Principles of drug action
After reading this chapter, the reader will be able to:
1. Define key terms that pertain to principles of drug action
2. Define the drug administration phase
3. Describe the various routes of administration available
4. Define the pharmacokinetic phase
5. Discuss the key factors in the pharmacokinetic phase (e.g., absorption, distribution, metabolism, and elimination)
6. Describe the first-pass effect
7. Differentiate between systemic and inhaled drugs in relation to the pharmacokinetic phase
9. Define the pharmacodynamic phase
10. Discuss the importance of structure-activity relationships
11. Discuss the role of drug receptors
Chemical or drug that binds to a receptor and creates an effect on the body.
Chemical or drug that binds to a receptor but does not create an effect on the body; it blocks the receptor site from accepting an agonist.
Amount of drug that reaches the systemic circulation.
Method by which a drug is made available to the body.
Use of the intestine.
Initial metabolism in the liver of a drug taken orally before the drug reaches the systemic circulation.
Allergic or immune-mediated reaction to a drug, which can be serious, requiring airway maintenance or ventilatory assistance.
Abnormal or unexpected reaction to a drug, other than an allergic reaction, as compared with the predicted effect.
Taking a substance, typically in the form of gases, fumes, vapors, mists, aerosols, or dusts, into the body by breathing in.
Limited to the area of treatment (e.g., inhaled drug to treat constricted airways).
Lung availability/total systemic availability ratio (L/T ratio)
Amount of drug that is made available to the lung out of the total available to the body.
Any way other than the intestine, most commonly an injection (e.g., intravenous, intramuscular, subcutaneous, intrathecal, or intraosseous).
Mechanisms of drug action by which a drug molecule causes its effect in the body.
Study of genetic factors and their influence on drug response.
Time course and disposition of a drug in the body, based on its absorption, distribution, metabolism, and elimination.
Cell component that combines with a drug to change or enhance the function of the cell.
Structure-activity relationship (SAR)
Relationship between a drug’s chemical structure and the outcome it has on the body.
Drug interaction that occurs from two or more drug effects that are greater than if the drugs were given alone.
Pertains to the whole body, whereas the target for the drug is not local, possibly causing side effects (e.g., capsule of acetaminophen for a headache).
Rapid decrease in response to a drug.
Difference between the minimal therapeutic and toxic concentrations of a drug; the smaller the difference, the greater chance the drug will be toxic.
Decreasing intensity of response to a drug over time.
Use of the skin or mucous membrane (e.g., lotion).
Use of the skin (e.g., patch).
The entire course of action of a drug, from dose to effect, can be understood in three phases: drug administration phase, pharmacokinetic phase, and pharmacodynamic phase. This useful conceptual framework, based on the principles offered by Ariëns and Simonis,1 organizes the steps of a drug’s action from drug administration (method by which a drug dose is made available to the body) through effect and ultimate elimination from the body. This framework is illustrated in Figure 2-1 and provides an overview of the interrelationship of the three phases of drug action, each of which is discussed in this chapter.
Drug administration phase
Drug dosage forms
The drug administration phase entails the interrelated concepts of drug formulation (e.g., compounding a tablet for particular dissolution properties) and drug delivery (e.g., designing an inhaler to deliver a unit dose). Two key topics of this phase are the drug dosage form and the route of administration. The drug dosage form is the physical state of the drug in association with nondrug components. Tablets, capsules, and injectable solutions are common drug dosage forms. The route of administration is the portal of entry for the drug into the body, such as oral (enteral), injection, or inhalation. The form in which a drug is available must be compatible with the route of administration desired. The injectable route (e.g., intravenous route) requires a liquid solution of a drug, whereas the oral route can accommodate capsules, tablets, or liquid solutions. Some common drug formulations for each of the common routes of drug administration are listed in Table 2-1.
TABLE 2-1
Common Drug Formulations for Various Routes of Administration
| ENTERAL | PARENTERAL | INHALATION | TRANSDERMAL | TOPICAL |
| Tablet | Solution | Gas | Patch | Powder |
| Capsule | Suspension | Aerosol | Paste | Lotion |
| Suppository | Depot | Ointment | ||
| Elixir | Solution | |||
| Suspension |
Drug formulations and additives
A drug is the active ingredient in a dose formulation, but it is usually not the only ingredient in the total formulation. For example, in a capsule of an antibiotic, the capsule itself is a gelatinous material that allows the drug to be swallowed. The capsule material disintegrates in the stomach, and the active drug ingredient is released for absorption. The rate at which the active drug is liberated from a capsule or tablet can be controlled during the formulation process, by altering drug particle size or by using a specialized coating or formulation matrix. Aerosolized agents for inhalation and treatment of the respiratory tract also contain ingredients other than the active drug, such as preservatives, propellants for metered dose inhaler (MDI) formulations, dispersants (surfactants), and carrier agents with dry powder inhalers (DPIs). Table 2-2 presents the various formulations with different ingredients for the β-adrenergic bronchodilator albuterol. In the nebulizer solution, benzalkonium chloride is a preservative, and sulfuric acid adjusts the pH of the solution. In the CFC-MDI, chlorofluorocarbons are propellants and oleic acid is a dispersing agent. In the HFA MDI, a hydrofluoroalkane is used in place of chlorofluorocarbon.
TABLE 2-2
| DOSAGE FORM | ACTIVE DRUG | INGREDIENTS |
| Nebulizer solution | Albuterol sulfate | Benzalkonium chloride, sulfuric acid |
| MDI CFC | Albuterol-ipratropium | Trichloromono-fluoromethane, dichlorodifluoro-methane, oleic acid |
| Tablets | Albuterol sulfate | Lactose, butylparaben, sugar |
| MDI HFA | Albuterol | 1,1,1,2-Tetrafluoroethane, ethanol, oleic acid |
CFC, Chlorofluorocarbons; HFA, hydrofluoroalkane; MDI, metered dose inhaler.
Routes of administration
Enteral
The term enteral refers literally to the small intestine, but the enteral route of administration is more broadly applicable to administration of drugs intended for absorption anywhere along the gastrointestinal tract. The most common enteral route is by mouth (oral) because it is convenient, is painless, and offers flexibility in possible dosage forms of the drug, as seen in Table 2-1. The oral route requires the patient to be able to swallow; therefore, airway-protective reflexes should be intact. If the drug is not destroyed or inactivated in the stomach and can be absorbed into the bloodstream, distribution throughout the body and a systemic effect can be achieved. Other enteral routes of administration include suppositories inserted in the rectum, tablets placed under the tongue (sublingual), and drug solutions introduced though an indwelling gastric tube.
Parenteral (injectable)
• Intravenous (IV): Injected directly into the vein, allowing nearly instantaneous access to the systemic circulation. Drugs can be given as a bolus, in which case the entire dose is given rapidly, leading to a sharp increase in the plasma concentration, or a steady infusion can be used to avoid this precipitous increase.
• Intramuscular (IM): Injected deep into a skeletal muscle. Because the drug must be absorbed from the muscle into the systemic circulation, the drug effects occur more gradually than with intravenous injection, although typically more rapidly than by the oral route.
• Subcutaneous (SC): Injected into the subcutaneous tissue beneath the epidermis and the dermis.
• Intrathecal (IT): Injected into the arachnoid membrane of the spinal cord to diffuse throughout the spinal fluid.
Inhalation
Drugs can be given by inhalation for either a systemic effect or a local effect in the lung. Two of the most common drug formulations given by this route are gases, which usually are given by inhalation for anesthesia (a systemic effect), and aerosolized agents intended to target the lung or respiratory tract in the treatment of respiratory disease (local effect). The technology and science of aerosol drug delivery to the respiratory tract continue to develop and are described in detail in Chapter 3. Box 2-1 provides a summary of devices commonly used for inhaled aerosol drug delivery. The general rationale for aerosolized drug delivery to the airways for treating respiratory disease is the local delivery of the drug to the target organ, with reduced or minimal body exposure to the drug and, it is hoped, reduced prevalence or severity of possible side effects.
Pharmacokinetic phase
Absorption
After traversing these layers, a drug can reach the smooth muscle or glands of the airway. The mechanisms by which drugs move across membrane barriers include aqueous diffusion, lipid diffusion, active or facilitated diffusion, and pinocytosis. Generally, a drug must be sufficiently water-soluble to reach a lipid (cell) membrane and sufficiently lipid-soluble to diffuse across the cell barrier. Figure 2-2 illustrates these basic mechanisms, which are briefly discussed.
Lipid diffusion
Weak acid: Because an acid contributes protons (H+ ions), the protonated form is neutral, or nonionized.
Weak base: Because a base accepts protons (H+ ions), the unprotonated form is neutral, or nonionized.
• The protonated weak acid is neutralized by the addition of H+ ions in an acidic environment, is nonionized, and is lipid-soluble.
• The protonated weak base gains a charge by adding H+ ions in an acidic environment, is ionized, and is not lipid-soluble.
Figure 2-2 conceptually illustrates the principle of lipid diffusion and absorption for weak acids and bases.
Distribution
The plasma concentration of a drug is partially determined by the rate and extent of absorption versus the rate of elimination for a given dose amount. The volume in which the drug is distributed also determines the concentration achieved in plasma. Those compartments and their approximate volumes in a 70-kg adult are given in Table 2-3.
TABLE 2-3
Volumes (Approximate) of Major Body Compartments
| COMPARTMENT | VOLUME (L) |
| Vascular (blood) | 5 |
| Interstitial fluid | 10 |
| Intracellular fluid | 20 |
| Fat (adipose tissue) | 14-25 |
