What allows drugs to gather in high concentration in a cell or body compartment?

Figure 1-1. Externaland Internal Threats

Invading organisms such as bacteria, viruses, fungi, and helminths can threaten the health of the host. Cancer cells are abnormal and differ from normal cells in terms of chromosome alterations, uncontrolled proliferation, dedifferentiation and loss of function, and invasiveness. Drug therapy (chemotherapy) aims to kill invading organisms or aberrant cells directly or to reduce their numbers to a level that can be managed by a host-mounted defense. Typical drug targets for invading organisms include biochemical processes needed for cell wall synthesis or integrity. Drug targets for abnormal cells include cell-cycle regulation and enzymes involved in protein synthesis, so as to inhibit cancer cell replication. In both cases, optimal treatment occurs when a drug or combination of drugs displays selectivity against invaders or cancer cells. Such therapy—with separation between a desired therapeutic effect and unwanted (adverse or side) effects—minimizes harmful drug effects.

Figure 1-2. Endogenous Chemical Balance

When the amount of an endogenous substance is insufficient for normal functions, it may be possible to supply it from sources outside of the body (exogenous supply). Examples include insulin used for diabetes and dopamine used for parkinsonism. The exogenous material may originate from humans, animals, microorganisms, or minerals or it may be synthesized—a product of technology. It can be the substance itself or a precursor metabolized to the substance (eg, levodopa is metabolized to dopamine). Excess amounts can also be harmful, eg, excess stomach acid can cause or exacerbate ulcer formation. Gastric acid levels can be reduced directly by using an antacid (a base such as calcium carbonate or magnesium hydroxide). An alternative approach—–inhibiting acid secretion—can be achieved by antagonizing the action of histamine on H2 receptors of parietal cells (eg, with cimetidine) or by interfering with the proton pump that transports acid across parietal cells (eg, with omeprazole).

Figure 1-3. Modulate Physiologic Processes

Drugs use different mechanisms to modify normal homeostatic and biochemical communication in cellular and physiologic processes. They mimic (eg, carbachol) or block neurotransmitters that transmit information across synapses. Chemical substances such as hormones also act over long distances in the body. Drugs that mimic hormones include oxandrolone; mifepristone blocks hormone action. Drugs selectively modify physiologic processes by targeting enzymes, DNA, neurotransmitters, or other chemical mediators or components of signaling processes such as receptors. The total effect depends on whether a drug promotes or reduces endogenous activity. Drugs with other mechanisms of action are chelating agents (contain metal atoms that form chemical bonds with toxins or drugs), antimetabolites (masquerade as endogenous substances but are inactive or less active than these substrates), irritants (stimulate physiologic processes), and nutritional or replacement agents (eg, vitamins, minerals).

Figure 1-4. Chemical Transmissionatthe Synapse

Communication (transmission of information) across synapses occurs via chemical messengers—neurotransmitters—stored in vesicles in presynaptic neurons. Action potentials at presynaptic axon terminals initiate steps that release neurotransmitter molecules into a synapse, which cross the synaptic cleft and bind reversibly to postsynaptic receptors. Receptor activation leads to cellular response. Receptor activators (eg, drugs) areagonists;antagonists are drugs that combine with but do not activate receptors. Transmitters are removed from synapses by enzymatic destruction, diffusion, and active reuptake into presynaptic neurons. Major peripheral neurotransmitters are acetylcholine and catecholamines (eg, epinephrine, dopamine). In the brain and spinal cord, major excitatory neurotransmitters are glutamate and aspartate; major inhibitory neurotransmitters are GABA and glycine. 5-HT, or serotonin, and neuropeptides are other neurotransmitters.

Figure 1-5. Synapse Morphology

Asynapse is a region including the axon terminal of a presynaptic neuron, the plasma membrane of the postsynaptic (receiving) cell, and the physical space between the cells (synaptic cleft). Postsynaptic cells can be neurons or other cells (eg, effector cells in muscle). At synapses, electrical transmissions—action potentials along presynaptic neurons—are translated into chemical signals, which lead to postsynaptic cell responses: increase (excitation), decrease (inhibition), or modulation of neuron activity or biochemistry. Synaptic transmission involves many steps, all possible drug targets. Steps occur in presynaptic neurons (eg, neurotransmitter synthesis and storage in vesicles), at presynaptic membranes (eg, vesicle docking with membranes, neurotransmitter exocytosis), in synaptic clefts (eg, enzymatic reuptake), on postsynaptic membranes (eg, binding to receptors, change in ion channel function), and in postsynaptic neurons (eg, effects on second-messenger transduction).

Figure 1-6. Receptorsand Signaling

Receptors are the first molecules in or on a cell that respond to a neurotransmitter, a hormone, or another endogenous or exogenous signaling molecule (ligand) and transmit messages (via transduction) from the molecule to the cell machinery. Receptors ensure fidelity of the intended communication by responding only to the intended signaling molecule or to molecules with closely related chemical structures (such as drugs with the required shape). Receptors are composed primarily of long sequences (typically hundreds) of amino acids. The body has dozens of receptor types to maintain communication pathways that must be differentiated from each other and serve different purposes. An individual cell may express one or many types of receptors, with the number depending on age, health, or other factors.

Figure 1-7. Receptor Subtypes

Receptors can be classified into subtypes, as first noted for receptors for the structurally related catecholamines epinephrine, isoproterenol, and norepinephrine. The order of potency (structure-activity relation, or SAR) of these drugs in some tissues is norepinephrine > epinephrine > isoproterenol; in other tissues, it is the reverse. Catecholamine receptors (adrenoceptors) exist in pharmacologically distinct types (α and β) and subtypes (eg, α1, α2, and so on). Subtypes are differentiated by amino acid sequence and posttranslational processing, as shown for dopamine receptor subtypes. A clinical example of receptor subtype targeting involves asthma treatment. Activation of adrenoceptors in the lung relaxes smooth muscles and dilates bronchioles to ease breathing. To avoid stimulation of heart adrenoceptors, β2-selective drugs (eg, albuterol, metaproterenol, ritodrine, terbutaline) were developed to activate only lung adrenoceptors; β1-selective drugs would affect the heart.

Figure 1-8. Agonists

Certain molecules have physiochemical and stereochemical (3-dimensional) characteristics that impartaffinity for a receptor, affinity being the quantifiable tendency of a drug molecule to form a complex with (bind to) a receptor. Binding involves interaction between a ligand molecule (L) and a receptor molecule (R) to form a ligand-receptor complex (LR): L + R ↔ LR. Affinity is quantified by the reciprocal of the equilibrium constant of this interaction and is commonly reported (often designatedKd orKi); the greater the affinity is, the smaller theK value is. Drugs can activate receptors and thus elicit a biologic effect (ie, have intrinsic activity, or efficacy). Such molecules have shapes complementary to receptor shapes and somehow alter the activity of a receptor. Full agonists possess high efficacy and can elicit a maximal tissue response, whereas partial agonists have intermediate levels of efficacy (the tissue response is submaximal even when all receptors are occupied).

Figure 1-9. Antagonists

Some molecules have physiochemical and stereochemical traits that impart affinity for a receptor but cannot activate it. Such molecules bind to (occupy) receptors and block access of agonists, thereby reducing the effects of agonists. Such pharmacologic antagonists do not elicit biologic effects directly; they modify the physiologic process that is maintained by agonist action (eg, by neurotransmitters). Examples of drugs that are receptor antagonists are atropine (muscarinic cholinergic),d-tubocurarine (nicotinic cholinergic), atenolol (adrenoceptor), spironolactone (mineralocorticoid), diphenhydramine (histamine H1), ondansetron (5-HT), flumazenil (benzodiazepine), haloperidol (dopamine), and naloxone (opioid). Chemical antagonism (eg, neutralization of gastric acid by chemical bases) or physiologic antagonism, in which an effect of one drug opposes an effect of another agent (eg, epinephrine used to counteract the histamine response to a bee sting), of drug effects can also occur.

Figure 1-10. Stereochemistryand 3-Dimensional Fit

One enantiomer of a racemic pair is often observed to bind more avidly to (has greater affinity for) a receptor than does the other enantiomer of the pair. Because the only difference between them is the stereochemistry, the 3-dimensional shape of a molecule must be a crucial characteristic for binding affinity. The relation between chemical structure and biologic response is known as theSAR and is a common focus of drug discovery efforts. Computer modeling of the ligand-receptor fit provides a visual representation of the fit of a ligand into the receptor pocket. It can also be used for virtual screening for goodness of fit of potential drug candidates before they are synthesized.

Figure 1-11. Receptor-Effector Coupling

In most cases, a drug activates or inhibits only 1 molecule in a long series of biochemical reactions. When a drug binds to a receptor on a cell membrane, the extracellular drug signal must be passed to the intracellular physiologic processes, ie, it must be converted (transduced) to an intracellular message, the process termedsignal transduction, which occurs via many mechanisms. The effect of a drug depends on its receptors, the transduction pathways to which it is coupled, its level of receptor expression in cells, and its cellular response capacity. In the simplest case (A), a drug binds to 1 receptor coupled to 1 effector (transduction pathway) and produces 1 effect. A drug can bind to 1 receptor coupled to more than 1 effector (B) so it produces more than 1 effect in the same or different cells. A drug can also have affinity for more than 1 receptor (C), with each receptor coupled to a different effector. Effect 2 can be a therapeutic end point or an adverse effect.

Figure 1-12. Signal Transductionand Cross Talk

Receptors provide specificity for cell responses to only certain extracellular chemical signals. Different receptor types can have 1 or more intracellular second-messenger transduction mechanisms without loss of ligand specificity. Different ligands acting through different receptors can thus have the same or different effects via 1 messenger system. In some invertebrate organisms all ionotropic (ion channel) receptors shown here regulate Cl− influx and have the effects shown. In mamals only the GABA receptor regulates Cl− influx. The others have other transduction mechanisms and produce different effects. The effect depends on ligand concentration, cell type, and expression of receptor and second messenger system components. Integrated communication between and within cells thus occurs. A cell with multiple receptor types can be regulated by various ligands and by interaction among receptor types. Interaction among receptor types constitutes receptor cross talk, which allows cells diverse and sophisticated response possibilities.

Figure 1-13. Second-Messenger Pathways

Signal transduction commonly occurs by means of several general mechanisms: (1) ligand-gated ion channels modulate the influx or outflow of ions that alter transmembrane potential or modulate intracellular biochemical reactions (eg, the calcium-calmodulin system); (2) ligand binding to GPCRs modulates enzyme activity (eg, adenylyl cyclase or phospholipase C); (3) ligand binding activates a catalytic portion of the receptor (eg, tyrosine kinase activity); (4) a ligand enters the cell nucleus and alters protein (receptor) synthesis; and (5) a ligand amplifies or attenuates nitric oxide synthesis and the subsequent production of cGMP.

Figure 1-14. Ligand-Gated Ion Channels

Some drugs bind to molecules (ion channels) that form transmembrane pores for ions (usually Na+, K+, Ca2+, Cl−), the channels being composed of many subunits. A drug's binding to 1 or more subunits modifies the receptor function (ion passage), ie, the channels are ligand gated. A single ion channel can accommodate multiple drugs, with each drug binding to a different subunit or site on or within (extracellular, transmembrane, or intracellular) the channel. Membrane-bound channels include nicotinic cholinergic, ionotropic glutamate, GABAA, 5-HT3 (serotonin), and glycine receptors. Intracellular channels include those for Ca2+ on the sarcoplasmic reticulum, endoplasmic reticulum, and mitochondria. Barbiturates, for example, bind to sites on the GABAA receptor complex, which increases Cl− influx and produces increased resting transmembrane potential difference and decreased cell excitability. One drug that modifies activity of an intracellular ligand-gated ion (Ca2+) channel is caffeine.

Figure 1-15. G Protein–Coupled Receptors

Some drugs bind to receptors whose transduction involves a physical association of a receptor with G proteins—the GPCRs. GPCRs, a large family of receptors, mediate effects of neurotransmitters, hormones, and drugs. GPCRs are large proteins that span a cell membrane many times; many drug-related GPCRs, the 7-TM GPCRs, do this 7 times (amino terminus is outside the cell; carboxy terminus is inside). Examples are receptors for epinephrine, norepinephrine, dopamine, 5-HT, ACh (muscarinic), histamine, adenosine, purines, GABA, glutamate, opioids, and vasopressin. Binding of an agonist (drug or endogenous ligand) to a GPCR activates associated G proteins by GTP-GDP exchange, which stimulates dissociation of α from βγ subunits. Inherent GTPase activity within the α subunit restores the initial conditions. One receptor can be coupled to more than 1 type of G protein. Some G proteins activate and others inhibit biochemical steps in signal transduction.

Figure 1-16. Trk Receptors

Some drugs bind to receptors that are composed of an extracellular ligand-binding domain, a transmembrane region, and an intracellular domain that has tyrosine kinase (trk) activity. When activated, these receptors catalyze the intracellular phosphorylation of tyrosine residues in target proteins that are important for cellular growth and differentiation and responses to metabolic stimuli. Examples of ligands (and drug mimetics) that bind totrk receptors include insulin, nerve growth factor, platelet-derived growth factor, cytokines, and other growth factors. It is hypothesized that agonists cause a change in the conformation of the receptor, thereby promoting its action as a tyrosine kinase.

Figure 1-17. Nuclear Receptors

Some drugs produce their effects by binding to receptors located in the cytoplasm or the nucleus of the cell. For example, steroid hormones, thyroid hormone, corticosteroids, vitamin D, and retinoids diffuse through the plasma membrane of the cell and bind to their respective receptors in the cytoplasm. The complex or activated receptors then act as transcription factors by entering the nucleus and binding to DNA hormone-response elements within the nucleus. The DNA-binding domain recognizes certain base sequences, which leads to promotion or repression of particular genes. Regulation of gene transcription by this mechanism can lead to long-term effects. One class of nuclear receptors functions in increased expression of drug-metabolizing enzymes induced by many drugs.

Figure 1-18. Up-regulationand Down-regulationof Receptors

The type and number of receptors that a cell expresses are the net effect of simultaneous receptor synthesis and destruction. In addition to other factors, the number of receptors is modified by long-term exposure to drugs. Chronic stimulation by agonists tends to decrease receptor number (down-regulation), whereas chronic inhibition by antagonists tends to increase the number of receptors (up-regulation). The cellular response opposes the drug-induced effect and may be a defense mechanism. Also, the effect of subsequent administration of drug is greater (or less) than that of initial exposure, and abrupt withdrawal of drug leaves the cell overresponsive or underresponsive to the endogenous ligand. Down-regulation is one mechanism by which pharmacologic tolerance can occur, in which increasing doses of a drug must be used to achieve the same effect.

Figure 1-19. Dose-Response Curves

A direct relation exists between the concentration or dose of a drug and the magnitude of its biologic effect. As a graph, this relation is commonly referred to as aDRC. A DRC can be plotted by using a continuous (graded) or binary (quantal) measure of effect and a linear or logarithmic representation of dose (the latter producing the familiar S-shaped DRC). Each of a drug's usually multiple effects can be represented by a DRC. When the effect is mediated by receptors, the shape of the DRC is consistent with a reversible interaction between ligand (L) and receptor (R):nL +mR ↔ LnRm, wherem andn usually equal 1. The general relation between ligand [L] (drug concentration) and effectE is given by

E=Emax⋅[L][L]+[L]50%effect.

Figure 1-20. Potency

Potency is the drug quantity required for a specified level of a specified effect. For the drug with a DRC given by line A (A), potency is 1 mg/kg for the 50% level of effect A. The 50% level is usually used, with potency shown as an ED50 value. Potency represents ADME and PD properties. Potency for desirable and adverse effects can be established: the potency of one drug for effects A, B, and C (A) is 1, 10, and 100 mg/kg. Potency is thus related to the relative position of a DRC along the horizontal axis. Potency is also used to compare drugs with similar effects (B): 1 mg/kg of drug A is needed for 50% of the effect. Ten times the amount of drug B (10 mg/kg) is required for this level, so drug A is more potent than drug B; both are more potent than drug C. Potency is clinically important only if a drug is expensive or the amount needed is too large. The ED50/LD50 ratio (therapeutic index) is used to compare potency (ED50) with lethality (LD50).

Figure 1-21. Efficacy

At a molecular level,efficacy is the ability of a drug to produce an effect (agonists have positive efficacy, and antagonists have zero efficacy) and the degree of effect per drug molecule bound. At an organism level, it refers to the maximum effect of a drug. Maximum effects of drugs whose DRCs are given by lines A, B, and C is 100%, 50%, and 25%, with the order of efficacy being A > B > C. Efficacy is thus associated with the position of a DRC along the vertical axis. Drugs with a maximal possible effect arefull agonists;partial agonists are drugs whose effect is less than maximal. Some agonists elicit this effect by occupying less than 100% of available receptors, and the other receptors are calledspare receptors. Efficacy is associated with the molecular actions of a drug, not its PK properties. Efficacy can be determined for each of a drug's effects. Unlike potency, efficacy is relatively important clinically because it indicates the maximum attainable effect of a drug.

Figure 1-22. Inverse Agonists

Drug receptors were first thought to be binary switches—either on (activated) or off (resting). Agonists turned the switch on; antagonists blocked agonists' access to receptors. Today, a receptor is viewed as a continuous switch, with the resting state between on or off. Two types of agonists can exist at these receptors: those that move the receptor from resting toward on and those that move it toward off. Both types are agonists, because both have affinity and intrinsic activity. For example, the channel pore of a ligand-gated ion-channel receptor may have a certain resting diameter; some agonists bind to the receptor and increase pore size (increase ion flux), whereas others decrease pore size (decrease ion flux). Which agonist is said to be the inverse of another is arbitrary and depends on which was discovered first. Classic examples of inverse agonists reduce Cl− flow through a GABAA receptor and cause rather than inhibit anxiety. The same antagonist should block both types of agonist.

Figure 1-23. Antagonists: Surmountable (Reversible)and Nonsurmountable (Irreversible)

The ability of an antagonist to alter an agonist effect depends on the affinity of the antagonist for the shared receptor. With weak, reversible antagonist binding (eg, hydrogen bonds), thermal agitation causes some antagonist molecules to uncouple from receptor and agonists successfully compete for receptor sites. If the agonist DRC with surmountable antagonists shifts to the right along the horizontal (dose) axis, the same maximal effect can occur. If antagonist molecules bind to a receptor irreversibly (eg, covalent chemical bonds) or irreversibly alter receptor sites, those sites are unavailable for agonist molecules. Antagonist molecules do not uncouple from a receptor; agonist molecules cannot compete for unoccupied sites. Fewer drug-receptor complexes mean diminished drug effect. The agonist DRC with irreversible antagonists shifts to the right along the dose axis and downward. The same maximal effect cannot be achieved by the agonist at any dose (nonsurmountable antagonism).

Figure 1-24. Routesof Administration

The oral route is generally the most convenient, economic, and safe. Most drugs are rapidly and well absorbed along the GI tract, although some (eg, insulin) are not because of inactivation by enzymes. Drugs given intravenously enter the systemic circulation rapidly; drugs given intra-arterially reach a target site in high concentration. Subcutaneous and intramuscular routes rely on diffusion of the drug into the bloodstream, which can be influenced by warming or cooling the area or by other drugs. Inhalation produces a rapid response to a drug because of the large surface area of the lungs and their extensive blood supply. Transdermal application is becoming an increasing popular mode of administration. Other routes or sites of drug administration include dermal (for local action), mucous membranes (for systemic action), insufflation (lungs), intraneural (nerves), optic (eyes), otic (ears), intraperitoneal (abdomen), and epidural (spinal cord).

Figure 1-25. First-Pass Effect

Drugs that are administered into the GI tract (orally or rectally) are subject to a first-pass effect. Venous drainage of blood from most portions of the GI tract enters the portal circulation, which delivers blood to the liver. In the liver (sometimes the gut wall), drug molecules can be biotransformed (term preferred tometabolized) to less active substances (usually). The amount of active drug that enters the systemic circulation after GI administration is thus less—by the amount of the first-pass effect—than that after another route of administration. The magnitude of this effect on a drug's systemic bioavailability (F) is expressed as the extraction ratio (ER):

F=f×(1−ER)=f×(1−Clliver/Q),

wheref is the extent of absorption,Clliver is the hepatic clearance, andQ is the hepatic blood flow (normally approximately 90 L/h in a 70-kg person). Two related drugs that have comparable bioavailability and similartmax (time to peak concentration) are said to bebioequivalent.

Figure 1-26. Membrane Transport

The biologic membrane is a phospholipid bilayer, a hydrophobic core (lipid layer) between 2 hydrophilic portions (phospho groups). Small molecules can pass through membrane pores. Drugs can pass across membranes by passive diffusion (through lipid or aqueous channels), by active transport (combining with carriers), or by pinocytosis. To cross membranes, most drugs must be both water soluble (hydrophilic or lipophobic) and fat soluble (lipophilic or hydrophobic), which is achieved by weak acids (HA ↔ H+ + A−) and weak bases (BH+ ↔ B + H+), whose charged (hydrophilic) and uncharged (lipophilic) forms are in equilibrium. The extent of drug absorption is a function of pKa of the drug and pH of the local environment. Equations for determining distribution of protonated and nonprotonated forms of a drug across a membrane are

Acids:pKa=pH+log(HA/A−)

Bases:pKa= pH+log(BH+/B).

For reference, pH values in the stomach are 1.0 to 1.5; that in blood plasma is approximately 7.4.

Figure 1-27. Distribution

After absorption, drugs enter the systemic circulation and are distributed widely in the body; they leave the bloodstream and enter cells, with the amount entering depending on local blood flow, capillary permeability, and relative drug lipophilicity. Drugs in the blood are either unbound or bound reversibly to plasma proteins (eg, albumin) in equilibrium. The unbound portion is bioactive. Binding of drugs to these proteins is determined by affinity between drug and protein and protein binding capacity. Only a few binding sites are available, so a high dose can saturate binding sites, and additional drug circulates unbound in the bloodstream. If 2 or more drugs have affinity for the same binding sites, the one with highest affinity will bind, which increases plasma concentration of displaced drug. These effects, which may have clinical consequences, must be considered for the dosing regimen. Drugs with high plasma protein binding (≥95%) include lithium, midazolam, and warfarin (99%).

Figure 1-28. Barriers

Because of various anatomical and physiologic features, endothelial cells of the capillaries can limit passage of drugs from the bloodstream to tissues. For example, endothelial cells of brain capillaries, whose tight junctions merge into a continuous wall, are highly impermeable to many substances. Thus, a blood-brain barrier is established that generally limits accessibility of a good number of drugs, many of which are ionized in the blood at pH 7.4, to the brain. Water-soluble drugs, polar drugs, and ionized forms of drugs cannot cross this blood-brain barrier because they cannot pass through slit junctions and have difficulty traversing the lipid cell membrane. Lipid-soluble drugs pass more readily through cell membranes. In the liver, large fenestrations allow most drugs free access to the hepatic interstitium (with subsequent metabolism of the drugs). The placenta limits but does not prevent entry of drugs into the fetal circulation.

Figure 1-29. Metabolism (Biotransformation)of Drugs

Drugs undergo biotransformation by many of the same reactions as endogenous compounds. Drugs are usually metabolized to less active and more ionized (water-soluble) forms, but equally or more active metabolites can also be created. An inactive parent drug that forms active metabolites is called aprodrug. Although drug metabolism occurs in almost all tissues, including the GI tract, the liver is the major site because of its strategic place in the portal circulation and its many metabolic enzymes. Two general types of drug metabolic reactions occur: phase 1, involving chemical modification, typically by oxidation, reduction, or hydrolysis; and phase 2, in which an endogenous chemical is covalently attached (conjugated) (glucose conjugation, or glucuronidation, the most common). Drugs often undergo multiple phase 1 and 2 reactions, which produces many metabolites, each with its own pharmacologic profile. Liver disease alters drug metabolism, so appropriate dosage adjustment is required.

Figure 1-30. Cytochrome P-450 (CYP450) Enzymes

A major enzyme system that catalyzes phase 1–type drug metabolism reactions is the microsomal CYP450 mixed-function oxidase (monooxygenase) system located in the endoplasmic reticulum in liver, GI tract, lungs, kidney, and other tissues. These enzymes catalyze an oxidation-reduction process that requires CYP450, CYP450 reductase, NADPH (reducing agent), and O2. The only common feature of the many drugs metabolized by this pathway is lipid solubility. The pie chart shown above indicates the approximate percent of current drugs that are metabolized by the indicated CYP isozymes. Known polymorphisms in these enzymes require a drug dosage adjustment. If 2 drugs are metabolized by the same CYP isozyme, they can interfere with each other's normal route or rate of metabolism, and a drug interaction may decrease or increase plasma drug concentrations. An example is interaction between fluoxetine (a selective serotonin reuptake inhibitor) and St John's wort.

Figure 1-31. Metabolic Enzyme Inductionand Inhibition

Multiple factors, including drugs, can either increase or decrease metabolic enzyme activity. Long-term administration of drugs often induces CYP450 activity dramatically by enhancing the rate of synthesis or reducing the rate of degradation of these hepatic microsomal enzymes. Enzyme induction results in more rapid metabolism of the drug and all other drugs metabolized by the same enzymes. As a result, plasma levels and biologic effects of the drugs decrease (except for prodrugs, whose biologic effects increase). Barbiturates are well-known strong inducers of CYP450 enzymes. Other substances can inhibit CYP450 enzymatic activity. In this case, the metabolism of other drugs through this pathway is reduced, which results in increased blood levels of these other drugs. The clinical consequences of the altered blood levels can be greater biologic effects (except for prodrugs) or increased toxicity.

Figure 1-32. Elimination

The major route of drug elimination is through the kidneys, which receive one fifth to one fourth of the cardiac output. Other routes are feces and lungs (especially for anesthetic gases). The rate of elimination of most drugs follows first-order kinetics (exponential decline). The time for the plasma levels of a drug to reach half the initial value is thehalf-life (t1/2). A notable exception is ethanol, which follows zero-order (linear) kinetics at subintoxicating concentrations. Theclearance of a drug from the body is the sum of clearances from all elimination routes, eg, clearance from the kidney is given by the volume of plasma that is completely cleared of the drug per unit time (usually 1 minute). In this case, the amount of drug in urine is measured. Kidney clearance of drug X (CX) is calculated from drug concentrations in urine (UX) and plasma (PX), and urine volume (V):CLX = (UX ×V)/PX. A kidney disorder alters the rate of drug elimination, so the dosage must be adjusted.

Figure 2.14. Noncompetitive Antagonism in Functional Assays.

Simulations showing the effect of a noncompetitive antagonist on responses to the same agonist in a system with high receptor reserve (A) or low receptor reserve (B). Increasing concentrations of the antagonist (3, 10, 30 nM) cause more marked depression of the agonist maximum effect in the low reserve system. Data was simulated using a form of the Operational Model of agonism that assumes that antagonist binding precludes binding of the agonist [32]. The model parameters used were Em=100, n=1, τ=100 (high reserve) or τ=3 (low reserve), pKA=5.0, pKB=9.0. Estimates of the antagonist affinity (pKB) can be made by fitting data directly to this model or approximated as pA2=−log[B]+log(r−1) when a concentration-ratio (r) measured at low response levels is used (B).

Figure 2.15. Allosteric Antagonism.

(A) The effects of acetylcholine (Ach) on the electrically evoked contractions of the guinea pig left atrium in the absence (■) or presence of the allosteric modulator gallamine at the following concentrations: 10 μM (▴), 30 μM (▾), 100 μM (♦), 300 μM (□), and 500 μM (●). (B) The Schild plot of the data shown in (A). The solid line (slope=1) denotes the behavior expected for a competitive antagonist, whereas the dashed line shows the best fit linear regression (and associated slope factor) through the points. The curve through the points and associated parameter estimates represent the fit to an allosteric model. The estimated pKB was 6.03 and the α value of 5.3×10−3 equates to a gallamine-induced decrease in the affinity of ACh of 189-fold.

Figure 4.9. The kinetics of reequilibration of agonists, antagonists and receptors. (A) For simple competitive antagonist systems where there is sufficient time for reequilibration between receptors. The reduction in antagonist receptor occupancy (dotted line) rapidly adjusts as the agonist binds to receptors (solid line). (B) For a slowly dissociating antagonist (broken line), the agonist binding is biphasic, characterized by an initial rapid phase (where the agonist binds to open receptors) and a slow phase whereby the agonist must deal with a slowly dissociating antagonist. The gray rectangle represents the window of opportunity to measure agonist response in the presence of the antagonist; if this is less than the time required for complete reequilibration of agonist, antagonist and receptors then the agonist receptor occupancy will be less than would be defined by true competitive interactions.

Figure 4.10. The effects of a noncompetitive antagonist in two different tissue systems. The top left panel is a system possessing a receptor reserve for the agonist (100% response can be obtained by occupancy of 70% of the receptors). Therefore, noncompetitive (pseudo-irreversible) blockade of receptors will result in dextral displacement of the agonist dose–response curve with no depression of maximal response until concentrations of antagonist that block >70% are present. The response system to the right has no reserve for the agonist (note the linear relationship between percentage agonist occupancy and response). Under these circumstances, the noncompetitive antagonist will produce depression of the maximal response to the agonist at all concentrations.

Figure 4.11. Effects of a noncompetitive antagonist on an agonist dose–response curve (left panel); open circles show the effects of the antagonist on a selected dose of agonist that produces 80% maximal response in the absence of the antagonist. Right panel shows the responses to that same selected dose of agonist as a function of the concentrations of competitive antagonist producing the blockade. It can be seen that an inverse sigmoidal curve results (pIC50 curve). The value of the abscissa corresponding to the half-maximal ordinate value of this curve is the IC50, namely the molar concentration of antagonist that produces half-maximal inhibition of the defined agonist response. The same pIC50 curve would be obtained for any level of response.

Figure 4.12. Antagonist hemi-equilibrium. Shown are the effects of increasing concentrations of a competitive antagonist in a system where there is insufficient time for complete reequilibration between agonist, antagonist and receptors within the time-frame available to measure response to the agonist in the presence of the antagonist. This type of system is characterized by a depression of maximal response to a new steady-state level below that of the control curve but greater than zero. The antagonist potency can be estimated with Schild analysis or through estimation of the pA2 (shaded rectangle).

Figure 4.13. Dose–response curves obtained in the presence of increasing concentrations of a noncompetitive antagonist fit to the model for noncompetitive antagonism (Eq. 4.6).

Figure 4.14. Effect of different time periods to measure agonist response (in the presence of a slowly dissociating orthosteric antagonist) shown in top panel. Panel on the left shows observed antagonism when the period for measurement of response is too short for complete reequilibration (noncompetitive antagonism is observed). Panel on the right shows the same system when sufficient time for the slowly dissociating antagonist is allowed for proper reequilibration between agonist, antagonist and receptors. Under these circumstances, simple competitive antagonism is observed.

Figure 4.15. Effects of an antagonist in vivo where a level of basal activity is present. The dose–response curve to the endogenous agonist will be shifted to the right and/or depressed by the antagonist; the panel on the right shows the observed response in vivo. As the antagonist enters the receptor compartment and binds, the elevated basal response is depressed; as the antagonist washes out of the receptor compartment, the response returns.

Figure 4.16. In vivo effects (see Fig. 4.15) of a competitive versus a noncompetitive antagonist on endogenous elevated basal response.