General Principles of Pharmacology Quizzes – Part 2

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General Principles of Pharmacology- Part 2

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Question 1

The official “package insert” for prescription drugs identifies (among many other things) the specific use(s) or indication(s) for the drug approved by the It i s also l ikely to note one or several more so-called “off-label” uses: uses that have not been sanctioned officially by the FDA, but for which there i s reasonable evidence that the drug i s both safe and effective. For which other uses can you, as a l i censed physician, administer or prescribe these FDA-approved drugs?

A	Anything you wish, provided no specific laws (eg, controlled-substance laws) prohibit i t
B	None—only FDA approved and written off-label uses
C	Only approved and off-label uses for older drugs in the same chemical class (eg, another thiazide diuretic, benzodiazepine, etc)
D	Only approved and off-label uses of older drugs used for the same purpose (eg, another antihypertensive, antidepressant, or cancer chemotherapeutic agent, etc)
E	Only uses for which there i s some evidence of drug efficacy and safety in the experimental l i terature

Question 1 Explanation: 

nce the FDA approves a drug, you, as a licensed physician, can prescribe it for anything you desire. Of course, there should be some scientific basis for your new-found or hypothesized use, hopefully supporting or other rational evidence in solid peer-reviewed clinical literature. (You probably won’t, for example, see a β-blocker being used for treating anal warts, but if you wanted to use one that way you are not violating any federal laws. Just be sure you have a good reason to do so, and a good attorney should something bad happen and you get sued.) And if you are conducting a clinical trial at your institution to determine new information about future clinical efficacy of a drug for which there are other approved uses, and even printed off-label uses, you’ll probably need Institutional Review Board approval and will have to provide written informed consent to your study subjects. Note: Let’s consider just one drug in one drug class: fluoxetine, the prototype of the SSRI class of antidepressants. What is it approved for? Well, depression, of course. But other approved or off-label uses for this antidepressant (and the identical chemical entity, same dose as used for depression but “approved” under a different trade name for premenstrual dysphoric disorder) include the following: obsessive-compulsive disorder; bulimia nervosa; alcoholism; anorexia nervosa; ADHD; bipolar II affective disorder; borderline personality disorder; narcolepsy; kleptomania; migraine; chronic daily headaches and tension-type headache; post-traumatic stress disorder; schizophrenia; levodopa-induced dyskinesia; social phobia; chronic rheumatoid pain; panic disorder; and diabetic peripheral neuropathy. Oh, one more: trichotillomania—but don’t start pulling out your own hair, or get depressed, trying to memorize this incomplete list of sometimes-odd uses

Question 2

When new drugs undergo preclinical testing, one of many things to know i s whether i t’s largely confined to the vascular compartment or distributed more widely, perhaps to specific ti ssues such as the l ipid-rich This i s , of course, ultimately cl inically important i f the drug eventually gets FDA approval. One way to get a handle on that i s to calculate the apparent volume of distribution (Vd). The table and graph below show some data concerning a new amino-glycoside antibiotic. We give an IV dose (5 mg/kg) of the drug to a 70-kg 21- year-old volunteer, who i s healthy and taking no other drugs. After allowing time for redistribution and equilibration of the drug in various body compartments, we measure plasma concentrations at various times. Which value comes closest to the apparent Vd for this drug? (By all means, feel free to use your favorite calculator.)

A	0.62 L
B	19 L
C	50 L
D	110 L
E	350 L

Question 2 Explanation: 

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, we use the value of the plasma concentration, based on data such as those shown here, that has been extrapolated back to “time zero”. Plotting the drug concentration (y-axis) on a logarithmic scale, as shown here, allows us to do the extrapolation easily. In this example, that is about 7 mcg/mL. Therefore, the apparent Vd is calculated as: The total amount of drug in the body initially is the dose we gave (100% bioavailability, since we gave it IV), 350 mg (ie, 5 mg/kg × 70 kg). The estimated plasma concentration at zero time is 7 mcg/mL (0.007 mg/mL). Putting these numbers in the equation yields the apparent Vd: 21. The answer is d. (Brunton, pp 24-27; Katzung, pp 1057-1058.) Most excessive and adverse effects from a single drug occur because of dec

Question 3

You are reviewing the data from several meta-analyses that addressed the most common causes of adverse or otherwise excessive effects of prescription drugs in young adults and in the elderly (>60 years of age). Interactions between multiple drugs were not Which variable would you find to be decreased, and be the most common general cause of these problems, in the elders?

A	Body fat content
B	Lean body mass
C	Liver function
D	Renal function/clearance
E	Plasma albumin levels

Question 3 Explanation: 

Most excessive and adverse effects from a single drug occur because of declines in renal excretory function. It affects drugs that are eliminated without prior metabolism, those for which metabolic inactivation plays a relatively small role in elimination, and those drugs that form one or more active metabolites. Declines of hepatic function clearly occur in advanced age, whether in the presence or absence of other factors that might impair hepatic drug metabolism, but that does not seem to account for the majority of cases of excessive drug effects. Body fat content tends to rise, not decrease, with age (a)

Question 4

Some texts state that the ability of one drug (sometimes called the “object drug”) to displace molecules of another drug (the “target drug”) from plasma protein binding s i tes, thereby raising the concentration and activity of free target drug in the blood, i s not cl inically The claimed reason? “Drug molecules that are displaced are rapidly eliminated and the equilibrium between bound and free drug i s rapidly reestablished.” This interpretation may be correct for some drugs, but not for others. Considering only the pharmacokinetics or other relevant properties of the target drug, upon which drug-related variable does the speed of elimination and reestablishment of the bound versus free equilibrium—indeed, whether the interaction i s apt to be cl inically relevant—depend the most?

A	Bioavailability
B	Overall elimination t1/2
C	pK (acid or base)
D	Renal clearance
E	Whether the drug i s metabolized, or excreted without prior metabolism

Question 4 Explanation: 

The speed of any redistribution or re-equilibration of bound/free concentrations of the target drug depends on the drug’s overall elimination half-life (which, in turn, is a composite of either or both excretion and metabolism, depending on the drug). If a drug has an overall short elimination half-life, relatively speaking, the re-equilibrium between bound and free molecules will, indeed, be reached quickly. If the drug has a relatively long half-life (and especially if relatively large amounts of the interacting drug are present and/or the interactant binds avidly to plasma proteins), then it will take longer for equilibrium to be established once again (if it occurs at all). If the drugs are in the circulation largely unbound, the consequences are less. However, consider warfarin: normally 99% of all warfarin molecules at any given time are bound to plasma proteins. Displacement of even a small fraction of those bound molecules will have a large impact on the number of free (active) molecules, and warfarin’s normal average half-life is about 2.5 days. Bioavailability of the drug (a) is not important or relevant. No matter whether bioavailability is great (at or near 1.0) or small, once the drug is in the circulatory system the interaction will occur, and reequilibrium will be reestablished neither slower nor faster than under any other circumstances. Likewise, unless blood pH changes (I did not say it did, and there is no reason to speculate that it would), the pK of the drugs (c) is largely irrelevant. Renal clearance (d) may be important, but recall that many drugs are eliminated mainly or completely by metabolism, so whether clearance is important depends on the drug(s). The same reasoning applies to answer e: it is not important how the drug is eliminated, it is the rate at which overall elimination occurs.

Question 5

Upon evaluating the effects of certain sympathomimetic drugs in a variety of in vi tro and in vivo models, you find that the responses exhibit the phenomenon of tachyphylaxis. What does the term tachyphylaxis mean?

A	An increase in the rate of the response, for example, an increase of the rate of muscle contraction
B	Immediate hypersensitivity reactions (ie, anaphylaxis
C	Prompt conformational changes of the receptor such that agonists, but not antagonists, are able to bind and cause a response
D	Quick and progressive ri ses in the intensity of drug response, with repeated administration, even when the doses are unchanged
E	Rapid development of tolerance to the drug’s effects

Question 5 Explanation: 

Tachyphylaxis is defined as rapidly developing tolerance to the effects of an agonist that is administered repeatedly, even if the dosages given after the first one are not changed—or even progressively increased to overcome thephenomenon. It is sometimes also called desensitization or downregulation of the receptor(s), but those phenomena do not explain all the mechanisms by which tachyphylaxis (or tolerance in general) occurs. The mechanism behind the development of tachyphylaxis—or slowerdeveloping drug tolerance in general—varies depending on which drug is being used, the biochemical processes by which the drug exerts its effects, and what the effector and the response(s) are. For example, consider the rapidly diminished response of a variety of cells/tissues to repeated administration of amphetamine, which acts by releasing neuronal norepinephrine. Challenge the system repeatedly and the amount of intraneuronal NE available to be released—which is essential for causing the ultimate response—goes down. Another example, with more clinical relevance, is the somewhat slower development of “tolerance” of airway smooth muscles, and their ability to relax (ie, cause bronchodilation) in response to repeated administration of β-adrenergic agonists, such as albuterol, arguably the most widely used adrenergic bronchodilator for asthma. [Note: There is no “magical” number—hours or days, for example—that distinguishes between tachyphylaxis and “regular” tolerance. The brevity with which the tolerance develops is the key point.]

Question 6

A postoperative patient will require prolonged We choose a drug that has the following pharmacokinetic properties: Half-life: 12 hours Clearance: 0.08 L/min Volume of distribution: 60 L The patient has an indwelling venous catheter with a s low drip of 0.9% Na Cl , and we will use this to administer intermittent injections of the drug every 4 hours. The target blood level of the drug, following each injection, i s 8 mcg/mL. With this plan in mind, and using no loading dose of the drug, which one of the following comes closest to the dose that should be administered every 4 hours?

A	0.960 mg (or 1 mg)
B	6.4 mg (or 6 mg)
C	25.6 mg (or 25 mg)
D	150 mg
E	550 mg

Question 6 Explanation: 

The dose (D) to give equals the product of the target blood concentration and the drug’s clearance. To simplify things, let’s get the units of volume the same for both clearance and concentration. The clearance of 0.08 L/min = 80 mL/min. Therefore The stated dosing interval is 4 hours, so which (rounded) is closest to 150 mg.

Question 7

A patient i s experiencing severe postoperative pain, and we need to give a loading dose of an analgesic drug for prompt relief of The drug we choose has the same pharmacokinetic properties as the one described in Question 24: Half-life: 12 hours Clearance: 0.08 L/min Volume of distribution: 60 L Our target plasma concentration for the drug i s 8 mcg/mL. What number comes closest to the correct loading dose?

A	0.48 mg (rounded to 0.5 mg)
B	150 mg
C	320 mg
D	480 mg
E	640 mg

Question 7 Explanation: 

The answer is d. (Brunton, pp 36-37; Katzung, pp 41-47.) Here the loading dose (D) equals the product of the target blood concentration (Cdesired) and the volume of distribution (Vd). As always, convert units to make things consistent. The volume of distribution, 60 L, is, of course, 60,000 mL

Question 8

We administer a highly l ipid-soluble drug and monitor i ts elimination in vivo and in vi All the data indicate that i t i s transformed to  a variety of more polar and oxidized metabolites by a group of heme proteins that activate molecular oxygen to a form that i s capable of interacting with organic substrates such as our test drug. What enzyme or enzyme system i s most l ikely involved in the initial metabolism of this drug?

A	Cyclooxygenase
B	Cytochrome P450s (CYP system, mixed-function oxidases)
C	Monoamine oxidase (MAO
D	Nicotinamide adenine dinucleotide phosphate (NADPH)
E	UDP-glucuronosyltransferase

Question 8 Explanation: 

There are four major components to this 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 shows the catalytic cycle for the general reactions dependent on cytochrome P450s. (Not all reaction steps or intermediates are shown.) In simple terms, the system acts as a monooxygenase, converting a reduced form of a drug (RH) to an oxidized form (ROH). For some drugs, those metabolic steps are followed by Phase II reactions, such as conjugation (with glucuronic acid, sulfate, etc) that further enhance the elimination of drug metabolites. Cytochrome P450s catalyze diverse oxidative reactions involved in drug biotransformation; they undergo reduction and oxidation during the 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. NADPH gives up protons to the flavoprotein (FP) NADPH-cytochrome P450 reductase. 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 reducing equivalents, and NADPH-cytochrome P450 reductase passes them on to the catalytic enzymes that comprise cytochrome P450. Cyclooxygenase (COX; answer a) is a general term for two main enzymes, COX-1 and 2, that metabolize endogenous arachidonic acid to prostaglandins, prostacyclins, and other eicosanoids. Its substrate specificity is largely limited to the endogenous molecules derived from arachidonic acid, not xenobiotics. A good example of COX-1 and COX-2 is aspirin. Most other nonsteroidal anti-inflammatory drugs are also COX-1 and COX-2 inhibitors. The exemplar of a selective COX-2 inhibitor is celecoxib. Monoamine oxidase (MAO; c) is a flavoprotein enzyme that is found on the outer membrane of mitochondria in certain neurons, and also in hepatocytes. It oxidatively deaminates short-chain monoamines only, and it is not part of the drug-metabolizing microsomal system. ATP is involved in the transfer of reducing equivalents through the mitochondrial respiratory chain, not the microsomal system. There are various forms of MAO, distinguished mainly by their cellular locations, their substrates, and their inhibitors. MAO-A, for example, is found in rather diverse locations, such as in the liver and other cells. MAO-B is the predominant form in certain parts of the brain (hence, “B”). UDP-glucuronosyltransferase, along with such enzymes as glutathione-S-transferase, methyltransferases, and N-acetyltransferases, are important in Phase II metabolism of various drugs. Substrates for these enzymes generally are drugs or xenobiotics that were previously transformed by Phase I reactions, such as the actions of the CYP450 mixed-function oxidases. These enzymes add a functional group to a substrate, rather than chemically modifying the original substrate via oxidation, reduction, deamination, and the like—all of which are responsibilities of the mixed-function oxidase systems. Note: How did the cytochrome P450 system get the “450” designation? Similar to hemoglobin, cytochrome P450 is inhibited by carbon monoxide. This interaction results in molecules with a spectrophotometric absorbance spectrum peak at 450 nm, hence the designation 450

Question 9

We measure the heart rate of a healthy subject under the conditions noted below, allowing ample time for return to baseline conditions and full elimination of drugs between each step:

1. At rest
2. During treadmill exercise sufficient to activate the sympathetic nervous system at a time when maximum heart rate i s reached
3. After administration of acebutolol, a drug with affinity for β-adrenergic receptors
4. After giving acebutolol, followed by exercise at the same level used in condition 2

Acebutolol given at rest causes a s l ight but consistent increase in heart rate. Give  a  bigger dose at rest and heart rate  ri ses a  bit more. When the patient exercises after receiving a low-dose acebutolol, heart rate ri ses s ignificantly less than i t did in the absence of acebutolol. With exercise after the higher dose of acebutolol, the tachycardia i s blunted even more. The figure below summarizes the main findings. Which statement best summarizes the actions of acebutolol?

A	Has higher affinity for adrenergic receptors than the endogenous agonists, epinephrine, and norepinephrine
B	Is a partial agonist for β-adrenergic receptors
C	Is activating spare receptors on myocardial cells
D	Is an i rreversible or noncompetitive β-blocker
E	Is changing conformation of the adrenergic receptors

Question 9 Explanation: 

Partial agonists have both the ability to bind to receptors (affinity) and the ability to evoke a response by activating those receptors (efficacy), albeit weakly, under basal conditions. Thus, when acebutolol is administered at rest (a condition under which endogenous catecholamine levels are low), heart rate rises slightly due to β-1 receptor activation via weak agonist activity.However, the occupation of adrenergic receptors by this weak agonist reduces the number of receptors available to bind and respond to stronger agonists (epinephrine, norepinephrine). As a result, the magnitude of the response to stronger agonists in the presence of the partial agonist is lower than in the absence of it (all other things being equal).

Question 10

We are planning to infuse a drug intravenously at a constant amount per unit time (rate). It has a fi rst-order elimination rate constant (kel) of 35/h. No loading dose will be given. Approximately how long will i t take for blood levels to reach steady state after the infusion begins?

A	0.7 hour
B	1.2 hours
C	3.5 hours
D	9 hours
E	24 hours

Question 10 Explanation: 

With first-order elimination of a drug, we get a straight line if we plot the log of drug concentration in the blood versus time once dosing has stopped. The slope of the line is the elimination rate constant (kel). The drug’s half-life—a value we will need to use momentarily—is related to kel as follows: t1/2 × (kel)/0.693. So, for the drug noted in the question, t1/2 = 0.693/0.35, or approximately 2 hours. It takes approximately four to five half-lives to reach a steady-state blood concentration. Do the math and you’ll see that the time for this drug to reach steady state is approximately 8 to 10 hours.

Question 11

A patient who i s supposed to be taking a drug once a day gets confused and for a couple of days takes excessive daily doses, leading to The drug has a mean plasma half-life of 40 hours. Right now the patient’s plasma concentration of the drug i s 6 mcg/mL. Although what to do next will depend on actual blood tests for drug levels, the usual plan in this case i s to have the patient skip one or several daily doses of the drug until blood levels fi rst enter the therapeutic and nontoxic range, which in this case i s 0.8 mcg/mL. Assume the drug i s eliminated by fi rst-order kinetics. How many daily doses should be withheld?

A	1
B	2
C	3
D	4
E	5

Question 11 Explanation: 

After a 40-hour (about 1.67 days) drug-free interval passes the concentration of the drug will fall, as predicted by the half-life, to 3 mcg/mL; to 1.5 mcg/mL 40 hours after that; and to 0.75 mcg (now in the nontoxic range) after yet another 40 hours passes. Thus we have to wait 120 hours, or five daily doses skipped, to achieve the goal.

Question 12

We want to calculate the apparent volume of distribution (Vd) for a hypothetical drug (drug A) that has a half-life of 4 All (100%) of an absorbed dose of this drug undergoes Phase I oxidation, followed by conjugation (Phase II reaction) and then renal excretion. We rapidly inject a known dose, and 30 minutes later begin taking serial blood samples (30 min apart) and quantifying drug concentration in each sample. What one other piece of information must be measured or otherwise determined to calculate Vd in the easiest way?

A	Area under the drug concentration-time curve (AUC)
B	Bioavailability (F)
C	Clearance (Cl)
D	El imination rate constant (kel)
E	Maximum blood concentration after the bolus injection (C0)

Question 12 Explanation: 

You should recall that Vd = Dose/C0. We know what the dose is. What we must calculate is the initial drug concentration (C0)—the peak drug concentration that is reached “instantaneously” after giving the IV bolus dose. Unfortunately, we’ve waited 30 minutes before taking our first blood sample, but that is not a significant problem: plot the log of drug concentration versus time and extrapolate to where the line intercepts the log-concentration axis (t0). This gives us a good estimate of C0. Plug the extrapolated C0 into the equation and you have your answer. Note that bioavailability is not a factor in this instance, because with IV administration bioavailability is, by definition, 1.0 (100%). Knowing or calculating the elimination rate constant won’t help either, because it is inextricably linked to the half-life, which we already know as kel = 0.693/t1/2 (and you can rearrange the equation easily.) Calculating the AUC (concentration vs. time integral) with a bolus injection will give us no information more useful than what we already have. Clearance (generally referring to renal clearance) is irrelevant in this situation: I’ve stated that the drug is completely metabolized to other products; thus, there is no drug A to measure in the urine.

Question 13

A patient with a bacterial infection requires intravenous antibiotic The chosen drug has a clearance (Cl) of 70 mL/min. The apparent volume of distribution (Vd) i s 50 L. The plan i s to administer the drug intravenously every 6 hours and achieve a 4 mg/L steady-state blood level of the drug. No loading dose strategy i s to be used. What maintenance dose i s needed to achieve this?

A	14 mg
B	24 mg
C	100 mg
D	300 mg.
E	1200 mg

Question 13 Explanation: 

The scenario above makes calculations relatively straightforward, particularly because no loading dose therapy will be used. Steady-state blood levels occur when the rate of “drug in” equals the rate of “drug out.” The volume of distribution, given in the question, is irrelevant for the calculations. The rate of drug out is given as a Cl = 70 mL/min Recall that the dose (D) = Cl × CSS Therefore, with a little rearranging, the dose can be computed as: Convert the units so they’re consistent for both variables, and don’t forget to calculate how many minutes there are in the dosing interval, 6 hours. Now, the rest of the math: The target blood level of 4 mg/L is the same as 4 mcg/mL, and this is a reasonable change of volume units to make for subsequent calculations, since clearance is given in units of mL/min. And since the drug will be given every 6 hours:

Question 14

A pharmacologically inert but easily measured substance, X, i s eliminated in a manner that follows l inear kinetics (fi rst-order plot of log drug concentration vs time during elimination i s a straight l ine). The plasma half-life i s 30 Bolus IV doses well in excess of 100 mg must be given in order to saturate the enzymes responsible for metabolizing the drug, which will then lead to zero-order elimination kinetics. We infuse a solution of X intravenously. The concentration of the solution i s 2 mg/mL; the infusion rate i s 1 mL/min and i s kept constant at that. We continue the infusion for 24 hours. After allowing ample time for the drug to be eliminated completely, we repeat the administration. This time the concentration of the solution  of X i s 4 mg/mL, and we infuse i t at a rate of 2 mL/min. Which other variable will also be changed as a result of the stated changes to the infusion protocol?

A	El imination rate constant
B	Half-life
C	Plasma concentration when CSS i s reached
D	Time to reach steady-state concentration (CSS) e.
E	Total body clearance
F	Volume of distribution

Question 14 Explanation: 

Only the drug concentration at steady state will change: it will be greater with this altered protocol. Do not be misled by the numbers. The time to reach CSS with a constant drug infusion is a function of half-life (or the elimination rate constant, which is related to it: kel = 0.693/t1/2), and that will not change under the conditions stated. Likewise, with the vast majority of drugs eliminated by first-order kinetics, there will be no change of total body clearance or of volume of distribution. (Note: I described substance X as being pharmacologically inert simply so you didn’t conjure up confounding but largely irrelevant issues, such as an active drug that is able to cause residual or long-lasting effects on its elimination or elimination rate, for example, a drug that caused long-lasting induction of hepatic drug-metabolizing enzymes.)

Question 15

A new drug, drug A, undergoes a series of Phase I metabolic reactions before i ts metabolites ultimately are Which statement best describes the characteristics of drug A, or the role of Phase I reactions in i ts metabolism or actions?

A	Complete metabolism of drug A by Phase I reactions will yield products that are less l ikely to undergo renal tubular reabsorption
B	Drug A i s a very polar substance
C	Drug A will be biologically inactive until i t i s metabolized
D	Phase I metabolism of drug A involves conjugation, as with glucuronic acid or sulfate
E	Phase I metabolism of drug A will increase i ts intracellular access and actions

Question 15 Explanation: 

Phase I metabolic reactions generally convert (via addition or unmasking of such polar functional groups as –NH2 or –OH through, say, oxidations, reductions, or deamination) very nonpolar (ie, very lipid-soluble) drugs into more polar (more water-soluble) metabolites. Among other things, polar metabolites of drugs in general are less likely to undergo tubular reabsorption. We can generalize by saying that Phase I reactions play a role in forming metabolites that are “more easily excreted.” If drug A, the parent drug, was already very polar (answer b), there would be little need for Phase I metabolism. There is no reason to assume that drug A will lack intrinsic biological activity (answer c); and because it is quite lipid-soluble to begin with, once in the circulation it should have good ability to diffuse across membranes and reach intracellular sites (hence, e is incorrect). Finally, note that those reactions described as Phase II are the ones that further increase polarity (water-solubility) of some drugs via forming conjugates with glucuronic acid or sulfate.

Question 16

Dopamine, epinephrine (or norepinephrine), and histamine are important neurotransmitter When these l igands interact with their cellular receptors, how do they mainly elicit their responses?

A	Activating adenylyl cyclase, leading to increased intracellular cAMP levels
B	Activating phospholipase C
C	Inducing or inhibiting synthesis of l igand-specific intracellular proteins
D	Opening or closing l igand-gated ion channels
E	Regulating intracellular second messengers through G protein-coupled receptors

Question 16 Explanation: 

The general issue of ligand-receptor-response coupling involves signal transduction, and is addressed in Question 5. The specific agonists noted in the question transduce their signals and eventually cause a response by processes involving G proteins—a family of guanine nucleotide-binding proteins. These ligands bind to the extracellular face of the transmembrane protein. The various G proteins (eg, Gi, Gq, and Gs) bind to intracellular portions of the receptor. They then couple the initial ligand interaction to theeventual response through a series of effector enzymes or enzyme systems that are G protein-regulated. For example, adenylyl cyclase can be activated, catalyzing the formation of cAMP that then activates a particular kinase that phosphorylates specific intracellular proteins. However, the actual steps that occur after ligand binding depend on what the ligand is, what specific G protein is involved, which kinases are activated, and what proteins they phosphory-late. And what happens (ie, what the response is) depends on all of the above and, of course, which cell type is being affected. Activation of adenylyl cyclase and increased cAMP levels may occur in one system, but the opposite may occur in another. Some signal transduction pathways involve phospholipase C, others do not. A calcium channel may be affected in one system and a potassium channel (or no ion channel) in others. By way of review, recall that there are three other main mechanisms or pathways for signal transduction about which we have reasonable knowledge. One uses a receptor protein that spans the cell membrane, but G proteins are not involved. On the inner membrane face the protein possesses enzymatic activity that is regulated by the presence or absence of ligand bound to the extracellular face. The tyrosine kinase pathway is an example, and the overall pathway is responsible for the activity of various growth factors and insulin (which is also a growth-regulating hormone). Another mechanism is used by very lipid-soluble ligands that cross cell membranes easily and act on some intracellular receptor. For example, glucocorticosteroids ultimately act in the nucleus and, through interaction with heat-shock protein (hsp90), eventually alter transcription of specific genes. The third involves transmembrane ion channels, the “open” or “closed” states of which are controlled by ligand binding to the channel. This process applies to some of the important neurotransmitters, especially those in the brain (GABA, the main inhibitory neurotransmitter) and such amino acids as glycine, which exert “excitatory” actions. The nicotinic receptor for ACh fits in this category too.

Question 17

You have just evaluated and started treatment on a 40-year-old woman in whom you have diagnosed malignant hypertension, based on her history, her cl inical presentation, and the blood pressure changes you measured over the relatively short time you’ve  been at the  You now go to the family, in the waiting room, and explain your diagnosis. You explain that hypertension means high blood pressure. But when they heard the word malignant one of the family members says “Oh, her blood pressure i s high because she has cancer?” How should you best explain the term to the family?

A	Blood pressure i s ri s ing very quickly and dangerously
B	Cancer i s present, but i t i s not the cause of the high blood pressure
C	Her high blood pressure i s , indeed, caused by a cancer (“malignancy”—in this case probably an adrenal cortical tumor—a pheochromocytoma)
D	Her high blood pressure did not fall in response to a blood pressure medication that i s effective for most patients
E	The hypertension i s l ikely to prove fatal (eg, from a ruptured aneurysm in the brain or elsewhere)

Question 17 Explanation: 

You may not find the definition of malignant in a pharmacology book, but you ought to know what it is. Many people think “malignant” invariably means cancer, but that isn’t true. Remember malignant hypertension, malignant hyperthermia, neuroleptic malignant syndrome? The term simply means a condition is rapidly getting worse. Nothing necessarily linked to cancer; no implication that the condition will not respond to usually effective (or even second- or third-line) therapies and medications (refractory is the term for resistance to intervention); no guarantee, or even a likelihood, that the condition will be fatal if it is treated properly

Question 18

The Food and Drug Administration has broad regulatory authority over prescription drugs, over-the-counter (OTC) drugs, and nutritional supplements (herbals and other so-called nutriceuticals). This authority includes approval, marketing (advertising), and withdrawal of drugs from the Which statement summarizes an element of FDA rules or guidelines?

A	Drugs approved for sale OTC fi rst received FDA approval for sale and marketing “by prescription only”
B	If a pharmaceutical manufacturer provides data sufficient to obtain FDA approval for sale by prescription, the manufacturer i s then allowed to sell the drug over-the-counter (OTC)
C	If the FDA approves a prescription drug for sale (prescribing), the physician can prescribe the drug only for the FDA-approved indication (use)
D	Nutritional supplements can be marketed without providing proof of efficacy or safety to the FDA
E	Phase III testing of prescription drugs that have been approved by the FDA gives complete information about adverse responses and pertinent drug-drug interactions

Question 18 Explanation: 

One of the most controversial aspects of marketing herbals, nutritional supplements, and other “nutriceuticals” is that manufacturers and sellers have to provide no prior or scientific proof of safety or efficacy to the FDA—something that must be provided, and with abundant and scientifically sound data, before the FDA will approve a drug for sale by prescription. Herbals, for example, came under the umbrella of the Dietary Supplement Health and Education Act (DSHEA) of 1994. Such products, you may have noted, come with labels that state “serving size,” rather than dose, as if we are going to be ingesting some carrots instead of a potentially active and dangerous drug. Sellers of such products as herbals cannot make explicit claims that their products will prevent, diagnose, treat, or cure any disease. DSHEA allows a seller of a nutritional supplement to say such obtuse things as “boosts your memory,” or “improves urinary tract health,” but they cannot state “helps prevent or treat Alzheimer disease” or “reduces urinary frequency and nocturia if you have benign prostatic hypertrophy.” In fact, DSHEA simply requires that the label on the product states, in essence, that the FDA hasn’t evaluated any of the claims the manufacturer has made, plainly or implicitly, on the label. Moreover, while a drug company must provide and pay for the obligatory preclinical and clinical studies before a prescription drug gets the OK, if there is a reason or attempt to pull a nutriceutical from the market the FDA must do the work and pay the costs to prove that the product is unsafe or ineffective. Drugs needn’t be approved by the FDA as prescription drugs (answer a) before they can be sold OTC. While such prior approval is the trend, if not the norm (for example, consider many antihistamines for allergy or insomnia; or drugs that inhibit gastric acid secretion being marketed for “heartburn” or “acid indigestion), consider aspirin. It’s been available OTC for decades and for its common uses (pain, fever, inflammation) it has never gotten an FDA blessing as a prescription drug. Indeed, some say that if aspirin were being considered for approval as a prescription drug today, it might not be approved because of the risks of serious adverse responses (eg, bleeding tendencies from antiplatelet effects; bronchospasm in many asthmatics) and drug-drug interactions. Nonetheless, we have many OTC drugs nowadays that first got approval for sale “by prescription only,” for example, antihistamines, inhibitors of gastric acid secretion (noted above), and others. Approval for OTC sale was petitioned by the manufacturer, and then approved only after reviews by and recommendations from FDA’s expert advisory panels. Answer c is incorrect. Once a drug gets approval for sale and use as a prescription drug, and for a given indication (or more, depending on data submitted and approved), the physician can prescribe that drug for any (reasonable) purpose that he or she thinks is appropriate, safe, and effective. Physicians and scientists learn or hypothesize about new uses for a drug, conduct clinical studies, and overall can legally prescribe drugs for the off-label or unlabeled uses. Phase III testing of drugs is conducted in usually no more than 5000 patients with a disease for which the drug is to be marketed. The main goal is to assess effectiveness for the stated use, and for overall safety. These are rather tightly controlled studies. The number of subjects, and the conditions in which the drug is given, are quite different from what happens in the “real world”—including Phase IV, which is the postmarketing surveillance phase of drug approval, where tens or hundreds of thousands of patients may get the drug in largely uncontrolled circumstances. Many drugs have come (been FDA-approved) and gone (pulled from the market because of adverse reactions or interactions, including those leading to death) because of what we’ve learned after the drug was approved by the FDA, and was approved for use by physicians in conditions that weren’t nearly as well controlled as those involved in pre-approval studies.

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Part 1 | Part 2 |

II. Preview all questions below

1.The official “package insert” for prescription drugs identifies (among many other things) the specific use(s) or indication(s) for the drug approved by the It i s also l ikely to note one or several more so-called “off-label” uses: uses that have not been sanctioned officially by the FDA, but for which there i s reasonable evidence that the drug i s both safe and effective. For which other uses can you, as a licensed physician, administer or prescribe these FDA-approved drugs?

1. Anything you wish, provided no specific laws (eg, controlled-substance laws) prohibit i t
2. None—only FDA approved and written off-label uses
3. Only approved and off-label uses for older drugs in the same chemical class (eg, another thiazide diuretic, benzodiazepine, etc)
4. Only approved and off-label uses of older drugs used for the same purpose (eg, another antihypertensive, antidepressant, or cancer chemotherapeutic agent, etc)
5. Only uses for which there i s some evidence of drug efficacy and safety in the experimental l i terature

2. When new drugs undergo preclinical testing, one of many things to know i s whether i t’s largely confined to the vascular compartment or distributed more widely, perhaps to specific ti ssues such as the l ipid-rich This i s , of course, ultimately cl inically important i f the drug eventually gets FDA approval. One way to get a handle on that i s to calculate the apparent volume of distribution (Vd).

The table and graph below show some data concerning a new amino-glycoside antibiotic. We give an IV dose (5 mg/kg) of the drug to a 70-kg 21- year-old volunteer, who i s healthy and taking no other drugs. After allowing time for redistribution and equilibration of the drug in various body compartments, we measure plasma concentrations at various times.

Which value comes closest to the apparent Vd for this drug? (By all means, feel free to use your favorite calculator.)

1. 0.62 L
2. 19 L
3. 50 L
4. 110 L
5. 350 L

3. You are reviewing the data from several meta-analyses that addressed the most common causes of adverse or otherwise excessive effects of prescription drugs in young adults and in the elderly (>60 years of age). Interactions between multiple drugs were not Which variable would you find to be decreased, and be the most common general cause of these problems, in the elders?

1. Body fat content
2. Lean body mass
3. Liver function
4. Renal function/clearance
5. Plasma albumin levels

4. Some texts state that the ability of one drug (sometimes called the “object drug”) to displace molecules of another drug (the “target drug”) from plasma protein binding s i tes, thereby raising the concentration and activity of free target drug in the blood, i s not cl inically The claimed reason? “Drug molecules that are displaced are rapidly eliminated and the equilibrium between bound and free drug i s rapidly reestablished.” This interpretation may be correct for some drugs, but not for others.

Considering only the pharmacokinetics or other relevant properties of the target drug, upon which drug-related variable does the speed of elimination and reestablishment of the bound versus free equilibrium—indeed, whether the interaction i s apt to be cl inically relevant—depend the most?

1. Bioavailability
2. Overall elimination t1/2
3. pK (acid or base)
4. Renal clearance
5. Whether the drug i s metabolized, or excreted without prior metabolism

5. Upon evaluating the effects of certain sympathomimetic drugs in a variety of in vi tro and in vivo models, you find that the responses exhibit the phenomenon of tachyphylaxis. What does the term tachyphylaxis mean?

1. An increase in the rate of the response, for example, an increase of the rate of muscle contraction
2. Immediate hypersensitivity reactions (ie, anaphylaxis)
3. Prompt conformational changes of the receptor such that agonists, but not antagonists, are able to bind and cause a response
4. Quick and progressive ri ses in the intensity of drug response, with repeated administration, even when the doses are  unchanged
5. Rapid development of tolerance to the drug’s effects

6. A postoperative patient will require prolonged We choose a drug that has the following pharmacokinetic properties: Half-life: 12 hours

Clearance: 0.08 L/min Volume of distribution: 60 L

The patient has an indwelling venous catheter with a s low drip of 0.9% Na Cl , and we will use this to administer intermittent injections of the drug every 4 hours. The target blood level of the drug, following each injection, i s 8 mcg/mL.

With this plan in mind, and using no loading dose of the drug, which one of the following comes closest to the dose that should be administered every 4 hours?

1. 0.960 mg (or 1 mg)
2. 6.4 mg (or 6 mg)
3. 25.6 mg (or 25 mg)
4. 150 mg
5. 550 mg

7. A patient i s experiencing severe postoperative pain, and we need to give a loading dose of an analgesic drug for prompt relief of The drug we choose has the same pharmacokinetic properties as the one described in Question 24:

Half-life: 12 hours

Clearance: 0.08 L/min Volume of distribution: 60 L

Our target plasma concentration for the drug i s 8 mcg/mL. What number comes closest to the correct loading dose?.

1. 0.48 mg (rounded to 0.5 mg)
2. 150 mg
3. 320 mg
4. 480 mg
5. 640 mg

8. We administer a highly l ipid-soluble drug and monitor i ts elimination in vivo and in vi All the data indicate that i t i s transformed to  a variety of more polar and oxidized metabolites by a group of heme proteins that activate molecular oxygen to a form that i s capable of interacting with organic substrates such as our test drug. What enzyme or enzyme system i s most l ikely involved in the initial metabolism of this drug?

1. Cyclooxygenase
2. Cytochrome P450s (CYP system, mixed-function oxidases)
3. Monoamine oxidase (MAO)
4. Nicotinamide adenine dinucleotide phosphate (NADPH)
5. UDP-glucuronosyltransferase

9. We measure the heart rate of a healthy subject under the conditions noted below, allowing ample time for return to baseline conditions and full elimination of drugs between each step:

1. At rest
2. During treadmill exercise sufficient to activate the sympathetic nervous system at a time when maximum heart rate i s reached
3. After administration of acebutolol, a drug with affinity for β-adrenergic receptors
4. After giving acebutolol, followed by exercise at the same level used in condition 2

Acebutolol given at rest causes a s l ight but consistent increase in heart rate. Give  a  bigger dose at rest and heart rate  ri ses a  bit more. When the patient exercises after receiving a low-dose acebutolol, heart rate ri ses s ignificantly less than i t did in the absence of acebutolol.

With exercise after the higher dose of acebutolol, the tachycardia i s blunted even more.

The figure below summarizes the main findings.

Which statement best summarizes the actions of acebutolol?

1. Has higher affinity for adrenergic receptors than the endogenous agonists, epinephrine, and norepinephrine
2. Is a partial agonist for β-adrenergic receptors
3. Is activating spare receptors on myocardial cells
4. Is an i rreversible or noncompetitive β-blocker
5. Is changing conformation of the adrenergic receptors

10. We are planning to infuse a drug intravenously at a constant amount per unit time (rate). It has a first-order elimination rate constant (kel) of 35/h. No loading dose will be given. Approximately how long will i t take for blood levels to reach steady state after the infusion begins?

1. 0.7 hour
2. 1.2 hours
3. 3.5 hours
4. 9 hours
5. 24 hours

11. A patient who i s supposed to be taking a drug once a day gets confused and for a couple of days takes excessive daily doses, leading to The drug has a mean plasma half-life of 40 hours.

Right now the patient’s plasma concentration of the drug i s 6 mcg/mL. Although what to do next will depend on actual blood tests for drug levels, the usual plan in this case i s to have the patient skip one or several daily doses of the drug until blood levels fi rst enter the therapeutic and nontoxic range, which in this case i s 0.8 mcg/mL. Assume the drug i s eliminated by fi rst-order kinetics. How many daily doses should be withheld?

1. 1
2. 2
3. 3
4. 4
5. 5

12. We want to calculate the apparent volume of distribution (Vd) for a hypothetical drug (drug A) that has a half-life of 4 All (100%) of an absorbed dose of this drug undergoes Phase I oxidation, followed by conjugation (Phase II reaction) and then renal excretion.

We rapidly inject a known dose, and 30 minutes later begin taking serial blood samples (30 min apart) and quantifying drug concentration in each sample. What one other piece of information must be measured or otherwise determined to calculate Vd in the easiest way?

1. Area under the drug concentration-time curve (AUC)
2. Bioavailability (F)
3. Clearance (Cl)
4. El imination rate constant (kel)
5. Maximum blood concentration after the bolus injection (C₀)

13. A patient with a bacterial infection requires intravenous antibiotic The chosen drug has a clearance (Cl) of 70 mL/min. The apparent volume of distribution (Vd) i s 50 L. The plan i s to administer the drug intravenously every 6 hours and achieve a 4 mg/L steady-state blood level of the drug. No loading dose strategy i s to be used. What maintenance dose i s needed to achieve this?

1. 14 mg
2. 24 mg
3. 100 mg
4. 300 mg.
5. 1200 mg

14. A pharmacologically inert but easily measured substance, X, i s eliminated in a manner that follows l inear kinetics (fi rst-order plot of log drug concentration vs time during elimination i s a straight l ine). The plasma half-life i s 30 Bolus IV doses well in excess of 100 mg must be given in order to saturate the enzymes responsible for metabolizing the drug, which will then lead to zero-order elimination kinetics.

We infuse a solution of X intravenously. The concentration of the solution i s 2 mg/mL; the infusion rate i s 1 mL/min and i s kept constant at that.

We continue the infusion for 24 hours.

After allowing ample time for the drug to be eliminated completely, we repeat the administration. This time the concentration of the solution  of X i s 4 mg/mL, and we infuse i t at a rate of 2 mL/min.

Which other variable will also be changed as a result of the stated changes to the infusion protocol?

1. El imination rate constant
2. Half-life
3. Plasma concentration when CSS i s reached
4. Time to reach steady-state
5. concentration (CSS) e.
6. Total body clearance
7. Volume of distribution

15. A new drug, drug A, undergoes a series of Phase I metabolic reactions before i ts metabolites ultimately are Which statement best describes the characteristics of drug A, or the role of Phase I reactions in i ts metabolism or actions?

1. Complete metabolism of drug A by Phase I reactions will yield products that are less l ikely to undergo renal tubular reabsorption
2. Drug A i s a very polar substance
3. Drug A will be biologically inactive until i t i s metabolized
4. Phase I metabolism of drug A involves conjugation, as with glucuronic acid or sulfate
5. Phase I metabolism of drug A will increase i ts intracellular access and actions

16. Dopamine, epinephrine (or norepinephrine), and histamine are important neurotransmitter When these l igands interact with their cellular receptors, how do they mainly elicit their responses?

1. Activating adenylyl cyclase, leading to increased intracellular cAMP levels
2. Activating phospholipase C
3. Inducing or inhibiting synthesis of l igand-specific intracellular proteins
4. Opening or closing l igand-gated ion channels
5. Regulating intracellular second messengers through G protein-coupled receptors

17. You have just evaluated and started treatment on a 40-year-old woman in whom you have diagnosed malignant hypertension, based on her history, her cl inical presentation, and the blood pressure changes you measured over the relatively short time you’ve  been at the  You now go to the family, in the waiting room, and explain your diagnosis. You explain that hypertension means high blood pressure. But when they heard the word malignant one of the family members says “Oh, her blood pressure i s high because she has cancer?” How should you best explain the term to the family?

1. Blood pressure i s ri s ing very quickly and dangerously
2. Cancer i s present, but i t i s not the cause of the high blood pressure
3. Her high blood pressure i s , indeed, caused by a cancer (“malignancy”—in this case probably an adrenal cortical tumor—a pheochromocytoma)
4. Her high blood pressure did not fall in response to a blood pressure medication that i s effective for most patients
5. The hypertension i s l ikely to prove fatal (eg, from a ruptured aneurysm in the brain or elsewhere)

18. The Food and Drug Administration has broad regulatory authority over prescription drugs, over-the-counter (OTC) drugs, and nutritional supplements (herbals and other so-called nutriceuticals). This authority includes approval, marketing (advertising), and withdrawal of drugs from the Which statement summarizes an element of FDA rules or guidelines?

1. Drugs approved for sale OTC fi rst received FDA approval for sale and marketing “by prescription only”
2. If a pharmaceutical manufacturer provides data sufficient to obtain FDA approval for sale by prescription, the manufacturer i s then allowed to sell the drug over-the-counter (OTC)
3. If the FDA approves a prescription drug for sale (prescribing), the physician can prescribe the drug only for the FDA-approved indication (use)
4. Nutritional supplements can be marketed without providing proof of efficacy or safety to the FDA
5. Phase III testing of prescription drugs that have been approved by the FDA gives complete information about adverse responses and pertinent drug-drug interactions