A drug may be defined as any substance that brings about a change in biologic function through its chemical actions.
The drug molecule interacts as an agonist (activator) or antagonist (inhibitor) with a specific target molecule that plays a regulatory role in the biologic system.
This target molecule is called a receptor.
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To interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a location distant from its intended site of action, eg, a pill taken orally to relieve a headache. Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action. Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration.
Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide, nitric oxide, xenon). These factors often determine the best route of administration. The most common routes of administration are described in Chapter 3, Table 3–3. The various classes of organic compounds—carbohydrates, proteins, lipids, and smaller molecules—are all represented in pharmacology. As noted above, many proteins have been approved and some oligonucleotides, in the form of small segments of RNA, have entered clinical trials and are on the threshold of introduction into therapeutics.
A number of inorganic elements, eg, fluoride, lithium, iron, and heavy metals, are both useful and dangerous drugs. Many organic drugs are weak acids or bases. This fact has important implications for the way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of weak acids and bases (see text that follows).
The molecular size of drugs varies from very small (lithium ion, molecular weight [MW] 7) to very large (eg, alteplase [t-PA], a protein of MW 59,050). Many antibodies are even larger; eg, erenumab, an antibody used in the management of migraine, has a MW of more than 145,000. However, most drugs have molecular weights between 100 and 1000. The lower limit of this narrow 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 must be sufficiently unique in shape, charge, and other properties to prevent its binding to other receptors. To achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW units in size. The upper limit in molecular weight is determined primarily by the requirement that most drugs must be able to move within the body (eg, from the site of administration to the site of action and then to the site of elimination). Drugs much larger than MW 1000 do not diffuse readily between compartments of the body (discussed under Permeation, in following text). Therefore, very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect. In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into the vascular compartment by intravenous or intra-arterial infusion.
Drugs interact with receptors by means of chemical forces or bonds. These are of three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. Thus, the covalent bond formed between the acetyl group of acetylsalicylic acid (aspirin) and cyclooxygenase, its enzyme target in platelets, is not readily broken. The platelet aggregation–blocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes) and is reversed only by the synthesis of new enzyme in new platelets, a process that takes several days. Other examples of highly reactive, covalent bond-forming drugs include the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor.
Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds.
Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “pockets.”
The specific nature of a particular drug-receptor bond is of less practical importance than the fact that drugs that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such a precise fit for a particular drug structure. Thus, if we wished to design a highly selective drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose a molecule that forms weaker bonds.
A few substances that are almost completely inert in the chemical sense nevertheless have significant pharmacologic effects. For example, xenon, an “inert” gas, has anesthetic effects at elevated pressures.
The shape of a drug molecule must be such as to permit binding to its target site via the bonds just described. Optimally, the drug’s shape is complementary to that of the target site (usually a receptor) in the same way that a key is complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so common in biology that more than half of all useful drugs are chiral molecules; that is, they can exist as enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a sympathomimetic drug. In most cases, one of these enantiomers is much more potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. If one imagines the receptor site to be like a glove into which the drug molecule must fit to bring about its effect, it is clear why a “left-oriented” drug is more effective in binding to a left-hand receptor than its “right-oriented” enantiomer.
The more active enantiomer at one type of receptor site may not be more active at another receptor type, eg, a type that may be responsible for some other effect. For example, carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Table 1–2). One of these enantiomers, the (S)(–) isomer, is a potent β-receptor blocker. The (R)(+) isomer is 100-fold weaker at the β receptor. However, the isomers are approximately equipotent as α-receptor blockers. Ketamine, a chiral molecule with two isomers, was introduced as an anesthetic. When administered as an anesthetic, the racemic mixture is administered intravenously. In contrast, the (S) enantiomer has recently been approved for use in nasal spray form as a rapid-acting antidepressant.
Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other. Similarly, drug transporters may be stereoselective.
Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried out with racemic mixtures of drugs rather than with the separate enantiomers. At present, less than half of the chiral drugs used clinically are marketed as the active isomer—the rest are available only as racemic mixtures. As a result, a majority of patients receive drug doses of which 50% is less active or inactive. A few drugs are currently available in both the racemic and the pure, active isomer forms. However, proof that administration of the pure, active enantiomer decreases adverse effects relative to those produced by racemic formulations has not been established.