CHP 1 General Principles
DIRECTIONS: Each item below contains a question or incomplete statement followed by suggested responses. Select the one best response to each question.
1. Of the many types of data plots that are used to help explain the pharmacodynamics of drugs, which plot is very useful for determining the total number of receptors and the affinity of a drug for those receptors in a tissue or membrane?
a. Graded dose-response curve
b. Quantal dose-response curve
c. Scatchard plot
d. Double-reciprocal plot
e. Michaelis-Menten plot
ANS: C
Note:
Based on the concept that, for most situations, the association of a drug with its receptor is reversible, the following reaction applies:
 |
| where D is the concentration of free drug, R is the concentration of receptors, DR is the concentration of drug bound to its receptors, and KD (equal to k2/k1) is the equilibrium dissociation constant. |
The affinity of a drug for its receptor is estimated from the dissociation constant in that its reciprocal, 1/KD, is the affinity constant. All of the plots listed in the question can be used to quantitate some aspect of drug action. For example, KD can be determined from the Michaelis-Menten relationship, graded dose-response curves, and the Scatchard plot.
 |
| (From Neubig RR, Gantros RD, and Brasier RS: Mol Pharmacol 28:475–486, 1985, with permission.) |
However, only the Scatchard plot can be used to determine the total number of receptors in a tissue or membrane. This is accomplished by measuring the binding of a radioactively labeled drug to a membrane or tissue preparation in vitro. A Scatchard plot of the binding of 3H-yohimbine to α2-adrenergic receptors on human platelet membranes is shown on the previous page as an example. A plot of DR/D (bound/free drug) vs. DR (bound drug) yields a slope of 1/KD (the affinity constant) and an x intercept of R (total number of receptors).
Scatchard analysis is very useful in certain therapeutic situations. For example, this type of analysis is used to determine the number of estrogen receptors present in a biopsy of breast tissue prior to developing a drug treatment regimen for breast cancer in a patient.
2. Which route of administration is most likely to subject a drug to a firstpass effect?
a. Intravenous
b. Inhalational
c. Oral
d. Sublingual (SL)
e. Intramuscular
ANS: C
Note:
The first-pass effect is commonly considered to involve the biotransformation of a drug during its first passage through the portal circulation of the liver. Drugs that are administered orally and rectally enter the portal circulation of the liver and can be biotransformed by this organ prior to reaching the systemic circulation. Therefore, drugs with a high first-pass effect are highly biotransformed quickly, which reduces the oral bioavailability and the systemic blood concentrations of the compounds. Administration by the intravenous, intramuscular, and sublingual routes allows the drug to attain concentrations in the systemic circulation and to be distributed throughout the body prior to hepatic metabolism. In most cases, drugs administered by inhalation are not subjected to a significant first-pass effect unless the respiratory tissue is a major site for the drug’s biotransformation.
3. Two drugs may act on the same tissue or organ through independent receptors, resulting in effects in opposite directions. This is known as
a. Physiologic antagonism
b. Chemical antagonism
c. Competitive antagonism
d. Irreversible antagonism
e. Dispositional antagonism
ANS: A
Note:
Physiologic, or functional, antagonism occurs when two drugs produce opposite effects on the same physiologic function, often by interacting with different types of receptors. A practical example of this is the use of epinephrine as a bronchodilator to counteract the bronchoconstriction that occurs following histamine release from mast cells in the respiratory tract during a severe allergic reaction. Histamine constricts the bronchioles by stimulating histamine H1 receptors in the tissue; epinephrine relaxes this tissue through its agonistic activity on β2-adrenergic receptors.
Chemical antagonism results when two drugs combine with each other chemically and the activity of one or both is blocked. For example, dimercaprol chelates lead and reduces the toxicity of this heavy metal.
Competitive antagonism, or inactivation, occurs when two compounds compete for the same receptor site; this is a reversible interaction. Thus, atropine blocks the effects of acetylcholine on the heart by competing with the neurotransmitter for binding to cardiac muscarinic receptors.
Irreversible antagonism generally results from the binding of an antagonist to the same receptor site as the agonist by covalent interaction or by a very slowly dissociating noncovalent interaction. An example of this antagonism is the blockade produced by phenoxybenzamine on α-adrenergic receptors, resulting in a long-lasting reduction in the activity of norepinephrine.
Dispositional antagonism occurs when one drug alters the pharmacokinetics (absorption, distribution, biotransformation, or excretion) of a second drug so that less of the active compound reaches the target tissue. For example, phenobarbital induces the biotransformation of warfarin, reducing its anticoagulant activity.
Questions 4–7
A new aminoglycoside antibiotic (5 mg/kg) was infused intravenously over 30 min to a 70-kg volunteer. The plasma concentrations of the drug were measured at various times after the end of the infusion, as recorded in the table and shown in the figure below.
4. The elimination half-life (t1/2) of the aminoglycoside in this patient was approximately
a. 0.6 h
b. 1.2 h
c. 2.1 h
d. 3.1 h
e. 4.2 h
ANS: D
Note:
The figure that accompanies the question shows an elimination pattern with two distinct components, which typifies a two-compartment model. The upper portion of the line represents the α phase, which is the distribution of the drug from the tissues that receive high rates of blood flow [the central compartment (e.g., the brain, heart, kidney, and lungs)] to the tissues with lower rates of blood flow [the peripheral compartment (e.g., skeletal muscle, adipose tissue, and bone)]. Once distribution to all tissue is complete, equilibrium occurs throughout the body. The elimination of the drug from the body (the β phase) is represented by the lower linear portion of the line; this part of the line is used to determine the elimination half-life of the drug.
At 2 h after dosing, the plasma concentration was 4.6 mg/mL; at 5 h, the concentration was 2.4 mg/mL. Therefore, the plasma concentration of this aminoglycoside decreased to one-half in approximately 3 h—its half-life. In addition, drug elimination usually occurs according to first-order kinetics (i.e., a linear relationship is obtained when the drug concentration is plotted on a logarithmic scale vs. time on an arithmetic scale (a semilogarithmic plot)].
5. The elimination rate constant (ke) of the aminoglycoside in this patient was approximately
a. 0.15 h−1
b. 0.22 h−1
c. 0.33 h−1
d. 0.60 h−1
e. 1.13 h−1
ANS: B
Note:
The fraction change in drug concentration per unit of time for any first-order process is expressed by ke. This constant is related to the half-life (t1/2) by the equation ket1/2 = 0.693. The units of ke are time−1, while the t1/2 is expressed in units of time. By substitution of the appropriate value for half-life estimated from the data from the graph or table accompanying the question (the β phase) into the preceding equation, rearranged to solve for ke, the answer is calculated as follows:
The problem can also be solved mathematically:
 |
| ke will equal 0.22 h−1. |
6. The apparent volume of distribution (Vd) of the drug in this patient was approximately
a. 0.62 L
b. 19 L
c. 50 L
d. 110 L
e. 350 L
ANS: C
Note:
The apparent Vd is defined as the volume of fluid into which a drug appears to distribute with a concentration equal to that of plasma, or the volume of fluid necessary to dissolve the drug and yield the same concentration as that found in plasma. By convention, the value of the plasma concentration at zero time is used. In this problem, a hypothetical plasma concentration of the drug at zero time (7 mg/mL) can be estimated by extrapolating the linear portion of the elimination curve (the β phase) back to zero time. Therefore, the apparent Vd is calculated by
7. The total body clearance (CLtotal) of the drug in this patient was approximately
a. 11 L/h
b. 23 L/h
c. 35 L/h
d. 47 L/h
e. 65 L/h
ANS: A
Note:
Clearance by an organ is defined as the apparent volume of a biologic fluid from which a drug is removed by elimination processes per unit of time. The total body clearance (CLtotal) is defined as the sum of clearances of all the organs and tissues that eliminate a drug. CLtotal is influenced by the apparent Vd and ke. The more rapidly a drug is cleared, the greater is the value of CLtotal. Therefore, for the new aminoglycoside in this patient,
8. If a drug is repeatedly administered at dosing intervals that are equal to its elimination half-life, the number of doses required for the plasma concentration of the drug to reach the steady state is
a. 2 to 3
b. 4 to 5
c. 6 to 7
d. 8 to 9
e. 10 or more
ANS: B
Note:
When a drug is administered in multiple doses and each dose is given prior to the complete elimination of the previous dose, the mean plasma concentration (C) of the drug during each dose interval rises as shown in the following figure:
 |
| (From DiPalma and DiGregorio, with permission.) |
The plasma concentration will continue to rise until it reaches a plateau, or steady state. At this time, the plasma concentration will fluctuate between a maximum (Cmax) and a minimum (Cmin) level, but, more important, the amount of drug eliminated per dose interval will equal the amount of drug absorbed per dose. When a drug is given at a dosing interval that is equal to its elimination half-life, it will reach 50% of its steady-state plasma concentration after one half-life, 75% after two half-lives, 87.5% after three, 93.75% after four, and 96.87% after five. Thus, from a practical viewpoint, regardless of the magnitude of the dose or the half-life, the steady state will be achieved in four to five half-lives.
9. The pharmacokinetic value that most reliably reflects the amount of drug reaching the target tissue after oral administration is the
a. Peak blood concentration
b. Time to peak blood concentration
c. Product of the Vd and the first-order rate constant
d. Vd
e. Area under the blood concentration-time curve (AUC)
ANS: E
Note:
The fraction of a drug dose absorbed after oral administration is affected by a wide variety of factors that can strongly influence the peak blood levels and the time to peak blood concentration. The Vd and the total body clearance (Vd × first-order ke) also are important in determining the amount of drug that reaches the target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors; it is the most reliable and popular method of evaluating bioavailability.
10. It was determined that 95% of an oral 80-mg dose of verapamil was absorbed in a 70-kg test subject. However, because of extensive biotransformation during its first pass through the portal circulation, the bioavailability of verapamil was only 25%. Assuming a liver blood flow of 1500 mL/min, the hepatic clearance of verapamil in this situation was
a. 60 mL/min
b. 375 mL/min
c. 740 mL/min
d. 1110 mL/min
e. 1425 mL/min
ANS: D
Note:
Bioavailability is defined as the fraction or percentage of a drug that becomes available to the systemic circulation following administration by any route. This takes into consideration that not all of an orally administered drug is absorbed and that a drug can be removed from the plasma and biotransformed by the liver during its initial passage through the portal circulation. A bioavailability of 25% indicates that only 20 mg of the 80-mg dose (i.e., 80 mg × 0.25 = 20 mg) reached the systemic circulation. Organ clearance can be determined by knowing the blood flow through the organ (Q) and the extraction ratio (ER) for the drug by the organ, according to the equation
CLorgan = Q × ER
The extraction ratio is dependent upon the amounts of drug entering (Ci) and exiting (Co) the organ:
11. Drug products have many types of names. Of the following types of names that are applied to drugs, the one that is the official name and refers only to that drug and not to a particular product is the
a. Generic name
b. Trade name
c. Brand name
d. Chemical name
e. Proprietary name
ANS: A
Note:
When a new chemical entity is first synthesized by a pharmaceutical company, it is given a chemical name (e.g., acetylsalicylic acid). During the process of investigation of the usefulness of the new chemical as a drug, it is given a generic name by the United States Adopted Names (USAN) Council, which negotiates with the pharmaceutical manufacturer in the choice of a meaningful and distinctive generic name for the new drug. This name will be the established, official name that can only be applied to that one unique drug compound (e.g., aspirin). The trade name (or brand name, or proprietary name) is a registered name given to the product by the pharmaceutical company that is manufacturing or distributing the drug and identifies a particular product containing that drug (e.g., Ecotrin). Thus, acetylsalicylic acid, aspirin, and Ecotrin, for example, all refer to the same therapeutic drug entity; however, only aspirin is the official generic name.
12. Which of the following is classified as belonging to the tyrosine kinase family of receptors?
a. GABAA receptor
b. β-adrenergic receptor
c. Insulin receptor
d. Nicotinic II receptor
e. Hydrocortisone receptor
ANS: C
Note: There are four major classes of receptors:
(1) ion channel receptors, (2) receptors coupled to G proteins, (3) receptors with tyrosine-specific kinase activity, and (4) nuclear receptors.
In most cases, drugs that act via receptors do so by binding to extracellular receptors that transduce the information intracellularly by a variety of mechanisms. Activated ion channel receptors enhance the influx of extracellular ions into the cell;
for example, the nicotinic-II cholinergic receptor selectively opens a channel for sodium ions and the GABAA receptor functions as an ionophore for chloride ions. Receptors coupled to guanine nucleotide-binding proteins (G proteins) act either by opening an ion channel or by stimulating or inhibiting specific enzymes (e.g., β-adrenergic receptor stimulation leads to an increase in cellular adenylate cyclase activity).
When stimulated, receptors with tyrosine-specific protein kinase activity activate this enzyme to enhance the transport of ions and nutrients across the cell membrane; for example, insulin receptors function in this manner and increase glucose transport into insulin-dependent tissues. Steroid hormone receptors are different from all the above in that they are associated with the nucleus of the cell and are activated by steroid hormones (e.g., hydrocortisone) that penetrate into target cells. These receptors interact with DNA to enhance genetic transcription.
13. Identical doses of a capsule preparation (X) and a tablet preparation (Y) of the same drug were compared on a blood concentration-time plot with respect to peak concentration, time to peak concentration, and AUC after oral administration as shown in the figure below. This comparison was made to determine which of the following?
a. Potency
b. Extent of plasma protein binding
c. Bioequivalence
d. Therapeutic effectiveness
e. None of the above
ANS: C
Note:
Drug absorption can vary significantly depending upon the product formulation used and the route of administration. The degree to which a drug achieves a particular concentration in the blood following administration by a route other than intravenous injection is a measure of its efficiency of absorption—its bioavailability. When a drug is produced by different processes (e.g., at different manufacturing sites or using different manufacturing or production techniques) or in a different dosage form (e.g., capsule, tablet, suspension) and contains the same amount of active ingredient and is to be used for the same therapeutic purpose, the extent to which the bioavailability of one dosage form differs from that of another must be evaluated. In the body, these dosage forms should produce similar blood or plasma concentration-time curves. The comparison of the bioavailability of two such dosage forms is called bioequivalence.
The bioequivalence of different preparations is assessed by an evaluation of three parameters:
(1) the peak height concentration achieved by the drug in the dosage form,
(2) the time to reach the peak concentration of the drug, and
(3) the area under the concentration-time curve.
The ascending limb of the curve is considered to be a general reflection of the rate of drug absorption from the dosage form. The descending limb of the concentration-time curve is a general indication of the rate of elimination of the drug from the body.
None of the other choices in the question (i.e., potency, effectiveness, or plasma protein binding) can be evaluated using this type of comparison.
14. Of the following characteristics, which is unlikely to be associated with the process of facilitated diffusion of drugs?
a. The transport mechanism becomes saturated at high drug concentrations
b. The process is selective for certain ionic or structural configurations of the drug
c. If two compounds are transported by the same mechanism, one will competitively inhibit the transport of the other
d. The drug crosses the membrane against a concentration gradient and the process requires cellular energy
e. The transport process can be inhibited noncompetitively by substances that interfere with cellular metabolism
ANS: D
Note:
Drugs can be transferred across biologic membranes by passive processes (i.e., filtration and simple diffusion) and by specialized processes (i.e., active transport, facilitated diffusion, and pinocytosis). Active transport is a carrier-mediated process that shows all of the characteristics listed in the question. Facilitated diffusion is similar to active transport except that the drug is not transported against a concentration gradient and no energy is required for this carrier-mediated system to function. Pinocytosis usually involves transport of proteins and macromolecules by a complex process in which a cell engulfs the compound within a membrane-bound vesicle.
15. In comparing the following possible routes, which is associated with the excretion of quantitatively small amounts of drugs or their metabolic derivatives?
a. Biliary tract
b. Kidneys
c. Lungs
d. Feces
e. Milk
ANS: E
Note:
The amounts of drugs that are excreted in milk are small compared with those that are excreted by other routes, but drugs in milk may have significant, undesired pharmacologic effects on breast-fed infants. The principal route of excretion of the products of a given drug varies with the drug. Some drugs are predominantly excreted by the kidneys, whereas others leave the body in the bile and feces. Inhalation anesthetic agents are eliminated by the lungs. The path of excretion may affect the clinical choice of a drug, as is the case with renal failure or hepatic insufficiency.
16. Of the following, which is a phase II biotransformation reaction?
a. Sulfoxide formation
b. Nitro reduction
c. Ester hydrolysis
d. Sulfate conjugation
e. Deamination
ANS: D
Note:
Biotransformation reactions involving the oxidation, reduction, or hydrolysis of a drug are classified as phase I (or nonsynthetic) reactions; these chemical reactions may result in either the activation or inactivation of a pharmacologic agent. There are many types of these reactions; oxidations are the most numerous. Phase II (or synthetic) reactions, which almost always result in the formation of an inactive product, involve conjugation of the drug (or its derivative) with an amino acid, carbohydrate, acetate, or sulfate. The conjugated form(s) of the drug or its derivatives may be more easily excreted than the parent compound.
17. Which of the following is unlikely to be associated with oral drug administration of an enteric-coated dosage form?
a. Irritation to the gastric mucosa with nausea and vomiting
b. Destruction of the drug by gastric acid or digestive enzymes
c. Unpleasant taste of the drug
d. Formation of nonabsorbable drug-food complexes
e. Variability in absorption caused by fluctuations in gastric emptying time
ANS: E
Note:
Tasteless enteric-coated tablets and capsules are formulated to resist the acidic pH found in the stomach. Once the preparation has passed into the intestine, the coating dissolves in the alkaline milieu and releases the drug. Therefore, gastric irritation, drug destruction by gastric acid, and the forming of complexes of the drug with food constituents will be avoided.
18. Of the following, which is unlikely to be associated with receptors bound to plasma membranes, their interaction with ligands, and the biologic response to this interaction?
a. Structurally, these receptors have hydrophobic amino acid domains, which are in contact with the membrane, and hydrophilic regions, which extend into the extracellular fluid and the cytoplasm
b. Chemical interactions of ligands with these receptors may involve the formation of many types of bonds, including ionic, hydrogen, van der Waals’, and covalent
c. Ligand-receptor interactions are often stereospecific (i.e., one stereoisomer is usually more potent than the other)
d. In some cases, a ligand that acts as an agonist at membrane-bound receptors increases the activity of an intracellular second messenger
e. Activation of membrane-bound receptors and subsequent intracellular events elicit a biologic response through the transcription of DNA
ANS: E
Note:
Based upon the molecular mechanisms with which receptors transduce signals, four major classes of receptors have been identified: (1) ion channel receptors, (2) receptors that interact with G proteins, (3) receptors with tyrosine kinase activity, and (4) nuclear receptors.
The first three types of receptors are complex membrane-bound proteins with hydrophilic regions located within the lipoid cell membrane and hydrophilic portions found protruding into the cytoplasm of the cell and the extracellular milieu; when activated, all of these receptors transmit (or transduce) information presented at the extracellular surface into ionic or biochemical signals within the cell (i.e., second messengers). Nuclear receptors are found in the nucleus of the cell, not bound to plasma membranes. In addition, these receptors do not transduce information by second-messenger systems; rather, they bind to nuclear chromatin and elicit a biologic response through the transcription of DNA and alterations in the formation of cellular proteins. Ligand binding to all types of receptors may involve the formation of ionic, hydrogen, hydrophobic, van der Waals’, and covalent bonds. In most cases, ligand-receptor interactions are stereospecific; for example, natural (−)-epinephrine is 1000 times more potent than (+)-epinephrine.
19. Of the following, which is unlikely to be associated with the binding of drugs to plasma proteins?
a. Acidic drugs generally bind to plasma albumin; basic drugs preferentially bind to α1-acidic glycoprotein
b. Plasma protein binding is a reversible process
c. Binding sites on plasma proteins are nonselective, and drugs with similar physicochemical characteristics compete for these limited sites
d. The fraction of the drug in the plasma that is bound is inactive and generally unavailable for systemic distribution
e. Plasma protein binding generally limits renal tubular secretion and biotransformation
ANS: E
Note:
Because only the free (unbound) fraction of a drug can cross biologic membranes, binding to plasma proteins limits a drug’s concentration in tissues and, therefore, decreases the apparent Vd of the drug. Plasma protein binding will also reduce glomerular filtration of the drug because this process is highly dependent on the free drug fraction. Renal tubular secretion and biotransformation of drugs are generally not limited by plasma protein binding because these processes reduce the free drug concentration in the plasma. If a drug is avidly transported through the tubule by the secretion process or is rapidly biotransformed, the rates of these processes may exceed the rate of dissociation of the drug-protein complex (in order to restore the free:bound drug ratio in plasma) and, thus, become the rate-limiting factor for drug elimination. This assumes that equilibrium conditions exist and that other influences (e.g., changes in pH or the presence of other drugs) do not occur.
20. Of the following, which is unlikely to be associated with drug distribution into and out of the central nervous system (CNS)?
a. The blood-brain barrier, which involves drug movement through glial cell membranes as well as capillary membranes, is the main hindrance to drug distribution to the CNS
b. Most drugs enter the CNS by simple diffusion at rates that are proportional to the lipid solubility of the nonionized form of the drug
c. Receptor-mediated transport allows certain peptides to gain access to the brain
d. Strongly ionized drugs freely enter the CNS through carrier-mediated transport systems
e. Some drugs leave the CNS by passing from the cerebrospinal fluid into the dural blood sinuses through the arachnoid villi
ANS: D
Note:
Drugs can enter the brain from the circulation by passing through the blood-brain barrier. This boundary consists of several membranes, including those of the capillary wall, the glial cells closely surrounding the capillary, and the neuron. In most cases, lipidsoluble drugs diffuse through these membranes at rates that are related to their lipid-to-water partition coefficients. Therefore, the greater the lipid solubility of the nonionized fraction of a weak acid or base, the more freely permeable the drug is to the brain. Some drugs enter the CNS through specific carrier-mediated or receptor-mediated transport processes. Carriermediated systems appear to be involved predominantly in the transport of a variety of nutrients through the blood-brain barrier; however, the thyroid hormone 3,5,3′-triiodothyronine and drugs such as levodopa and methyldopa, which are structural derivatives of phenylalanine, cross the bloodbrain barrier via carrier-mediated transport. Receptor-mediated transport functions to permit a peptide (e.g., insulin) to enter the CNS; therefore, some peptide-like drugs are believed to gain access to the brain by this mechanism. Regardless of the process by which drugs can enter the CNS, strongly ionized drugs (e.g., quaternary amines) are unable to enter the CNS from the blood.
The exit of drugs from the CNS can involve
(1) diffusion across the blood-brain barrier in the reverse direction at rates determined by the lipid solubility and degree of ionization of the drug,
(2) drainage from the cerebrospinal fluid (CSF) into the dural blood sinuses by flowing through the wide channels of the arachnoid villi, and
(3) active transport of certain organic anions and cations from the CSF to blood across the choroid plexuses.
21. The greater proportion of the dose of a drug administered orally will be absorbed in the small intestine. However, on the assumption that passive transport of the nonionized form of a drug determines its rate of absorption, which of the following compounds will be absorbed to the least extent in the stomach?
a. Ampicillin (pKa = 2.5)
b. Aspirin (pKa = 3.0)
c. Warfarin (pKa = 5.0)
d. Phenobarbital (pKa = 7.4)
e. Propranolol (pKa = 9.4)
ANS: E
Note:
Weak acids and weak bases are dissociated into nonionized and ionized forms, depending upon the pKa of the molecule and the pH of the environment. The nonionized form of a drug passes through cellular membranes more easily than the ionized form because it is more lipid soluble. Thus, the rate of passive transport varies with the proportion of the drug that is nonionized. When the pH of the environment in which a weak acid or weak base drug is contained is equal to the pKa, the drug is 50% dissociated. Weak acids (e.g., salicylates, barbiturates) are more readily absorbed from the stomach than from other regions of the alimentary canal because a large percentage of these weak acids are in the nonionized state. The magnitude of this effect can be estimated by applying the Henderson-Hasselbalch equation:
DIRECTIONS: Each group of questions below consists of lettered options followed by a set of numbered items. For each numbered item, select the one lettered option with which it is most closely associated. Each lettered option may be used once, more than once, or not at all.
Questions 22–24
For each type of drug interaction below, select the pair of substances that illustrates it with a reduction in drug effectiveness:
a. Tetracycline and milk
b. Amobarbital and secobarbital
c. Isoproterenol and propranolol
d. Soap and benzalkonium chloride
e. Sulfamethoxazole and trimethoprim
22. Therapeutic interaction
23. Physical interaction
24. Chemical interaction
ANS: 22-C; 23-D; 24-A
Note:
A therapeutic drug interaction is one that reduces drug effectiveness results when two drugs with opposing pharmacologic effects are administered. For example, isoproterenol, a β-adrenergic stimulator, will antagonize the effect of propranolol, a β-adrenergic blocking agent. The combined use of amobarbital and secobarbital, both barbiturate sedativehypnotics, represents a drug interaction that causes an additive (enhanced) pharmacologic response (i.e., depression of the CNS). The combination of the antimicrobials sulfamethoxazole and trimethoprim is an example of a very useful drug interaction in which one drug potentiates the effects of another.
Physical interactions result when precipitation or another change in the physical state or solubility of a drug occurs. A common physical drug interaction takes place in the mixture of oppositely charged organic molecules [e.g., cationic (benzalkonium chloride) and anionic (soap) detergents].
Chemical drug interactions result when two administered substances combine with each other chemically. Tetracyclines complex with Ca (in milk), with aluminum (Al) and magnesium (Mg) (often components of antacids), and with Fe (in some multiple vitamins) to reduce the absorption of the tetracycline antibiotic.
Questions 25–27
For each description of a drug response below, choose the term with which it is most likely to be associated:
a. Supersensitivity
b. Tachyphylaxis
c. Tolerance
d. Hyposensitivity
e. Anaphylaxis
25. Immunologically mediated reaction to drug observed soon after administration
26. A rapid reduction in the effect of a given dose of a drug after only one or two doses
27. Hyperreactivity to a drug seen as a result of denervation
ANS: 25-E; 26-B; 27-A
Note:
Anaphylaxis refers to an acute hypersensitivity reaction that appears to be mediated primarily by immunoglobulin E (IgE). Specific antigens can interact with these antibodies and cause sensitized mast cells to release vasoactive substances, such as histamine. Anaphylaxis to penicillin is one of the best-known examples; the drug of choice to relieve the symptoms is epinephrine.
Decreased sensitivity to a drug, or tolerance, is seen with some drugs such as opiates and usually requires repeated administration of the drug. Tachyphylaxis, in contrast, is tolerance that develops rapidly, often after a single injection of a drug. In some cases, this may be due to what is termed as the down regulation of a drug receptor, in which the number of receptors becomes decreased.
A person who responds to an unusually low dose of a drug is called hyperreactive.
Supersensitivity refers to increased responses to low doses only after denervation of an organ. At least three mechanisms are responsible for supersensitivity: (1) increased receptors, (2) reduction in tonic neuronal activity, and (3) decreased neurotransmitter uptake mechanisms.
Questions 28–30
For each component of a time-action curve listed below, choose the lettered interval (shown on the diagram) with which it is most closely associated:
a. T to U
b. T to V
c. T to W
d. T to Z
e. U to V
f. U to W
g. U to X
h. U to Y
i. V to X
j. X to Y
28. Time to peak effect
29. Time to onset of action
30. Duration of action
ANS: 28-C; 29-A, 30-H
Note:
Timeaction curves relate the changes in intensity of the action of a drug dose and the times that these changes occur. There are three distinct phases that characterize the time-action pattern of most drugs:
(1) The time to onset of action is from the moment of administration (T on the figure that accompanies the question) to the time when the first drug effect is detected (U).
(2) The time to reach the peak effect is from administration (T) until the maximum effect has occurred (W), whether this is above or below the level that produces some toxic effect.
(3) The duration of action is described as the time from the appearance of a drug effect (U) until the effect disappears (Y).
For some drugs, a fourth phase occurs (interval Y to Z), in which residual effects of the drug may be present. These are usually undetectable, but may be uncovered by readministration of the same drug dose (observed as an increase in potency) or by administration of another drug (leading to some drug-drug interaction).
Questions 31–33
For each description below, select the transmembranal transport mechanism it best defines:
a. Filtration
b. Simple diffusion
c. Facilitated diffusion
d. Active transport
e. Endocytosis
31. Lipid-soluble drugs cross the membrane at a rate proportional to the concentration gradient across the membrane and the lipid:water partition coefficient of the drug
32. Bulk flow of water through membrane pores, resulting from osmotic differences across the membrane, transports drug molecules that fit through the membrane pores
33. After binding to a proteinaceous membrane carrier, drugs are carried across the membrane (with the expenditure of cellular energy), where they are released
ANS: 31-B; 32-A; 33-D
Note:
The absorption, distribution, and elimination of drugs require that they cross various cellular membranes. The descriptions that are given in the question define the various transport mechanisms. The most common method by which ionic compounds of low molecular weight (100 to 200) enter cells is via membrane channels. The degree to which such filtration occurs varies from cell type to cell type because their pore sizes differ.
Simple diffusion is another mechanism by which substances cross membranes without the active participation of components in the membranes. Generally, lipid-soluble substances employ this method to enter cells. Both simple diffusion and filtration are dominant factors in most drug absorption, distribution, and elimination.
Pinocytosis is a type of endocytosis that is responsible for the transport of large molecules such as proteins and colloids. Some cell types (e.g., endothelial cells) employ this transport mechanism extensively, but its importance in drug action is uncertain.
Membrane carriers are proteinaceous components of the cell membrane that are capable of combining with a drug at one surface of the membrane. The carrier-solute complex moves across the membrane, the solute is released, and the carrier then returns to the original surface where it can combine with another molecule of solute. There are two primary types of carrier-mediated transport: (1) active transport and (2) facilitated diffusion.
During active transport,
(1) the drug crosses the membrane against a concentration gradient, (2) the transport mechanism becomes saturated at high drug concentrations and thus shows a transport maximum, and (3) the process is selective for certain structural configurations of the drug. Active transport is responsible for the movement of a number of organicacids and bases across membranes of renal tubules, choroid plexuses, and hepatic cells.
With facilitated diffusion, the transport process is selective and saturable, but the drug is not transferred against a concentration gradient and does not require the expenditure of cellular energy. Glucose transport into erythrocytes is a good example of this process. In both situations, if two compounds are transported by the same mechanism, one will competitively inhibit the transport of the other, and the transport process can be inhibited noncompetitively by substances that interfere with cellular metabolism.
Questions 34–36
Lipid-soluble xenobiotics are commonly biotransformed by oxidation in the drug-metabolizing microsomal system (DMMS). For each description below, choose the component of the microsomal mixed-function oxidase system with which it is most closely associated:
a. Nicotinamide adenine dinucleotide phosphate (NADPH)
b. Cytochrome a
c. Adenosine triphosphate (ATP)
d. NADPH–cytochrome P450 reductase
e. Monoamine oxidase (MAO)
f. Cyclooxygenase
g. Cytochrome P450
34. A group of iron (Fe)-containing isoenzymes that activate molecular oxygen to a form that is capable of interacting with organic substrates
35. The component that provides reducing equivalents for the enzyme system
36. A flavoprotein that accepts reducing equivalents and transfers them to the catalytic enzyme
ANS: 34-G, 35-A, 36-D
Note:
There are four major components to the mixed-function oxidase system: (1) cytochrome P450, (2) NADPH, or reduced nicotinamide adenine dinucleotide phosphate, (3) NADPH–cytochrome P450 reductase, and (4) molecular oxygen. The figure that follows shows the catalytic cycle for the reactions dependent upon cytochrome P450.
Cytochrome P450 catalyzes a diverse number of oxidative reactions involved in drug biotransformation; it undergoes reduction and oxidation during its catalytic cycle. A prosthetic group composed of Fe and protoporphyrin IX (forming heme) binds molecular oxygen and converts it to an activated form for interaction with the drug substrate. Similar to hemoglobin, cytochrome P450 is inhibited by carbon monoxide. This interaction results in an absorbance spectrum peak at 450 nm, hence the name P450.
NADPH gives up hydrogen atoms to the flavoprotein NADPH–cytochrome P450 reductase and becomes NADP+. The reduced flavoprotein transfers these reducing equivalents to cytochrome P450. The reducing equivalents are used to activate molecular oxygen for incorporation into the substrate, as described above. Thus, NADPH provides the reducing equivalents, while NADPH–cytochrome P450 reductase passes them on to the catalytic enzyme cytochrome P450.
MAO is a flavoprotein enzyme that is found on the outer membrane of mitochondria. It oxidatively deaminates short-chain monoamines only, and it is not part of the DMMS. ATP is involved in the transfer of reducing equivalents through the mitochondrial respiratory chain, not the microsomal system.
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