General Principles of Pharmacology Quizzes – Part 1

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General Principles of Pharmacology- Part 1

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Question 1

You want to estimate, following drug administration, some measure that reliably reflects the total amount of drug reaching target ti ssue(s) over The drug i s being given orally. What would you assess to get the desired information?

A	Area under the blood concentration-time curve (AUC)
B	Peak (maximum) blood concentration
C	Product of the apparent volume of distribution (Vd) and the fi rst-order rate constant
D	Time-to-peak blood concentration e.
E	Vd

Question 1 Explanation: 

We obtain the AUC orally, by measuring drug concentrations measured in sequential blood samples. However, we must compare those data to measurements of AUC obtained with giving the same drug intravenously (where bioavailability is, by definition, 1.0). The fraction of a drug dose absorbed after oral administration is affected by a 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 also are important in determining the amount of drug that reaches a target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors, and their interactions; it is the most reliable method of evaluating bioavailability overall.

Question 2

The FDA assigns the letters A, B, C, D, and X to drugs i t approves for human use. To what does this  classification refer or apply?

A	Amount of dosage reduction needed as plasma creatinine clearances fall
B	Amount of dosage reduction needed in the presence of l iver dysfunction
C	Fetal ri sk when given to pregnant women
D	Relative margins of safety (or therapeutic index) e.
E	The number of unlabeled uses for a drug

Question 2 Explanation: 

These are FDA “pregnancy categories.” The short table presented below summarizes what each of the five FDA pregnancy classes means. The actual adverse fetal effect(s), and the trimester(s) of pregnancy at which their risks are greatest, depend on the drug class or, in many instances, on the actual drug. The adverse effects may include teratogenesis, fetal death, or such other responses as endocrine imbalances (eg, neonatal hypothyroidism—cretinism—if mother received certain antithyroid drugs). You can look up information for specific drugs, and the trimester(s) during which the fetal risk is greatest or applicable (for example, the main risks of embryopathy from warfarin, a widely used oral anticoagulant, apply to the first 12 or so weeks of gestation), as the need arises (eg, during your obgyn and perhaps other clerkships)

Question 3

You orally administer a weak acid drug (A) with a pKa of 4. Gut pH i s 1.4 and blood pH i s 7.4. Assume the drug crosses membranes by s imple passive diffusion (eg, no transporters are involved). Which observation would be true?

A	Only the ionized form of the drug, A, will be absorbed from the gut
B	The concentration ratio of total drug (A + HA–) would be 10,000:1 (gut:plasma)
C	The drug will be hydrolyzed by reaction with HCl, and so cannot be absorbed
D	The drug will not be absorbed unless we raise gastric pH to equal pKa, as might be done with an antacid
E	The drug would be absorbed, and at equilibrium the plasma concentration of the nonionized moiety (HA) would be 104 times higher than the plasma concentration of A–.

Question 3 Explanation: 

Recall the two Henderson-Hasselbach equations, which apply to how local pH affects the ionization of molecules (eg, of a drug) in an aqueous environment. Assume that membranes are permeable only to nonionized (and more lipidsoluble) forms of a drug. Thus, we are making the assumption that ionized drugs tend to stay, or concentrate, in an environment that favors that pH-dependent ionization; conversely, in an environment that favors formation of nonionized drug molecules, a concentration gradient will favor passive diffusion of nonionized molecules to another locale. Our drug was an acid with pKa = 3.4. In the stomach (assume pH = 1.4 as noted) the ratio of nonionized to ionized molecules will be about 1:0.01. The nonionized molecules will diffuse across the membrane. Once in the plasma, pH 7.4, the ratio of HA:A– will become 1:10,000. And the concentration ratio of total drug across the membrane will be 10,000:1, but with the larger amount being in the plasma, not the gut.

Question 4

Experiments show that 95% of an oral 80-mg dose of verapamil i s absorbed in a 70-kg test However, because of extensive biotransformation during i ts fi rst pass through the hepatic portal ci rculation, the bioavailability was only 0.25 (25%). Assuming a l iver blood flow of 1500 mL/min, what i s the hepatic clearance of verapamil in this s i tuation?

A	60 mL/min
B	375 mL/min
C	740 mL/min
D	1110 mL/min
E	1425 mL/min

Question 4 Explanation: 

Bioavailability is defined as the fraction or percentage of a drug that becomes available to the systemic circulation following administration by any route, compared with bioavailability when the drug is given IV (since IV bioavailability is defined as 1.0, or 10%). 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 metabolized by the liver during its initial passage through the portal circulation (ie, a “first-pass” effect). An oral bioavailability of 0.25 (25%) indicates that only 20 mg of the 80-mg dose (ie, 80 mg × 0.25 = 20 mg) reached the systemic circulation. Organ clearance can be determined by knowing the blood flow through the organ (Q, expressed as a volume per unit time, eg, mL/min) and the extraction ratio (ER) for the drug by the organ, according to the equation: The extraction ratio is a function of the amounts of drug entering the organ (arterial side; CA) and leaving it on the venous side (CV), and the ratio is calculated as: In this problem, the amount of verapamil entering the liver per unit time was 76 mg (80 mg × 0.95) and the amount leaving was 20 mg. Therefore

Question 5

Such substances as inositol tri sphosphate (IP₃), diacetyl glycerol (DAG), cyclic AMP (cAMP), cAMP-dependent protein kinases, and changes in such functions as membrane ion conductance (eg, of gK+ and gCa 2+) are important with respect to the effects of l igands on cell responses. Which best summarizes where they are found or what they do?

A	Are present in nerve cells, but not the various types of muscles or glands
B	Are the receptors for various agonists and antagonist drugs
C	Interact with neurotransmitters or hormones (endogenous l igands), but not to chemicals that are not found naturally in the body
D	Mediate excitatory, but not inhibitory, responses in various target structures
E	Transduce a chemical “s ignal” from a l igand into the final cell response(s)

Question 5 Explanation: 

The substances and functions listed above provide signal transduction between ligand interactions with specific receptors, and responses that are characteristic of the agonist and the target cell(s). Suitable ligands include neurotransmitters (ACh, catecholamines, various amino acids [γ-aminobutyric acid, glycine, glutamate, aspartate] opioids, serotonin, and histamine to name a few) and hormones (insulin, glucagon, thyroid hormones, etc)—or drugs with suitable structures. They are not, however, the actual receptors (b) for agonists or antagonists. These substances will also participate in ligand binding-response coupling to suitable foreign substances—drugs (c). Again, depending on the ligand and the type of cell, responses can be either excitatory or inhibitory (d), and they occur in various neural, muscle, and gland cells (a).

Question 6

Azithromycin, an antibiotic, has an apparent volume of distribution (Vd) of approximately 30 L/kg. What i s the main interpretation of this information?

A	Effective only when given intravenously
B	El iminated mainly by renal excretion, without prior metabolism
C	Extensively distributed to s i tes outside the vascular and interstitial spaces
D	Not extensively bound to plasma proteins
E	Unable to cross the blood-brain or placental “barriers”

Question 6 Explanation: 

For a 70-kg individual, total body water is about 40 L (0.6 L/kg); interstitial plus plasma water occupies about 12 L (0.17 L/kg). Azithromycin, with a Vd of 30 L/kg, would be distributed in an apparent volume of about 2100 L in a typical 70-kg person. Use simple logic to answer this question, but look at the answer to Question 20 if you wish. Even if you don’t remember what total body water is (about 40 L or 0.6 L/kg), or the approximate value for interstitial plus plasma water (about 12 L or 0.17 L/kg), do the quick math. If you take the stated 30 L/kg and compute the total (and very hypothetical) apparent volume for a 70-kg individual, you would arrive at 2100 L. That number not only reflects distribution into a hypothetical volume far in excess of vascular and interstitial volumes, but is also far beyond what could be physically real. After all, 2100 L of water equal 2100 kg; you won’t find human beings weighing that much! Without more information, you cannot make definitive conclusions about the other properties listed as answer choices.

Question 7

A cardiovascular pharmacologist i s assessing the inotropic (contractile) responses of cardiac muscle to a variety of She uses a small animal i solated papillary muscle preparation to gain her data. The experimental setup i s shown here: The papillary muscle has been excised from the animal’s heart and put into a “physiologic” solution that will keep the muscle alive and fully functional for several hours. The muscle i s electrically stimulated at a constant rate so that there are no usual rate-dependent effects on contractile force development, and all neural influences on papillary muscle function or drug responses are absent. A reference standard positive inotropic drug i s administered, in varying concentrations, to determine the maximum increase of contractile force (the inotropic response; maximum i s set at 100% as caused by the standard drug). Thereafter, three other drugs—X, Y, and Z—are tested and their ability to increase contractile force development (compared with the standard or reference drug) i s measured. The  dose-response curves  to  X, Y, and Z are shown here: Which statement describes the findings of this experimental study involving drugs X, Y, and Z?

A	Drug X i s the most efficacious because i ts ED50 i s lowest
B	Drug Y i s the least potent drug among the three drugs shown
C	Drug Z i s the most potent cardiac inotrope
D	Drug Y i s more potent than drug Z, and more efficacious than drug X
E	Drug X i s more potent than drug Y, and more efficacious thandrug Z

Question 7 Explanation: 

“Our product is the most potent pain reliever (or whatever) you can buy without a prescription,” the TV ads say far too often for me. What those claims don’t say is how efficacious a particular drug is, particularly compared with another (eg, a competing product). So, let’s address some fundamentals. The most basic definition of efficacy is simply the ability to cause an effect. More important is the question “how big an effect?” Aspirin, for example, will alleviate headache for many patients, but it simply cannot, at safe doses, alleviate severe pain from, for example, an abdominal incision. So, in the setting of severe pain, aspirin is less efficacious than, say, morphine. If relief of simple headache is the goal, then such drugs as aspirin, acetaminophen, and ibuprofen, are equally efficacious. What differs is how many milligrams of each are necessary to do that. Ibuprofen is more potent than acetaminophen, which is slightly more potent than aspirin: 400 mg of ibuprofen, 600 mg of acetaminophen, and 650 mg of aspirin are reasonable numbers. In the question provided here, drugs X, Y, and Z all have efficacy: they all increase contractile force development by the isolated cardiac muscle preparation shown and described in the question. However, it should be obvious that drugs Y and Z are more efficacious than drug X. The ED50 of drug X is lower than that of the other drugs (a), but that doesn’t mean that it is more efficacious: indeed, its maximal effect on the test muscle’s force of contraction is about less than half of that for drugs Y and Z. Answer b is incorrect: Drug Y is more potent than drug Z: its ED50 is lower than that of drug Z, but Y and Z are equally efficacious since their peak effects are identical. This also eliminates answer c as a correct answer: again, the ED50 for drug Z is higher than that of drug Y, and so Z is less potent. Answer e cannot be correct: although the ED50 of drug X is lower than the ED50s of Y and Z, the maximum intensity of drug X’s response is much lower than those of Y and Z.

Question 8

A patient needs a drug that has an apparent volume of distribution of 20 L. The plan i s to administer a loading dose to reach a target plasma level of 5 mcg/mL. This plasma concentration i s the target steady-state concentration (CSS), and i t will be maintained by subsequent oral maintenance doses. What IV loading dose would be needed to yield that 5 mcg/mL target?

A	1 mg
B	5 mg
C	10 mg
D	20 mg
E	100 mg

Question 8 Explanation: 

Since the volume of distribution is expressed in the volume unit of liters, and the target concentration is per mL, convert one of the volume units to be the same as the other. For example, the target concentration of 5 mcg/mL equals 5 mg/L. We can find the answer by using following simple equations:

Question 9

We are repeatedly administering a drug Every dose i s 50 mg; the interval between doses i s 8 h, which i s identical to the drug’s plasma (overall elimination) half-life. The bioavailability i s 0.5. For as long as the drug i s administered no interacting drugs are added or stopped, and there are no applicable factors affecting such things as absorption or elimination that might change the drug’s pharmacokinetics. Which formula gives the best estimate of how long i t will take for the drug to reach steady-state plasma concentrations (CSS)?

Abbreviations:

Cl = clearance (mL/min) D = dose (mg) F = bioavailability ke = elimination rate constant t₁/2 = half-life (h) Vd = volume of distribution

A	(0.693 × Vd)/Cl
B	1/ke
C	4.5 × t1/2
D	(t1/2) ×(ke)
E	D/(F ×t1/2)

Question 9 Explanation: 

This question, with its many variables and equations, was written intentionally to see whether you would take a needlessly complicated approach to a concept that is, when reduced to its essential point, relatively straightforward. If you give doses of a drug repeatedly at intervals that are equal to or less than the drug’s overall elimination half-life, and keep every other pertinent variable constant (dose, route, elimination status, etc), you simply multiply the half-life by 4 or 5 (hence, my use of 4.5 to take a middle ground) to arrive at the approximate time until CSS: the time at which “drug in = drug out” is reached. You can see in the figure below that with repeated administration of a drug at intervals equal to the drug’s half-life. Note that the average plasma concentration (Cav) does not appear to “flatten-out,” or reach a plateau, until at least four doses (= 4 half-lives) have been given. After that, and assuming nothing else changes (dose, dose interval, route of administration, elimination kinetics, starting, or stopping other drugs), although there will still be fluctuations in peak and trough drug levels around the mean (right after each dose, right before the next), the average blood concentration will not change.

Question 10

A classmate i s doing summer research, in your school’s cl inical pharmacology division, between her fi rst and second years of medical school. Her topic involves new investigations into the roles of P-glycoprotein. Which statement accurately summarizes the biologic role of P-glycoproteins, particularly as i t affects drugs and their actions?

A	Conjugates a variety of drugs, or their metabolites, to facilitate their ultimate renal elimination from the body
B	Maintains structural integrity of cell membranes and the surface receptors found on them
C	Phosphorylates certain substances, such as in the conversion of adenosine monophosphate (AMP) into the diphosphate and triphosphate forms (ADP, ATP)
D	Transports certain drugs and xenobiotics across cell membranes
E	Works, in conjunction with various G-proteins, to transduce (convert) interactions between drugs and their receptors into biologic responses

Question 10 Explanation: 

P-glycoprotein (PGP; the P stands for “permeability”) is part of a super-family of transmembrane transporter proteins, substrates for which include many xenobiotics (chemicals not found naturally in the body), including many therapeutic agents. An important member of the P-glycoprotein family is involved in an ATP-dependent (ie, active transport; this is part of the ABC —ATP-binding cassette—family) mechanism that pumps drugs and other chemically diverse xenobiotics out of certain cells, against the usual concentration gradient. That is, PGP serves an ATP-driven efflux pump. PGP does not form drug conjugates (a) or participate in other Phase II reactions; maintain membrane/receptor structure and function (b); phosphorylate any substrates (c); or play a role in signal transduction (e). Here are some of the sites where PGP is abundant and important, and some important effects at those sites: • in hepatocytes (where it transports substrates into the bile); • in the intestinal epithelium (important for transporting a variety of drugs across membranes during absorption); • in the kidneys (certain proximal tubule cells, where substrates are transported into the urine for eventual elimination); and • in capillary endothelial cells of the “blood-brain barrier,” where certain drugs that may have diffused across the barrier, into the CNS, are transported back out to the systemic circulation. This reduces exposure of the brain to the drugs. What are some clinically relevant phenomena related to PGP activity? For starters, PGP activity is important in the development of multidrug resistance (MRP—multi-drug resistance-associated protein), particularly cellular resistance to certain chemotherapeutic agents and antiviral/antiretroviral drugs. PGP promptly transports those cellular toxins out of the cells the drugs are meant to kill. There is broader importance. Consider, for example, PGP activity in the intestinal epithelia. Many drugs that are substrates for PGP diffuse from the intestinal lumen into the epithelial cells during absorption, but PGP pumps a portion of those drug molecules right back into the lumen, fromwhich they may not be reabsorbed to gain access to the circulation. Thus, PGP has an important role in absorption and bioavailability of many orally administered drugs. Just as there are substrates, inducers, and inhibitors for the cytochrome P450 system, so there are substrates, inducers, and inhibitors for PGP. If PGP activity is increased by an inducer, the oral bioavailability of PGP substrates will be reduced (by virtue of greater transport back into the lumen), plasma levels in response to a dose (or doses) will be reduced (absolute decreases of plasma levels and of the “area under the [timeconcentration] curve), and the intensity of drug responses will be reduced. Conversely, PGP inhibitors can increase oral bioavailability, plasma levels (AUC), and response intensity of PGP substrates. Thus, there are both pharmacokinetic and pharmacodynamic consequences of PGP activity. In some cases the clinical significance of an interaction involving PGP is weak or otherwise inconsequential; however, with many other drugs, inducers or inhibitors may cause clinically significant differences in bioavailability, drug blood levels, and the magnitude of drug responses. The short table that follows lists some of the drugs, mentioned in this book, that are PGP substrates, inducers, or inhibitors.

Question 11

You are conducting pharmacokinetic studies on a new drug that we hope will be approved for cl inical We insert a venous catheter to sample blood at various times after drug administration, and also take a sample for the immediate pre-drug blood concentrations of the drug (which should be zero). After assaying the blood samples for the drug we make a graph that plots plasma drug concentrations over time, continuing until tests reveal undetectable blood levels. What can you calculate or estimate based on the ratio of the area under the curve (AUC) obtained by oral administration versus the AUC for intravenous administration of the same drug?

A	Absorption
B	Bioavailability
C	Clearance
D	El imination rate constant
E	Extraction ratio
F	Volume of distribution

Question 11 Explanation: 

Among other things, knowing the AUC of a drug given intravenously (which, by definition, is associated with a bioavailability of 1.0, or 100%) is a prerequisite for determining the bioavailability of the same drug given by any other route; bioavailability is calculated as the ratio of AUC for any non-IV route and the AUCIV.

Question 12

Identical doses of a drug are given orally and We sample blood at various times, measure blood concentrations of the drug, and plot the data (shown below). Further analysis of only these data will allow you to determine which of the following?

A	El imination route(s)
B	Extent of plasma protein binding
C	Oral bioavailability
D	Potency
E	Therapeutic effectiveness

Question 12 Explanation: 

We are making these data comparison to determine the drug’s bioavailability. We define the bioavailability of a drug given intravenously as 1.0 (100%), since with IV administration we avoid all the applicable barriers to drug absorption. But, of course, it’s important to know how much total drug, over a period of time, gets into the bloodstream with other administration routes that we might want to use clinically. Drugs given by routes other than IV must be absorbed (and be exposed to all the barriers that limit or slow or otherwise affect absorption); and because they might not be absorbed from their administration site, or might be susceptible to such processes as hepatic first-pass metabolism, they usually have a bioavailability <1.0. The calculation of bioavailability is based on the ratio of the area under the concentration-time curve (AUC) for the administration route being considered (oral, IM, etc) and the AUC obtained with IV administration. Measurement of blood levels of a drug at a single time point will not give us the information we need to determine bioavailability. Note that with oral absorption there is a delay until there is some detectable drug in the blood; that reflects both the time needed for absorption of the drug and, in most cases, the sensitivity of the assay to measure the drug (which may be present, but at undetectable levels). With IV administration blood levels rise instantaneously. With oral administration you should also note that as blood levels of the drug rise toward the peak the rates of drug entry into the blood exceed rates of elimination (whether by metabolism, excretion, or both, depending on what the drug is) because blood levels are rising. Once blood concentrations start to fall, the amount of drug entering the system becomes less than the amount being eliminated, per unit time. That is, “amount in = amount out.” Finally—and although you can’t tell precisely from the graph—the half-lives for the drug, measured under different experimental conditions, are identical: in general (and it depends on the drug and its blood level), the drug will be eliminated at the same rate (based on usual kinetic influences, such as first-order kinetics) regardless of administration route. None of the other choices in the question (ie, potency, effectiveness, or plasma protein binding) can be evaluated using this type of comparison.

Question 13

During your career you may have patients in age ranges from very young to very old, and adjustments in drug dosages or intervals between repeated doses may be required based on Assume you consider only the effects of one drug; no interacting drugs  or comorbidities  are involved. What statement best describes the general relationship between chronologic age and the overall elimination plasma half-lives of drugs?

A	Depends on chemical class of drug (eg, benzodiazepine, catecholamine, and dihydropyridine)
B	Depends on renal function (eg, creatinine clearance), not age per se
C	Linear: half-life lengthens in direct proportion to age
D	No generally applicable relationship because elimination half-life depends on the drug, not i ts class
E	Peaks at around age 18 to 20 years, with half-lives being much longer at younger or older ages

Question 13 Explanation: 

How (or even whether) age or extremes of age affect the overall elimination halflife of a drug (and thus the right dose and dosing interval) depends on what the drug is. While renal function, such as that reflected by the creatinine clearance (b), will change over certain age ranges, renal function per se is not universally important to the elimination or elimination rates of all drugs. Remember that many drugs are completely metabolized to inactive substances, and so changes of renal function are largely unimportant in their elimination (and plasma half-lives). Usually, too, there are expected age-related changes in such variables as body water or fat content. They also affect pharmacokinetics, but there is no overarching relationship that applies to all drugs. Consider some examples. • Theophylline’s half-life is shortest between the ages of 6 months to about 9 years, being much longer at younger or older ages. That is because of differences in the rate of the drug’s metabolism. Thus, the dose of this old bronchodilator, normalized to body weight, is much higher for that age range; indeed, it is likely to be excessive for and toxic to younger or older individuals. This rather odd relationship certainly does not apply to all (or even many) drugs, and so answer e is not correct for most drugs. • When comparing the half-life of penicillin G in adults >60 years old to adults in the 20- to 30-year range, the half-life is twice as long in the older patients; it’s nearly twice as long with lidocaine, too; 50% longer with digoxin; and virtually not different, age-wise with warfarin. Other drugs for which there are significant differences (here, in terms of hepatic clearance): most barbiturates; imipramine; meperidine; propranolol; and quinidine. And no significant age-related changes? Examples are aspirin, ethanol, prazosin, and as noted above, warfarin. The chemical class to which a drug belongs (a) also does not invariably predict age-related changes. Consider the benzodiazepines. There are significant age-related pharmacokinetic changes with diazepam (its half-life is more or less directionally proportional to age). In contrast, there are no significant age-related differences in the half-lives of lorazepam or nitrazepam

Question 14

The elimination of a drug and i ts numerous metabolites i s described as being heavily dependent on Phase II metabolic Which of the following i s a Phase II reaction?

A	Glucuronidation
B	Decarboxylation
C	Ester hydrolysis
D	Nitro reduction
E	Sulfoxide formation

Question 14 Explanation: 

Biotransformation reactions involving the oxidation, reduction, or hydrolysis of a drug are classified as Phase I (or nonsynthetic) reactions; these 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 (occasionally called 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, sulfate —or glucuronic acid as noted in the question. The conjugated form(s) of the drug or its derivatives may be more easily excreted than the parent compound.

Question 15

The hospital pharmacy sends up a solution of a drug that i s to be infused intravenously at a constant, specified It has been diluted to the proper concentration in a suitable IV administration fluid. Assuming that no patient- or drug-related variables change during the administration period, which one of the following will be the main determinant of how long i t will take for blood concentrations of this drug to reach steady state (plateau; no change of mean blood levels over time)?

A	Bioavailability of the drug
B	Concentration of the drug in the solution that will be infused
C	Half-life of the drug
D	Presence or absence of cardiovascular or renal disease
E	Plasma creatinine concentration (or creatinine clearance)
F	Total dose per 24 hours
G	Volume of drug administered per minute

Question 15 Explanation: 

With intravenous infusions of a drug, only the drug’s halflife determines how long it will take for blood levels to reach a steady state (on average, neither rising nor falling thereafter) so long as the infusion rate is not changed. By definition, when steady state is reached, the amount of drug entering the blood per unit time is equal to the rate at which drug is being eliminated, whether by excretion, metabolism, or a combination of both (depending on the drug). The apparent volume of distribution has no impact on time to CSS. Bioavailability does not, either, because with intravenous drug administration the bioavailability is 1.0 (100%). Clearance, a parameter that relates elimination rate of a drug to the drug’s concentration [Cl = rate of elimination (mg/h)/drug concentration (mg/mL)]. Because clearance considers a rate of drug elimination, it affects the CSS, but it is not a determinant of it. The infusion rate clearly affects the blood concentration reached at steady state, but it does not affect the time needed to reach it. For example, if we had a drug with a half-life of 4 hours, infused it at a rate of x mg/min, and then repeated the experiment with the same drug at an infusion rate of 2x mg/min, blood concentrations at steady state would clearly be different. However, it would still take the same amount of time (roughly four to five half-lives), to reach steady state. (See the answer to Question 9 for related information.)

Question 16

Yee et (Effect of grapefruit juice on blood cyclosporine concentration. Lancet 1995;345:955–956) examined several pharmacokinetic variables related to oral cyclosporine administration with water, grapefruit juice, and orange juice: The numbers l i sted are arithmetic means ± one standard deviation of the mean. Cmax i s the peak blood concentration, and Tmax i s the time after administration at which peak plasma concentrations of the drug are reached. The p values are based on analysis of variance (ANOVA) corrected for repeated measures. These data, and what you should have learned from your basic pharmacology studies, are most consistent with an hypothesis that grapefruit juice does which of the following?

A	Acidifies the urine, favoring cyclosporine’s tubular reabsorption via a pH-dependent effect
B	Activates an intestinal wall transporter for cyclosporine
C	Alters the route(s) of elimination for cyclosporine
D	Inhibits metabolism of cyclosporine
E	Reduces binding of cyclosporine to plasma proteins, thereby raising free (active) drug levels in the ci rculation

Question 16 Explanation: 

Grapefruit juice (but not most other citrus juices) and juice from Seville oranges (not others; see notes at end of the answer) contain compounds (eg, naringin, furanocoumarins) that can inhibit the metabolism of several drugs, one of which is cyclosporine, via inhibitory effects on CYP3A4). The route (pathway) of elimination (c) is not changed, however. (Other drugs involved in this interaction include verapamil, some of the statin-type cholesterol-lowering medications; most of the second-generation antihistamines, including fexofenadine; and several antidepressants and antihypertensives.) The result is increased bioavailability of an orally administered dose and increased area under the curve in a concentration versus time plot. The potential outcome is excessive (and, occasionally, truly toxic)effects. The “grapefruit juice effect” neither alters the main route(s) of drug absorption or elimination, nor affects plasma protein binding capacity, because those are properties related to the drug, not how—or how well or quickly—it enters the circulation. Note that these data are consistent with the hypothesis that grapefruit juice does not statistically significantly accelerate or slow entry of cyclosporine into the blood, such as by affecting intestinal transporters (b). Changes of urine pH (a) or effects that involve drug binding to plasma proteins (e) are not applicable, nor can such changes be gleaned from the data presented in the question. Notes: (1) The fruit-derived interactants are found in the “fleshy” material under the skin and between fruit segments. (2) Seville oranges (also known as blood orange) are rarely used as juice oranges because of their very bitter taste (and so they are also called bitter oranges). However, Seville/blood orange juice is now appearing more and more in health food stores and other retail grocery stores that sell organic or other “natural” foods. (3) There are several books, and many web sites, that state dogmatically that “ordinary” oranges or orange juices interact with many medications just as grapefruit juice does. This has, naturally, alarmed many individuals. So far, solid research evidence points to no drug interactions involving oranges other than Seville. (4) Don’t be surprised to see furanocoumarin-free grapefruit juice on the market soon.

Question 17

  A 60-year-old man with rheumatoid arthritis will be started on a nonsteroidal anti-inflammatory drug (NSAID) to suppress the joint Published pharmacokinetic data for this drug include: Bioavailability (F): 1.0 (100%) Plasma half-life (t1/2) = 0.5 hour Apparent volume of distribution (Vd): 45 L For this drug i t i s important to maintain an average steady-state concentration of 2.0 mcg/mL in order to ensure adequate and continued anti- inflammatory activity. The drug will be given (taken) every 4 hours. What dose will be needed to obtain this 2 mcg/mL average steady-state drug concentration?

A	5 mg
B	100 mg
C	325 mg
D	500 mg
E	625 mg

Question 17 Explanation: 

Here is how you solve the problem. Note: It’s easy to be misled by inconsistent use of units of measurement (mcg vs. mg, mL vs. L), so be sure you first convert units as necessary for consistency. Calculate the drug’s elimination rate constant: Then calculate the clearance: Recall that C ave = (F/Cl) × (Dose/t), where F is the bioavailability (between 0 and 1.0) and t is the dosing interval (given as 4 hours). Rearrange to solve for the dose. Thus, Dose = 499,000 mcg, or 499 mg (close enough to 500 mg)

Question 18

We take a blood sample from a patient (baseline measurement) and then administer drug A We take additional blood samples periodically thereafter and measure drug concentration in each sample. We repeat the experiment, this time giving the same drug orally. Then we plot the logarithm of drug concentration versus time with data from both administration routes  to  find comparable elimination “curves” indicative of fi rst-order elimination. What do the s lopes of the resulting concentration versus time curves indicate about the pharmacokinetics of drug A?

A	Area under the curve (AUC)
B	Bioavailability
C	El imination rate constant
D	Extraction ratio
E	Volume of distribution

Question 18 Explanation: 

Regardless of which administration route has been used, if we plot the log of plasma concentration of a drug versus time (and assuming first-order kinetics, which applies to the elimination of most drugs when blood levels are therapeutic after initial redistribution), we get a straight line. It is described by the equation: The slope of this line, k, is the elimination rate constant. An arguably more useful (and familiar) measure of the rate at which a drug is eliminated is the half-life (t1/2). It is equal to 0.693/k, and is defined as the time it takes for the concentration of a drug in the blood to fall to precisely one-half of what it is now (or at any specified time). The area under the curve (AUC) is the integration of a time versus concentration plot for a drug. It is a linear—not a logarithmic or semilog—plot. One use for plots of AUC is to estimate one’s “total exposure” to a drug, usually from “time zero” (instantaneously upon administration) until blood concentrations of drug are no longer reliably detectable or further measurements are impractical. The AUC can be used to estimate total body clearance of a drug, without the need to know the drug’s volume of distribution or its half-life, since Determining AUC also enables us to calculate a drug’s bioavailability. Bioavailability (F) is a measure of the fraction of an administered dose that is absorbed systemically and is detectable in the plasma. Note that when a drug is given intravenously, bioavailability is, by definition, 1.0 (100%), since there are no barriers that might prevent the absorption of drug from the administration site. So by administering a drug intravenously, and also giving it by another route, we can calculate bioavailability. For example, assume the other route we use is oral (PO). If we do our bioavailability determinations by giving the same dose of the drug, the dosage units in the above equation cancel out, and so The extraction ratio (ER) is a measure of a drug’s removal from the blood as it passes through an organ (eg, the liver) that can metabolize (or otherwise extract) it, for example, from the arterial to the venous side of that organ. The rate of drug entry to an organ is the product of blood flow (Q) and the arterial concentration of the drug (CA). The rate at which the drug leaves is flow × the venous concentration (CV). If flow into and out of an organ are identical (as it often is), then the extraction ratio can be expressed asWe can also use the extraction ratio to calculate the organ clearance of a drug—that is, the volume per unit time from which an organ removes a drug The volume of distribution (Vd) relates the amount of drug in the body to its concentration in the blood (or plasma). It is typically calculated as the administered dose divided by the concentration of drug in the blood To simplify the assessment of the kinetics we typically give the drug intravenously (so we know how much drug enters the system—the entire dose, since bioavailability = 1.0) and measure the concentration immediately thereafter (or use a plot of the log of drug concentration vs. time), then extrapolate to find drug concentration at “time zero” (the y-axis intercept).

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Part 1 | Part 2 |

II. Preview all questions below

1.You want to estimate, following drug administration, some measure that reliably reflects the total amount of drug reaching target ti ssue(s) over The drug i s being given orally. What would you assess to get the desired information?

1. Area under the blood concentration-time curve (AUC)
2. Peak (maximum) blood concentration
3. Product of the apparent volume of distribution (Vd) and the fi rst-order rate constant
4. Time-to-peak blood concentration
5. Vd

2. The FDA assigns the letters A, B, C, D, and X to drugs i t approves for human To what does this classification refer or apply?

1. Amount of dosage reduction needed as plasma creatinine clearances fall
2. Amount of dosage reduction needed in the presence of l iver dysfunction
3. Fetal ri sk when given to pregnant women
4. Relative margins of safety (or therapeutic index)
5. The number of unlabeled uses for a drug

3. You orally administer a weak acid drug (A) with a pKa of 4. Gut pH i s 1.4 and blood pH i s 7.4. Assume the drug crosses membranes by s imple passive diffusion (eg, no transporters are involved). Which observation would be true?

1. Only the ionized form of the drug, A, will be absorbed from the gut
2. The concentration ratio of total drug (A + HA–) would be 10,000:1 (gut:plasma)
3. The drug will be hydrolyzed by reaction with HCl, and so cannot be absorbed
4. The drug will not be absorbed unless we raise gastric pH to equal pKa, as might be done with an antacid
5. The drug would be absorbed, and at equilibrium the plasma concentration of the nonionized moiety (HA) would be 104 times higher than the plasma concentration of A–.

4. Experiments show that 95% of an oral 80-mg dose of verapamil i s absorbed in a 70-kg test However, because of extensive biotransformation during i ts fi rst pass through the hepatic portal ci rculation, the bioavailability was only 0.25 (25%). Assuming a l iver blood flow of 1500 mL/min, what i s the hepatic clearance of verapamil in this s i tuation?

1. 60 mL/min
2. 375 mL/min
3. 740 mL/min
4. 1110 mL/min
5. 1425 mL/min

5. Such substances as inositol tri sphosphate (IP₃), diacetyl glycerol (DAG), cyclic AMP (cAMP), cAMP-dependent protein kinases, and changes in such functions as membrane ion conductance (eg, of gK+ and gCa 2+) are important with respect to the effects of l igands on cell responses. Which best summarizes where they are found or what they do?

1. Are present in nerve cells, but not the various types of muscles or glands
2. Are the receptors for various agonists and antagonist drugs
3. Interact with neurotransmitters or hormones (endogenous l igands), but not to chemicals that are not found naturally in the body
4. Mediate excitatory, but not inhibitory, responses in various target structures
5. Transduce a chemical “s ignal” from a l igand into the final cell response(s)

6. Azithromycin, an antibiotic, has an apparent volume of distribution (Vd) of approximately 30 L/kg. What i s the main interpretation of this information?

1. Effective only when given intravenously
2. El iminated mainly by renal excretion, without prior metabolism
3. Extensively distributed to s i tes outside the vascular and interstitial spaces
4. Not extensively bound to plasma proteins
5. Unable to cross the blood-brain or placental “barriers”

7. A cardiovascular pharmacologist i s assessing the inotropic (contractile) responses of cardiac muscle to a variety of She uses a small animal i solated papillary muscle preparation to gain her data. The experimental setup i s shown here:

The papillary muscle has been excised from the animal’s heart and put into a “physiologic” solution that will keep the muscle alive and fully functional for several hours. The muscle i s electrically stimulated at a constant rate so that there are no usual rate-dependent effects on contractile force development, and all neural influences on papillary muscle function or drug responses are absent.

A reference standard positive inotropic drug i s administered, in varying concentrations, to determine the maximum increase of contractile force (the inotropic response; maximum i s set at 100% as caused by the standard drug). Thereafter, three other drugs—X, Y, and Z—are tested and their ability to increase contractile force development (compared with the standard or reference drug) i s measured. The  dose-response curves  to  X, Y, and Z are shown here:

Which statement describes the findings of this experimental study involving drugs X, Y, and Z?

1. Drug X i s the most efficacious because i ts ED₅₀ i s lowest
2. Drug Y i s the least potent drug among the three drugs shown
3. Drug Z i s the most potent cardiac inotrope
4. Drug Y i s more potent than drug Z, and more efficacious than drug X
5. Drug X i s more potent than drug Y, and more efficacious thandrug Z

8. A patient needs a drug that has an apparent volume of distribution of 20 L. The plan i s to administer a loading dose to reach a target plasma level of 5 mcg/mL. This plasma concentration i s the target steady-state concentration (CSS), and i t will be maintained by subsequent oral maintenance What IV loading dose would be needed to yield that 5 mcg/mL target?

1. 1 mg
2. 5 mg
3. 10 mg
4. 20 mg
5. 100 mg

9. We are repeatedly administering a drug Every dose i s 50 mg; the interval between doses i s 8 h, which i s identical to the drug’s plasma (overall elimination) half-life. The bioavailability i s 0.5. For as long as the drug i s administered no interacting drugs are added or stopped, and there are no applicable factors affecting such things as absorption or elimination that might change the drug’s pharmacokinetics.

Which formula gives the best estimate of how long i t will take for the drug to reach steady-state plasma concentrations (CSS)?

Abbreviations:

Cl = clearance (mL/min)

D = dose (mg)

F = bioavailability

ke = elimination rate constant

t₁/2 = half-life (h)

Vd = volume of distribution

1. (0.693 × Vd)/Cl
2. 1/ke
3. 4.5 × t1/2
4. (t1/2) ×(ke)
5. D/(F ×t1/2)

10. A classmate i s doing summer research, in your school’s cl inical pharmacology division, between her fi rst and second years of medical school. Her topic involves new investigations into the roles of P-glycoprotein. Which statement accurately summarizes the biologic role of P-glycoproteins, particularly as i t affects drugs and their actions?

1. Conjugates a variety of drugs, or their metabolites, to facilitate their ultimate renal elimination from the body
2. Maintains structural integrity of cell membranes and the surface receptors found on them
3. Phosphorylates certain substances, such as in the conversion of adenosine monophosphate (AMP) into the diphosphate and triphosphate forms (ADP, ATP)
4. Transports certain drugs and xenobiotics across cell membranes
5. Works, in conjunction with various G-proteins, to transduce (convert) interactions between drugs and their receptors into biologic responses

11. You are conducting pharmacokinetic studies on a new drug that we hope will be approved for cl inical We insert a venous catheter to sample blood at various times after drug administration, and also take a sample for the immediate pre-drug blood concentrations of the drug (which should be zero). After assaying the blood samples for the drug we make a graph that plots plasma drug concentrations over time, continuing until tests reveal undetectable blood levels. What can you calculate or estimate based on the ratio of the area under the curve (AUC) obtained by oral administration versus the AUC for intravenous administration of the same drug?

1. Absorption
2. Bioavailability
3. Clearance
4. El iminationrate constant e. Extraction ratio
5. Volume of distribution

12. Identical doses of a drug are given orally and We sample blood at various times, measure blood concentrations of the drug, and plot the data (shown below).

Further analysis of only these data will allow you to determine which of the following?

1. El imination route(s)
2. Extent of plasma protein binding
3. Oral bioavailability
4. Potency
5. Therapeutic effectiveness

13. During your career you may have patients in age ranges from very young to very old, and adjustments in drug dosages or intervals between repeated doses may be required based on Assume you consider only the effects of one drug; no interacting drugs  or comorbidities  are involved. What statement best describes the general relationship between chronologic age and the overall elimination plasma half-lives of drugs?

1. Depends on chemical class of drug (eg, benzodiazepine, catecholamine, and dihydropyridine)
2. Depends on renal function (eg, creatinine clearance), not age per se
3. Linear: half-life lengthens in direct proportion to age
4. No generally applicable relationship because elimination half-life depends on the drug, not i ts class
5. Peaks at around age 18 to 20 years, with half-lives being much longer at younger or older ages

14. The elimination of a drug and i ts numerous metabolites i s described as being heavily dependent on Phase II metabolic Which of the following i s a Phase II reaction?

1. Glucuronidation
2. Decarboxylation
3. Ester hydrolysis
4. Nitro reduction
5. Sulfoxide formation

15. The hospital pharmacy sends up a solution of a drug that i s to be infused intravenously at a constant, specified It has been diluted to the proper concentration in a suitable IV administration fluid. Assuming that no patient- or drug-related variables change during the administration period, which one of the following will be the main determinant of how long i t will take for blood concentrations of this drug to reach steady state (plateau; no change of mean blood levels over time)?

1. Bioavailability of the drug
2. Concentration of the drug in the solution that will be infused
3. Half-life of the drug
4. Presence or absence of cardiovascular or renal disease
5. Plasma creatinine concentration (or creatinine clearance)
6. Total dose per 24 hours
7. Volume of drug administered per minute

16. Yee et (Effect of grapefruit juice on blood cyclosporine concentration. Lancet 1995;345:955–956) examined several pharmacokinetic variables related to oral cyclosporine administration with water, grapefruit juice, and orange juice:

The numbers l i sted are arithmetic means ± one standard deviation of the mean. Cmax i s the peak blood concentration, and Tmax i s the time after administration at which peak plasma concentrations of the drug are reached. The p values are based on analysis of variance (ANOVA) corrected for repeated measures.

These data, and what you should have learned from your basic pharmacology studies, are most consistent with an hypothesis that grapefruit juice does which of the following?

1. Acidifies the urine, favoring cyclosporine’s tubular reabsorption via a pH-dependent effect
2. Activates an intestinal wall transporter for cyclosporine
3. Alters the route(s) of elimination for cyclosporine
4. Inhibits metabolism of cyclosporine
5. Reduces binding of cyclosporine to plasma proteins, thereby raising free (active) drug levels in the ci rculation

17. A 60-year-old man with rheumatoid arthritis will be started on a nonsteroidal anti-inflammatory drug (NSAID) to suppress the joint Published pharmacokinetic data for this drug include:

Bioavailability (F): 1.0 (100%) Plasma half-life (t1/2) = 0.5 hour

Apparent volume of distribution (Vd): 45 L

For this drug i t i s important to maintain an average steady-state concentration of 2.0 mcg/mL in order to ensure adequate and continued anti- inflammatory activity.

The drug will be given (taken) every 4 hours.

What dose will be needed to obtain this 2 mcg/mL average steady-state drug concentration?

1.  5 mg
2. 100 mg
3. 325 mg
4. 500 mg
5. 625 mg

18. We take a blood sample from a patient (baseline measurement) and then administer drug A We take additional blood samples periodically thereafter and measure drug concentration in each sample. We repeat the experiment, this time giving the same drug orally. Then we plot the logarithm of drug concentration versus time with data from both administration routes  to  find comparable elimination “curves” indicative of fi rst-order elimination. What do the s lopes of the resulting concentration versus time curves indicate about the pharmacokinetics of drug A?

1. Area under the curve (AUC)
2. Bioavailability
3. El imination rate constant
4. Extraction ratio
5. Volume of distribution