Page 17 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation 3

sometimes harmful remedies and the growth of a huge “alternative location distant from its intended site of action, eg, a pill given
health care” industry. Furthermore, manipulation of the legislative orally to relieve a headache. Therefore, a useful drug must have
process in the United States has allowed many substances pro- the necessary properties to be transported from its site of admin-
moted for health—but not promoted specifically as “drugs”—to istration to its site of action. Finally, a practical drug should be
avoid meeting the Food and Drug Administration (FDA) stan- inactivated or excreted from the body at a reasonable rate so that
dards described in the second part of this chapter. Conversely, its actions will be of appropriate duration.
lack of understanding of basic scientific principles in biology and Drugs may be solid at room temperature (eg, aspirin, atro-
statistics and the absence of critical thinking about public health pine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide).
issues have led to rejection of medical science by a segment of the These factors often determine the best route of administration.
public and to a common tendency to assume that all adverse drug The most common routes of administration are described in
effects are the result of malpractice. Chapter 3, Table 3–3. The various classes of organic compounds—
General principles that the student should remember are carbohydrates, proteins, lipids, and smaller molecules—are all rep-
(1) that all substances can under certain circumstances be toxic; resented in pharmacology. As noted above, oligonucleotides, in the
(2) that the chemicals in botanicals (herbs and plant extracts, form of small segments of RNA, have entered clinical trials and are
“nutraceuticals”) are no different from chemicals in manufactured on the threshold of introduction into therapeutics.
drugs except for the much greater proportion of impurities in A number of useful or dangerous drugs are inorganic elements,
botanicals; and (3) that all dietary supplements and all therapies eg, lithium, iron, and heavy metals. Many organic drugs are weak
promoted as health-enhancing should meet the same standards of acids or bases. This fact has important implications for the way
efficacy and safety as conventional drugs and medical therapies. they are handled by the body, because pH differences in the vari-
That is, there should be no artificial separation between scientific ous compartments of the body may alter the degree of ionization
medicine and “alternative” or “complementary” medicine. Ideally, of weak acids and bases (see text that follows).
all nutritional and botanical substances should be tested by the
same types of randomized controlled trials (RCTs) as synthetic Drug Size
compounds.
The molecular size of drugs varies from very small (lithium ion,
molecular weight [MW] 7) to very large (eg, alteplase [t-PA], a
■ I GENERAL PRINCIPLES OF protein of MW 59,050). However, most drugs have molecular
weights between 100 and 1000. The lower limit of this narrow
PHARMACOLOGY range is probably set by the requirements for specificity of action.
To have a good “fit” to only one type of receptor, a drug molecule
THE NATURE OF DRUGS must be sufficiently unique in shape, charge, and other properties
to prevent its binding to other receptors. To achieve such selective
In the most general sense, a drug may be defined as any sub- binding, it appears that a molecule should in most cases be at least
stance that brings about a change in biologic function through 100 MW units in size. The upper limit in molecular weight is
its chemical actions. In most cases, the drug molecule interacts determined primarily by the requirement that drugs must be able
as an agonist (activator) or antagonist (inhibitor) with a specific to move within the body (eg, from the site of administration to
target molecule that plays a regulatory role in the biologic system. the site of action). Drugs much larger than MW 1000 do not dif-
This target molecule is called a receptor. The nature of recep- fuse readily between compartments of the body (see Permeation,
tors is discussed more fully in Chapter 2. In a very small number in following text). Therefore, very large drugs (usually proteins)
of cases, drugs known as chemical antagonists may interact must often be administered directly into the compartment where
directly with other drugs, whereas a few drugs (osmotic agents) they have their effect. In the case of alteplase, a clot-dissolving
interact almost exclusively with water molecules. Drugs may be enzyme, the drug is administered directly into the vascular
synthesized within the body (eg, hormones) or may be chemicals compartment by intravenous or intra-arterial infusion.
not synthesized in the body (ie, xenobiotics). Poisons are drugs
that have almost exclusively harmful effects. However, Paracelsus Drug Reactivity & Drug-Receptor Bonds
(1493–1541) famously stated that “the dose makes the poison,” Drugs interact with receptors by means of chemical forces or
meaning that any substance can be harmful if taken in the wrong bonds. These are of three major types: covalent, electrostatic, and
dosage. Toxins are usually defined as poisons of biologic origin, ie, hydrophobic. Covalent bonds are very strong and in many cases
synthesized by plants or animals, in contrast to inorganic poisons not reversible under biologic conditions. Thus, the covalent bond
such as lead and arsenic.
formed between the acetyl group of acetylsalicylic acid (aspirin)
and cyclooxygenase, its enzyme target in platelets, is not readily
The Physical Nature of Drugs broken. The platelet aggregation–blocking effect of aspirin lasts
To interact chemically with its receptor, a drug molecule must long after free acetylsalicylic acid has disappeared from the blood-
have the appropriate size, electrical charge, shape, and atomic stream (about 15 minutes) and is reversed only by the synthesis
composition. Furthermore, a drug is often administered at a of new enzyme in new platelets, a process that takes several days.