Principles of drug action

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CHAPTER 2

Principles of drug action

Key terms and definitions

Agonist

Chemical or drug that binds to a receptor and creates an effect on the body.

Antagonist

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.

Bioavailability

Amount of drug that reaches the systemic circulation.

Drug administration

Method by which a drug is made available to the body.

Enteral

Use of the intestine.

First-pass effect

Initial metabolism in the liver of a drug taken orally before the drug reaches the systemic circulation.

Hypersensitivity

Allergic or immune-mediated reaction to a drug, which can be serious, requiring airway maintenance or ventilatory assistance.

Idiosyncratic effect

Abnormal or unexpected reaction to a drug, other than an allergic reaction, as compared with the predicted effect.

Inhalation

Taking a substance, typically in the form of gases, fumes, vapors, mists, aerosols, or dusts, into the body by breathing in.

Local effect

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.

Parenteral

Any way other than the intestine, most commonly an injection (e.g., intravenous, intramuscular, subcutaneous, intrathecal, or intraosseous).

Pharmacodynamics

Mechanisms of drug action by which a drug molecule causes its effect in the body.

Pharmacogenetics

Study of genetic factors and their influence on drug response.

Pharmacokinetics

Time course and disposition of a drug in the body, based on its absorption, distribution, metabolism, and elimination.

Receptor

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.

Synergism

Drug interaction that occurs from two or more drug effects that are greater than if the drugs were given alone.

Systemic effect

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).

Tachyphylaxis

Rapid decrease in response to a drug.

Therapeutic index (TI)

Difference between the minimal therapeutic and toxic concentrations of a drug; the smaller the difference, the greater chance the drug will be toxic.

Tolerance

Decreasing intensity of response to a drug over time.

Topical

Use of the skin or mucous membrane (e.g., lotion).

Transdermal

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        

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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

Three Different Dosage Forms for the Bronchodilator Drug Albuterol, Indicating Ingredients Other Than Active Drug

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

Advances in drug formulation and delivery systems have yielded a wide range of routes by which a drug can be administered. In the following discussion, routes of administration have been divided into five broad categories: enteral, parenteral, transdermal, inhalation, and topical.

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)

Technically, the term parenteral means “besides the intestine,” which implies any route of administration other than enteral. However, the parenteral route commonly refers to injection of a drug. Various options are available for injection of a drug, the most common of which are the following:

• 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.

• Intraosseous (IO): Injected into the marrow of the bone.

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

The pharmacokinetic phase refers to the time course and disposition of a drug in the body, based on its absorption, distribution, metabolism, and elimination. Once presented to the body, as described in the drug administration phase, a drug crosses local anatomic barriers to varying extents depending on its chemical properties and the physiologic environment of the body compartment it occupies. For a systemic effect, it is desirable for the drug to get into the bloodstream for distribution to the body; for a local effect, this is not desirable and can lead to unwanted side effects throughout the body. Absorption, distribution, metabolism, and elimination are the factors influencing and determining the course of a drug after it is introduced to the body. In essence, pharmacokinetics describes what the body does to a drug, and pharmacodynamics describes what the drug does to the body.

Absorption

When given orally for a systemic effect, a pill must first dissolve to liberate the active ingredient. The free drug must then reach the epithelial lining of the stomach or intestine and traverse the lipid membrane barriers of the gastric and vascular cells before reaching the bloodstream for distribution into the body. The lining of the lower respiratory tract also presents barriers to drug absorption. This mucosal barrier consists of the following five identifiable elements:

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

Lipid diffusion is an important mechanism for drug absorption because of the many epithelial membranes that must be crossed if a drug is to distribute in the body and reach its target organ. Epithelial cells have lipid membranes, and a drug must be lipid-soluble (nonionized, nonpolar drug) to diffuse across such a membrane. Lipid-insoluble drugs tend to be ionized, or have positive and negative charges separated on the molecule (polar), and are water-soluble.

Many drugs are weak acids or weak bases, and the degree of ionization of these molecules is dependent on the pKp (the pH at which the drug is 50% ionized and 50% nonionized), the ambient pH, and whether the drug is a weak acid or base. The direction of increasing ionization is opposite for weak acids and weak bases, as ambient pH changes.

Figure 2-2 conceptually illustrates the principle of lipid diffusion and absorption for weak acids and bases.

Some drugs, such as ethanol, are neutral molecules and are always nonionized. They are well absorbed into the bloodstream and across the blood-brain barrier. Other drugs, such as ipratropium bromide and d-(+)-tubocurarine, are quaternary amines, have no unshared electrons for reversible binding of H+ ions, and are permanently positively charged. Ipratropium is not lipid-soluble and does not absorb and distribute well from the mouth or the lung with oral inhalation. A secondary or tertiary amine, such as atropine, can give up its H+ ion and become nonionized, increasing its absorption and distribution, and consequent side effects, in the body.

Factors affecting absorption

The route of administration determines which barriers to absorption must be crossed by a drug. These barriers can affect the drug’s time to onset and time to peak effect. Intravenous administration bypasses the need for absorption from the gastrointestinal tract seen with oral administration, generally gives a very rapid onset and peak effect, and provides 100% availability of the drug in the bloodstream. The term bioavailability indicates the proportion of a drug that reaches the systemic circulation. For example, the bioavailability of oral morphine is 0.24 because only about a quarter of the morphine ingested actually arrives in the systemic circulation. Bioavailability is influenced not only by absorption, but also by inactivation caused by stomach acids and by metabolic degradation, which can occur before the drug reaches the main systemic compartment. Another important variable governing absorption and bioavailability is blood flow to the site of absorption.

Distribution

To be effective at its desired site of action, a drug must have a certain concentration. An antibiotic is investigated for its minimal inhibitory concentration (MIC)—the lowest concentration of a drug at which a microbial population is inhibited. Drug distribution is the process by which a drug is transported to its sites of action, eliminated, or stored. When given intravenously, most drugs distribute initially to organs that receive the most blood flow. After this brief initial distribution phase, subsequent phases of distribution occur on the basis of the principles of diffusion and transport just outlined and the drug’s physical/chemical nature and ability to bind to plasma proteins. The initial distribution phase is clinically important for lipophilic anesthetics (e.g., propofol and thiopental) because they produce rapid onset of anesthesia as a function of the high blood flow to the brain, and their effects are quickly terminated during redistribution to other tissues. The binding of drugs to plasma proteins can also be clinically relevant in rare instances, such as when a large portion of a drug is inactive because it is bound to plasma proteins but subsequently becomes displaced (and thus active) by a second drug that binds to the same proteins.

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

Volume of distribution

Suppose a certain drug that distributes exclusively in the plasma compartment is administered intravenously. If a 10-mg bolus of the drug is given, and the volume of the patient’s plasma compartment is 5 L, the concentration in the plasma (barring degradation or elimination) would be 2 mg/L. In this simple example, the volume of distribution (VD) is the same as the volume of the plasma compartment. In practice, drug distribution is usually more complex, and the actual tissue compartments occupied by the drug are unknown. Nonetheless, VD describes a useful mathematical equation relating the total amount of drug in the body to the plasma concentration:

< ?xml:namespace prefix = "mml" />Volume of distribution (VD)=tDrug amount/plasma concentration

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The drug can be absorbed and distributed into sites other than the vascular compartment, which is only approximately 5 L, and the calculated volume of distribution can be much larger than the blood volume, as in the case of theophylline, which has a VD of 35 L in a 70-kg adult. For this reason, VD is referred to as the apparent volume of distribution to emphasize that VD does not refer to an actual physiologic space. Drugs such as fluoxetine (an antidepressant) and inhaled anesthetics are sequestered in peripheral tissues and can have apparent volumes of distribution many times greater than the entire volume of the body.

In a clinical setting, VD is rarely measured but is nonetheless important for estimating the dose needed for a given therapeutic level of drug. By rearranging the equation for VD, the drug amount should equal the VD multiplied by the concentration.