Lecture # 2
THEME: BIOTRANSFORMATION OF MEDICATIONS IN THE ORGANISM. ELIMINATION OF MEDICATIONS.
Both metabolism and excretion can be viewed as processes responsible for elimination of drug (parent and metabolite) from the body. Drug metabolism changes the chemical structure of a drug to produce a drug metabolite, which is frequently but not universally less pharmacologically active. Metabolism also renders the drug compound more water soluble and therefore more easily excreted.
Drug metabolism reactions are carried out by enzyme systems that evolved over time to protect the body from exogenous chemicals. The enzyme systems for this purpose for the most part can be grouped into two categories: phase I oxidative or reductive enzymes and phase II conjugative enzymes. Enzymes within these categories exhibit some limited specificity in relation to the substrates acted upon; a given enzyme may interact with only a limited number of drugs. Some nonspecific hydrolytic enzymes, such as esterases and amidases, have not received much research attention. The focus of this discussion therefore is on phase I and phase II reactions and the enzymes that carry out these processes.
PHASE I REACTIONS
Phase I enzymes act by causing the drug molecule to undergo oxidation or more rarely, reduction. However, as discussed later, there is still a great deal of substrate specificity within a given enzyme family.
Cytochrome P450 Enzymes
The cytochrome P450 (CYP450) enzyme superfamily is the primary phase I enzyme system involved in the oxidativemetabolism of drugs and other chemicals. These enzymes also are responsible for all or part of the metabolism and synthesis of a number of endogenous compounds, such as steroid hormones and prostaglandins. Though it was originally described as the CYP450 enzyme, it is now apparent that it is a group of related enzymes, each with its own substrate specificity. To date, 12 unique isoforms (e.g., CYP3A4, CYP2D6) have been identified as playing a role in human drug metabolism, and others may be discovered.
More than one CYP isoform may be involved in the metabolism of a particular drug. For example, the calcium channel blocking drug verapamil is primarily metabolized by CYP3A4, but CYPs 2C9, 2C8 and 2D6 participate to some degree, particularly in the secondary metabolism of the verapamil metabolites. Thus, the degree to which a drug interaction involving competition for a CYP isoform may occur will depend on the extent of metabolism of each compound that can be attributed to that isoform.
The more isoforms involved in the metabolism of a drug, the less likely is a clinically significant drug interaction.
Substrate Specificity of the CYP Enzymes
CYP3A4 is thought to be the most predominant CYP isoform involved in human drug metabolism, both in terms of the amount of enzyme in the liver and the variety of drugs that are substrates for this enzyme isoform. This isoform may account for more than 50% of all CYP-mediated drug oxidation reactions, and CYP3A4 is likely to be involved in the greatest number of drug–drug interactions.
Regulation of the CYP Enzymes
CYP450 enzymes can be regulated by the presence of other drugs or by disease states. This regulation can either decrease or increase enzyme function, depending on the modulating agent. These phenomena are commonly referred to as enzyme inhibition and enzyme induction, respectively.
Enzyme Inhibition
Enzyme inhibition is the most frequently observed result of CYP modulation and is the primary mechanism for drug–drug pharmacokinetic interactions. The most common type of inhibition is simple competitive inhibition, wherein two drugs are vying for the same active site and the drug with the highest affinity for the site wins out. In this scenario, addition of a second drug with greater affinity for the enzyme inhibits metabolism of the primary drug, and an elevated primary drug blood or tissue concentration is the result. In the simplest case, each drug has its own unique degree of affinity for the CYP enzyme active site, and the degree of inhibition depends on how avidly the secondary (or effector) drug binds to the enzyme active site. For example, ketoconazole and triazolam compete for binding to the CYP3A4 active site and thus exhibit their own unique rate of metabolism.
However, when given concomitantly, the metabolism of triazolam by the CYP3A4 enzyme (essentially the only enzyme that metabolizes triazolam) is decreased to such a degree that the patient is exposed to 17 times as much of parent triazolam as when ketoconazole is not present.
A second type of CYP enzyme inhibition is mechanism-based inactivation (or suicide inactivation). In this type of inhibition, the effector compound (i.e., the inhibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme and prevents any further metabolism by the enzyme.
This mechanism-based inactivation lasts for the life of the enzyme molecule and thus can be overcome only by the proteolytic degradation of that particular enzyme molecule and subsequent synthesis of new enzyme protein. A drug that is commonly used in clinical practice and yet is known to be a mechanism-based inactivator of CYP3A4 is the antibiotic erythromycin.
Enzyme Induction
Induction of drug-metabolizing activity can be due either to synthesis of new enzyme protein or to a decrease in the proteolytic degradation of the enzyme. Increased enzyme synthesis is the result of an increase in messenger RNA (mRNA) production (transcription) or in the translation of mRNA into protein. Regardless of the mechanism, the net result of enzyme induction is the increased turnover (metabolism) of substrate. Whereas one frequently associates enzyme inhibition with an increase in potential for toxicity, enzyme induction is most commonly associated with therapeutic failure due to inability to achieve required drug concentrations.
TimotThe time course of enzyme induction is important, since it may play a prominent role in the duration of the effect and therefore the potential onset and offset of the drug interaction. Both time required for synthesis of new enzyme protein (transcription and translation) and the half-life of the inducing drug affect the time course of induction. An enzyme with a slower turnover rate will require a longer time before induction reaches equilibrium (steady state), and conversely, a faster turnover rate will result in a more rapid induction. With respect to the drug inducer, drugs with a shorter halflife will reach equilibrium concentrations sooner (less time to steady state) and thus result in a more rapid maximal induction, with the opposite being true for drugs with a longer half-life.
Flavin Monooxygenases
The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1–5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins.
CONJUGATIVE ENZYMES: PHASE II REACTIONS
Phase II conjugative enzymes metabolize drugs by attaching (conjugating) a more polar molecule to the original drug molecule to increase water solubility, thereby permitting more rapid drug excretion. This conjugation can occur following a phase I reaction involving the molecule, but prior metabolism is not required.
The phase II enzymes typically consist of multiple isoforms, analogous to the CYPs, but to date are less well defined.
Glucuronosyl Transferases
Glucuronosyl transferases (UGTs) conjugate the drug molecule with a glucuronic acid moiety, usually through establishment of an ether, ester, or amide bond. The glucuronic acid moiety, being very water soluble, generally renders the new conjugate more water soluble and thus more easily eliminated.
Typically this conjugate is inactive, but sometimes it is active. For example, UGT-mediated conjugation of morphine at the 6- position results in the formation of morphine-6-glucuronide, which is 50 times as potent an analgesic as morphine. It is now apparent that UGTs are also a superfamily of enzyme isoforms, each with differing substrate specificities and regulation characteristics. Of the potential products of the UGT1 ene family, only expression of UGT1A1, 3, 4, 5, 6, 9 and 10 occurs in humans. Depending on the isoform, these enzymes have varying reactivity toward a number of pharmacologically active compounds, such as opioids, androgens, estrogens, progestins, and nonsteroidal antiinflammatory drugs; UGT1A1 is the only physiologically significant enzyme involved in the conjugation of bilirubin. UGT1A4 appears to be inducible by phenobarbital administration, and UGT1A7 is induced by the chemopreventive agent oltipraz.
UGT2B7 is probably the most important of the UGT2 isoforms and possibly of all of the UGTs. It exhibits broad substrate specificity encompassing a variety of pharmacological agents, including many already mentioned as substrates for the UGT1A family. Little is known about the substrate specificities of the other UGT2B isoforms or the inducibility of this enzyme family.
N-Acetyltransferases
As their name implies, the N-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. The net result of this conjugation is an increase in water solubility and increased elimination of the compound. The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2. Little overlap in substrate specificities of the two isoforms appears to exist. NAT-2 is a polymorphic enzyme, a property found to have important pharmacological consequences (discussed later). To date, little information exists on the regulation of the NAT enzymes, such as whether they can be induced by chemicals. However, reports have suggested that disease states such as acquired immunodeficiency syndrome (AIDS) may down-regulate NAT-2, particularly during active disease.
Sulfotransferases and Methyltransferases
Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3_-phosphoadenosine 5_-phosphosulfate (PAPS). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs 1A1 to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULT1B1 possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULT1E1 has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the antihypertensive minoxidil. SULT2A1 also is active against steroid hormones. Little is known about the substrate specificity of SULT1C1. Regulation of the SULT enzymes appears to be controlled by levels of the available sulfate pool in the body or that of PAPS. Patients who consume a low-sulfate diet or have ingested multiple SULT substrates may be susceptible to inadequate metabolism by this enzyme and thus drug toxicity.
The methyltransferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-Omethyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. N-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine.
Possibly the most clinically relevant example of MT activity involves S-methylation by the enzyme thiopurine methyltransferase (TPMT). Patients who are high risk for development of severe bone marrow suppression when giveormal doses of the chemotherapeutic agent 6-mercaptopurine. Patients are now studied for TPMT activity prior to administration of 6-mercaptopurine so that the dose may be adjusted downward if they are found to be deficient in this enzyme.
TISSUE SPECIFICITY OF HUMAN DRUG METABOLISM ENZYMES
Though most drug metabolism enzymes reside in the liver, other organs may also play an important role. All of the enzymes previously mentioned are found in the human liver, but other tissues and organs may have some complement of these enzymes. CYP3A4 and CYP3A5 have been found in the human gut and can contribute to substantial metabolism of orally administered drugs, even before the compound reaches the liver. For example, CYP3A4 may play a substantial role in the low bioavailability of cyclosporine. Drug-metabolizing enzymes have also been found in measurable quantities in the kidney, brain, placenta, skin, and lungs.
EXCRETION OF DRUGS
Despite the reduction in activity that occurs as a drug leaves its site of action, it may remain in the body for a considerable period, especially if it is strongly bound to tissue components. Thus, reduction in pharmacological activity and drug elimination are to be seen as related but separate phenomena.
Excretion, along with metabolism and tissue redistribution, is important in determining both the duration of drug action and the rate of drug elimination.
Excretion is a process whereby drugs are transferred from the internal to the external environment, and the principal organs involved in this activity are the kidneys, lungs, biliary system, and intestines.
RENAL EXCRETION
Although some drugs are excreted through extrarenal pathways, the kidney is the primary organ of removal for most drugs, especially for those that are water soluble and not volatile.
The three principal processes that determine the urinary excretion of a drug are glomerular filtration, tubular secretion, and tubular reabsorption (mostly passive back-diffusion). Active tubular reabsorption also may have some influence on the rate of excretion for a limited number of compounds.
Glomerular Filtration
The ultrastructure of the glomerular capillary wall is such that it permits a high degree of fluid filtration while restricting the passage of compounds having relatively large molecular weights. This selective filtration is important in that it prevents the filtration of plasma proteins (e.g., albumin) that are important for maintaining an osmotic gradient in the vasculature and thus plasma volume. Several factors, including molecular size, charge, and shape, influence the glomerular filtration of large molecules.
The restricted passage of macromolecules can be thought of as a consequence of the presence of a glomerular capillary wall barrier with uniform pores.
Since approximately 130 mL of plasma water is filtered across the porous glomerular capillary membranes each minute (190 L/day), the kidney is admirably suited for its role in drug excretion. As the ultrafiltrate is formed, any drug that is free in the plasma water, that is, not bound to plasma proteins or the formed elements in the blood (e.g., red blood cells), will be filtered as a result of the driving force provided by cardiac pumping. All unbound drugs will be filtered as long as their molecular size, charge, and shape are not excessively large.
Compounds with an effective radius above 20 Å may have their rate of glomerular filtration restricted; hindrance to passage increases progressively as the molecular radius increases, and passage approaches zero when the compound radius becomes greater than about 42Å. Charged substances (e.g., sulfated dextrans) are usually filtered at slower rates thaeutral compounds (e.g., neutral dextrans), even when their molecular sizes are comparable. The greater restriction to filtration of charged molecules, particularly anions, is probably due to an electrostatic interaction between the filtered molecule and the fixed negative charges within the glomerular capillary wall. These highly anionic structural components of the wall contribute to an electrostatic barrier and are most likely in the endothelial or glomerular basement membrane regions. Molecular configuration also may influence the rate of glomerular filtration of drugs. Differences in the three-dimensional shape of macromolecules result in a restriction of glomerular passage of globular molecules (e.g., proteins) to a greater extent than of random coil or extended molecules (e.g., dextrans). Thus, the efficient retention of proteins within the circulation is attributed to a combination of factors, including their globular structure, their large molecular size, and the magnitude of their negative charge.
Factors that affect the glomerular filtration rate (GFR) also can influence the rate of drug clearance. For instance, inflammation of the glomerular capillaries may increase GFR and hence drug filtration. Most drugs are at least partially bound to plasma proteins, and therefore their actual filtration rates are less than the theoretical GFR. Anything that alters drug–protein binding, however, will change the drug filtration rate.
The usual range of half-lives seen for most drugs that are cleared solely by glomerular filtration is 1 to 4 hours. However, considerably longer half-lives will be seen if extensive protein binding occurs. Also, since water constitutes a larger percentage of the total body weight of the newborn than of individuals in other age groups, the apparent volume of distribution of water-soluble drugs is greater ieonates. This results in a lower concentration of drug in the blood coming to the kidneys per unit of time and hence a decreased rate of drug clearance. The lower renal plasma flow in the newborn also may decrease the glomerular filtration of drugs.
Passive Diffusion
An important determinant of the urinary excretion of drugs (i.e., weak electrolytes) is the extent to which substances diffuse back across the tubular membranes and reenter the circulation. In general, the movement of drugs is favored from the tubular lumen to blood, partly because of the reabsorption of water that occurs throughout most portions of the nephron, which results in an increased concentration of drug in the luminal fluid. The concentration gradient thus established will facilitate movement of the drug out of the tubular lumen, given that the lipid solubility and ionization of the drug are appropriate.
The pH of the urine (usually between 4.5 and 8) can markedly affect the rate of passive back-diffusion. The back-diffusion occurs primarily in the distal tubules and collecting ducts, where most of the urine acidification takes place. Since it is the un-ionized form of the drug that diffuses from the tubular fluid across the tubular cells into the blood, it follows that acidification increases reabsorption (or decreases elimination) of weak acids, such as salicylates, and decreases reabsorption (or promotes elimination) of weak bases, such as amphetamines. However, should the un-ionized form of the drug not have sufficient lipid solubility, urinary pH changes will have little influence on urinary drug excretion. Effects of pH on urinary drug elimination may have important applications in medical practice, especially in cases of overdose. For example, one can enhance the elimination of a barbiturate (a weak acid) by administering bicarbonate to the patient. This procedure alkalinizes the urine and thus promotes the excretion of the now more completely ionized drug. The excretion of bases can be increased by making the urine more acidic through the use of an acidifying salt, such as ammonium chloride.
Active Tubular Secretion
A number of drugs can serve as substrates for the two active secretory systems in the proximal tubule cells. These transport systems, which actively transfer drugs from blood to luminal fluid, are independent of each other; one secretes organic anions, and the other secretes organic cations. One drug substrate can compete for transport with a simultaneously administered or endogenous similarly charged compound; this competition will decrease the overall rate of excretion of each substance.The secretory capacity of both the organic anion and organic cation secretory systems can be saturated at high drug concentrations. Each drug will have its own characteristic maximum rate of secretion (transport maximum,Tm).
Some drugs that are not candidates for active tubular secretion may be metabolized to compounds that are. This is often true for metabolites that are formed as a result of conjugative reactions. Because the conjugates are generally not pharmacologically active, increases in their rate of elimination through active secretion usually have little effect on the drug’s overall duration of action. These active secretory systems are important in drug excretion because charged anions and cations are often strongly bound to plasma proteins and therefore are not readily available for excretion by filtration. However, since the protein binding is usually reversible, the active secretory systems can rapidly and efficiently remove many protein-bound drugs from the blood and transport them into tubular fluid.
Any drug known to be largely excreted by the kidney that has a body half-life of less than 2 hours is probably eliminated, at least in part, by tubular secretion. Some drugs can be secreted and have long half-lives, however, because of extensive passive reabsorption in distal segments of the nephron (see Passive Diffusion). It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional capacity may be diminished in the elderly. Thus, This age dependence of the rate compounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult.of renal drug secretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups. Finally, compounds that undergo active tubular secretion also are filtered at the glomerulus (assuming protein binding is minimal). Hence, a reduction in secretory activity does not reduce the excretory process to zero but rather to a level that approximates the glomerular filtration rate.
Active Tubular Reabsorption
Some substances filtered at the glomerulus are reabsorbed by active transport systems found primarily in the proximal tubules.Active reabsorption is particularly important for endogenous substances, such as ions, glucose, and amino acids, although a small number of drugs also may be actively reabsorbed. The probable location of the active transport system is on the luminal side of the proximal cell membrane. Bidirectional active transport across the proximal tubule also occurs for some compounds; that is, a drug may be both actively reabsorbed and secreted. The occurrence of such bidirectional active transport mechanisms across the proximal tubule has been described for several organic anions, including the naturally occurring uric acid.The major portion of filtered urate is probably reabsorbed, whereas that eventually found in the urine is mostly derived from active tubular secretion.
Most drugs act by reducing active transport rather than by enhancing it.Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide,which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate excretion, while high doses have a uricosuric effect. This is offered as an explanation for the apparently paradoxical effects of low and high doses of drugs on the total excretory pattern of compounds that are handled by renal active transport.
Clinical Implications of Renal Excretion
The rate of urinary drug excretion will depend on the drug’s volume of distribution, its degree of protein binding, and the following renal factors:
1. Glomerular filtration rate
2. Tubular fluid pH
3. Extent of back-diffusion of the unionized form
4. Extent of active tubular secretion of the compound
5. Possibly, extent of active tubular reabsorption
Changes in any of these factors may result in clinically important alterations in drug action. In the final analysis, the amount of drug that finally appears in the urine will represent a balance of filtered, reabsorbed (passively and actively), and secreted drug. For many drugs, the duration and intensity of pharmacological effect will be influenced by the status of renal function, because of the major role played by the kidneys in drug and metabolite elimination. Ultimately, whether or not dosage adjustment (e.g., prolongation of dosing interval, reduction in the maintenance dose, or both) becomes necessary will depend on an assessment of the degree of renal dysfunction, the percentage of drug cleared by the kidney, and the potential for drug toxicity, especially if renal function is reduced.
Biliary Excretion
The liver secretes about
At least three groups of compounds enter the bile. Compounds of group A are those whose concentration in bile and plasma are almost identical (bile–plasma ratio of 1). These include glucose, and ions such as Na_, K_, and Cl_. Group B contains the bile salts, bilirubin glucuronide, sulfobromophthalein, procainamide, and others, whose ratio of bile to blood is much greater than 1, usually 10 to 1,000. Group C is reserved for compounds for which the ratio of bile to blood is less than 1, for example, insulin, sucrose, and proteins. Drugs can belong to any of these three categories. Only small amounts of most drugs reach the bile by diffusion. However, biliary excretion plays a major role (5–95% of the administered dose) in drug removal for some anions, cations, and certain un-ionized molecules, such as cardiac glycosides. In addition, biliary elimination may be important for the excretion of some heavy metals.
Cardiac glycosides, anions, and cations are transported from the liver into the bile by three distinct and independent carrier-mediated active transport systems, the last two closely resembling those in the renal proximal tubules that secrete anions and cations into tubular urine. As is true for renal tubular secretion, proteinbound drug is completely available for biliary active transport. In contrast to the bile acids, the actively secreted drugs generally do not recycle, because they are not substrates for the intestinal bile acid transport system, and they are generally too highly charged to backdiffuse across the intestinal epithelium.Thus, the ability of certain compounds to be actively secreted into bile accounts for the large quantity of these drugs removed from the body by way of the feces. On the other hand, most drugs that are secreted by the liver into the bile and then into the small intestine are not eliminated through the feces. The physicochemical properties of most drugs are sufficiently favorable for passive intestinal absorption that the compound will reenter the blood that perfuses the intestine and again be carried to the liver. Such recycling may continue (enterohepatic cycle or circulation) until the drug either undergoes metabolic changes in the liver, is excreted by the kidneys, or both.This process permits the conservation of such important endogenous substances as the bile acids, vitamins D3 and B12, folic acid, and estrogens.
Extensive enterohepatic cycling may be partly responsible for a drug’s long persistence in the body. Orally administered activated charcoal and/or anion exchange resins have been used clinically to interrupt enterohepatic cycling and trap drugs in the gastrointestinal tract. As stated earlier, many foreign compounds are either partially or extensively metabolized in the liver. Conjugation of a compound or its metabolites is especially important in determining whether the drug will undergo biliary excretion. Frequently, when a compound is secreted into the intestine through the bile, it is in the form of a conjugate. Conjugation generally enhances biliary excretion, since it both introduces a strong polar (i.e., anionic) center into the molecule and increases its molecular weight. Molecular weight may, however, be less important in the biliary excretion of organic cations. Conjugated drugs will not be reabsorbed readily from the gastrointestinal tract unless the conjugate is hydrolyzed by gut enzymes such as _–glucuronidase. Chloramphenicol glucuronide, for example, is secreted into the bile,where it is hydrolyzed by gastrointestinal flora and largely reabsorbed. Such a continuous recirculation may lead to the appearance of drug-induced toxicity. The kidney and liver are, in general, capable of actively transporting the same organic anion substrates. However, the two organs have certain quantitative differences in drug affinity for the transporters. It has been suggested that several subsystems of organic anion transport may exist and that the binding specificities of the transporters involved are not absolute but overlapping. Liver disease or injury may impair bile secretion and thereby lead to accumulation of certain drugs, for example probenecid, digoxin, and diethylstilbestrol. Impairment of liver function can lead to decreased rates of both drug metabolism and secretion of drugs into bile. These two processes, of course, are frequently interrelated, since many drugs are candidates for biliary secretion only after appropriate metabolism has occurred.
Decreases in biliary excretion have been demonstrated at both ends of the age continuum. For example, ouabain, an unmetabolized cardiac glycoside that is secreted into the bile, is particularly toxic in the newborn. This is largely due to a reduced ability of biliary secretion to remove ouabain from the plasma.
Increases in hepatic excretory function also may take place. After the chronic administration of either Phenobarbital or the potassium-sparing diuretic spironolactone the rate of bile flow is augmented. Such an increase in bile secretion can reduce blood levels of drugs that depend on biliary elimination.
Finally, the administration of one drug may influence the rate of biliary excretion of a second coadministered compound. These effects may be brought about through an alteration in one or more of the following factors: hepatic blood flow, uptake into hepatocytes, rate of biotransformation, transport into bile, or rate of bile formation. In addition, antibiotics may alter the intestinal flora in such a manner as to diminish the presence of sulfatase and glucuronidase-containing bacteria. This would result in a persistence of the conjugated form of the drug and hence a decrease in its enterohepatic recirculation.
PULMONARY EXCRETION
Any volatile material, irrespective of its route of administration, has the potential for pulmonary excretion. Certainly, gases and other volatile substances that enter the body primarily through the respiratory tract can be expected to be excreted by this route. No specialized transport systems are involved in the loss of substances in expired air; simple diffusion across cell membranes is predominant. The rate of loss of gases is not constant; it depends on the rate of respiration and pulmonary blood flow.
The degree of solubility of a gas in blood also will affect the rate of gas loss. Gases such as nitrous oxide, which are not very soluble in blood, will be excreted rapidly, that is, almost at the rate at which the blood delivers the drug to the lungs. Increasing cardiac output has the greatest effect on the removal of poorly soluble gases; for example, doubling the cardiac output nearly doubles the rates of loss. Agents with high blood and tissue solubility, on the other hand, are only slowly transferred from pulmonary capillary blood to the alveoli. Ethanol, which has a relatively high blood gas solubility, is excreted very slowly by the lungs. The arterial concentration of a highly soluble gas falls much more slowly, and its rate of loss depends more on respiratory rate than on cardiac output.
EXCRETION IN OTHER BODY FLUIDS
Sweat and Saliva
Excretion of drugs into sweat and saliva occurs but has only minor importance for most drugs. The mechanisms involved in drug excretion are similar for sweat and saliva. Excretion mainly depends on the diffusion of the un-ionized lipid-soluble form of the drug across the epithelial cells of the glands. Thus, the pKa of the drug and the pH of the individual secretion formed in the glands are important determinants of the total quantity of drug appearing in the particular body fluid. It is not definitely established whether active drug transport occurs across the ducts of the glands.
Lipid-insoluble compounds, such as urea and glycerol, enter saliva and sweat at rates proportional to their molecular weight, presumably because of filtration through the aqueous channels in the secretory cell membrane.Drugs or their metabolites that are excreted into sweat may be at least partially responsible for the dermatitis and other skin reactions caused by some therapeutic agents. Substances excreted into saliva are usually swallowed, and therefore their fate is the same as that of orally administered drugs (unless expectoration is a major characteristic of a person’s habits). The excretion of a drug into saliva accounts for the drug taste patients sometimes report after certain compounds are given intravenously.
Milk
Many drugs in a nursing mother’s blood are detectable in her milk (Table 4.7). The ultimate concentration of the individual compound in milk will depend on many factors, including the amount of drug in the maternal blood, its lipid solubility, its degree of ionization, and the extent of its active excretion. Thus, the physicochemical properties that govern the excretion of drugs into saliva and sweat also apply to the passage of drugs into milk.
Since milk is more acidic (pH 6.5) than plasma, basic compounds (e.g., alkaloids, such as morphine and codeine) may be somewhat more concentrated in this fluid. In contrast, the levels of weak organic acids will probably be lower than those in plasma. In general, a high maternal plasma protein binding of drug will be associated with a low milk concentration. A highly lipid-soluble drug should accumulate in milk fat. Low-molecularweight un-ionized water-soluble drugs will diffuse passively across the mammary epithelium and transfer into milk. There they may reside in association with one or more milk components, for example, bound to protein such as lactalbumin, dissolved within fat globules, or free in the aqueous compartment. Substances that are not electrolytes, such as ethanol, urea, and antipyrine, readily enter milk and reach approximately the same concentration as in plasma. Compounds used in agriculture also may be passed from cows to humans by this route. Finally, antibiotics such as the tetracyclines, which can function as chelating agents and bind calcium, have a higher milk than plasma concentration. Both maternal and infant factors determine the final amount of drug present in the nursing child’s body at any particular time. Variations in the daily amount of milk formed within the breast (e.g., changes in blood flow to the breast) as well as alterations in breast milk pH will affect the total amount of drug found in milk. In addition, composition of the milk will be affected by the maternal diet; for example, a high-carbohydrate diet will increase the content of saturated fatty acids in milk.
The greatest drug exposure occurs when feeding begins shortly after maternal drug dosing. Additional factors determining exposure of the infant include milk volume consumed (about 150 mL/kg/day) and milk composition at the time of feeding. Fat content is highest in the morning and then gradually decreases until about 10 P.M. A longer feed usually results in exposure of the infant to more of a fat-soluble drug, since milk fat content increases somewhat during a giveursing period.
Whether or not a drug accumulates in a nursing child is affected in part by the infant’s ability to eliminate via metabolism and excretion the ingested compound.
In general, the ability to oxidize and conjugate drugs is low in the neonate and does not approach full adult rates until approximately age 6. It follows, therefore, that drug accumulation should be less in an older infant who breast-feeds than in a suckling neonate. Although abnormalities in fetal organ structure and function can result from the presence of certain drugs in breast milk, it would be quite inappropriate to deny the breast-feeding woman appropriate and necessary drug therapy. A pragmatic approach on the part of both the physician and patient is necessary. Breast-feeding should be discouraged when inherent drug toxicity is known or when adverse pharmacological actions of the drug on the infant are likely. Infant drug exposure can be minimized, however, through short intermittent maternal drug use and by drug dosing immediately after breastfeeding.
VARIABLES THAT AFFECT DRUG ACTIONS
Expected responses to drugs are largely based on those occurring when a particular drug is given to healthy adult men (18 to 65 years of age) of average weight (
However, other groups of people (eg, women, children, older adults, different ethnic or racial groups, and clients with diseases or symptoms that the drugs are designed to treat) receive drugs and respond differently than healthy adult men. Therefore, current clinical trials are including more representatives of these groups. In any client, however, responses may be altered by both drug- and client-related variables.
Drug–Diet Interactions
Food may alter the absorption of oral drugs. In many instances, food slows absorption by slowing gastric emptying time and altering GI secretions and motility. When tablets or capsules are taken with or soon after food, they dissolve more slowly; therefore, drug molecules are delivered to absorptive sites in the small intestine more slowly. Food also may decrease absorption by combining with a drug to form an insoluble drug–food complex. In other instances, however, certain drugs or dosage forms are better absorbed with certain types of meals. For example, a fatty meal increases the absorption of some sustained-release forms of theophylline. Interactions that alter drug absorption can be minimized by spacing food and medications. In addition, some foods contain substances that react with certain drugs. One such interaction occurs between tyraminecontaining foods and monoamine oxidase (MAO) inhibitor drugs. Tyramine causes the release of norepinephrine, a strong vasoconstrictive agent, from the adrenal medulla and sympathetic neurons. Normally, norepinephrine is active for only a few milliseconds before it is inactivated by MAO. However, because MAO inhibitor drugs prevent inactivation of norepinephrine, ingesting tyramine-containing foods with an MAO inhibitor may produce severe hypertension or intracranial hemorrhage. MAO inhibitors include the antidepressants isocarboxazid and phenelzine and the antineoplastic procarbazine. These drugs are infrequently used nowadays, partly because of this potentially serious interaction and partly because other effective drugs are available. Tyramine-rich foods to be avoided by clients taking MAO inhibitors include beer, wine, aged cheeses, yeast products, chicken livers, and pickled herring.
An interaction may occur between warfarin, a frequently used oral anticoagulant, and foods containing vitamin K. Because vitamin K antagonizes the action of warfarin, large amounts of spinach and other green leafy vegetables may offset the anticoagulant effects and predispose the person to thromboembolic disorders. A third interaction occurs between tetracycline, an antibiotic, and dairy products, such as milk and cheese. The drug combines with the calcium in milk products to form an insoluble, unabsorbable compound that is excreted in the feces.
Client-Related Variables
Age
The effects of age on drug action are most pronounced ieonates, infants, and older adults. In children, drug action depends largely on age and developmental stage. During pregnancy, drugs cross the placenta and may harm the fetus. Fetuses have no effective mechanisms for metabolizing or eliminating drugs because their liver and kidney functions are immature. Newborn infants (birth to 1 month) also handle drugs inefficiently. Drug distribution, metabolism, and excretion differ markedly ieonates, especially premature infants, because their organ systems are not fully developed.
Older infants (1 month to 1 year) reach approximately adult levels of protein binding and kidney function, but liver function and the blood–brain barrier are still immature. Children (1 to 12 years) experience a period of increased activity of drug-metabolizing enzymes so that some drugs are rapidly metabolized and eliminated. Although the onset and duration of this period are unclear, a few studies have been done with particular drugs. Theophylline, for example, is cleared much faster in a 7-year-old child than in a neonate or adult (18 to 65 years). After approximately 12 years of age, healthy children handle drugs similarly to healthy adults.
In older adults (65 years and older), physiologic changes may alter all pharmacokinetic processes. Changes in the GI tract include decreased gastric acidity, decreased blood flow, and decreased motility. Despite these changes, however, there is little difference in absorption. Changes in the cardiovascular system include decreased cardiac output and therefore slower distribution of drug molecules to their sites of action, metabolism, and excretion. In the liver, blood flow and metabolizing enzymes are decreased. Thus, many drugs are metabolized more slowly, have a longer action, and are more likely to accumulate with chronic administration. In the kidneys, there is decreased blood flow, decreased glomerular filtration rate, and decreased tubular secretion of drugs. All of these changes tend to slow excretion and promote accumulation of drugs in the body. Impaired kidney and liver function greatly increase the risks of adverse drug effects. In addition, older adults are more likely to have acute and chronic illnesses that require multiple drugs or long-term drug therapy. Thus, possibilities for interactions among drugs and between drugs and diseased organs are greatly multiplied.
Body Weight
Body weight affects drug action mainly in relation to dose. The ratio between the amount of drug given and body weight influences drug distribution and concentration at sites of action. In general, people heavier than average need larger doses, provided that their renal, hepatic, and cardiovascular functions are adequate. Recommended doses for many drugs are listed in terms of grams or milligrams per kilogram of body weight.
Genetic and Ethnic Characteristics
Drugs are given to elicit certain responses that are relatively predictable for most drug recipients. When given the same drug in the same dose, however, some people experience inadequate therapeutic effects, and others experience unusual or exaggerated effects, including increased toxicity. These interindividual variations in drug response are often attributed to genetic or ethnic differences in drug pharmacokinetics or pharmacodynamics. As a result, there is increased awareness that genetic and ethnic characteristics are important factors and that diverse groups must be included in clinical trials.
Genetics
A person’s genetic characteristics may influence drug action in several ways. For example, genes determine the types and amounts of proteins produced in the body. When most drugs enter the body, they interact with proteins (eg, in plasma, tissues, cell membranes, and drug receptor sites) to reach their sites of action, and with other proteins (eg, drug-metabolizing enzymes in the liver and other organs) to be biotransformed and eliminated from the body. Genetic characteristics that alter any of these proteins can alter drug pharmacokinetics or pharmacodynamics.
One of the earliest genetic variations to be identified derived from the observation that some people taking usual doses of isoniazid (an antitubercular drug), hydralazine (an antihypertensive agent), or procainamide (an antidysrhythmic) showed no therapeutic effects, whereas toxicity developed in other people. Research established that these drugs are normally metabolized by acetylation, a chemical conjugation process in which the drug molecule combines with an acetyl group of acetyl coenzyme A. The reaction is catalyzed by a hepatic drug-metabolizing enzyme called acetyltransferase. It was further established that humans may acetylate the drug rapidly or slowly, depending largely on genetically controlled differences in acetyltransferase activity. Clinically, rapid acetylators may need larger-than-usual doses to achieve therapeutic effects, and slow acetylators may need smaller-than-usual doses to avoid toxic effects. In addition, several genetic variations of the cytochrome P450 drugmetabolizing system have been identified. Specific variations may influence any of the chemical processes by which drugs are metabolized.
As another example of genetic variation in drug metabolism, some people lack the plasma pseudocholinesterase enzyme that normally inactivates succinylcholine, a potent muscle relaxant used in some surgical procedures. These people may experience prolonged paralysis and apnea if given succinylcholine. Other people are deficient in glucose-6-phosphate dehydrogenase, an enzyme normally found in red blood cells and other body tissues. These people may have hemolytic anemia when given antimalarial drugs, sulfonamides, analgesics, antipyretics, and other drugs.
Ethnicity
Most drug information has been derived from clinical drug trials using white men; few subjects of other ethnic groups are included. Interethnic variations became evident when drugs and dosages developed for white people produced unexpected responses, including toxicity, when given to other ethnic groups. One common interethnic variation is that African Americans are less responsive to some antihypertensive drugs than are white people. For example, angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking drugs are less effective as single-drug therapy. In general, African-American hypertensive clients respond better to diuretics or calcium channel blockers than to ACE inhibitors and beta blockers. Another interethnic variation is that Asians usually require much smaller doses of some commonly used drugs, including beta blockers and several psychotropic drugs (eg, alprazolam, an antianxiety agent, and haloperidol, an antipsychotic).
Gender
Except during pregnancy and lactation, gender has been considered a minor influence on drug action. Most research studies related to drugs have involved men, and clinicians have extrapolated the findings to women. Several reasons have been advanced for excluding women from clinical drug trials, including the risks to a fetus if a woman becomes pregnant and the greater complexity in sample size and data analysis. However, because differences between men and women in responses to drug therapy are being identified, the need to include women in drug studies is evident. Some gender-related differences in responses to drugs may stem from hormonal fluctuations in women during the menstrual cycle. Although this area has received little attention in research studies and clinical practice, altered responses have been demonstrated in some women taking clonidine, an antihypertensive; lithium, a mood-stabilizing agent; phenytoin, an anticonvulsant; propranolol, a beta-adrenergic blocking drug used in the management of hypertension, angina pectoris, and migraine; and antidepressants. In addition, a significant percentage of women with arthritis, asthma, depression, diabetes mellitus, epilepsy, and migraine experience increased symptoms premenstrually.
The increased symptoms may indicate a need for adjustments in their drug therapy regimens. Women with clinical depression, for example, may need higher doses of antidepressant medications premenstrually, if symptoms exacerbate, and lower doses during the rest of the menstrual cycle. Another example is that women with schizophrenia require lower dosages of antipsychotic medications than men. If given the higher doses required by men, women are likely to have adverse drug reactions.
