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.

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:

Transdermal

An increasing number of drugs are being formulated for application to the skin (i.e., transdermal administration) to produce a systemic effect. The advantage of this route is that it can supply long-term continuous delivery to the systemic circulation. The drug is absorbed percutaneously, obviating the need for a hypodermic needle and decreasing the fluctuations in plasma drug levels that can occur with repeated oral administration.

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.

Topical

Drugs can be applied directly to the skin or mucous membranes to produce a local effect. Such drugs are often formulated to minimize systemic absorption. Examples of topical administration include the application of corticosteroid cream to an area of contact dermatitis (e.g., poison ivy), administration of an eye drop containing a β-adrenergic antagonist to control glaucoma, and instillation of nasal drops containing an α-adrenergic agonist to relieve congestion.

Aqueous diffusion

Aqueous diffusion occurs in the aqueous compartments of the body, such as the interstitial spaces or within a cell. Transport across epithelial linings is restricted because of small pore size; capillaries have larger pores, allowing passage of most drug molecules. Diffusion occurs by a concentration gradient.

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 pK_p (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.

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.

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.

Carrier-mediated transport

Special carrier molecules embedded in the membrane can transport some substances, such as amino acids, sugars, or naturally occurring peptides and the drugs that resemble these substances. In some instances, a drug can compete with the endogenous substance normally transported by the carrier.

Pinocytosis

Pinocytosis refers to the incorporation of a substance into a cell by a process of membrane engulfment and transport of the substance to the cell interior in vesicles, allowing translocation across a membrane barrier.

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.

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 (V_D) 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, V_D 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

EXAMPLE

If 350 mg of theophylline results in a concentration in the plasma of 10 mg/L (equivalent to 10 μg/mL), the volume of distribution (V_D) is calculated as:

VD=350 mg/(10 mg/L)VD=35 L

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 V_D of 35 L in a 70-kg adult. For this reason, V_D is referred to as the apparent volume of distribution to emphasize that V_D 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, V_D is rarely measured but is nonetheless important for estimating the dose needed for a given therapeutic level of drug. By rearranging the equation for V_D, the drug amount should equal the V_D multiplied by the concentration.

EXAMPLE

To achieve a concentration of theophylline of 15 mg/L with a V_D of 35 L, we calculate a dose of:

Drug amount (drug dose)=plasma concentration×VDtDose=15 mg/L×35LtDose=525 mg

The following points should be noted:

Site of drug biotransformation

The liver is the principal organ for drug metabolism, although other tissues, including the lung, intestinal wall, and endothelial vascular wall, can transform or metabolize drugs. For example, epinephrine, a weak base, is absorbed into the intestinal wall, where sulfatase enzymes inactivate it as the drug diffuses into the circulation. The liver contains intracellular enzymes that usually convert lipophilic (lipid-soluble) drug molecules into water-soluble metabolites that are more easily excreted. The major enzyme system in the liver is the cytochrome P450 oxidase system. There are many forms of cytochrome P450, which are hemoproteins with considerable substrate versatility and the ability to metabolize new drugs or industrial compounds. The various forms of cytochrome P450 have been divided into about a dozen subcategories, termed isoenzyme families. The four most important isoenzyme families for drug metabolism have been designated CYP1, CYP2, CYP3, and CYP4. A given drug may be metabolized predominantly by only one member of an isoenzyme family, whereas another drug may be metabolized by multiple enzymes in the same family or by several distinct enzymes across families. Knowing which particular CYP enzyme metabolizes a drug can be important for predicting drug interactions, as described further subsequently.

Enzyme induction and inhibition

Chronic administration or abuse of drugs that are metabolized by the enzyme systems in the liver can induce (increase) or inhibit the levels of the enzymes (enzyme induction and inhibition). Examples of drugs or agents that can induce or inhibit CYP enzymes are listed in Table 2-4.

Enzyme induction can affect the therapeutic doses of drugs required. Rifampin can induce CYP enzymes and increase the metabolism of several drugs, including warfarin and oral contraceptives. Likewise, cigarette smoking can increase the breakdown of theophylline in patients with chronic lung disease, shortening the half-life of the drug from approximately 7.0 to 4.3 hours. Dosages would need to be adjusted accordingly to maintain a suitable plasma level of theophylline. Conversely, a substantial portion of drug interactions involves inhibition of CYP enzymes. A given drug is not likely to inhibit all the CYP isoenzymes equally. For example, the antibiotic ciprofloxacin is a potent inhibitor of an enzyme in the CYP family that also metabolizes theophylline. Coadministration of ciprofloxacin with theophylline can increase theophylline levels, the opposite effect of cigarette smoking.

First-pass effect

Another clinically important effect of the liver on drug metabolism is referred to as the first-pass effect of elimination. When a drug is taken orally and absorbed into the blood from the stomach or intestine, the portal vein drains this blood directly into the liver (Figure 2-3). The blood from the liver is drained by the right and left hepatic veins directly into the inferior vena cava and on into the general circulation.

If a drug is highly metabolized by the liver enzymes and is administered orally, most of the drug’s activity is terminated in its passage through the liver before it ever reaches the general circulation and the rest of the body. This is the first-pass effect. Examples of drugs with a high first-pass effect are propranolol; nitroglycerin (sublingual is preferred to oral); and fluticasone propionate, an aerosolized corticosteroid. The first-pass effect causes difficulties with oral administration that must be overcome by increasing the oral dose (compared with the parenteral dose) or by using a delivery system that circumvents first-pass metabolism. The following routes avoid first-pass circulation through the liver: injection, buccal or sublingual (e.g., tablets), transdermal (e.g., patch), rectal (e.g., suppositories), and inhalation. These routes of administration bypass the portal venous circulation, allowing drugs to be generally distributed in the body before being circulated through the liver and ultimately metabolized. They also bypass metabolic degradation occurring in the gut as a result of specific metabolic enzymes (e.g., CYP3) or bacterial flora.

Plasma clearance

Just as the term V_D is an abstraction that does not usually correspond to any real physiologic volume, so the term plasma clearance (Cl_p) refers to a hypothetical volume of plasma that is completely cleared of all drug over a given period. Consequently, Cl_p is usually expressed as liters per hour (L/hr) or, if body weight is taken into account, liters per hour per kilogram. Because Cl_p gives an indication of the quantity of drug removed from the body over a given time, it can be used to estimate the rate at which a drug must be replaced to maintain a steady plasma level.

Maintenance dose

To achieve a steady level of drug in the body, dosing must equal the rate of elimination:

Dosing rate (mg/hr)=(CIP)(L/hr)×tplasma concentration (mg/L)

EXAMPLE

The clearance of theophylline is given as 2.88 L/hr/70 kg. For an average 70-kg adult, to maintain a plasma drug level of 15 mg/L (equivalent to 15 μg/mL), calculate the dosing rate as follows:

Dosing rate=2.88 L/hr×15 mg/L=43.2 mg/h

The preceding simplified calculation assumes total bioavailability of the drug, which may not be true for some routes of administration, and is intended for conceptual illustration only. Actual patient treatment must take other factors into account. The drug could be given by constant infusion or divided into dosing intervals (e.g., where half the daily dose is given every 12 hours). When deciding on a dosing interval, it is desirable to know the plasma half-life.

Plasma half-life

The plasma half-life (T_½) (the time required for the plasma concentration of a drug to decrease by one-half) is a measure of how quickly a drug is eliminated from the body. More pertinent to dosing schedules, however, T_½ indicates how quickly a drug can accumulate and reach steady-state plasma levels. Drugs with a short T_½ (e.g., amoxicillin) reach steady-state levels quickly and must be given more frequently to maintain plasma levels, whereas the opposite is true of drugs with a long T_½, such as digoxin. Table 2-5 lists selected drugs in common use with their plasma half-lives.

Time-plasma curves

The concentration of a drug in the plasma over time can be graphed as a time-plasma curve (Figure 2-4). The shape of this curve describes the interplay of the kinetic factors of absorption, distribution, metabolism, and elimination. These curves can indicate whether the dose given is sufficient to reach and maintain a critical threshold of concentration needed for the desired therapeutic effect. Such a curve can also be plotted for concentrations of an aerosol drug in respiratory tract secretions. However, the duration of the clinical effect rather than the concentration of the drug is often represented in studies of aerosol drugs, particularly bronchodilators. The clinical effect is more helpful than a blood level in describing the pharmacokinetics of inhaled aerosols, which rely on topical delivery with a local effect in the airway.

Figure 2-5 illustrates hypothetical curves for the peak effect and duration of effect of three bronchodilator drugs on expiratory flow rates. The short-acting curve could represent a drug such as isoetharine, a catecholamine bronchodilator. On the basis of its time curve, this agent is too short-acting for maintenance therapy but could be useful for a before-and-after pulmonary function evaluation, where rapid peak effect and short duration would be desirable. The intermediate curve could represent an agent such as albuterol, with a peak effect of 30 to 60 minutes by inhalation and a duration of action of approximately 4 to 6 hours. These kinetics are useful for as-required bronchodilation or for maintenance therapy if a subject uses the drug four times daily. The kinetics indicate that bronchodilation with albuterol, an intermediate-acting drug, would not be maintained during an entire night. Finally, a long-acting agent such as the bronchodilator salmeterol could provide a 12-hour duration of effect, although time to peak effect is slower (less than 2 hours). These kinetics are useful for convenient twice-daily dosing and around-the-clock bronchodilation. This example illustrates how pharmacokinetics of an inhaled aerosol can help determine the choice of a particular drug for a given clinical application and the dosing schedule needed for the therapeutic effect. Other factors in the choice of a drug, whether inhaled aerosol or oral/injectable, include the side-effect profile, the individual’s reaction to the drug, allergies, and compliance factors (patient adherence to dosing instructions) such as delivery formulations and dose timing.

Local versus systemic effect

Inhaled aerosols are deposited on the surface of the upper or lower airway and are a form of topically administered drug. As topically deposited agents, inhaled aerosols can be intended either for a local effect in the upper or lower airway or for a systemic effect as the drug is absorbed and distributed in the blood. A local effect is exemplified by a nasally inhaled vasoconstricting agent (decongestant), such as oxymetazoline (Afrin), or by an inhaled bronchodilator aerosol, such as albuterol (Proventil-HFA, Ventolin-HFA, Proair HFA), to dilate the lower airways. A systemic effect might be exemplified by the administration of inhaled zanamivir (Relenza) to treat influenza, inhaled morphine for pain control, or inhaled insulin aerosol for systemic control of diabetes.²

Inhaled aerosols in pulmonary disease

Inhaled aerosols used in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, or cystic fibrosis are intended for a local, targeted effect in the lung and airway. The rationale for the inhalation route in therapy of the lung is to maximize lung deposition while minimizing body (systemic) exposure and unwanted side effects. If the ratio of drug in the lung is high relative to the amount of drug in the overall body (systemic drug level), the inhalation route offers an advantage over direct systemic administration (oral, intravenous) in treating the lung.

Distribution of inhaled aerosols

Because a portion of an inhaled aerosol is swallowed, the inhalation route leads to gastrointestinal absorption as well as lung absorption of the drug (Figure 2-6). After inhalation of an aerosol by a spontaneously breathing patient with no artificial airway, a proportion of the aerosol impacts in the oropharynx and is swallowed, and a proportion is inhaled into the airway. The traditional percentages given for stomach and airway proportions, based on Newman’s classic measures³ in 1981 with an MDI, are approximately 90% (stomach) and 10% (airway). Similar percentages have been found with other aerosol delivery devices.

Approximately 50% to 60% of the drug impacts in the mouth or oropharynx and contributes to the 90% reaching the stomach. These amounts are used in discussing the pathways of metabolism for an inhaled drug. Although the remaining 10% is traditionally accepted as the proportion of inhaled drug reaching the lower respiratory tract with current delivery devices, the exact percentage can vary with different delivery devices or techniques of patient use from 10% to 30%. Lung deposition with an inhaled corticosteroid, budesonide (Pulmicort), has been reported as 15% with a pressurized MDI (pMDI) and 32% with a DPI (Pulmicort Turbuhaler; AstraZeneca, Wilmington, Delaware).⁴ Use of reservoir devices with MDIs or delivery through endotracheal tubes can significantly change oropharyngeal impaction or airway delivery (see Chapter 3).

Lung availability/total systemic availability ratio

The lung availability/total systemic availability ratio (L/T ratio) quantifies the efficiency of aerosol drug delivery to the lung and is based on the distribution to the airway and gastrointestinal tract just described. For an aerosol drug (e.g., a bronchodilator or corticosteroid) that targets the respiratory tract, the L/T ratio can be defined as the proportion of drug available from the lung, out of the total systemically available drug.

The clinical or therapeutic effect of a bronchoactive aerosol comes from the inhaled drug deposited in the airways. The systemic or extrapulmonary side effects come from the total amount of drug absorbed into the system. The total systemic drug level is due to airway absorption plus the amount absorbed from the gastrointestinal tract. The L/T ratio can quantify and compare the efficiency of drug delivery systems targeting the respiratory tract. Any action that reduces the swallowed portion of the inhaled drug, such as a reservoir device (spacer, holding chamber), or high first-pass metabolism, can increase the L/T ratio. Factors that can increase the L/T ratio are summarized in Box 2-3. A perfectly efficient inhalation device would deliver all of the drug to the lung and none to the oropharynx or gastrointestinal tract, giving a ratio of 1 (lung availability = total systemic availability; all systemic drug comes only from the lung absorption).

This concept was proposed in 1991 by Borgström⁵ and elaborated by Thorsson.⁶ An example, based on the data of Thorsson for albuterol inhalation using two different delivery devices, is given in Figure 2-7. Using an MDI, approximately 30% of the inhaled drug reaches the lung, with 70% going to the stomach. With complete absorption from the stomach, half of this 70% is broken down in the liver, so that 35% reaches the systemic circulation. The total amount of the original 100% dose reaching the circulation is 65% (lung, 30%; stomach and liver, 35%). Because 30% of the 65% comes from the lung, this gives an L/T ratio of 30/65 = 0.46.

The data for the DPI, using a Rotahaler (GlaxoSmithKline, Research Triangle Park, North Carolina), which is no longer available, gives an L/T ratio of 0.23 (lung, 13%; stomach and liver, 44%). On the basis of these ratios, inhalation of albuterol via an MDI gives more efficient lung delivery with less systemic availability compared with inhalation via a DPI such as the Rotahaler. With the MDI, 46% of the systemic exposure is due to the lung, whereas with the DPI, 23% is due to the lung. A high L/T ratio is desired; Table 2-6 gives examples of various L/T ratios, along with lung deposition for several drugs and delivery devices.

The L/T ratio is determined by the rate of first-pass metabolism and the efficiency of the inhalation device in placing drug in the airway. A high L/T ratio can be achieved even with poor lung delivery and efficient stomach absorption if there is a high first-pass effect on the swallowed drug. Comparisons of L/T ratios must be between the same drugs with different delivery devices. Two drugs with different first-pass metabolism rates can have different L/T ratios even if the airway deposition or delivery device is the same. A good example is provided in Table 2-6 by comparing albuterol and terbutaline, both administered with a Turbuhaler(DPI). Albuterol and terbutaline have first-pass metabolism rates of 50% and 90%, respectively. With approximately the same lung delivery of 22% to 23% for both drug-device systems, the L/T ratio is 0.45 for albuterol but 0.79 for terbutaline. The improved L/T ratio of terbutaline compared with albuterol is not caused by a difference in device efficiency but by the higher rate of metabolism of terbutaline that reduces systemic blood levels from gastrointestinal absorption. The L/T ratio also suggests that aerosol delivery devices should be evaluated together with the drug to be used. “Each combination of active drug and device is a unique pharmaceutical formulation, as both the drug itself and the device can influence the overall properties of the formulation.”⁵ The L/T ratio does not determine whether systemic toxicity or side effects will occur. First, systemic effects depend on the amount of active drug absorbed into the system, whether from the lung or gastrointestinal tract. An inhaled corticosteroid, such as flunisolide, is rapidly metabolized in a first-pass effect. As a result, the swallowed portion gives minimal systemic levels. Good absorption of the aerosol drug from the lungs in sufficiently high doses could cause systemic effects, however. Second, delivery to the oropharynx and gastrointestinal tract by a less efficient aerosol delivery device or method may be irrelevant if the drug is largely inactivated when taken orally and causes no local oropharyngeal effects. Catecholamine bronchodilators would be examples of such a drug. The L/T ratio indicates clearly how close an aerosol drug delivery system comes to the ideal of having all of the systemic drug exposure come from only the lung dose.

Drug receptors

Most drug receptors are proteins, or polypeptides, whose shape and electric charge provide a match to a drug’s corresponding chemical shape or charge. Drug receptor proteins include receptors on cell surfaces and within the cell.

The process by which attachment of a drug to its receptor results in a clinical response involves complex molecular mechanisms. This process sends a signal from the drug chemical into an intracellular sequence that controls cell function. Usually the drug attaches to a receptor protein that spans the cell membrane, and so the process is one of “transmembrane signaling.”

Four mechanisms for transmembrane signaling are well understood. Each mechanism can transduce signals for a group of different drug receptors and for different drugs. The four mechanisms are as follows:

The first, third, and fourth mechanisms are reviewed in more detail because these are the basis for the activity of drugs commonly used in respiratory care.

Lipid-soluble drugs and intracellular receptor activation

Intracellular receptor activation by lipid-soluble drugs is the basis on which corticosteroids, an important class of drugs in respiratory care, cause a cell response. Examples of corticosteroid drugs are inhaled beclomethasone and flunisolide and oral prednisone. In this drug-receptor mechanism, the drug is sufficiently lipid-soluble to cross the lipid bilayer of the cell membrane, diffuse into the cytoplasm, and attach to an intracellular polypeptide receptor. The drug-receptor complex translocates to the cell nucleus and binds to specific DNA sequences termed hormone response elements, which can either stimulate or repress the transcription of genes in the nucleus. An example of such drug-receptor signaling is illustrated in Figure 2-9 for glucocorticoid drugs, such as inhaled flunisolide or oral prednisone. The glucocorticoid diffuses across the cell membrane and attaches to a receptor in the cytoplasm. Attachment of the drug to the receptor causes displacement of certain proteins, termed heat shock proteins, and a change in the receptor configuration to an active state. The newly coupled drug-receptor complex moves or translocates to the nucleus of the cell, where it pairs with other drug-receptor complexes, which then bind to a glucocorticoid response element (GRE) of the cell’s DNA. This binding initiates or represses transcription of target genes and cell response (see Chapter 11 for a discussion of the mechanism and effects of glucocorticoids).

Drugs that act by diffusing into the cell and regulating gene responses have longer periods for observed responses, ranging from 30 minutes to several hours. Typically, there is also a persistence of effect for hours or days, even after the drug has been eliminated from the body.

Drug-regulated ion channels

Another process of drug signal transduction regulates the flow of ions such as sodium or potassium through cell membrane channels. This can be seen in Figure 2-10. The drug binds to a receptor on the cell membrane surface. The receptor has a portion above or on the surface of the cell membrane and extends through the membrane into the cytoplasm of the cell. When activated by the drug (or by an endogenous ligand), the receptor opens an ion channel to allow increased transmembrane conductance of an ion. An example of such a receptor is that for acetylcholine, a neurotransmitter, on skeletal muscle. This acetylcholine receptor is termed a nicotinic receptor because it responds to the substance nicotine as well as acetylcholine. Attachment of acetylcholine or nicotine opens an ion channel and allows the high sodium (Na⁺) concentration in extracellular fluid to flow into the lower concentration of the cell. This produces a reversal of voltage, or depolarization, and a corresponding muscle twitch. Acetylcholine is the neurotransmitter for voluntary muscle contraction and movement, and stimulation by nicotine can increase skeletal muscle tremor.

Receptors linked to g proteins

G protein–linked receptors mediate bronchodilation and bronchoconstriction in the airways, in response to endogenous stimulation by neurotransmitters epinephrine and acetylcholine. These same airway responses can be elicited by adrenergic bronchodilator drugs (discussed in Chapter 6) or blocked by acetylcholine-blocking (anticholinergic) agents such as ipratropium bromide (discussed in Chapter 7). G proteins and G protein–linked receptors also mediate the effects of other chemicals, including the effects of histamine and glucagon, and the phototransduction of light in retinal rods and cones. Drug receptor signaling with G protein–linked receptors involves three main components: drug receptor, G protein, and effector system. When a drug attaches to a G protein–linked receptor, these three components interact to cause a cellular response to the drug. The effector system triggers the cell response ultimately by activating or inhibiting a second messenger within the cell. Figure 2-11 shows the main elements of a G protein–linked receptor. Each of the major elements in this signaling mechanism complex is described briefly, along with the dynamics of their interaction.

Receptors that couple with G proteins have been well characterized and show a similar structure, in which a polypeptide chain crosses the cell membrane seven times, giving a serpentine appearance to the receptor. The polypeptide chain has an amino (NH₂, or N)-terminal site outside the cell membrane and a carboxyl (COOH, or C) terminus inside the cell. Although the seven transmembrane segments of the receptor are illustrated in Figure 2-12 as side by side, the receptor appears to form a cylindrical structure if viewed perpendicular to the surface of the cell membrane, with the transmembrane loops forming the sides of the cylinder. The drug usually couples to the receptor at a site surrounded by the transmembrane regions of the receptor protein, that is, within the interior of the cylinder. The receptor activates a G protein on the cytoplasmic (inner) surface of the cell membrane. The site of the interaction of the G protein with the receptor polypeptide is thought to be at the third cytoplasmic loop of the receptor chain.

G proteins are so termed because they are a family of guanine nucleotide-binding proteins with a three-part, or heterotrimeric, structure. The three subunits of the G protein are designated by the Greek letters alpha (α), beta (β), and gamma (γ). The α subunit differentiates members of the G protein family. On the basis of the α subunit, the G protein is classified into subgroups, such as G_s, which stimulates an effector system, and G_i, which inhibits the effector system. Other types of G proteins have been identified as well; they are not reviewed in this chapter.

The activated G protein changes the activity of an effector system, which may be either an enzyme, which catalyzes the formation of a second messenger, or an ion channel, which allows the outflow of K⁺ ions from the cell. One of the second messengers is the well-known cyclic adenosine 3′,5′-monophosphate (cAMP). The effector enzyme for increasing cAMP is adenylyl cyclase (previously termed adenyl cyclase), which converts adenosine triphosphate (ATP) to cAMP. The G protein that stimulates adenylyl cyclase is the G_s (for stimulatory) protein. β receptors, which couple with β-adrenergic bronchodilators, activate G_s proteins. Another G protein, G_i (for inhibitory), inhibits the activation of adenylyl cyclase; G_i proteins are activated by cholinergic (muscarinic) agonists such as acetylcholine or the drug methacholine.

The dynamics of cell signaling by G protein–linked receptors are illustrated schematically in Figure 2-12. When there is no drug attached to the receptor site, the α subunit of the G protein is bound to guanosine diphosphate (GDP), and the G protein is in an inactive state. When a drug attaches to the receptor, there is a change in the receptor conformation that causes the release of GDP and the binding of guanosine triphosphate (GTP) to the α subunit. This is the active state for the G protein. The GTP-bound α subunit dissociates, or unlinks, from the β-γ portion and couples with the effector system to stimulate or inhibit a second messenger within the cell. The GTP bound to the α subunit is hydrolyzed by a GTPase enzyme, dissociates from the effector, and reassociates with the β-γ dimer. The G protein–linked receptor is then ready for reactivation.

Details on specific G proteins, their effector systems, and their second messengers are presented for neurotransmitters such as epinephrine and acetylcholine in the nervous system (see Chapter 5) and for the classes of drugs that link to such receptors, such as adrenergic bronchodilators (see Chapter 6) and anticholinergic bronchodilators (see Chapter 7).

Potency versus maximal effect

Dose-response curves are the basis for defining and illustrating several concepts used to characterize and compare drugs. Two concepts that allow comparison of drugs are potency and maximal effect, both illustrated in Figure 2-14.

The lower the ED₅₀ for a given drug, the more potent the drug is, as seen in Figure 2-14. Curves for drugs A and B show different potencies. If the ED₅₀ for drug B is 5 mg and for drug A is 1 mg, then drug A is five times more potent than drug B:

ED50 (B)/ED50 (A)=5 mg/1 mg=5

Drug B requires five times the amount of drug A to produce 50% of its maximal effect. Potency is not the same as maximal effect, also illustrated in Figure 2-14. Potency is relatively defined using the ED₅₀ values of two drugs, whereas maximal effect is absolutely defined as a physiologic or clinical response. The curves indicate that drugs B and C have the same potency; that is, the same dose produces 50% of the maximal response. However, drug B has a greater maximal effect than drug C. Because the ED₅₀ is the dose causing a response that is half the maximal response of the same drug, two drugs can have different maximal responses but the same ED₅₀ (and the same potency), as seen in Figure 2-14.

Therapeutic index

The therapeutic index (TI) can be defined as the ratio of the LD₅₀ to the ED₅₀ for a given drug, with ED₅₀ and LD₅₀ indicating half of the test subjects rather than a 50% clinical response. The TI is also based on the dose-response curve of a drug. Instead of a graded clinical or physiologic response such as an increase in heart rate, however, we substitute an all-or-nothing response of improvement for each subject, or toxicity/death for each subject. In this case, the ED₅₀ represents the dose of the drug at which half of the test subjects improve. Similarly, the LD₅₀ is the lethal dose for 50% of the test population. Doses are established for a test population of animals (as illustrated in Figure 2-15).

The ratio of the dose that is toxic to 50% of test subjects to the dose that provides relief to 50% of the subjects is the clinical TI. This index represents the safety margin of the drug. The smaller the TI, the greater is the possibility of crossing from a therapeutic effect to a toxic effect. Theophylline is a drug used in respiratory care that has a narrow therapeutic margin. As a result, toxic side effects can be seen at close to therapeutic dose levels in some individuals.

Agonists and antagonists

An agonist is a drug or chemical that binds to a corresponding receptor (has affinity) and initiates a cellular effect or response (has efficacy). An antagonist is a drug or chemical that is able to bind to a receptor (has affinity) but causes no response (zero efficacy). Because the antagonist drug is occupying the receptor site, it can prevent other drugs or an endogenous chemical from reaching and activating the receptor site. By doing so, an antagonist inhibits or blocks the agonist at the receptor. Agonists are divided further into full and partial agonists. A full agonist is a drug that gives a higher maximal response than a partial agonist. The dose-response curves for a partial agonist and a full agonist are represented in Figure 2-16. Both have receptor affinity, but a partial agonist has less efficacy than a full agonist.

Drug interactions

The concept of drug antagonism just discussed is an example of a drug interaction in which one drug can block the effect of another. Mechanisms of drug antagonism are as follows:

The following terms are used to describe positive interactions between two drugs:

Terms for drug responsiveness

Individuals exhibit variation in their responses to drugs; the dose-response curves previously illustrated represent an average of an entire group. The following terms are encountered in pharmacology to describe individual reactions to drugs: