Pharmacology: Drug Action and Routes of Administration PDF

Pharmacology Reference: Lippincott Illustrated Reviews Pharmacology 7th Ed. Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes....

Pharmacology Reference: Lippincott Illustrated Reviews Pharmacology 7th Ed. Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamic processes. These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. The actions of the body on the drug are called pharmacokinetic processes. Pharmacokinetic processes govern the absorption, distribution, and elimination of drugs and are of great practical importance in the choice and administration of a particular drug for a particular patient, eg, a patient with impaired renal function. Pharmacokinetics Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma. Distribution: Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids. Metabolism: Third, the drug may be biotransformed by metabolism by the liver or other tissues. Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces. Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including the route of administration, the dose, the frequency, and the duration of treatment. 2 Routes of drugs administration: The route of administration is determined by properties of the drug and by the therapeutic objectives (for example, the need for a rapid onset, the need for long-term treatment, or restriction of delivery to a local site). Major routes of drug administration include enteral, parenteral, and topical, among others. A. Enteral: Enteral administration (administering a drug by mouth) is the safest and most common, convenient, and economical method of drug administration. The drug may be swallowed, allowing oral delivery, or it may be placed under the tongue (sublingual), or between the gums and cheek (buccal), facilitating direct absorption into the bloodstream. 1. Oral: Oral administration provides many advantages. Oral drugs are easily self- administered, and toxicities and/or overdose of oral drugs may be overcome with antidotes, such as activated charcoal. However, the pathways involved in oral drug absorption are the most complicated, and the low gastric pH inactivates some drugs. A wide range of oral preparations is available including enteric-coated and extended-release preparations. a. Enteric-coated preparations: An enteric coating is a chemical envelope that protects the drug from stomach acid, delivering it instead to the less acidic intestine, where the coating dissolves and releases the drug. Enteric coating is useful for certain drugs {for example, omeprazole) that are acid labile, and for drugs that are irritating to the stomach, such as aspirin. b. Extended-release preparations: Extended-release {abbreviated ER, XR, XL, SR, etc.) medications have special coatings or ingredients that control drug release, thereby allowing for slower absorption and prolonged duration of action. ER formulations can be dosed less frequently and may improve patient compliance. In addition, ER formulations may maintain concentrations within the therapeutic range over a longer 3 duration, as opposed to immediate release dosage forms, which may result in larger peaks and troughs in plasma concentration. ER formulations are advantageous for drugs with short half-lives. For example, the half-life of oral morphine is 2 to 4 hours, and it must be administered six times daily to provide continuous pain relief. However, only two doses are needed when extended-release tablets are used. 2. Sublingual/buccal: The sublingual route involves placement of drug under the tongue. The buccal route involves placement of drug between the cheek and gum. Both the sublingual and buccal routes of absorption have several advantages, including ease of administration, rapid absorption, bypass of the harsh gastrointestinal (GI) environment, and avoidance of first-pass metabolism B. Parenteral: The parenteral route introduces drugs directly into the body by the injection. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (for example, heparin) or unstable in the GI tract (for example, insulin). Parenteral administration is also used if a patient is unable to take oral medications (unconscious patients) and in circumstances that require a rapid onset of action. In addition, parenteral routes have the highest bioavailability and are not subject to first-pass metabolism or the harsh GI environment. Parenteral administration provides the most control over the actual dose of drug delivered to the body. However, these routes of administration are irreversible and may cause pain, fear, local tissue damage, and infections. The three major parenteral routes are intravascular (intravenous or intra-arterial), intramuscular, and subcutaneous. 4 1. Intravenous (IV): IV injection is the most common parenteral route. It is useful for drugs that are not absorbed orally, such as the neuromuscular blocker rocuronium. IV delivery permits a rapid effect and a maximum degree of control over the amount of drug delivered. When injected as a bolus, the full amount of drug is delivered to the systemic circulation almost immediately. If administered as an IV infusion, the drug is infused over a longer period, resulting in lower peak plasma concentrations and an increased duration of circulating drug. 2. Intramuscular (IM): Drugs administered IM can be in aqueous solutions, which are absorbed rapidly, or in specialized depot preparations, which are absorbed slowly. Depot preparations often consist of a suspension of drug in a nonaqueous vehicle, such as polyethylene glycol. As the vehicle diffuses out of the muscle, drug precipitates at the site of injection. The drug then dissolves slowly, providing a sustained dose over an extended interval. 3. Subcutaneous (SC): Like IM injection, SC injection provides absorption via simple diffusion and is slower than the IV route. SC injection minimizes the risks of hemolysis or thrombosis associated with IV injection and may provide constant, slow, and sustained effects. This route should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur. Drugs commonly administered via the subcutaneous route include insulin and heparin. 4. Intradermal: The intradermal (I D) route involves injection into the dermis, the more vascular layer of skin under the epidermis. Agents for diagnostic determination and desensitization are usually administered by this route 5 C. Other: 1. Oral inhalation and nasal preparations: Both the oral inhalation and nasal routes of administration provide rapid delivery of drug across the large surface area of mucous membranes of the respiratory tract and pulmonary epithelium. Drug effects are almost as rapid as are those with IV bolus. Drugs that are gases (for example, some anesthetics) and those that can be dispersed in an aerosol are administered via inhalation. This route is effective and convenient for patients with respiratory disorders such as asthma or chronic obstructive pulmonary disease, because drug is delivered directly to the site of action, thereby minimizing systemic side effects. The nasal route involves topical administration of drugs directly into the nose, and it is often used for patients with allergic rhinitis. 2. Intrathecal/intraventricular: The blood-brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid. 3. Topical: Topical application is used when a local effect of the drug is desired. 4. Transdermal: This route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application, as well as the lipid solubility of the drug. 5. Rectal: Because 50% of the drainage of the rectal region bypasses the portal circulation, the biotransformation of drugs by the liver is minimized with rectal administration. The rectal route has the additional advantage of preventing destruction of the drug in the Gl environment. This route is also useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious. Rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa. Following figure summarizes characteristics of the common routes of administration, along with example drugs. 6 7  Schematic representation of a transdermal patch. Absorption of drugs: Absorption is the transfer of a drug from the site of administration to the bloodstream. The rate and extent of absorption depend on the environment where the drug is absorbed, chemical characteristics of the drug, and the route of administration (which influences bioavailability). Routes of administration other than intravenous may result in partial absorption and lower bioavailability. A. Mechanisms of absorption of drugs from the GI tract Depending on their chemical properties, drugs may be absorbed from the GI tract by passive diffusion, facilitated diffusion, active transport, or endocytosis. 8 1. Passive diffusion: The driving force for passive diffusion of a drug is the concentration gradient across a membrane separating two body compartments. In other words, the drug moves from an area of high concentration to one of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows low structural specificity. The vast majority of drugs are absorbed by this mechanism. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas lipid-soluble drugs readily move across most biologic membranes due to solubility in the membrane lipid bilayers. 2. Facilitated diffusion: Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells. This process is known as facilitated diffusion. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier. 3. Active transport: This mode of drug entry also involves specific carrier proteins that span the membrane. However, active transport is energy dependent, driven by the hydrolysis of adenosine triphosphate (ATP). It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher concentration. The process is saturable. Active transport systems are selective and may be competitively inhibited by other co-transported substances. 9 4. Endocytosis and exocytosis: This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. Exocytosis is the reverse of endocytosis. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. Vitamin B12 is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and released by exocytosis. Figure: A. Diffusion of the nonionized form of a weak acid through a lipid membrane. B. Diffusion of the nonionized form of a weak base through a lipid membrane B. Factors influencing absorption 1. Effect of pH on drug absorption: Acidic drugs (HA) release a proton (H+), causing a charged anion (A−) to form: Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B): 10  Most drugs are either weak acids or weak bases. A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A− cannot. For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa. 2. Blood flow to the absorption site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach. 3. Total surface area available for absorption: With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. 4. Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. 5. Expression of P-glycoprotein: P-glycoprotein is a trans-membrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved in transportation of drugs from tissues to blood. That is, it “pumps” drugs out of the cells. Thus, in areas of high expression, P-glycoprotein reduces drug absorption. In addition to transporting many drugs out of cells, it is also associated with multidrug resistance. 11 C. Bioavailability Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. For example, if 100 mg of a drug is administered orally and 70mg is absorbed unchanged, the bioavailability is 0.7 or 70%. Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration. 1. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with levels achieved by IV administration. After IV administration, 100% of the drug rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured. 2. Factors that influence bioavailability: In contrast to IV administration, which confers 100% bioavailability, orally administered drugs often undergo first-pass metabolism. This biotransformation, in addition to chemical and physical characteristics of the drug, determines the rate and extent to which the agent reaches the systemic circulation. a. First-pass hepatic metabolism: When a drug is absorbed from the Gl tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased. This is referred to as first pass metabolism. [Note: First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. For example, more than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is primarily administered via the sublingual, transdermal, or intravenous route.] Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action. b. Solubility of the drug: Very hydrophilic drugs are poorly absorbed because of the inability to cross lipid-rich cell membranes. Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous body fluids 12 and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases. In contrast to IV administration, which confers 100% bioavailability, orally administered drugs often undergo first-pass metabolism. This biotransformation, in addition to the chemical and physical characteristics of the drug, determines the rate and extent to which the agent reaches the systemic circulation. c. Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of gastric contents. Others, such as insulin, are destroyed in the Gl tract by degradative enzymes. d. Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients {such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. Drug distribution: Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues. For drugs administered IV, absorption is not a factor, and the initial phase (from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which the drug rapidly leaves the circulation and enters the tissues. The distribution of a drug from the plasma to the interstitium depends on cardiac output and local blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug. 13 A. Blood flow The rate of blood flow to the tissue capillaries varies widely. For instance, blood flow to "vessel-rich organs" (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. Variation in blood flow partly explains the short duration of hypnosis produced by an IV bolus of propofol. High blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia. A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration so that the drug diffuses out of the CNS, down the concentration gradient, and consciousness is regained. B. Capillary permeability Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between endothelial cells. In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. In the brain, the capillary structure is continuous, and there are no slit junctions. To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or undergo active transport. For example, a specific transporter carries levodopa into the brain. Lipid soluble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane. By contrast, ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endothelial cells that have no slit junctions. These closely juxtaposed cells form tight junctions that constitute the blood- brain barrier. 14 C. Binding of drugs to plasma proteins and tissues 1. Binding to plasma proteins: Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows transfer out of the vascular compartment. Albumin is the major drug binding protein, and it may act as a drug reservoir. As the concentration of free drug decreases due to elimination, the bound drug dissociates from albumin. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma. 2. Binding to tissue proteins: Many drugs accumulate in tissues, leading to higher concentrations in tissues than in interstitial fluid and blood. Drugs may accumulate because of binding to lipids, proteins, or nucleic acids. Drugs may also undergo active transport into tissues. Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity. (For example, acrolein, the metabolite of cyclophosphamide, can cause hemorrhagic cystitis because it accumulates in the bladder.) D. Lipophilicity The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic membranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. The major factor influencing the distribution of lipophilic drugs is blood flow to the area. By contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions. E. Volume of distribution The apparent volume of distribution, Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0). Amount of drug in the body Vd = --------------------------------------- C0 15 Although Vd has no physiologic or physical basis, it can be useful to compare the distribution of a drug with the volumes of the water compartments in the body. 1. Distribution into the water compartments in the body: Once a drug enters the body, it has the potential to distribute into any one of the three functionally distinct compartments of body water or to become sequestered in a cellular site. a. Plasma compartment: If a drug has a high molecular weight or is extensively protein bound, it is too large to pass through the slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. As a result, it has a low Vd that approximates the plasma volume, or about 4 L in a 70-kg individual. Heparin shows this type of distribution. b. Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it can pass through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid. Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the interstitial fluid, which together constitute the extracellular fluid (about 20% of body weight or 14L in a 70-kg individual). Aminoglycoside antibiotics show this type of distribution. c. Total body water: If a drug has a low molecular weight and has enough lipophilicity, it can move into the interstitium through the slit junctions and pass through the cell membranes into the intracellular fluid. These drugs distribute into a volume of about 60% of body weight or about 42 L in a 70-kg individual. Ethanol exhibits this apparent Vd. [Note: In general, a larger Vd indicates greater distribution into tissues; a smaller Vd suggests confinement to plasma or extracellular fluid.] 2. Determination of Vd: The fact that drug clearance is usually a first order process allows calculation of Vd. First order means that a constant fraction of the drug is eliminated per unit of time. This process can be most easily analyzed by plotting the log of the plasma drug concentration (Cp) versus time. The concentration of drug in the plasma can be extrapolated back to time zero (the time of IV bolus) on the Y axis to determine C0, which is the concentration of drug that would have been 16 achieved if the distribution phase had occurred instantly. This allows calculation of Vd as: Dose Vd = ------------ C0 For example, if 10 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C0 = 1 mg/L, then Vd = 10 mg/1 mg/L = 10 L. Figure: Drug concentrations in plasma after a single injection of drug at time = 0. A. Concentration data are plotted on a linear scale. B. Concentration data are plotted on a log scale. Drug clearance through metabolism: Once a drug enters the body, the process of elimination begins. The three major routes of elimination are hepatic metabolism, biliary elimination, and urinary elimination. Together, these elimination processes decrease the plasma concentration exponentially. That is, a constant fraction of the drug present is eliminated in a given unit of time. Most drugs are eliminated according to first-order kinetics, although some, such as aspirin in high doses, are eliminated according to zero-order or nonlinear kinetics. Metabolism leads to production of products with increased polarity, which allows the drug to be eliminated. Clearance (CL) estimates the amount of drug cleared from the body per unit of time. The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble 17 agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called phase I and phase II. Figure: The biotransformation of drugs Drug clearance through kidney: Drugs must be sufficiently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes, the most important being elimination through the kidney into the urine. Patients with renal dysfunction may be unable to excrete drugs and are at risk for drug accumulation and adverse effects. Elimination of drugs via the kidneys into urine involves the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption. 1. Glomerular filtration: Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate. The glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish significantly in renal disease. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, variations in GFR and protein binding of drugs do affect this process. 18 2. Proximal tubular secretion: Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for anions (for example, deprotonated forms of weak acids) and one for cations (for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system. Figure: Drug elimination by the kidney 3. Distal tubular reabsorption: As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.” For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. Excretion by other routes: Drug excretion may also occur via the intestines, bile, lungs, and breast milk, among others. Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are excreted in the feces. The lungs are primarily involved in the elimination of anesthetic gases (for example, desflurane). Elimination of drugs in breast milk may expose the breast-feeding infant to medications 19 and/ or metabolites being taken by the mother and is a potential source of undesirable side effects to the infant. Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. Total body clearance and drug half-life are important measures of drug clearance that are used to optimize drug therapy and minimize toxicity. A. Total body clearance The total body (systemic) clearance, Cltotal, is the sum of all clearances from the drug- metabolizing and drug-eliminating organs. The kidney is often the major organ of excretion. The liver also contributes to drug clearance through metabolism and/or excretion into the bile. Total clearance is calculated using the following equation: CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother where CLhepatic + CLrenal are typically the most important. B. Clinical situations resulting in changes in drug half-life When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. Patients who may have an increase in drug half-life include those with 1) diminished renal or hepatic blood flow, for example, in cardiogenic shock, heart failure, or hemorrhage; 2) decreased ability to extract drug from plasma, for example, in renal disease; and 3) decreased metabolism, for example, when a concomitant drug inhibits metabolism or in hepatic insufficiency, as with cirrhosis. These patients may require a decrease in dosage or less frequent dosing intervals. In contrast, the half-life of a drug may be decreased by increased hepatic blood flow, decreased protein binding, or increased metabolism. This may necessitate higher doses or more frequent dosing intervals. 20  Drug–Receptor Interactions and Pharmacodynamics Pharmacodynamics describes the actions of a drug on the body and the influence of drug concentrations on the magnitude of the response. Most drugs exert their effects, both beneficial and harmful, by interacting with receptors (that is, specialized target macromolecules) present on the cell surface or within the cell. The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction. Signal Transduction: Drugs act as signals, and receptors act as signal detectors. A drug is termed an "agonist' if it binds to a site on a receptor protein and activates it to initiate a series of reactions that ultimately result in a specific intracellular response. "Second messenger'' or effector molecules are part of the cascade of events that translates agonist binding into a cellular response. A. The drug-receptor complex Cells have many different types of receptors, each of which is specific for a particular agonist and produces a unique response. Cardiac cell membranes, for example, contain p-adrenergic receptors that bind and respond to epinephrine or norepinephrine. Cardiac cells also contain muscarinic receptors that bind and respond to acetylcholine. These two receptor populations dynamically interact to control the heart's vital functions. The magnitude of the cellular response is proportional to the number of drug- receptor complexes. This concept is conceptually similar to the formation of complexes between enzyme and substrate and shares many common features, such as specificity of the receptor for a given agonist. Although much of this chapter centers on the interaction of drugs with specific receptors, it is important to know that not all drugs exert effects by interacting with a receptor. Antacids, for instance, chemically neutralize excess gastric acid, thereby reducing stomach upset. 21 B. Receptor states Receptors exist in at least two states, inactive (R) and active (R*), that are in reversible equilibrium with one another, usually favoring the inactive state. Binding of agonists causes the equilibrium to shift from R to R* to produce a biologic effect. Antagonists are drugs that bind to the receptor but do not increase the fraction of R*, instead stabilizing the fraction of R. Some drugs (partial agonists) shift the equilibrium from R to R*, but the fraction of R* is less than that caused by an agonist. The magnitude of biological effect is directly related to the fraction of R*. In summary, agonists, antagonists, and partial agonists are examples of molecules or ligands that bind to the activation site on the receptor and can affect the fraction of R*. C. Major receptor families A receptor is defined as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes, nucleic acids, and structural proteins can act as receptors for drugs or endogenous agonists. However, the richest sources of receptors are membrane bound proteins that transduce extracellular signals into intracellular responses. These receptors may be divided into four families: 1) ligand-gated ion channels 2) G protein-coupled receptors 3) enzyme-linked receptors. 4) intracellular receptors. Generally, hydrophilic ligands interact with receptors that are found on the cell surface. In contrast, hydrophobic ligands enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells. Transmembrane signaling mechanisms. 22 1. Transmembrane ligand-gated ion channels: The extracellular portion of ligand-gated ion channels usually contains the ligand binding site. This site regulates the shape of the pore through which ions can flow across cell membranes. The channel is usually closed until the receptor is activated by an agonist, which opens the channel briefly for a few milliseconds. Depending on the ion conducted through these channels, these receptors mediate diverse functions, including neurotransmission, and cardiac or muscle contraction. For example, stimulation of the nicotinic receptor by acetylcholine results in sodium influx and potassium outflux, generating an action potential in a neuron or contraction in skeletal muscle. On the other hand, agonist stimulation of the γ-aminobutyric acid (GABA) receptor increases chloride influx and hyperpolarization of neurons. Voltage-gated ion channels may also possess ligand-binding sites that can regulate channel function. For example, local anesthetics bind to the voltage-gated sodium channel, inhibiting sodium influx and decreasing neuronal conduction. The recognition of chemical signals by G protein–coupled membrane receptors affects the activity of adenylyl cyclase. 2. Transmembrane G protein–coupled receptors: The extracellular domain of this receptor contains the ligand-binding area, and the intracellular domain interacts (when activated) with a G protein or effector molecule. There are many kinds of G proteins (for example, Gs, Gi, and Gq), but they all are composed of three protein subunits. The α subunit binds guanosine triphosphate 23 (GTP), and the β and γ subunits anchor the G protein in the cell membrane. Binding of an agonist to the receptor increases GTP binding to the α subunit, causing dissociation of the α-GTP complex from the βγ complex. These two complexes can then interact with other cellular effectors, usually an enzyme, a protein, or an ion channel, that are responsible for further actions within the cell. These responses usually last several seconds to minutes. Sometimes, the activated effectors produce second messengers that further activate other effectors in the cell, causing a signal cascade effect. A common effector, activated by Gs and inhibited by Gi, is adenylyl cyclase, which produces the second messenger cyclic adenosine monophosphate (cAMP). Gq activates phospholipase C, generating two other second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). DAG and cAMP activate different protein kinases within the cell, leading to a myriad of physiological effects. IP3 regulates intracellular free calcium concentrations, as well as some protein kinases. 3. Enzyme-linked receptors: This family of receptors consists of a protein that may form dimers or multisubunit complexes. When activated, these receptors undergo conformational changes resulting in increased cytosolic enzyme activity, depending on their structure and function (Figure 6). This response lasts on the order of minutes to hours. The most common enzyme-linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) possess tyrosine kinase activity as part of their structure. The activated receptor phosphorylates tyrosine residues on itself and then Insulin receptor other specific proteins. Phosphorylation can substantially modify the structure of the target protein, thereby acting as a molecular switch. For example, when the peptide hormone insulin binds to two of its 24 receptor subunits, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylates other peptides or proteins that subsequently activate other important cellular signals. This cascade of activations results in a multiplication of the initial signal, much like that with G protein– coupled receptors. 4. Intracellular receptors: The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular, and, therefore, the ligand must diffuse into the cell to interact with the receptor. In order to move across the target cell membrane, the ligand must have sufficient lipid solubility. The primary targets of these ligand– receptor complexes are transcription factors in the cell nucleus. Binding of the ligand with its receptor generally activates the receptor via dissociation from a variety of binding proteins. The activated ligand–receptor complex then translocates to the nucleus, where it often dimerizes before binding to transcription factors that regulate gene expression. The activation or inactivation of these factors causes the transcription of DNA into RNA and translation of RNA into an array of proteins. The time course of activation and response of these receptors is on the order of hours to days. For example, steroid hormones exert their action on target cells via intracellular receptors. Other targets of intracellular ligands are structural proteins, enzymes, RNA, and ribosomes. For example, tubulin is the target of antineoplastic agents such as paclitaxel, the enzyme dihydrofolate reductase is the target of antimicrobials such as trimethoprim, and the 50S subunit of the bacterial ribosome is the target of macrolide antibiotics such as erythromycin. D. Characteristics of signal transduction Signal transduction has two important features: 1) the ability to amplify small signals and 2) mechanisms to protect the cell from excessive stimulation. 1. Signal amplification: A characteristic of G protein-linked and enzyme-linked receptors is the ability to amplify signal intensity and duration via the signal cascade effect. Additionally, activated G proteins persist for a longer duration than does the original agonist-receptor complex. The binding of albuterol, for example, may only exist for a few milliseconds, but the subsequent activated G proteins may last for hundreds of milliseconds. Further prolongation and amplification of the initial signal 25 are mediated by the interaction between G proteins and their respective intracellular targets. Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response. Systems that exhibit this behavior are said to have spare receptors. About 99% of insulin receptors are "spare” providing an immense functional reserve that ensures that adequate amounts of glucose enter the cell. On the other hand, only about 5% to 10% of the total B3-adrenoceptors in the heart are spare. Therefore, little functional reserve exists in the failing heart, because most receptors must be occupied to obtain maximum contractility. 2. Desensitization and down-regulation of receptors: Repeated or continuous administration of an agonist or antagonist often leads to changes in the responsiveness of the receptor. The receptor may become desensitized due to too much agonist stimulation (Figure 2.6), resulting in a diminished response. This phenomenon, called tachyphylaxis, is often due to phosphorylation that renders receptors unresponsive to the agonist. In addition, receptors may be internalized within the cell, making them unavailable for further agonist interaction (down-regulation). Some receptors, particularly ion channels, require a finite time following stimulation before they can be activated again. During this recovery phase, unresponsive receptors are said to be "refractory." Repeated exposure of a receptor to an antagonist, on the other hand, results in up-regulation of receptors, in which receptor reserves are inserted into the membrane, increasing the number of receptors available. Up-regulation of receptors can make cells more sensitive to agonists and/or more resistant to effects of the antagonist. 26  Dose-Response Relationship: Agonist drugs mimic the action of the endogenous ligand for the receptor (for example, isoproterenol mimics norepinephrine on b1 receptors of the heart). The magnitude of the drug effect depends on receptor sensitivity to the drug and the drug concentration at the receptor site, which, in turn, is determined by both the dose of drug administered and by the drug's pharmacokinetic profile, such as rate of absorption, distribution, metabolism, and elimination. A. Graded dose-response relationship As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect). Plotting the magnitude of response against increasing doses of a drug produces a graded dose-response curve. Two important drug characteristics, potency and efficacy, can be determined by graded dose response curves. 1. Potency: Potency is a measure of the amount of drug necessary to produce an effect. The concentration of drug producing 50% of the maximum effect (EC50) is often used to determine potency. In below figure, The EC50 for Drugs A and B indicate that Drug A is more potent than Drug B, because a lesser amount of Drug A is needed to obtain 50% effect. Therapeutic preparations of drugs reflect their potency. For example, candesartan and irbesartan are angiotensin receptor blockers used to treat hypertension. The therapeutic dose range for candesartan is 4 to 32 mg, as compared to 75 to 300 mg for irbesartan. Therefore, candesartan is more potent than irbesartan (it has a lower EC50 value). Since the range of drug concentrations that cause from 1% to 99% of maximal response usually spans several orders of magnitude, semilogarithmic plots are 27 used to graph the complete range of doses. the curves become sigmoidal in shape, which simplifies the interpretation of the dose-response curve. The effect of dose on the magnitude of pharmacologic response. Panel A is a linear graph. Panel B is a semilogarithmic plot of the same data. EC50 = drug dose causing 50% of maximal response. 2. Efficacy: Efficacy is the magnitude of response a drug causes when it interacts with a receptor. Efficacy is dependent on the number of drug receptor complexes formed and the intrinsic activity of the drug (its ability to activate the receptor and cause a cellular response). Maximal efficacy of a drug (Emax) assumes that the drug occupies all receptors, and no increase in response is observed in response to higher concentrations of drug. The maximal response differs between full and partial agonists, even when the drug occupies 100% of the receptors. Similarly, even though an antagonist occupies 100% of the receptor sites, no receptor activation results and Emax is zero. Efficacy is a more clinically useful characteristic than potency, since a drug with greater efficacy is more therapeutically beneficial than one that is more potent. Intrinsic Activity: As mentioned above, an agonist binds to a receptor and produces a biologic response based on the concentration of the agonist and the fraction of activated receptors. The intrinsic activity of a drug determines its ability to fully or partially activate the receptors. Drugs may be categorized according to their intrinsic activity and resulting Emax values. 28 A. Full agonists If a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand, it is a full agonist. Full agonists bind to a receptor, stabilizing the receptor in its active state and are said to have an intrinsic activity of one. All full agonists for a receptor population should produce the same Emax. For example, phenylephrine is a full agonist at α1-adrenoceptors, because it produces the same Emax as does the endogenous ligand, norepinephrine. Upon binding to α1-adrenoceptors on vascular smooth muscle, phenylephrine stabilizes the receptor in its active state. This leads to the mobilization of intracellular Ca2+, causing interaction of actin and myosin filaments and shortening of the muscle cells. The diameter of the arteriole decreases, causing an increase in resistance to blood flow through the vessel and an increase in blood pressure. As this brief description illustrates, an agonist may have many measurable effects, including actions on intracellular molecules, cells, tissues, and intact organisms. 29  All of these actions are attributable to interaction of the drug with the receptor. For full agonists, the dose–response curves for receptor binding and each of the biological responses should be comparable. B. Partial agonists Partial agonists have intrinsic activities greater than zero but less than one. Even if all the receptors are occupied, partial agonists cannot produce the same Emax as a full agonist. However, a partial agonist may have an affinity that is greater than, less than, or equivalent to that of a full agonist. When a receptor is exposed to both a partial agonist and a full agonist, the partial agonist may act as an antagonist of the full agonist. Consider what would happen to the Emax of a receptor saturated with an agonist in the presence of increasing concentrations of a partial agonist. As the number of receptors occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of the partial agonist. This potential of partial agonists to act as both an agonist and antagonist may be therapeutically utilized. For example, aripiprazole, an atypical antipsychotic, is a partial agonist at selected dopamine receptors. Dopaminergic pathways that are overactive tend to be inhibited by aripiprazole, whereas pathways that are underactive are stimulated. This might explain the ability of aripiprazole to improve symptoms of schizophrenia, with a small risk of causing extrapyramidal adverse effects. C. Inverse agonists Typically, unbound receptors are inactive and require interaction with an agonist to assume an active conformation. However, some receptors show a spontaneous conversion from R to R* in the absence of an agonist (constitutive 30 activation). Inverse agonists, unlike full agonists, stabilize the inactive R form and cause R* to convert to R. This decreases the number of activated receptors to below that observed in the absence of drug. Thus, inverse agonists have an intrinsic activity less than zero, reverse the activity of receptors, and exert the opposite pharmacological effect of agonists. D. Antagonists Antagonists bind to a receptor with high affinity but possess zero intrinsic activity. An antagonist has no effect on biological function in the absence of an agonist, but can decrease the effect of an agonist when present. Antagonism may occur either by blocking the drug's ability to bind to the receptor or by blocking its ability to activate the receptor. 1. Competitive antagonists: If the antagonist binds to the same site on the receptor as the agonist in a reversible manner, it is "competitive’’ A competitive antagonist interferes with an agonist binding to its receptor and maintains the receptor in its inactive state. For example, the antihypertensive drug terazosin competes with the endogenous ligand norepinephrine at α1-adrenoceptors, thus decreasing vascular smooth muscle tone and reducing blood pressure. However, increasing the concentration of agonist relative to antagonist can overcome this inhibition. Thus, competitive antagonists characteristically shift the agonist dose- response curve to the right (increased EC50) without affecting Emax. 2. Irreversible antagonists: Irreversible antagonists bind covalently to the active site of the receptor, thereby permanently reducing the number of receptors available to the agonist. An irreversible antagonist causes a downward shift of the Emax. with no shift of EC50 values. In contrast to competitive antagonists, addition of more agonist does not overcome the effect of irreversible antagonists. Thus, irreversible antagonists and allosteric antagonists are both considered noncompetitive antagonists. 31 A fundamental difference between competitive and noncompetitive antagonists is that competitive antagonists reduce agonist potency (increase EC50) and noncompetitive antagonists reduce agonist efficacy (decrease Emax). 3. Allosteric antagonists: An allosteric antagonist binds to a site (allosteric site) other than the agonist-binding site and prevents receptor activation by the agonist. This type of antagonist also causes a downward shift of the Emax of an agonist, with no change in the EC50 value. An example of an allosteric agonist is picrotoxin, which binds to the inside of the GABA-controlled chloride channel. When picrotoxin binds inside the channel, no chloride can pass through the channel, even when GABA fully occupies the receptor. 4. Functional antagonism: An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist. A classic example is the functional antagonism by epinephrine to histamine-induced bronchoconstriction. Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing bronchoconstriction of the bronchial tree. Epinephrine is an agonist at B2- adrenoceptors on bronchial smooth muscle, which causes the muscles to relax. This functional antagonism is also known as "physiologic antagonism." Quantal Dose-Response Curve: Another important dose-response relationship is that between the dose of the drug and the proportion of a population of patients that responds to it. These responses are known as quantal responses, because, for any individual, either the effect occurs or it does not. Graded responses can be transformed to quantal responses by designating a predetermined level of the graded response as the point at which a response occurs or not. For example, a quantal dose response relationship can be determined in a population for the antihypertensive drug atenolol. A positive response is defined as a fall of at least 5 mm Hg in diastolic blood pressure. Quantal dose-response curves are useful for determining doses to which most of the population responds. They have 32 similar shapes as log dose-response curves, and the ED50 is the drug dose that causes a therapeutic response in half of the population. A. Therapeutic index The therapeutic index (TI) of a drug is the ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response (ED50) in half the population: TI = TD50/ED50 The Tl is a measure of a drug's safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic. B. Clinical usefulness of the therapeutic Index The Tl of a drug is determined using drug trials and accumulated clinical experience. These usually reveal a range of effective doses and a different (sometimes overlapping) range of toxic doses. Although high Tl values are required for most drugs, some drugs with low therapeutic indices are routinely used to treat serious diseases. In these cases, the risk of experiencing adverse effects is not as great as the risk of leaving the disease untreated. The responses to warfarin, an oral anticoagulant with a low TI, and penicillin, an antimicrobial drug with a large Tl. 1. Warfarin (example of a drug with a small therapeutic index): As the dose of warfarin is increased, a greater fraction of the patients responds (for this drug, the desired response is a two- to threefold increase in the international normalized ratio [INR]) until, eventually, all patients respond. However, at higher doses of warfarin, anticoagulation resulting in hemorrhage occurs in a small percent of patients. Agents with a low Tl (that is, drugs for which dose is critically important) are those drugs for which bioavailability critically alters the therapeutic effects. 33 2. Penicillin (example of a drug with a large therapeutic index): For drugs such as penicillin, it is safe and common to give doses in excess of that which is minimally required to achieve a desired response without the risk of adverse effects. In this case, bioavailability does not critically alter the therapeutic or clinical effects. 34  The Autonomic Nervous System The autonomic nervous system (ANS), along with the endocrine system, coordinates the regulation and integration of bodily functions. The endocrine system sends signals to target tissues by varying the levels of blood-borne hormones. In contrast, the nervous system exerts its influence by the rapid transmission of electrical impulses over nerve fibers that terminate at effector cells, which specifically respond to the release of neuromediator substances. Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the ANS are called autonomic drugs. These autonomic agents act either by stimulating portions of the ANS or by blocking the action of the autonomic nerves. The nervous system is divided into two anatomical divisions: the central nervous system (CNS), which is composed of the brain and spinal cord, and the peripheral nervous system, which includes neurons located outside the brain and spinal cord—that is, any nerves that enter or leave the CNS (Figure 1). The peripheral nervous system is subdivided into the efferent and afferent divisions. The efferent neurons carry signals away from the brain and spinal cord to the peripheral tissues, and the afferent neurons bring information from the periphery to the CNS. Afferent neurons provide sensory input to modulate the function of the efferent division through reflex arcs or neural pathways that mediate a reflex action. Functional divisions within the nervous system The efferent portion of the peripheral nervous system is further divided into two major functional subdivisions: the somatic and the ANS (Figure 1). The somatic efferent neurons are involved in the voluntary control of functions such as contraction of the skeletal muscles essential for locomotion. The ANS, conversely, regulates the everyday requirements of vital bodily functions without the conscious participation of the mind. Because of the Figure 1: Organization of the involuntary nature of the ANS as well as its functions, it nervous system is also known as the visceral, vegetative, or involuntary nervous system. 35