology or abnormal physiology to benefit the patient. Although physicians can observe the obvious functional effects of drug administration, the mechanism of drug action is less well recognized. With most drugs, observed effects provide little insight into the molecular events that occur following drug administration. Chapter 1 describes the principles governing how drugs interact with their targets to produce functional responses.
Pharmacokinetics is defined as what the body does to a drug. For almost all drugs, the magnitude of the pharmacological effect depends on its concentration at its site of action. Factors that influence rates of delivery, distribution, and disappearance of drug to and from its site of action are very important in determining the success of drug administration. How the concentration of drug varies with time in body fluids or tissues is the substance of pharmacokinetics. Chapter 2 presents the dynamics of drug absorption, distribution, metabolism, and the routes of elimination fundamental to understanding the effects of any compound in the body. Clinical pharmacokinetics and dosing schedules and how they are impacted at the extremes of age are described in Chapter 3. Temporal relationships between plasma concentrations of drugs and their pharmacological effects, including the concepts of half-life, steady-state, clearance, and bioavailability are also discussed.
Pharmacogenetics is the area of pharmacology concerned with unusual responses to drugs as a consequence of genetic differences between individuals. Such responses are different from toxic or side-effects of drugs that are generally similar in most people, or those that result from specific allergies. Pharmacogenetic differences are usually caused by an inherited defect resulting in variability in drug metabolism and may produce either a diminished or enhanced response. This topic is discussed in both Chapters 2 and 3. It is important to note that the term pharmacogenomics is often used interchangeably with pharmacogenetics. However, these terms differ in that pharmacogenomics refers broadly to the application of genomic technology to drug characterization and development, and involves the study of differences in gene expression as related to disease susceptibility and drug responses at all levels of the organism.
Pharmacovigilance is the area of pharmacology concerned with the safety of drugs. It involves the characterization, detection, and understanding of adverse effects that arise as a consequence of the short- or long-term use of drugs. Adverse drug reactions (ADRs), including drug-drug interactions, are estimated to be the 5th leading cause of mortality of inpatients in the United States, and represent a major health crisis. The high incidence of ADRs and inpatient medication problems support the importance of health professionals acquiring and maintaining up-to-date pharmacological knowledge, and providing safer and more effective medical practice. The adverse effects of drugs presented in this book are discussed in each chapter in which the actions of the compounds are presented.
Molecular therapies refer to novel therapeutic approaches that are being developed concurrent with advances in biology and medicine, and include gene therapy, other nucleic acid-based therapies, the use of specific antibodies, and strategies for targeted drug delivery. These advances are discussed in Chapters 5 and 6.
Nutraceutical is the term used to describe any substance that is considered a food or part of a food, including nutritional supplements that allege to provide health benefits. Chapter 7 discusses what we know and do not know about the dietary and herbal supplements and their potential to impact conventional drug therapy and medical interventions.
An overview of toxicology and poisons with an emphasis on general mechanisms of action of toxicants is presented in Chapter 8. Also included is a limited discussion of specific poisons including toxic gases and heavy metals. It is important to note, however, that any compound can produce toxic effects, depending on the dose and circumstances.
A synopsis of drug development, regulation, and marketing is presented in Chapter 4, along with prescription writing. An important aspect of drug therapy that often confounds both prescriber and patient is drug nomenclature. Serious errors in patient management can occur if this issue is not understood. It is critical to understand that a drug has three kinds of names:
1. The chemical name, which is often long and extremely complex, and is of interest to chemists but of little concern to medical professionals.
2. The generic, or nonproprietary name, which is the one recognized internationally and is used throughout this book. A drug has only one generic name, which often indicates that it is a member of a class of drugs having the same mechanism of action.
3. The proprietary, brand, or trade name, which is the patented exclusive property of the drug manufacturer. Trade names are often designed to be shorter and easier to remember than generic names, but they are often not helpful in identifying the pharmacological action or class of drug. In some instances, there may be as many as a dozen or more trade names for a single drug, marketed by different companies. Trade names in this book are used for recognition purposes only.
When proprietary patents expire, generic preparations of drugs become available, as discussed in Chapter 4. Generic and proprietary drugs are both subject to government regulation, but are not always completely equivalent due to potential differences in bioavailability. Using generic drug names is less likely to result in prescribing errors and can give the pharmacist the option of substituting a cheaper generic version, if available. In addition, trade names can sometimes be similar, yet refer to drugs with entirely different pharmacodynamic actions, increasing the hazard of prescribing error. Generic drugs are generally less expensive than brand-name drugs, which may contribute to lower health care costs.
Drug Potency and Efficacy
Lastly, to be able to evaluate drug responses and compare compounds, one must understand several terms including potency, efficacy, and therapeutic index. Potency refers to the amount of drug necessary to elicit a response. Thus, a drug that elicits a specific response at a dose of 1 mg is “more potent” than a drug that requires 10 mg to produce the same effect. Potency, however, is not always the most critical factor in selection of a drug, particularly if side effects produced by less potent drugs are tolerable.
Efficacy, or effectiveness, is often confused with potency, but has a very different meaning. The efficacy of a drug refers to its ability to produce the maximal desired response and is much more important in determining whether a drug will be useful clinically. For example, although morphine and codeine act through the same mu opioid receptors, no dose of codeine can produce the same degree of pain relief as morphine because morphine is more efficacious than codeine. In choosing a drug, efficacy is much more important than potency because if a drug does not produce a desired outcome, its potency is irrelevant. On the other hand, if drugs have similar efficacies, the most potent one is often the most desirable.
The therapeutic index TI or margin of safety of a drug is the ratio of the dose of drug producing undesirable effects to the dose producing the desired therapeutic response. Thus, drugs with a large TI have a large margin of safety, whereas drugs with a low TI often need to be monitored in plasma because small increases in plasma levels of these compounds may lead to toxic side effects.