The previous section discussed the definition of a drug. To gain a better understanding of a drug, one also must consider the physical actions of the drug on the cells and systems of the body. The process of determining the site in which drugs act and the mechanism in which this action occurs is called pharmacodynamics. In this section, we will discuss how drugs bind to receptors, how doses are determined, and how to identify the time response and length of time a drug is active within the body.
Drugs can be either endogenous—originating within the body, such as hormones produced by the thyroid, or exogenous—originating outside the body and not related to the body's natural hormone production. Most drugs do not produce changes everywhere in the body, but act at specific locations in tissues or organs. For a drug to act specifically, there must be a mechanism or site at the cellular level to which the drug, regardless of its size, shape, weight, or chemical structure, can attach and produce an effect. This mechanism of action between the drug and cellular components is commonly referred to as a drug-receptor interaction. A receptor is a component of a cell to which a drug binds to produce an effect. In most cases, receptors are located on or within the cell and are identified by their protein structure1.
When a drug is introduced into the body, it circulates through the bloodstream and attaches to a corresponding cell receptor. However, not all drug-receptor interactions have affinity (the force that makes two agents bind or unite) for all drugs. Each drug has a chemical structure that searches for target-specific cell receptors. When a specific drug molecule finds a corresponding receptor, it binds relatively easily. The binding of drugs to receptors is usually associated with the "lock and key" analogy, in which the receptor is the lock and the drug is the key (Fig. 2–1). When a drug fits into a lock, it will exert its effects within that cell. Occasionally, several drugs, or "keys," can fit the same receptor. The competition for the receptor therefore depends on the affinity (binding power) of the drug for that receptor.18 A drug with a high affinity will bind readily to the receptors even if the drug concentration is low. A drug with a low affinity usually requires higher drug concentrations before binding to receptors can occur.
"Lock and key" receptor analogy. The cell receptor has a specifically shaped "lock" or binding site that will accept only a same-shape "key" drug molecule.
A drug that interacts with a receptor to produce a pharmacological response is known as an agonist. Agonist drugs are said to have both affinity and efficacy (the capacity to elicit a response).1 Conversely, drugs that interact or bind with a receptor but do not produce a pharmacological response or prevent any effect of an agonist are called antagonists. Antagonist drugs are sometimes referred to "blockers" because they occupy the receptors and prevent agonist drugs from causing a change in cellular activity. An antagonist drug is said to have affinity but not efficacy.
The action of a drug on cellular activity is characterized by several variables, one of which is the dose or amount of the drug given. When a dose is administered, levels of the drug within the body usually increase gradually and smoothly. The lowest dose capable of producing a perceivable response is called the threshold. It varies according to the properties of the drug. The maximal effect of the drug is the greatest response produced regardless of the dose administered. When, after the maximal effect is reached, the dose of a drug increases, its efficacy will not increase. Instead, the incidence of associated adverse effects will increase. Hence, drugs have certain limitations regarding the amount that can be given over a period of time.
Dose-response curves are an appropriate method of evaluating and comparing the efficacy and potency of related drugs. Potency is the amount of drug necessary to produce a desired pharmacological effect. A more potent drug requires a lower dose and a less potent drug requires a higher dose to produce the same pharmacological effect. For example, it takes a higher dose of drug B (aspirin) to elicit the same pain-relief response as drug A (morphine) (Fig. 2–2). Therefore drug A is said to have a higher potency than drug B and a smaller dose of drug A can be given to bring about pain relief. Another example is the comparison between corticosteroids. Both hydrocortisone and dexamethasone are efficacious, but dexamethasone is approximately 20 times more potent than hydrocortisone. In this specific case, a larger dose of hydrocortisone will be required to create the desired response.
Typical dose response curve. At a mean response of 50 percent, it takes a higher dose of drug B to elicit the same response as drug A. Drug A therefore exhibits more potency.
When a drug is introduced into the system, its effects are not instantaneous. A period of time must elapse before the drug-induced effects occur. Some drug effects occur relatively quickly; others manifest their action over days. Moreover, the length of the drug-induced effect is not infinite. Metabolic processes occur in the body that affect the concentration of the drug and alter the therapeutic effect. In determining the time response of a dose, three factors must be considered: latency, maximal effect, and duration of action (Fig. 2–3).
Typical time response curve. After initial administration (single dose), the drug concentration will not be immediately measurable. A period of time will elapse before the drug concentration increases, reaches its potential, and then gradually decreases until it is eliminated from the body.
Latency, sometimes referred to as "onset of action," indicates the time required for a drug to produce an observable effect after being administered. Maximal effect is the length of time it takes for the drug to reach peak efficacy. Duration of action refers to the period of time over which a drug produces a response after a single dose. These metrics are influenced by a variety of attributes including (1) the specific route of administration (e.g., oral or intramuscular), (2) the solubility of the drug (the rate at which the drug is absorbed into the bloodstream from the site of administration), (3) how fast the drug is distributed to the site of action, and (4) the time it takes to be inactivated and excreted from the body.
Although drug potency can determine the dose required to achieve a desired effect, it does little to determine drug safety. Ultimately, drugs need to be administered in safe dosage ranges that will elicit the desired response without producing toxic or lethal effects. The range in which desired effects are produced is called the therapeutic index (Fig. 2–4). The therapeutic index is useful in determining the safety parameters of doses and is expressed by the ratio between the median effective dose (ED50), the dose required to produce a response, or effect, in 50 percent of the test subjects, and the toxic dose (TD50), the portion of the population in which 50 percent of individuals exhibit adverse effects. To be considered clinically relevant, the therapeutic index should be greater than 1:1, with higher numbers producing safer or less toxic drugs.
Therapeutic index. The ED50 of this specific dose is 20 mg and the TD50 is 50 mg. The therapeutic index for this particular drug is 2.5.
Generally, the level of response to a particular dose of a drug at the site of action is correlated with the plasma or serum level of that drug. The therapeutic window of a drug can be calculated over time by the plasma or serum concentrations of that drug (Fig. 2–5).We will assume that the concentration of a drug in the plasma is the same as the concentration of the drug at the site of action. When a dose is first administered, it can be detected in the plasma but may not have high enough concentrations to produce a pharmacological response. This period is said to be below the minimal effective concentration (MEC). As the drug concentration increases above the MEC, so does the intensity of response at the cellular level. The length of time the drug concentration remains above the MEC is termed the duration of action. It is the optimal range for the drug to produce its desired response. Drug plasma concentrations that exceed the level of the therapeutic window may produce toxic responses and are not considered safe. The point at which concentration reaches the toxic range is called the minimum toxic concentration (MTC).
Plasma response curve. The period of time during which the plasma drug concentration is above the MEC but below the MTC produces the desired therapeutic range (time in which the drug concentration in plasma must be maintained).
Some drugs have a very narrow therapeutic window. These drugs require more monitoring because an increase in the dose could be toxic or lethal. A drug with a narrow therapeutic window must be administered at appropriate times and under the proper conditions to maintain an effective level without putting too much of the drug into the body at one time.
After a drug is administered, it will remain in the system and produce its effects for a finite period of time. During this period, the drug will be slowly metabolized and eliminated from the body. The rate of metabolism and excretion determines the drug's biological half-life (t1/2). Half-life is calculated by determining the time required to reduce by one-half the amount of the drug present in the body. In other words, half-life is the amount of time required for 50 percent of the drug remaining in the body to be eliminated.3,12,15
The concept of half-life is important for several reasons. First, all drugs have different and distinct half-lives, from minutes to hours or days, depending on chemical properties. Second, it allows comparisons for drug elimination rates. Finally, it determines the frequency with which multiple doses of a drug can be safely administered to produce or sustain the MEC. For example, the half-life of Vicodin (an oral agent used for the treatment of pain) is 3 to 4 hours. Because of the short half-life, the drug is usually taken every 4 to 6 hours instead of once or twice per day to ensure adequate pain relief.
One final point must be made about half-life. Half-life does not change with the drug dose, meaning that it will always take the same amount of time to eliminate one-half of the drug present in the body even if the athlete takes half of the dosage (e.g., one tablet of ibuprofen instead of two) or more than the recommended dosage.
Thus far in this chapter, we have discussed what constitutes a drug, how it binds to cellular receptors, and the various quantitative methods used to measure the effectiveness of a drug. Different processes or events occur from the time a drug is introduced into the body until it is completely eliminated. This concept is called pharmacokinetics. It describes what the body does to or with a drug. Pharmacokinetics is concerned with four processes: absorption, distribution, metabolism, and excretion (Fig. 2–6).
The pharmacokinetic process. (Adapted from Lehne, RA. Pharmacokinetics. In Pharmacology for Nursing Care, ed 3, p. 30. Copyright 1998, with permission from Elsevier "Science".
As mentioned previously, a drug can exert its effects directly at the site of administration. However, most drugs are not administered at the site of action. For example, many drugs are taken orally. Therefore they must be absorbed into the bloodstream and carried to the site of action. The speed, rate, and extent at which a drug is absorbed and produces its pharmacological action is dependent on the physical and chemical properties of the drug. Such properties include the solubility of the drug, the surface area of the intended site of action, and, most importantly, the specific route of administration.
The major classes of administration are (1) enteral, (2) parenteral, (3) respiratory, and (4) topical (Table 2–1).
Table 2–1Routes of Drug Administration ||Download (.pdf) Table 2–1 Routes of Drug Administration
|Route Category ||Route ||Site ||Example |
|Enteral ||Sublingual ||Under tongue ||Nitroglycerin |
|Buccal ||Oral mucosa ||Miconazole (antifungal) |
|Oral ||Mouth ||Ibuprofen |
|Parenteral ||Subcutaneous ||Beneath skin ||Insulin |
|Intramuscular ||Into muscle ||Morphine |
|Intravenous ||Into vein ||Phenytoin (anticonvulsant) |
|Intrathecal ||Into spinal fluid ||Bupivacaine (anesthetic) |
|Intra-articular ||Into joint ||Dexamethasone (corticosteroid) |
|Intrasynovial ||Into joint fluid ||Triamcinolone (corticosteroid) |
|Inhalation ||Intrarespiratory ||Into lung ||Albuterol |
|Topical ||Transdermal ||On skin surface ||Nicotine patch |
|Ophthalmic ||Intraocular ||Into eye ||Timolol (antiglaucoma agent) |
|Otic ||Intraotic ||Into ear ||Cortisporin (antibiotic) |
|Miscellaneous ||Rectal ||Into rectum ||Acetaminophen |
|Vaginal ||Into vagina ||Clotrimazole (antifungal) |
Oral ingestion is the most commonly selected, safest, most convenient, and most economical route of administering medication. When medication is taken by mouth, the onset of drug action usually occurs within 1 hour. The drug is absorbed in several areas along the gastrointestinal (GI) tract. Gastric absorption begins when a drug that has been swallowed enters the stomach. How long a drug remains in the stomach, the pH of a patient's stomach acid, and gastric motility into the small intestine determine the amount of drug absorbed. Slowing down gastric emptying increases drug absorption and speeding up gastric emptying decreases it. Administering drugs on an empty stomach (with water to ensure dissolution) facilitates rapid delivery to the small intestine. Drugs are absorbed more readily in the small intestine because of its alkaline pH and large surface area.
By contrast, the oral mucosa, with a vast capillary blood supply, can dissolve certain drugs rapidly by the sublingual or buccal route. Drugs taken sublingually (e.g., nitroglycerin for angina) are placed under the tongue, where they dissolve in the saliva. Sublingual administration is often used in individuals who have difficulty in swallowing or who cannot be given drugs rectally.9 Drugs placed under the tongue are absorbed through the mucosal lining into the venous system and enter the systemic circulation within minutes, without preliminary passage through the liver.
Preliminary passage, or first-pass metabolism, can be described as the process by which a drug is ingested orally and then absorbed from the gastrointestinal tract into the portal venous system (Fig. 2–7). The drug must then pass through the liver before reaching the general systemic circulation. As a result of this process, many drugs are metabolized or broken down into inactive agents by the liver, which decreases the amount of active drug that is able to reach the site of action. For example, lidocaine, if given orally, is almost completely metabolized be the liver. This makes oral administration impractical and requires that the drug be introduced into the body by other methods.
First-pass effect. (From M.E. Winter, Bioavailability. In M.E. Winter, M.A. Koda-Kimble, and L.Y. Young [eds], Basic clinical pharmacokinetics, 2d ed. Applied Therapeutics, Vancouver, Wash., 1988, with permission.)
Drugs can be administered orally in many forms, including solutions, capsules, and tablets. Oral solutions—drugs in liquid form—are easier to swallow than drugs in solid forms. They may have coloring, flavoring, or sweetening agents and are usually dissolved in water. Syrups are a type of solution that contains high concentrations of sucrose or other sugars. Because water-soluble drugs are hard to dissolve in syrups, most often the drug is dissolved in water first and the flavoring syrup is added later. Elixirs are solutions in which the drug is dissolved in alcohol. The alcohol content usually ranges from 5 to 40 percent.
Capsules consist of one or more drugs plus various inactive substances in powder form, enclosed within a gelatin shell. The gelatin capsule can be either hard or soft and is intended to be swallowed whole. Tablets are the most commonly used solid dosage form. They can be swallowed whole or chewed. Tablets can also be coated (enteric coated) to delay the release of the drug and avoid gastric irritation. Enteric-coated tablets remain intact in the stomach but dissolve in the small intestine. These tablets are used to protect drugs from acid and pepsin in the stomach and to protect the stomach from discomfort.
Sustained-release capsules or tablets are specially coated and are designed to release a drug over a period of time. Individuals who want to decrease the number of daily doses often use sustained-release products. However, these products are usually more expensive. Allegra D, an antihistamine used for allergies, and Biaxin XL, an antibiotic, are examples of sustained-release products.
Drugs may also be absorbed in the lower gastrointestinal tract via suppository form. A suppository is a solid or semisolid compound that is inserted into a body orifice (rectum or vagina). Once inserted, the suppository melts as it reaches body temperature or dissolves into the aqueous secretions of the body cavity. Suppositories can produce local effects and, if used rectally, can also produce systemic effects. Common rectally administered medications include acetaminophen, aspirin, and anti-nausea preparations.
Parenteral administration means to give a drug by any non-oral route, usually by an injection directly into an internal body compartment or cavity. This route of administration usually allows the drug to be delivered directly to the target site. The action of the drug is therefore more predictable. In addition, parenteral administration is not subjected to first-pass metabolism in the liver. Common parenteral routes include subcutaneous, intramuscular, intravenous, intrathecal, and intra-articular.
A drug administered subcutaneously is usually injected beneath the skin into the connective tissue or fat deposits within the dermis. One example of this type of drug is injectable insulin, used by persons with diabetes. Drugs injected by this route can be slowly dispersed and absorbed into the bloodstream. However, only a small amount of a drug can be injected in this manner because of possible local irritation and the small volume the dermis can hold. A primary advantage of subcutaneous administration is that patients with proper training can inject themselves without the assistance of a health-care provider.
A drug injected into the skeletal muscle is absorbed more quickly than a subcutaneous injection because of the close proximity of blood vessels in the muscles. Common intramuscular agents include vaccines and pain medications. Drugs administered intramuscularly can cause local irritation, pain, soreness, and tenderness. Thus, different sites on the muscle are preferred for repeated injections.
Intravenous injections (drugs administered into the veins) produce an almost immediate response because they initially avoid the liver metabolism process. This method of drug introduction enables a drug to be delivered directly to target tissues. A drug administered intravenously can be precisely controlled in regard to quantity and reaches its target site rapidly. Most drugs are administered into the veins with intravenous cannulas (IVs) to produce the desired effects. This method of administration is convenient for prolonged drug therapy. However, any miscalculation of a drug dose can produce undesired consequences and make care difficult after administration.
Intrathecal injections are administered directly into the spinal cord or cerebrospinal fluid and can bypass the blood-brain barrier. Drugs commonly used by this route include narcotic analgesics, local anesthetics, antibiotics, anticancer agents, and antispasmodic drugs.
Intra-articular and intrasynovial injections are administered into the joints and synovial fluid, respectively. The sites normally injected are the elbow, knee, shoulder, wrist, and hip. The medications are usually anesthetics, antimicrobials, or corticosteroids.
Drugs administered by inhalation are in the form of gases or fine mists (aerosols). Because of their large surface area and rich blood supply, the lungs are an effective means of absorbing and transporting medications into the bloodstream rapidly.8 The small particles of these drugs ensure that gaseous exchange is not impeded within the lungs. This method of drug delivery is useful for applying medications directly to the alveolar and bronchial tissues for treatment of pulmonary conditions. Special inhalation devices are used to propel the agents into the alveolar and bronchial tissues. Common inhalation drugs include albuterol (Proventil), fluticasone (Flovent), and betamethasone (Beclovent), used in the treatment of asthma. Inhalation will be discussed further in Chapter 7, Respiratory Drugs.
Drugs administered topically are usually applied to the skin or mucous membranes. Lipid-soluble products are absorbed more readily through the skin than water-soluble products. Absorption of medications through the skin is inhibited by the epidermis, so drugs have a difficult time reaching the systemic circulation.2 Because of poor absorption, many medications are applied topically to treat problems on the skin. Topical drugs are usually manufactured as either ointments, creams, or transdermal patches. All these forms may produce either local or systemic effects.
Transdermal patches are controlled-release devices that may contain any number of drugs for local or systemic absorption. They are attached to the skin by an adhesive layer that ensures proper drug contact with the skin surface. For transdermal patches to be clinically effective, the drug must be able to permeate the skin, be nonirritating and non-sensitizing, and be unaffected by enzymes in the epidermis.7,11 In addition, mixing the drug in some type of oily base increases solubility and permeability through the dermis. 8 Transdermal agents provide a slow, controlled drug release that is effective in maintaining a relatively constant plasma level of the drug. Common transdermal agents include nicotine and estrogen patches. Drugs may also be administered transdermally via iontophoresis.
Ointments and creams are semisolid preparations for external use only. They include Neosporin and hydrocortisone. They can be easily spread and act as emollients, making the skin more pliable. Ointments and creams serve as protective barriers to prevent substances from coming in contact with the skin, and also as vehicles in which medications can be incorporated.
Powders are mixtures of finely divided drugs or chemicals in dry form that can be applied topically.
Before a drug can act on a specific receptor, it must pass through the different biological layers, then be transported to the site via the bloodstream. Passage through these layers depends not only on the characteristics of the drug itself—ionization, solubility, and size—but also on the rate of flow of the blood that carries the drug to its site of action. For example, a medication is taken orally to act on specific receptors located on the heart muscle. The drug must initially pass through various GI membranes, enter the bloodstream, pass through the liver, be distributed throughout the entire body via the bloodstream, reenter membranes on the heart, and eventually attach to a specific heart receptor. As you can see, this process takes time. Also, a portion of the active ingredient in the drug is lost by this process.
A brief review of cell physiology is warranted here to provide a better understanding of drug distribution through the biological membranes of the body. The typical cell membrane consists of a bimolecular layer of lipid (fatlike) molecules with protein molecules randomly embedded and protruding from one or both sides of the membrane. The protein molecules serve as carriers or receptors for drugs, and the lipid molecules permit fat-soluble molecules to pass easily into the cell while impeding water-soluble molecules. However, the cell membrane does allow some small-diameter water-soluble molecules (such as electrolytes and alcohol) to pass through specialized pores on the membrane.
The ability of a drug to cross cell membranes through the lipid barrier depends on the physical and chemical properties of the drug molecule. Most drugs exist as either weak organic acids or weak organic bases. When dissolved by body solutions, they form weak electrolytes. However, these electrolytes do not dissociate (form ions) completely in aqueous solution, but exist in solution as a mixture of ionized (charged) and nonionized (uncharged) forms. Ionized forms (e.g., ketoprofen) are usually water soluble and have difficulty passing through the cell membrane, whereas nonionized forms (e.g., dexamethasone) are lipid soluble and allow easier passage. The relative lipid solubility of the nonionized portion of a drug will determine if the drug will (1) be absorbed into the bloodstream, (2) be distributed throughout the body, (3) be able to cross the cell membranes and act within, and (4) be readily excreted in the urine.
How the drug passes through the cell membrane depends not only on ionization but also on the mode of transportation (Table 2–2). There are three common modes of transportation that most drugs use to cross cell membranes, either individually or using a combination of modes: filtration, diffusion, and active transport. The process of filtration allows small water-soluble molecules and ions to easily pass through cell membranes with small pores. Consequently, larger-diameter (lipid-soluble) molecules are unable to pass through the cell membrane by filtration. Instead, lipid-soluble molecules diffuse through the cell by dissolving in the lipid portion of the membrane. Diffusion is the most common method of travel across the membrane.
Table 2–2Modes of Drug Transportation Across Cell Membranes ||Download (.pdf) Table 2–2 Modes of Drug Transportation Across Cell Membranes
| ||Filtration ||Diffusion ||Active Transport |
|Drug size ||Small ||Small or large ||Small or large |
|Solubility ||Water or lipid ||Lipid ||Water or lipid |
|Energy requirements ||No ||No ||Yes |
|Movement against a concentration gradient ||No ||No ||Yes |
|Drug passage rate determined by: ||Size and concentration gradient ||Solubility and concentration gradient ||Energy, transport carrier saturation, and structural specificity |
Larger water-soluble molecules also have a more difficult time crossing the cell membrane by filtration. In order for these molecules to gain access to the cell, they need an active transport carrier or an energy-requiring system. Molecules outside the cell that do not have the specific physical and chemical properties to gain access into the cell must bind with a carrier that will transport them within the cell. After it deposits the molecules, the carrier is then free to return to the cell membrane to attach to another molecule. Only molecules with specific chemical properties can be actively transported, and only a certain number of molecules can be transported at one time.
Thus far, we have discussed the mechanisms by which a drug is absorbed and distributed throughout the body to produce a biological or therapeutic effect. However, a drug stays in the body for only a finite period of time before it is eliminated, as explained previously in the discussion of the half-life of a drug. Biotransformation, or metabolism, is the process of ridding the body of foreign substances. More specifically, biotransformation is the breakdown of an original drug compound into metabolites, which are then eliminated. The rate of metabolism is different for all individuals. Some metabolize the same drug at a slower rate than others. Factors such as disease, starvation, smoking, and age affect the rate of metabolism and the speed with which drugs are eliminated from the body.
The primary organ of metabolism is the liver,3,16 which has a specialized network of enzymes whose function is to metabolize drugs or foreign compounds. When a drug enters the hepatic enzyme system, it can lose some or all of its original pharmacological activity. In most cases, when a drug is metabolized, the end product is usually more water soluble than the original drug and is easily eliminated from the body.
As stated previously, a drug can stay within the body only for a certain period of time before it is eliminated. The main routes for drug elimination are through the urine, bile, and feces. Drug compounds may also be eliminated through the lungs and the salivary, sweat, and mammary glands. The main emphasis in this section is on drug elimination through the urine.
The kidney is the major organ of excretion.14 The process of excretion through the kidney is by glomerular filtration. Approximately 180 liters of plasma fluid are filtered each day, with 178.5 liters reabsorbed and 1.5 liters eliminated in the urine.19 As blood flows through the glomerulus, drugs are forced through the capillary wall and into the renal tubules. The glomeruli of the kidneys can easily filter unbound (water-soluble) drugs, but cannot filter protein-bound compounds as easily. Lipid-soluble compounds are reabsorbed after filtration and are not eliminated in the urine.
The relative pH of urine also determines whether a compound will be reabsorbed or excreted. Weak acids are eliminated faster in alkaline urine; weak bases are eliminated faster in acidic urine. One final factor controlling the rate of excretion is patient health. Patients with kidney disease or insufficient kidney function must be cautious when taking medications. Decreased kidney function leads to decreased elimination, causing the drug to accumulate and potentially cause toxicity.