To produce useful therapeutic effects, most drugs must be absorbed, distributed, and eliminated. Pharmacokinetic principles make rational dosing possible by quantifying these processes.
The Movement of Drugs in the Body
To reach its receptors and bring about a biologic effect, a drug molecule (eg, a benzodiazepine sedative) must travel from the site of administration (eg, the gastrointestinal tract) to the site of action (eg, the brain).
Permeation is the movement of drug molecules into and within the biologic environment. It involves several processes, the most important of which are discussed next.
Aqueous diffusion is the movement of molecules through the watery extracellular and intracellular spaces. The membranes of most capillaries have small water-filled pores that permit the aqueous diffusion of molecules up to the size of small proteins between the blood and the extravascular space. This is a passive process governed by Fick's law (see later discussion). The capillaries in the brain, testes, and some other organs lack aqueous pores, and these tissues are less exposed to some drugs.
Lipid diffusion is the passive movement of molecules through membranes and other lipid structures. Like aqueous diffusion, this process is governed by Fick's law (see later discussion).
Transport by Special Carriers
Drugs that do not readily diffuse through membranes may be transported across barriers by mechanisms that carry similar endogenous substances. A very large number of such transporter molecules have been identified, and many of these are important in the movement of drugs or as targets of drug action. Unlike aqueous and lipid diffusion, carrier transport is not governed by Fick's law and is capacity-limited. Important examples are transporters for ions (eg, Na+/K+ ATPase), for neurotransmitters (eg, transporters for serotonin, norepinephrine), for metabolites (eg, glucose, amino acids), and for foreign molecules (xenobiotics) such as anticancer drugs.
Selective inhibitors for these carriers may have clinical value; for example, several antidepressants act by inhibiting the transport of amine neurotransmitters back into the nerve endings from which they have been released. After release, such amine neurotransmitters (dopamine, norepinephrine, and serotonin) and some other transmitters are recycled into nerve endings by transport molecules. Probenecid, which inhibits transport of uric acid, penicillin, and other weak acids in the nephron, is used to increase the excretion of uric acid in gout. The family of P-glycoprotein transport molecules, previously identified in malignant cells as one cause of cancer drug resistance, has been identified in the epithelium of the gastrointestinal tract and in the blood-brain barrier.
Endocytosis occurs through binding of the transported molecule to specialized components (receptors) on cell membranes, with subsequent internalization by infolding of that area of the membrane. The contents of the resulting intracellular vesicle are subsequently released into the cytoplasm of the cell. Endocytosis permits very large or very lipid-insoluble chemicals to enter cells. For example, large molecules such as proteins may cross cell membranes by endocytosis. Smaller, polar substances such as vitamin B12 and iron combine with special proteins (B12 with intrinsic factor and iron with transferrin), and the complexes enter cells by this mechanism. Because the substance to be transported must combine with a membrane receptor, endocytotic transport can be quite selective. Exocytosis is the reverse process, that is, the expulsion of material that is membrane-encapsulated inside the cell from the cell. Most neurotransmitters are released by exocytosis.
Fick's law predicts the rate of movement of molecules across a barrier. The concentration gradient (C1 − C2) and permeability coefficient for the drug and the area and thickness of the barrier membrane are used to compute the rate as follows:
Thus, drug absorption is faster from organs with large surface areas, such as the small intestine, than from organs with smaller absorbing areas (the stomach). Furthermore, drug absorption is faster from organs with thin membrane barriers (eg, the lung) than from those with thick barriers (eg, the skin).
Water and Lipid Solubility of Drugs
The aqueous solubility of a drug is often a function of the electrostatic charge (degree of ionization, polarity) of the molecule, because water molecules behave as dipoles and are attracted to charged drug molecules, forming an aqueous shell around them. Conversely, the lipid solubility of a molecule is inversely proportional to its charge.
Many drugs are weak bases or weak acids. For such molecules, the pH of the medium determines the fraction of molecules charged (ionized) versus uncharged (nonionized). If the pKa of the drug and the pH of the medium are known, the fraction of molecules in the ionized state can be predicted by means of the Henderson-Hasselbalch equation:
“Protonated” means associated with a proton (a hydrogen ion); this form of the equation applies to both acids and bases.
Ionization of Weak Acids and Bases
Weak bases are ionized—and therefore more polar and more water-soluble—when they are protonated. Weak acids are not ionized—and so are less water-soluble—when they are protonated.
The following equations summarize these points:
The Henderson-Hasselbalch relationship is clinically important when it is necessary to estimate or alter the partition of drugs between compartments of differing pH. For example, most drugs are freely filtered at the glomerulus, but lipid-soluble drugs can be rapidly reabsorbed from the tubular urine. If a patient takes an overdose of a weak acid drug, for example, aspirin, the excretion of this drug is faster in alkaline urine. This is because a drug that is a weak acid dissociates to its charged, polar form in alkaline solution, and this form cannot readily diffuse from the renal tubule back into the blood; that is, the drug is trapped in the tubule. Conversely, excretion of a weak base (eg, pyrimethamine, amphetamine) is faster in acidic urine (Figure 1–2).
The Henderson-Hasselbalch principle applied to drug excretion in the urine. Because the nonionized form diffuses readily across the lipid barriers of the nephron, this form may reach equal concentrations in the blood and urine; in contrast, the ionized form does not diffuse as readily. Protonation occurs within the blood and the urine according to the Henderson-Hasselbalch equation. Pyrimethamine, a weak base of pKa 7.0, is used in this example. At blood pH, only 0.4 μmol of the protonated species will be present for each 1.0 μmol of the unprotonated form. The total concentration in the blood will thus be 1.4 μmol/L if the concentration of the unprotonated form is 1.0 μmol/L. In the urine at pH 6.0, 10 μmol of the nondiffusible ionized form will be present for each 1.0 μmol of the unprotonated, diffusible, form. Therefore, the total urine concentration (11 μmol/L) may be almost 8 times higher than the blood concentration.
Drugs usually enter the body at sites remote from the target tissue or organ and thus require transport by the circulation to the intended site of action. To enter the bloodstream, a drug must be absorbed from its site of administration (unless the drug has been injected directly into the vascular compartment). The rate and efficiency of absorption differ depending on a drug's route of administration. In fact, for some drugs, the amount absorbed may be only a small fraction of the dose administered when given by certain routes. The amount absorbed into the systemic circulation divided by the amount of drug administered constitutes its bioavailability by that route. Common routes of administration and some of their features are listed in Table 1–1.
Table 1–1 Common Routes of Drug Administration. ||Download (.pdf)
Table 1–1 Common Routes of Drug Administration.
|Oral (swallowed)||Offers maximal convenience; absorption is often slower. Subject to the first-pass effect, in which a significant amount of the agent is metabolized in the gut wall, portal circulation, and liver before it reaches the systemic circulation|
|Buccal and sublingual (not swallowed)||Direct absorption into the systemic venous circulation, bypassing the hepatic portal circuit and first-pass metabolism|
|Intravenous||Instantaneous and complete absorption (by definition, bioavailability is 100%). Potentially more dangerous|
|Intramuscular||Often faster and more complete (higher bioavailability) than with oral administration. Large volumes may be given if the drug is not too irritating. First-pass metabolism is avoided|
|Subcutaneous||Slower absorption than the intramuscular route. First-pass metabolism is avoided.|
|Rectal (suppository)||The rectal route offers partial avoidance of the first-pass effect. Larger amounts of drug and drugs with unpleasant tastes are better administered rectally than by the buccal or sublingual routes|
|Inhalation||Route offers delivery closest to respiratory tissues (eg, for asthma). Usually very rapid absorption (eg, for anesthetic gases)|
|Topical||The topical route includes application to the skin or to the mucous membrane of the eye, ear, nose, throat, airway, or vagina for local effect|
|Transdermal||The transdermal route involves application to the skin for systemic effect. Absorption usually occurs very slowly (because of the thickness of the skin), but the first-pass effect is avoided|
Blood flow influences absorption from intramuscular and subcutaneous sites and, in shock, from the gastrointestinal tract as well. High blood flow maintains a high drug depot-to-blood concentration gradient and thus facilitates absorption.
The concentration of drug at the site of administration is important in determining the concentration gradient relative to the blood as noted previously. As indicated by Fick's law (Equation 1), the concentration gradient is a major determinant of the rate of absorption. Drug concentration in the vehicle is particularly important in the absorption of drugs applied topically.
Determinants of Distribution
The distribution of drugs to the tissues depends on the following:
The size of the organ determines the concentration gradient between blood and the organ. For example, skeletal muscle can take up a large amount of drug because the concentration in the muscle tissue remains low (and the blood-tissue gradient high) even after relatively large amounts of drug have been transferred; this occurs because skeletal muscle is a very large organ. In contrast, because the brain is smaller, distribution of a smaller amount of drug into it will raise the tissue concentration and reduce to zero the blood-tissue concentration gradient, preventing further uptake of drug.
Blood flow to the tissue is an important determinant of the rate of uptake of drug, although blood flow may not affect the amount of drug in the tissue at equilibrium. As a result, well-perfused tissues (eg, brain, heart, kidneys, and splanchnic organs) usually achieve high tissue concentrations sooner than poorly perfused tissues (eg, fat, bone).
The solubility of a drug in tissue influences the concentration of the drug in the extracellular fluid surrounding the blood vessels. If the drug is very soluble in the cells, the concentration in the perivascular extracellular space will be lower and diffusion from the vessel into the extravascular tissue space will be facilitated. For example, some organs (such as the brain) have a high lipid content and thus dissolve a high concentration of lipid-soluble agents rapidly.
Binding of a drug to macromolecules in the blood or a tissue compartment tends to increase the drug's concentration in that compartment. For example, warfarin is strongly bound to plasma albumin, which restricts warfarin's diffusion out of the vascular compartment. Conversely, chloroquine is strongly bound to extravascular tissue proteins, which results in a marked reduction in the plasma concentration of chloroquine.
Apparent Volume of Distribution and Physical Volumes
The apparent volume of distribution (Vd) is an important pharmacokinetic parameter that reflects the above determinants of the distribution of a drug in the body. Vd relates the amount of drug in the body to the concentration in the plasma (Chapter 3). In contrast, the physical volumes of various body compartments are less important in pharmacokinetics (Table 1–2). However, obesity alters the ratios of total body water to body weight and fat to total body weight, and this may be important when using highly lipid-soluble drugs. A simple approximate rule for the aqueous compartments of the normal body is as follows: 40% of the body weight is intracellular water and 20% is extracellular water; thus, water constitutes approximately 60% of body weight.
Table 1–2 Average Values for Some Physical Volumes Within the Adult Human Body. ||Download (.pdf)
Table 1–2 Average Values for Some Physical Volumes Within the Adult Human Body.
|Compartment||Volume (L/kg body weight)|
|Total body water||0.6|
Drug disposition is sometimes used to refer to metabolism and elimination of drugs. Some authorities use disposition to denote distribution as well as metabolism and elimination. Metabolism of a drug sometimes terminates its action, but other effects of drug metabolism are also important. Some drugs when given orally are metabolized before they enter the systemic circulation. This first-pass metabolism was referred to in Table 1–1 as one cause of low bioavailability. Drug metabolism occurs primarily in the liver and is discussed in greater detail in Chapter 4.
Drug Metabolism as a Mechanism of Termination of Drug Action
The action of many drugs (eg, sympathomimetics, phenothiazines) is terminated before they are excreted because they are metabolized to biologically inactive derivatives. Conversion to a metabolite is a form of elimination.
Drug Metabolism as a Mechanism of Drug Activation
Prodrugs (eg, levodopa, minoxidil) are inactive as administered and must be metabolized in the body to become active. Many drugs are active as administered and have active metabolites as well (eg, morphine, some benzodiazepines).
Drug Elimination Without Metabolism
Some drugs (eg, lithium, many others) are not modified by the body; they continue to act until they are excreted.
Along with the dosage, the rate of elimination following the last dose (disappearance of the active molecules from the site of action, the bloodstream, and the body) determines the duration of action for most drugs. Therefore, knowledge of the time course of concentration in plasma is important in predicting the intensity and duration of effect for most drugs. Note: Drug elimination is not the same as drug excretion: A drug may be eliminated by metabolism long before the modified molecules are excreted from the body. For most drugs and their metabolites, excretion is primarily by way of the kidney. Anesthetic gases, a major exception, are excreted primarily by the lungs. For drugs with active metabolites (eg, diazepam), elimination of the parent molecule by metabolism is not synonymous with termination of action. For drugs that are not metabolized, excretion is the mode of elimination. A small number of drugs combine irreversibly with their receptors, so that disappearance from the bloodstream is not equivalent to cessation of drug action: These drugs may have a very prolonged action. For example, phenoxybenzamine, an irreversible inhibitor of α adrenoceptors, is eliminated from the bloodstream in less than 1 h after administration. The drug's action, however, lasts for 48 h, the time required for turnover of the receptors.
The term first-order elimination implies that the rate of elimination is proportional to the concentration (ie, the higher the concentration, the greater the amount of drug eliminated per unit time). The result is that the drug's concentration in plasma decreases exponentially with time (Figure 1–3, left). Drugs with first-order elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body. The concentration of such a drug in the blood will decrease by 50% for every half-life. Most drugs in clinical use demonstrate first-order kinetics.
Comparison of first-order and zero-order elimination. For drugs with first-order kinetics (left), rate of elimination (units per hour) is proportional to concentration; this is the more common process. In the case of zero-order elimination (right), the rate is constant and independent of concentration.
The term zero-order elimination implies that the rate of elimination is constant regardless of concentration (Figure 1–3, right). This occurs with drugs that saturate their elimination mechanisms at concentrations of clinical interest. As a result, the concentrations of these drugs in plasma decrease in a linear fashion over time. This is typical of ethanol (over most of its plasma concentration range) and of phenytoin and aspirin at high therapeutic or toxic concentrations.
After absorption into the circulation, many drugs undergo an early distribution phase followed by a slower elimination phase. Mathematically, this behavior can be simulated by means of a "two-compartment model" as shown in Figure 1–4. The two compartments consist of the blood and the extravascular tissues. (Note that each phase is associated with a characteristic half-life: t1/2α for the first phase, t1/2β for the second phase. Note also that when concentration is plotted on a logarithmic axis, the elimination phase for a first-order drug is a straight line.)
Serum concentration-time curve after administration of chlordiazepoxide as an intravenous bolus. The experimental data are plotted on a semilogarithmic scale as filled circles. This drug follows first-order kinetics and appears to occupy two compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (t1/2β) can be extracted graphically as shown by measuring the time between any two plasma concentration points on the elimination phase that differ by twofold. (See Chapter 3 for additional details.) (Modified and reproduced, with permission, from Greenblatt DJ, Koch-Weser J: Drug therapy: Clinical pharmacokinetics. N Engl J Med 1975;293:702. Copyright © 1975 Massachusetts Medical Society. All rights reserved.)
Other Distribution Models
A few drugs behave as if they were distributed to only 1 compartment (eg, if they are restricted to the vascular compartment). Others have more complex distributions that require more than 2 compartments for construction of accurate mathematical models.