The quizzes about Central Nervous System Pharmacology – Part 1

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Central Nervous System Pharmacology- Part 1

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Question 1

Guanfacine has recently been FDA-approved for managing attention-deficit hyperactivity disorder (ADHD) in patients between the ages of 6 and 17 In addition to i ts benefits for ADHD, i t appears to provide symptom relief in generalized anxiety disorder and post-traumatic stress disorder. Although the newly approved indications for guanfacine focus on the central nervous system, the drug can cause many important peripheral autonomic effects. They are as follows:  

• lowers total peripheral resistance (systemic vascular resistance);
• at usual doses i t does not block vasopressor responses to such drugs as phenylephrine;
• resting heart rate and ventricular stroke volume decline as effects of guanfacine build during long-term therapy;
• sympathetic-mediated increases of heart rate and stroke volume normally associated with such activities as exercise, or as a baroreceptor reflex response to a sudden fall of blood pressure, are blunted;
• miosis may occur; and
• guanfacine has no direct or indirect effects on airway smooth
• Based on this description, which one of the following drugs i s most s imilar to guanfacine?

A	Atropine
B	Clonidine
C	Phentolamine
D	Prazosin
E	Propranolol

Question 1 Explanation: 

Apologies for starting the chapter on CNS pharmacology with a question that definitely focuses on the autonomic nervous system. However, the question is helpful as yet another way to recognize the connections between ostensibly different areas of pharmacology and drug therapy. The description of guanfacine’s autonomic effects are extraordinarily similar to those of clonidine, which is generally considered the prototype of the “centrally acting antihypertensive drugs.” Clonidine and guanfacine act as postsynaptic α-adrenergic agonists (specifically, α2A; in the CNS, probably on prefrontal cortical neurons in terms of the effects on ADHD and anxiety; and in the medullary “cardiovascular control center” in terms of peripheral autonomic effects. Indeed, the overall “dialing-down” of sympathetic outflow, which accounts for guanfacine’s main autonomic action, also accounts for its much older use as an antihypertensive drug. None of the responses described for guanfacine are qualitatively or mechanistically similar to those expected with atropine (a) or any other drug with strong muscarinic receptor blocking activity. Phentolamine (c), the prototype peripherally acting α1- and α2-adrenergic blocker, would cause miosis (by unmasking opposing parasympathetic influences on pupil size), although as described in the question it would have no effect on airway smooth muscle (which is affected by drugs that either work directly on β2 adrenergic, or muscarinic-cholinergic, receptors). And, unlike the situation with guanfacine or clonidine, phentolamine will markedly antagonize vasopressor effects of α-agonists such as phenylephrine. Finally, phentolamine would not cause falls of resting heart rate or stroke volume, since both of those functions are regulated by activation of β1- adrenergic receptors in various parts of the heart. Prazosin (d) is a peripherally acting and selective α1 antagonist. Some of the effects of guanfacine are similar to those of prazosin, but there are three effects that were noted and that would argue against prazosin being the correct answer: (1) prazosin will indeed block the vasopressor responses to phenylephrine or any other drug that activates α-adrenergic receptors; (2, 3) it will not interfere with β-mediated increases of heart rate or stroke volume, whether mediated by the baroreceptor reflex or otherwise. In contrast, propranolol (d; or any other β-blocker that lacks vasodilator activity) would lower resting heart rate and also blunt baroreceptor-mediated increases of heart rate and stroke volume.

Question 2

The next five questions refer to the table below (shown earlier for Questions 78 to 84 in the chapter “Peripheral Nervous Systems/Autonomics”), which i s the anesthesia record from a patient undergoing two operative procedures during laparoscopic abdominal surgery. Here I ask you about some drugs not addressed before. Remember: This medication administration plan i s very typical of what you’ll see with many s imilar operative procedures. You see that midazolam was the fi rst drug given to the patient—actually right before she was transported into the  (The  notation IVP next to midazolam means “IV push,” ie, a  rapid bolus  injection.) In addition to  causing sedation, anxiety relief, and generally “smoothing” the induction of anesthesia, which of the following i s the most l ikely effect you would expect to achieve as a result of premedicating with midazolam?

A	Potentiating the analgesic effects of the morphine
B	Preventing an intraoperative fall of blood pressure
C	Preventing seizures l ikely to be caused by the propofol
D	Prophylaxis of cardiac arrhythmias
E	Providing amnestic effects (suppressing recall of perioperative events)

Question 2 Explanation: 

Benzodiazepines as a class tend to cause short-term memory loss following administration. The intensity of the effect depends on the unique drug (common and intense with midazolam, which has a fast onset and short half-life; and flunitrazepam [Rohypnol, known on the street mainly as “roofies”], for example), the drug’s pharmacokinetics, and the dose and administration route. The memory loss does not affect recall of prior events but rather events occurring shortly after the drug is given. This antegrade amnesia is valuable in settings such as described in the scenario, where many unpleasant and anxiety-provoking events may occur between preop medication, the trip to the operating room, and other unpleasantries that might occur before the patient is anesthetized. (The patient here had absolutely no recall of events occurring within about 30 seconds after the midazolam was given, up to about an hour after she regained consciousness in the OR. Many patients who receive midazolam for endoscopic procedures such as colonoscopy or bronchoscopy also lack recall.) Midazolam intensifies the overall sedative and mental clouding effects of opioids, but does not potentiate analgesia (a). It does not prevent or reverse hypotension (b), and if the dose is too large or it is administered too quickly, the drug may actually lower blood pressure in its own right. Midazolam has some anticonvulsant effects but it is seldom used for that purpose (lorazepam is one benzodiazepine that is routinely used for certain seizures, particularly status epilepticus). More importantly the question stated “…seizures likely to be caused by propofol,” but propofol rarely causes seizures (c). Benzodiazepines are not arrhythmogenic nor do they have antiarrhythmic activity (d).

Question 3

The record shows that propofol was given for What i s/are the most l ikely adverse response(s) associated with the administration of this widely used drug?

A	Hypotension and respiratory (ventilatory) depression
B	Laryngospasm
C	Long-term memory loss
D	Malignant hyperthermia
E	Seizures
F	Unintended or excessively prolonged skeletal muscle paralysis

Question 3 Explanation: 

Hypotension and respiratory/ventilatory depression is a common side effect with propofol and, indeed, with most other classes of CNS depressants injected for either anesthesia induction or maintenance. Laryngospasm (b) sometimes and rather uniquely applies to injection of rapidly acting barbiturate induction agents (see the next question). Memory loss (c)— specifically short-term antegrade amnesia—is associated with certain benzodiazepines (here, the midazolam, previous question). Propofol does not cause malignant hyperthermia (d), or interact with other medications (those listed in the MAR, or others) to cause it. Malignant hyperthermia is mainly linked, in the surgical setting, to the combined use of a halogenated hydrocarbon inhaled anesthetic (particularly halothane, the use of which is declining) and a neuromuscular blocker (typically succinylcholine more so than a curare-like nondepolarizing agents). Propofol does not cause seizures (e); of the injectable induction agents, seizures are mainly a problem with etomidate. Finally, aside from generalized suppression of the CNS, propofol causes no significant or clinically relevant effects on skeletal muscle, and tends not to cause nausea or emesis (when used alone) that is common with other reasonable alternatives.

Question 4

Assume that instead of inducing anesthesia with propofol, the nurse anesthetist used a parenteral barbiturate (eg, methohexital, thiamylal, and thiopental) with an extremely fast onset of action and short duration (sometimes called “ultrashort”). These barbiturate induction agents are effective, but are associated with a fairly high incidence of a  certain and rather unique adverse What best describes what that adverse effect i s?

A	Hyperalgesia (heightened perception of pain)
B	Hypertensive cris i s
C	Laryngospasm
D	Malignant hyperthermia
E	Seizures, typically monoclinic

Question 4 Explanation: 

Laryngospasm is associated with the barbiturate IV induction agents, whether the drug is an oxybarbiturate (methohexital) or a thiobarbiturate (thiamylal, thiopental, others; “thio” refers to a sulfur atom replacing an oxygen atom at a certain point in the molecule). The mechanism is not known for sure, but the phenomenon is, and the laryngospasm may be sufficient in a small number of cases to make airway intubation difficult. The barbiturates also cause ventilatory depressant effects (centrally mediated), but in the situation described here that is not worrisome, because the patient is receiving mechanical ventilation. Barbiturates lack analgesic effects (at blood levels not far lower than lethal). They can actually increase the sensation of pain (hyperalgesic effect, a) when therapeutic doses of oral agents (mainly phenobarbital nowadays) are given (inappropriately) to patients with pain and who are not being treated with true analgesic drugs suitable for the degree of pain the patient has. This is one of the reasons why barbiturates—and benzodiazepines for that matter—should never be used as analgesics. Note, however, that when the fast-acting injectable barbiturates are given at usual induction/anesthetic doses the hyperalgesic effect does not occur; in addition, this patient got other proper analgesics (morphine, ketorolac). Barbiturates, whether given parenterally or orally, and regardless of their pharmacokinetics, tend to lower blood pressure (not raise it, answer b; the probable sites of action are both central and directly on the heart). Barbiturates used as IV induction agents tend to lower blood pressure significantly and sometimes excessively. Malignant hyperthermia (d) is a serious adverse perioperative response that is associated with the combined administration of skeletal neuromuscular blockers (typically succinylcho-line) and certain inhaled halogenated hydrocarbon anesthetics (eg, halothane). Barbiturates do not interact or cause malignant hyperthermia in their own right. All the barbiturates have anticonvulsant activity (dose-dependent and also dependent on which barbiturate is being used), and they do not cause myoclonus or other types of seizures (e). The higher risk of myoclonic seizures is mainly associated with etomidate, which is another IV induction agent. (Etomidateinduced seizure risk can be reduced by premedication with an opioid or a benzodiazepine.)

Question 5

The patient received an intravenous dose of ketorolac shortly before the wounds were closed and surgery was What i s the most l ikely purpose for which i t was given?

A	Control of anticipated postoperative nausea and vomiting
B	Postoperative pain control
C	Reversal of CNS depression caused by multiple depressant drugs
D	Reversal of drug-induced neuromuscular blockade (paralysis)
E	Suppression of wound inflammation

Question 5 Explanation: 

Although ketorolac is usually presented in a chapter on NSAIDs, it has very weak (and not clinically useful) anti-inflammatory activity. However, it provides excellent analgesia that has been described as equivalent to that provided by usual starting doses of an opioid (eg, morphine) when pain is “moderate” and relatively short lived. The mechanism probably involves inhibited prostaglandin synthesis (as with all NSAIDs) and does not involve activation of any opioid receptors. The drug has no antiemetic effects (a); does not affect ventilatory rate or depth (c); has no effect on skeletal neuromuscular transmission or the effects of neuromuscular blockers (d). Unlike most opioids, ketorolac also lacks adverse effects on the biliary tract, usually making it a good choice for patients with nephrolithiasis or other conditions that trigger gall bladder/bile duct spasm and pain. Ketorolac is not suitable, alone, for severe pain (when an opioid truly is indicated) nor for chronic pain. In surgical settings such as the one described here it is used as a supplement to an opioid. What are the advantages of ketorolac, whether used alone or as a supplement, compared with an opioid? Ketorolac’s analgesia is not accompanied by typical opioid-like ventilatory depression; hypotension; sedation, mental clouding or euphoria; nor a potential for dependence or abuse. It is often used as an opioid supplement precisely because the main alternative approach— simply giving a higher dose of morphine—could lead to excessive ventilatory depression and hypotension. Despite the relative lack of anti-inflammatory activity, the main adverse responses to ketorolac are similar to those of traditional NSAIDs on the GI tract: the potential for gastric ulceration, potentially with GI bleeding or hemorrhage; for renal impairment; and for prolonged bleeding due to antiplatelet effects (weak and not therapeutically useful). These adverse effects are most likely to occur with long-term use, which is why ketorolac should be used only for short-term pain control (no more than 5 days). Most of the contraindications that apply to traditional NSAIDs apply to ketorolac, for example, peptic ulcer disease (active or a risk thereof); renal dysfunction; active bleeding (especially intracranial); pregnancy; and prior hypersensitivity. Notes: You should know about ketorolac because it is used widely in general surgical settings such as described in the question; in orthopedics; and in oral surgery and other settings where “good” short-term analgesia is needed and it is best to minimize or avoid other unwanted effects of opioids. When ketorolac was first approved, many practitioners used it frequently and prescribed it for chronic pain control. (Some described prescribing the drug “like candy.” After all, it provided excellent pain control with no opioid-like problems.) Not long thereafter prescribers realized the strong ulcerogenic actions of the drug, and so new guidelines and warnings were made to restrict use of the drug to no more than several days in a row.

Question 6

Ondansetron was administered about an hour before the anticipated end of What was the most l ikely reason for giving this to the patient?

A	Hasten recovery of consciousness while effects of anesthetics wear off
B	Intensify pain-relieving effects of other analgesics given to the patient
C	Lessen ri sks of postop urinary retention through effects on bladder musculature
D	Prevent or reduce the ri sk of postoperative paralytic i leus
E	Reduce the ri sk of postoperative nausea and vomiting

Question 6 Explanation: 

Ondansetron, like a related drug, dronabinol, is used to manage druginduced nausea and vomiting that can occur postoperatively or in response to emetogenic drugs (eg, many anticancer drugs). It is a serotonin receptor (5-HT3) blocker that acts mainly in the medullary chemoreceptor trigger zone and on vagal afferents (inhibited) to parts of the upper GI tract. Ondansetron has no general CNS or cortical stimulating effects that would help restore consciousness, alertness, or awareness of time and place (a); no analgesic-intensifying effects (b); no significant effects on the bladder (c); and does not reduce the risk of paralytic ileus (d) because vagal tone to intestinal smooth muscles is suppressed.

Question 7

Two inhaled general anesthetics, A and B, have the following MAC values: Based only on this information (note that we have not named any drugs), which statement i s true

A	Drug A has a longer duration of action than Drug B
B	Drug A i s more soluble in the blood than Drug B
C	Drug B causes greater analgesia and skeletal muscle relaxation than Drug A
D	The concentration of drug in inspired air that i s needed to cause adequate surgical anesthesia i s higher for Drug B than for Drug A
E	The time to onset of adequate general anesthesia i s 50 times longer for Drug B than for Drug A

Question 7 Explanation: 

MAC (minimum alveolar concentration) is an expression of inhaled anesthetic “potency.” It is defined as the minimum inspired concentration needed to abolish a specified painful response in 50% of treated patients. (Thus, it is much like the ED 50, measured in a population dose-response curve, for most other drugs.) Obviously, giving a drug at a dose that suppresses a response in only half the treated patients is not desirable, so inhaled anesthetics are typically given at a dose more than the MAC. (Recall, too, that MAC is not absolute: it can change depending on the use of other anesthesia adjuncts and such other factors as body temperature, ventilatory rate, presence of other diseases, etc.) A drug’s MAC gives us no useful and invariable information about onsets or durations of action (a, e). You cannot state correctly that drug Y (MAC ≈ 100%) causes greater analgesia and/or skeletal muscle relaxation than another drug any more than we can say that a drug with an ED50 of 5 mg causes a greater response than one with an ED50 of 1 mg. It all depends on the dose given, not the MAC or ED50

Question 8

A patient with Parkinson disease has s igns and symptoms that can be considered “moderate” now, but they are worsening and not responding well to current drug The physician decides to empirically assess an antiparkinson drug that i s a selective inhibitor of monoamine oxidase type B (MAO-B). What drug would that be?

A	Bromocriptine
B	Carbidopa
C	Phenelzine
D	Selegiline
E	Tranylcypromine

Question 8 Explanation: 

Two of the important types of MAO are: (1) MAO-A, which metabolizes norepinephrine and serotonin and other biogenic amines, and is the predominant hepatic form of the enzyme; and (2) MAO-B, which metabolizes dopamine and other monoamines in the brain. Selegiline is a selective inhibitor of MAO-B. It therefore inhibits the breakdown of dopa-mine and prolongs the therapeutic effectiveness of levodopa (endogenous or that provided pharmacologically) in parkinsonism. The risks of serious drug interactions in patients taking nonselective MAO inhibitors (eg, phenelzine, tranylcypromine), such as hypertensive crisis in response to mixedand indirect-acting sympathomimetics (tyramine, pseudoephedrine, and amphetamines) are much less (but still possible) with selegiline. Bromocriptine (a) is a dopamine receptor agonist. Carbidopa (b) inhibits the peripheral metabolism of levodopa by DOPA decarboxylase. Both are useful in the treatment of some cases of idiopathic (but not antipsychotic drug-induced) parkinsonism. Phenelzine (c) and tranylcypromine (e) are nonselective MAOIs. Combining them with L-dopa may lead to a potentially fatal hypertensive crisis, and thus they are not used in the therapy of parkinsonism. A similar interaction may occur with tyramine-rich foods and beverages; and with catecholamine-releasing sympathomimetics (ephedrine, pseudoephedrine, amphetamines, and amphetamine-like drugs). As a result of these common and potentially lethal interactions, non-selective MAO inhibitors are rarely used for anything unless no other usually effective therapies work adequately or are otherwise contraindicated.

Question 9

A patient who has been treated with levodopa i s switched to a regimen with a product that contains levodopa plus What i s the main action of carbidopa that provides the rationale for using i t in this dual-drug approach?

A	Blocks ACh release in the CNS, thereby facilitating levodopa’s ability to restore a dopamine-ACh balance
B	Helps activate dietary vi tamin B6, a deficiency of which occurs during levodopa therapy
C	Increases permeability of the blood-brain barrier to levodopa, giving levodopa better access to the CNS
D	Inhibits metabolic conversion of levodopa to dopamine outside the CNS
E	Reduces levodopa-induced hypotension by blocking vascular dopamine receptors

Question 9 Explanation: 

When levodopa is administered orally, the vast majority of the administered dose (about 90%) is metabolized in the gut to dopamine by DOPA decarboxylase. However dopamine cannot cross the blood-brain barrier, and so only a fraction of the parent drug gets into the CNS, to be metabolized and cause its desired effects there. Carbidopa inhibits DOPA decarboxylase in the periphery, reducing peripheral metabolism of levodopa to dopamine and “sparing” a bigger fraction of the administered levodopa dose so it can be metabolized in the nigrostriatum. By reducing peripheral conversion of levodopa to dopamine, the adjunctive use of carbidopa often enables management of parkinsonian signs and symptoms with doses of levodopa much lower than would be needed in the absence of carbidopa. One additional benefit of that is a reduction in the number and severity of peripheral side effects of the levodopa (or, more precisely, its metabolite, dopamine). Adding carbidopa to a regimen involving levodopa only may also help (at least transiently) combat such problems as dopamine’s “on-off phenomenon” and “end-of-dosefailure.” The on-off phenomenon is characterized by frequent, abrupt, and dramatic changes between what appears to be good symptom control to episodes that look like parkinsonian signs and symptoms weren’t improved at all (much like what happens when switching the lights on and off). With end-of-dose failure, symptom control between doses gets progressively less progressively sooner. For example, a patient who had good symptom control up to an hour or so before the next scheduled levodopa dose may gradually experience loss of that control 2 hours, 3 hours, or even much more, before they were to take their next dose. Carbidopa, whether considered in its own right or in the context of coadministration with levodopa has no effects (inhibitory or stimulatory) onACh release (a). Vitamin B6 deficiencies of the vitamin do not occur in response to therapy with either or both drugs (b); and it is important to note that ingesting large amounts of that vitamin, whether as part of the diet or in the form of supplements, will antagonize the desired effects of levodopa with or without added carbidopa. Carbidopa does give “better access” of levodopa to the CNS, but that effect has nothing to do with increasing blood-brain barrier permeability to dopamine (c). It is due, as noted, to increased concentrations of levodopa in the circulation due to inhibited peripheral conversion to dopamine. Carbidopa has no beneficial effects on dopamine-induced blood pressure changes, and has no ability to block dopamine receptors in the vasculature (e) or anywhere else.

Question 10

A 34-year-old man with mild anxiety and depression symptoms has heard about buspirone on TV and asks whether i t might be suitable for him. According to the most diagnostic and treatment cri teria, the drug would be appropriate, particularly for short-term symptom control. Which phrase correctly describes an important property of buspirone?

A	Associated with a withdrawal syndrome that, i f unsupervised or controlled, may be fatal
B	Has a s ignificant potential for abuse
C	Is l ikely to potentiate the CNS depressant effects of alcohol, benzodiazepines, and sedative antihistamines (eg, diphenhydramine), so such interactants must be avoided at all cost
D	Requires almost daily dosage ti trations in order to optimize the response
E	Seldom causes drowsiness

Question 10 Explanation: 

Buspirone is an attractive drug for managing mild short-term anxiety. Among the reasons (and especially when compared with more traditional anxiolytics, such as benzodiazepines) are a lack of sedation (buspirone is not a CNS depressant); very little (if any) potentiation of the effects of other CNS depressants, including alcohol; no known abuse potential (it is not regulated by the Controlled Substances Act) or tendency for development of tolerance; and no major withdrawal syndrome. One major drawback is a slow onset of symptom relief (a week or two), and typically it takes about a month from the onset of therapy for antianxiety effects to stabilize. (Knowing this slow onset, one should resist the temptation to titrate the dosage upward, to hasten or increase the drug’s effects, prematurely.) You should recall that long-term benzodiazepine administration is associated with withdrawal phenomena (and, depending on the use, dose, exact drug, and other patient-related factors, the syndrome can be severe). Thus, one can envisage a switch from a benzodiazepine to buspirone. Because buspirone lacks CNS depressant effects and its effects take some time to develop, one should start the buspirone several weeks before stopping the benzodiazepine and then taper the benzodiazepine dose once it’s time to stop the drug.

Question 11

A physician considers placing a patient on long-term (months, years) phenobarbital for control of a relatively common medical For most of these indications, newer and arguably more efficacious drugs, which participate in fewer drug interactions, are available and preferred. For which one of the following uses, nonetheless, i s this barbiturate sti l l considered reasonable and appropriate?

A	Alcohol withdrawal s igns/symptoms
B	Anxiety management
C	Certain epilepsies
D	Endogenous depression (adjunct to SSRIs)
E	Sleep disorders such as insomnia

Question 11 Explanation: 

Phenobarbital’s role in the primary management of all of the named conditions has waned dramatically, and appropriately, as newer drugs, with fewer risks of drug interactions and tolerance development, have come on the market. The only use in the options provided in the question, for which phenobarbital is still considered reasonable for long-term therapy in some patients, is for managing certain epilepsies (mainly as an alternative to phenytoin). The seizure types include, mainly, partial seizures and generalized tonicclonic seizures. Benzodiazepines are almost always preferred, and used, for managing alcohol withdrawal (a) and therapy of anxiety (b). Benzodiazepines, or the benzodiazepine-like agents zaleplon or zolpidem, are almost always turned to for insomnia (e). Phenobarbital—and other barbiturates for that matter—have no beneficial effects on depression signs and symptoms (d), and they are not properly used alone or in combination with an SSRI (or tricyclic or atypical antidepressant). Major reasons for selecting a benzodiazepine over a barbiturate include fewer drug-drug interactions (phenobarbital is a classic P450 inducer that hastens the elimination of many other drugs that are metabolized by the P450 system); a lesser risk of generalized risk of CNS depression (somnolence, etc); lower risk of dependence; withdrawal syndromes that are typically less severe or dangerous; lower risk of fatal ventilatory depression with oral overdoses (and the availability of flumazenil, the specific benzodiaze-pine antagonist, to treat them); and less narrowing between lethal and effective doses (better therapeutic index or margin of safety) as use continues. Note that even though benzodiazepines may be preferred, treatment for such problems as anxiety and insomnia should be kept as short as possible.

Question 12

One reason for the declining use of tri cyclic antidepressants such as imipramine, and the growing use of newer classes, i s the prevalence of common tri cyclic-induced s ide effects or adverse What s ide effect or adverse response, l i sted below, i s most l ikely to occur with usual therapeutic doses of a tri cyclic?

A	Anticholinergic (antimuscarinic) effects
B	Arrhythmias
C	Hepatotoxicity
D	Nephrotoxicity
E	Seizures

Question 12 Explanation: 

The most common side effects associated with tri-cyclic antidepressants are their antimuscarinic effects, which may occur and often be prominent in over 50% of patients. Clinically, these effects may manifest as dry mouth, blurred vision, constipation, tachycardia, dizziness, and urinary retention. These are, of course, some of the typical and common side effects associated with atropine or any other drug with substantial antimuscarinic effects. At therapeutic plasma concentrations these drugs usually do not cause changes in the ECG (b)—but with severe overdoses lethal arrhythmias often do occur. These drugs are not particularly hepatotoxic or nephrotoxic (c, d); seizures are not likely to occur unless the patient has a history of seizure disorders or massive overdoses have been taken. Note: In terms of tricyclic toxicity, ie, with overdoses, you might want to recall what some students learn as the “Three Cs:” coma, cardiotoxicity (mainly arrhythmias that are often difficult to treat), and convulsions. In addition, all the other manifestations of “atropine poisoning” will develop and usually be severe. This is an extremely difficult situation to treat, and to treat successfully, when the cause is a tricyclic antidepressant.

Question 13

A 42-year-old woman develops akathisias, parkinsonian-like dyskinesias, galactorrhea, and amenorrhea, as a consequence of psychotropic drug What drug-receptor-based mechanism, occurring in the central nervous system, most l ikely caused these responses?

A	Blockade of α-adrenergic receptors
B	Blockade of dopamine receptors
C	Blockade of muscarinic receptors
D	Supersensitivity of dopamine receptors
E	Stimulation of nicotinic receptors

Question 13 Explanation: 

Unwanted extrapyramidal side effects produced by antipsychotic drugs (eg, chlorpromazine, as the exemplar of the phenothiazines; and, more so, by haloperidol as the prototype of the butyrophenones) include Parkinsonlike syndrome, akathisia, dystonias, galactorrhea, amenorrhea, and infertility. These side effects are due to the ability of these agents to block dopamine receptors. The phenothiazines also block muscarinic and α-adrenergic receptors, which are responsible for other effects in both the CNS and (especially) in the periphery. The incidence and severity of these autonomic side effects is much greater with low-potency antipsychotics (eg, chlorpromazine and other phenothiazines) than with the high-potency butyrophenones (eg, haloperidol

Question 14

A patient on the trauma-burn unit received a drug to ease the pain of debridement and dressing changes for several severe He experiences good, prompt analgesia, but despite the absence of pain sensation during the procedure his heart rate and blood pressure ri se considerably, consistent with sympathetic nervous system activation by the pain and not affected by the analgesic drug. As the effects of the drug develop his skeletal muscle tone progressively increases. He appears awake at times because his eyes periodically open. As drug effects  wear off he hallucinates and behaves in a very agitated fashion. Hallucinations, “bad dreams,” and periods of delirium recur over several days  after receiving the drug. What drug was most l ikely given?

A	Fentanyl
B	Ketamine
C	Midazolam
D	Succinylcholine
E	Thiopental

Question 14 Explanation: 

The scenario describes most of the classic responses to ketamine, a “dissociative anesthetic”: analgesia; an ostensibly light sleep-like state; a trancelike and cataplectic state (including increased muscle tone); and activation of most cardiovascular/hemodynamic parameters. The various psychosis-like emergence reactions are the main disadvantages to using a drug that, otherwise, causes many of the desired elements of balanced anesthesia, usually without the need for complicated and expensive anesthesia administration devices or personnel. Ketamine undergoes significant metabolism in humans, with about 20% of the absorbed dose recovered as metabolites. The only other drug listed that provides adequate analgesia is fentanyl (a). Midazolam (c; benzodiazepine), succinylcholine (d; depolarizing neuro-muscular blocker), and thiopental (e; thiobarbiturate) lack analgesic activity; moreover, if any cardiovascular or autonomic changes were to occur in response to any of those drugs, they would be better characterized as depression, not activation.

Question 15

A 17-year-old male was diagnosed with epilepsy after developing repeated episodes of generalized tonic-clonic seizures following a motor vehicle accident in which he received a closed-head After treating acute seizures with the proper injectable drugs, he i s started on a regimen of oral phenytoin, the daily dose ti trated upward until symptom control and a therapeutic plasma concentration were reached. The elimination half-life of the drug during initial treatment was measured to be 24 hours, a value that i s quite typical for otherwise healthy adults taking no other drugs. Today he presents in the neurology cl inic with nystagmus, ataxia, diplopia, cognitive impairment, and other s igns and symptoms consistent with phenytoin toxicity. A blood sample, drawn at noon, has a plasma phenytoin concentration of 30 mcg/mL. That value i s 50% higher than typical peak therapeutic plasma concentrations, and twice the usual minimum effective blood level. These values are summarized in the figure below. The attending orders discontinuation of further doses of phenytoin until plasma levels fall into the therapeutic range, and the patient i s largely free of s igns and symptoms of phenytoin toxicity. In the interim, what would you do or expect to occur next?

A	Administer flumazenil, which will quickly reverse s igns and symptoms of phenytoin toxicity but may cause seizures to recur
B	Anticipate that elimination of phenytoin from the plasma will follow zero-order kinetics for several days
C	Give an amphetamine or other CNS stimulant to reverse generalized CNS depression due to the phenytoin excess
D	Give phenobarbital to induce the P450 system, thereby hastening phenytoin’s metabolic elimination
E	Plasma phenytoin concentrations will fall to 15 mcg/mL, in the middle of the therapeutic range, by noon tomorrow (24 hours later, per the usual half-life)

Question 15 Explanation: 

The hepatic enzymes responsible for phenytoin metabolism (mainly CYP2C9) become saturated at plasma drug concentrations above approximately 10 to 15 mcg/mL, which are clearly within the typical therapeutic range yet well below maximum or peak therapeutic levels. At daily dosages associated with or below those 10 to 15 mcg/mL values, dose increases give relatively proportional increases in plasma drug concentrations, and phenytoin elimination follows usual first-order kinetics (a constant fraction of drug is eliminated with the passing of each half-life). Once the metabolic capacity is exceeded (as it has in our patient, which may arise with intentional or inadvertent increases in the daily dose), small increases in dosage lead to disproportionately large increases of plasma concentrations (and effects) because, in essence, “drug in greatly exceeds drug out:” zero-order kinetics now describes the drug’s elimination, such that a constant amount (not fraction) of drug is eliminated per unit time. Therefore, the first-order half-life does not apply; elimination is slower, and the plasma concentration will be much greater than 15 mcg/mL (half of 30 mcg/mL; ans. e) 24 hours after the initial blood sample is taken. The figure below shows an approximation of the relationship between plasma phenytoin levels and daily doses (the placement of the curve canvary from patient to patient along the x-axis). From the rapid rise in the curve at dosages above about 300 mg/day you can deduce a significant reduction of clearance rates owing to slowed metabolism (since metabolism is the main pathway for phenytoin’s elimination)

Question 16

A 12-year-old boy has been treated with methylphenidate for the last 3 His younger s i ster finds the bottle of pills and consumes enough to cause s ignificant toxicity. Which of the following findings would you most l ikely expect?

A	Hypertension, tachycardia, seizures
B	Hypotension, bronchospasm
C	Drowsiness, obtunded reflexes, diarrhea
D	Miosis, bradycardia, profuse salivation, sweating
E	Hypothermia, skeletal muscle weakness or paralysis, pupils that are not responsive to l ight

Question 16 Explanation: 

Methylphenidate, which is widely used to manage ADHD, has amphetamine-like sympathetic and CNS-stimulating effects. Indeed, amphetamine itself (and derivatives or mixtures of amphetamine) is used for treatment of ADHD. Peripheral sympathetic (adrenergic) effects arise from the drug’s ability to release neuronal norepinephrine. Related findings would include increased vasoconstriction (greater α1-receptor activation of vascular smooth muscle), and therefore increased blood pressure; and tachycardia (plus increased cardiac contractility and electrical impulse conduction rates, probably accompanied by tachyarrhythmias, from β1 activation). At toxic doses, the CNS effect of the drug is likely to cause seizures. There is no mechanism by which direct effects of methylphenidate or amphetamine (whether at normal or toxic doses) would cause bronchospasm, bronchoconstriction, or even bronchodilation (because norepinephrine that is released by those drugs has no ability to activate or block β2 receptors on airway smooth muscle). Miosis (which occurs with either muscarinic activation or α blockade) would be the opposite of whatyou would predict in terms of ocular effects. In terms of autonomic effects, skeletal muscle weakness or paralysis are findings you would expect from drugs that either blocked nicotinic cholinergic receptors (eg, tubocurarine [no longer on the market in the United States], but related agents such as vecuronium are) or stimulated them in an excessive and prolonged fashion (eg, succinylcholine)

Question 17

Meperidine i s s imilar to morphine in many ways, but has some decided differences that are cl inically relevant: with very high blood levels or with true overdoses, meperidine can cause s ignificant adverse responses that s imply aren’t seen with morphine or most other opioid What i s that rather unique effect of meperidine?

A	Constipation leading to paralytic i leus
B	Heightened response to pain (paradoxical hyperalgesia)
C	Intense biliary tract spasm
D	Psychosis-like state, possibly seizures
E	Respiratory depression, apnea, ventilatory arrest

Question 17 Explanation: 

High or frankly toxic plasma levels of meperidine can cause seizures, hypertension, and a psychosis-like state, in addition to typical morphine-like effects (eg, analgesia and ventilatory depression). Interestingly, it appears that administration of naloxone to combat excessive effects of meperidine may increase the risk of seizures. This is something that is extraordinarily rare when naloxone is administered to counteract excessive effects of morphine and most other opioids. The rather unique adverse effects associated with meperidine are probably due to a major metabolite, normeperidine. A weak opioid analgesic, propoxyphene (structurally related to methadone), can produce toxic reactions similar to those of meperidine. It is off the United States market now, largely because of the risks and the drug’s overall poor efficacy. Nonetheless, the risks described here account for why meperidine doses should be kept as low as possible, and the duration of treatment with it should be kept short (usually no more than a day or two). Meperidine, like other opioids, can cause constipation (a) through its actions on longitudinal muscles and sphincters in the GI tract. Hyperalgesia (b), an increased perception of pain, does not occur. Biliary tract/sphincter of Oddi spasm (c) is much less likely to occur with meperidine than with most other opioids (say, the prototype, morphine). Indeed, the risks of biliary tract/gall bladder problems are said to be less with meperidine than any other opioid analgesic. And so, meperidine can be considered a preferred opioid (for short-term use) for patients with moderate-to-severe pain and gall bladder disease. Respiratory depression (e), possibly leading to ventilatory arrest, is a property shared by all the opioid analgesics, but of course to varying degrees based on their efficacy and dose. Note: Before the unusual risks of meperidine were fully appreciated, the drug was often prescribed for days or weeks on end. That should never be done anymore.

Question 18

Chlorpromazine and haloperidol can be considered prototypes of two relatively old but sti l l -used antipsychotic drug classes: the phenothiazines and the butyrophenones, While many of the actions and s ide effects of these drugs are qualitatively s imilar, they are different quantitatively: that i s , in terms of incidence and severity. Which effect or s ide effect typically occurs more frequently, i s usually more severe, and has a relatively rapid onset, with haloperidol?

A	Extrapyramidal reactions
B	Intense atropine-like s ide effects
C	Lethal blood dyscrasias
D	Orthostatic hypotension
E	Urinary retention necessitating bladder catheterization

Question 18 Explanation: 

In general, autonomic side effects are fairly common with phenothiazines such as chlorpromazine. These include muscarinic receptor blockade leading to dry mouth, blurred vision; and all the rest of the unwanted effects caused by atropine, or a drug with strong atropine-like actions. Haloperidol, the butyrophenone antipsychotic drug, tends to cause extrapyramidal side effects more often, more strongly, than autonomic side effects noted above. As a result, extrapyramidal (parkinsonian) side effects are more common. Indeed, when haloperidol is given by injection to help treat acute psychosis many treated patients develop (temporarily) muscle tremors and other manifestations of Parkinson disease.

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Part 1 | Part 2 | Part 3 | Part 4

II. Preview all questions below

1. Guanfacine has recently been FDA-approved for managing attention-deficit hyperactivity disorder (ADHD) in patients between the ages of 6 and 17 In addition to i ts benefits for ADHD, i t appears to provide symptom relief in generalized anxiety disorder and post-traumatic stress disorder.

Although the newly approved indications for guanfacine focus on the central nervous system, the drug can cause many important peripheral autonomic effects. They are as follows:

• lowers total peripheral resistance (systemic vascular resistance);
• at usual doses i t does not block vasopressor responses to such drugs as phenylephrine;
• resting heart rate and ventricular stroke volume decline as effects of guanfacine build during long-term therapy;
• sympathetic-mediated increases of heart rate and stroke volume normally associated with such activities as exercise, or as a baroreceptor reflex response to a sudden fall of blood pressure, are blunted;
• miosis may occur; and
• guanfacine has no direct or indirect effects on airway smooth
• Based on this description, which one of the following drugs i s most s imilar to guanfacine?

1. Atropine
2. Clonidine
3. Phentolamine
4. Prazosin
5. Propranolol

The next five questions refer to the table below (shown earlier for Questions 2 to 8 in the chapter “Peripheral Nervous Systems/Autonomics”), which i s the anesthesia record from a patient undergoing two operative procedures during laparoscopic abdominal surgery. Here I ask you about some drugs not addressed before. Remember: This medication administration plan i s very typical of what you’ll see with many s imilar operative procedures.

2. You see that midazolam was the fi rst drug given to the patient—actually right before she was transported into the  (The  notation IVP next to midazolam means “IV push,” ie, a  rapid bolus  injection.) In addition to  causing sedation, anxiety relief, and generally “smoothing” the induction of anesthesia, which of the following i s the most l ikely effect you would expect to achieve as a result of premedicating with midazolam?

1. Potentiating the  analgesic effects  of the morphine
2. Preventing an intraoperative fall of blood  pressure
3. Preventing seizures l ikely to be caused by the propofol
4. Prophylaxis of cardiac arrhythmias
5. Providing amnestic effects (suppressing recall of perioperative events)

3. The record shows that propofol was given for What i s/are the most l ikely adverse response(s) associated with the administration of this widely used drug?

1. Hypotension and respiratory (ventilatory) depression
2. Laryngospasm
3. Long-term memory loss
4. Malignant hyperthermia Seizures
5. Unintended or excessively prolonged skeletal muscle paralysis

4. Assume that instead of inducing anesthesia with propofol, the nurse anesthetist used a parenteral barbiturate (eg, methohexital, thiamylal, and thiopental) with an extremely fast onset of action and short duration (sometimes called “ultrashort”). These barbiturate induction agents are effective, but are associated with a fairly high incidence of a  certain and rather unique adverse What best describes what that adverse effect i s?

1. Hyperalgesia (heightened perception of pain)
2. Hypertensive cris i s
3. Laryngospasm
4. Malignant hyperthermia
5. Seizures, typically monoclinic

5. The patient received an intravenous dose of ketorolac shortly before the wounds were closed and surgery was What i s the most l ikely purpose for which i t was given?

1. Control of anticipated postoperative nausea and vomiting
2. Postoperative pain control
3. Reversal of CNS depression caused by multiple depressant drugs
4. Reversal of drug-induced neuromuscular blockade (paralysis)
5. Suppression of wound inflammation

6. Ondansetron was administered about an hour before the anticipated end of What was the most l ikely reason for giving this to the patient?

1. Hasten recovery of consciousness while effects  of anesthetics  wear off
2. Intensify pain-relieving effects  of other analgesics given to  the patient
3. Lessen ri sks of postop urinary retention through effects on bladder musculature
4. Prevent or reduce the ri sk of postoperative paralytic i leus
5. Reduce the ri sk of postoperative nausea and vomiting

7. Two inhaled general anesthetics, A and B, have the following MAC values:

1. Based only on this information (note that we have not named any drugs), which statement i s true?
2. Drug A has a longer duration of action than Drug B
3. Drug A i s more soluble in the blood than Drug B
4. Drug B causes greater analgesia and skeletal muscle relaxation than Drug A
5. The concentration of drug in inspired air that i s needed to cause adequate surgical anesthesia i s  higher for Drug B than for Drug A
6. The time to onset of adequate general anesthesia i s 50 times longer for Drug B than for Drug A

8. A patient with Parkinson disease has s igns and symptoms that can be considered “moderate” now, but they are worsening and not responding well to current drug The physician decides to empirically assess an antiparkinson drug that i s a selective inhibitor of monoamine oxidase type B (MAO-B). What drug would that be?

1. Bromocriptine
2. Carbidopa
3. Phenelzine
4. Selegiline
5. Tranylcypromine

9. A patient who has been treated with levodopa i s switched to a regimen with a product that contains levodopa plus What i s the main action of carbidopa that provides the rationale for using i t in this dual-drug approach?

1. Blocks ACh release in the CNS, thereby facilitating levodopa’s ability to restore a dopamine-ACh balance
2. Helps activate dietary vi tamin B₆, a deficiency of which occurs during levodopa therapy
3. Increases permeability of the blood-brain barrier to levodopa, giving levodopa better access to the CNS
4. Inhibits metabolic conversion of levodopa to dopamine outside the CNS
5. Reduces levodopa-induced hypotension by blocking vascular dopamine receptors

10. A 34-year-old man with mild anxiety and depression symptoms has heard about buspirone on TV and asks whether i t might be suitable for him. According to the most diagnostic and treatment cri teria, the drug would be appropriate, particularly for short-term symptom control. Which phrase correctly describes an important property of buspirone?

1. Associated with a withdrawal syndrome that, i f unsupervised or controlled, may be fatal
2. Has a s ignificant potential for abuse
3. Is l ikely to potentiate the CNS depressant effects of alcohol, benzodiazepines, and sedative antihistamines (eg, diphenhydramine), so such interactants must be avoided at all cost
4. Requires almost daily dosage ti trations in order to optimize the response
5. Seldom causes drowsiness

11. A physician considers placing a patient on long-term (months, years) phenobarbital for control of a relatively common medical For most of these indications, newer and arguably more efficacious drugs, which participate in fewer drug interactions, are available and preferred. For which one of the following uses, nonetheless, i s this barbiturate sti l l considered reasonable and appropriate?

1. Alcohol withdrawal s igns/symptoms
2. Anxiety management
3. Certain epilepsies
4. Endogenous depression (adjunct to SSRIs)
5. Sleep disorders such as insomnia

12. One reason for the declining use of tri cyclic antidepressants such as imipramine, and the growing use of newer classes, i s the prevalence of common tri cyclic-induced s ide effects or adverse What s ide effect or adverse response, l i sted below, i s most l ikely to occur with usual therapeutic doses of a tri cyclic?

1. Anticholinergic (antimuscarinic) effects
2. Arrhythmias
3. Hepatotoxicity
4. Nephrotoxicity
5. Seizures

13. A 42-year-old woman develops akathisias, parkinsonian-like dyskinesias, galactorrhea, and amenorrhea, as a consequence of psychotropic drug What drug-receptor-based mechanism, occurring in the central nervous system, most l ikely caused these responses?

1. Blockade of α-adrenergic receptors
2. Blockade of dopamine receptors
3. Blockade  of muscarinic receptors
4. Supersensitivity of dopamine receptors
5. Stimulation of nicotinic receptors

14. A patient on the trauma-burn unit received a drug to ease the pain of debridement and dressing changes for several severe He experiences good, prompt analgesia, but despite the absence of pain sensation during the procedure his heart rate and blood pressure ri se considerably, consistent with sympathetic nervous system activation by the pain and not affected by the analgesic drug. As the effects of the drug develop his skeletal muscle tone progressively increases. He appears awake at times because his eyes periodically open. As drug effects  wear off he hallucinates and behaves in a very agitated fashion. Hallucinations, “bad dreams,” and periods of delirium recur over several days  after receiving the drug. What drug was most l ikely given?

1. Fentanyl
2. Ketamine
3. Midazolam
4. Succinylcholine
5. Thiopental

15. A 17-year-old male was diagnosed with epilepsy after developing repeated episodes of generalized tonic-clonic seizures following a motor vehicle accident in which he received a closed-head After treating acute seizures with the proper injectable drugs, he i s started on a regimen of oral phenytoin, the daily dose ti trated upward until symptom control and a therapeutic plasma concentration were reached. The elimination half-life of the drug during initial treatment was measured to be 24 hours, a value that i s quite typical for otherwise healthy adults taking no other drugs.

Today he presents in the neurology cl inic with nystagmus, ataxia, diplopia, cognitive impairment, and other s igns and symptoms consistent with phenytoin toxicity. A blood sample, drawn at noon, has a plasma phenytoin concentration of 30 mcg/mL. That value i s 50% higher than typical peak therapeutic plasma concentrations, and twice the usual minimum effective blood level. These values are summarized in the figure below.

The attending orders discontinuation of further doses of phenytoin until plasma levels fall into the therapeutic range, and the patient i s largely free of s igns and symptoms of phenytoin toxicity. In the interim, what would you do or expect to occur next?

1. Administer flumazenil, which will quickly reverse s igns and symptoms of phenytoin toxicity but may cause seizures to recur
2. Anticipate that elimination of phenytoin from the plasma will follow zero-order kinetics for several days
3. Give an amphetamine or other CNS stimulant to reverse generalized CNS depression due to the phenytoin excess
4. Give phenobarbital to induce the P450 system, thereby hastening phenytoin’s metabolic elimination
5. Plasma phenytoin concentrations will fall to 15 mcg/mL, in the middle of the therapeutic range, by noon tomorrow (24 hours later, per the usual half-life)

16. A 12-year-old boy has been treated with methylphenidate for the last 3 His younger s i ster finds the bottle of pills and consumes enough to cause s ignificant toxicity. Which of the following findings would you most l ikely expect?

1. Hypertension, tachycardia, seizures
2. Hypotension, bronchospasm
3. Drowsiness, obtunded reflexes, diarrhea
4. Miosis, bradycardia, profuse salivation, sweating
5. Hypothermia, skeletal muscle weakness or paralysis, pupils that are not responsive to l ight

17. Meperidine i s s imilar to morphine in many ways, but has some decided differences that are cl inically relevant: with very high blood levels or with true overdoses, meperidine can cause s ignificant adverse responses that s imply aren’t seen with morphine or most other opioid What i s that rather unique effect of meperidine?

1. Constipation leading to paralytic i leus
2. Heightened response to pain (paradoxical hyperalgesia)
3. Intense biliary tract spasm
4. Psychosis-like state, possibly seizures
5. Respiratory depression, apnea, ventilatory arrest

18. Chlorpromazine and haloperidol can be considered prototypes of two relatively old but sti l l -used antipsychotic drug classes: the phenothiazines and the butyrophenones, While many of the actions and s ide effects of these drugs are qualitatively s imilar, they are different quantitatively: that i s , in terms of incidence and severity. Which effect or s ide effect typically occurs more frequently, i s usually more severe, and has a relatively rapid onset, with haloperidol?

1. Extrapyramidal reactions
2. Intense atropine-like s ide effects
3. Lethal blood dyscrasias
4. Orthostatic hypotension
5. Urinary retention necessitating bladder catheterization