The Quizzes about Autonomic and Somatic Nervous System Pharmacology – Part 2

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The Peripheral Nervous Systems: Autonomic and Somatic Nervous System Pharmacology- Part 2

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Question 1

A patient with a history of narrow-angle (angle-closure) glaucoma experiences a sudden ri se of intraocular pressure that i s  sufficiently In addition to pain there i s an imminent ri sk of permanent vis ion loss. They require immediate treatment, one element of which i s administration of echothiophate. What enzyme i s affected by this autonomic drug?

A	Tyrosine hydroxylase—stimulated
B	Acetylcholinesterase (AChE)—inhibited
C	Catechol-O-methyltransferase (COMT)—inhibited
D	Monoamine oxidase (MAO)—stimulated
E	DOPA decarboxylase—stimulated

Question 1 Explanation: 

Echothiophate iodide is a long-acting (“irreversible,” which basically means “very long acting” in terms of the duration of effects) acetylcholinesterase inhibitor. It is used topically on the eye for the treatment of various types of glaucoma. By increasing synaptic levels of acetylcholine, it increases contraction of the circular muscles of the eye, causing the pupils to constrict (miosis). That reduces mechanical obstruction of aqueous humor outflow via the Canal of Schlemm and the trabecular “meshwork” in the angle of the anterior chamber. (In contrast, sympathetic activation causes mydriasis by activating the radial muscles through α- agonist effects, and can lead to increased intraocular pressure.) Maximum reduction of intraocular pressure occurs within 24 hours, and the effect may persist for several days. The drug is water-soluble, which affords a practical advantage over the lipid-soluble isoflurophate (another cholinesterase inhibitor used to treat glaucoma). Note: Had I listed a drug with a generic name ending in the suffix “-stigmine,” you no doubt would have answered correctly and immediately. However, echothiophate is one of those cholinesterase inhibitors that is not a stigmine. If you’re unfamiliar with the drug—this one or any one as you work your way through the questions—by all means look it up! Tyrosine hydroxylase (a) is involved in the biosynthesis of catecholamines. COMT (c) is involved in extraneuronal metabolism of catecholamines, while MAO (d) is the major intraneuronal enzyme that degrades NE in adrenergic nerves. Forms of MAO are also found in, and important in, the liver and parts of the CNS. DOPA decarboxylase (e) catalyzes the metabolism of DOPA (dihydroxyphenylalanine) to dopamine as part of the catecholamine biosynthetic pathway.

Question 2

A patient has essential hypertension, and lab tests would show that their ci rculating catecholamine and plasma renin levels are unusually The chosen therapeutic approach for this patient i s to give a s ingle drug that blocks both α- and β-adrenergic receptors, thereby reducing blood pressure by reducing both cardiac output and total peripheral resistance (systemic vascular resistance). What drug i s most capable of doing that?

A	Labetalol
B	Metoprolol
C	Nadolol
D	Pindolol
E	Timolol

Question 2 Explanation: 

Labetalol is a competitive antagonist at both α- and β-adrenergic (both β1 and β2) receptors. [This “trick” might help you remember that labetalol blocks both main types of adrenergic receptors: take the first two letters in “labetalol” and reverse them—la tranposes to al, as in alpha—and then add the next four letters—beta. You’ll simply have to memorize the name of another important α-/β-blocker, carvedilol.) Note, too, that the generic names of all the drugs listed end in—olol—a great tip-off that a drug has β- blocking activity. In fact, every drug with a generic name that ends in -olol is a β-blocker. Labetalol’s α-blocking actions are weak compared with its actions at the β-receptors, but they are clinically important in terms of blood pressure control nonetheless. This difference is somewhat concentration-dependent: at relatively low blood levels, as might be achieved with typical oral doses, it is about three times more potent as a β-blocker than as an α-blocker (do not commit this to memory!). With higher concentrations, such as those often achieved with parenteral (eg, IV) dosing, the intensity of β-blockade increases considerably with little increase in α-blocking efficacy (another point that’s not priority knowledge now!). One of labetalol’s main uses is for managing essential hypertension (all the orally administered β-blockers are indicated for essential hypertension, and for chronic-stable angina). It lowers pressure in three ways: reduces heart rate, reduces contractility, and also reduces renin release, thereby reducing the formation of angiotensin II and, indirectly, release of aldosterone. All these effects are mediated by β1 blockade. Given parenterally (IV), labetalol is often a first-choice agent for managing urgent hypertensive crises when more efficacious (and potentially more dangerous) IV drugs aren’t indicated or cannot be given safely. Metoprolol (b; and atenolol and acebutolol, not listed) have a preferential (but certainly not absolute!) and dose-dependent effect on β1 receptors (“cardioselectivity”) versus β2, and have no α-blocking actions. Relatively high doses of those drugs can (and often do) block β2 receptors, and any dose may pose serious risks of bronchoconstriction or broncho-spasm for patients with asthma. Nadolol (c) and timolol (d) are nonselective β-blockers. (One property to remember for nadolol is its relatively long half-life; for timolol you might want to recall that a topical ophthalmic dosage form is often used for chronic openangle glaucoma.) Pindolol (d) is a nonselective β-blocker and also exerts strong intrinsic sympathomimetic activity (ISA; ie, partial agonist-antagonist activity).

Question 3

A man who has been “surfing the Web” in search of an aphrodisiac or some other agent to enhance “sexual prowess and performance” discovers He consumes the drug in excess and develops symptoms of toxicity that require your intervention. You consult your preferred drug reference and learn that yohimbine i s a selective α₂-adrenergic antagonist that acts mainly in the brain’s medullary “cardiovascular control center.” What would you expect as a response to this drug?

A	Bradycardia
B	Bronchoconstriction
C	Excessive secretions by exocrine glands (salivary, lacrimal, etc)
D	Reduced cardiac output from reduced left ventricular contractility
E	Rise of blood pressure

Question 3 Explanation: 

Whether you memorize that yohimbine is a selective α2 antagonist is up to you, but you should know what the main effects of a selective α2 antagonist are. That, of course, depends on knowing what α2 receptors—at least in the peripheral autonomic nervous system—do in the physiological sense. Recall that the preponderance of physiologically important α2 receptors are located on adrenergic nerve terminals (or nerve “endings”). When stimulated by a suitable agonist, the response is a turning-off of further NE release. Because NE is the neurotransmitter released from adrenergic nerves and it is an excellent α agonist, the presynaptic α2 receptors upon which NE acts serve as the main physiologic mechanism for regulating neurotransmitter release. So, when we block those receptors with yohimbine, we enhance the apparent overall activity of the sympathetic nervous system on its effectors by interfering with norepinephrine’s ability to turn-off its own release. Of the responses listed, only hypertension (owing to the vasoconstrictor effects of NE on postsynaptic α-adrenergic receptors) occurs as a result of yohimbine (or of NE excess). The other main effects you should anticipate would be cardiac stimulation (rate, contractility, electrical impulse conduction rates; all β1-mediated effects) and, usually of less clinical consequence, mydriasis (α).In terms of the aphrodisiac effects, the drug probably increases arousal via an action in the CNS, but the mechanism isn’t known for sure; and it increases the vigor of ejaculation, which is predominantly an α-mediated effect. (Recall that erection primarily involves muscarinic-cholinergic vascular effects, mediated by enhanced production of endothelium-derived relaxing factor, ie, nitric oxide.)

Question 4

You plan to prescribe scopolamine, as a transdermal drug delivery system (skin patch), for a patient who will be leaving for an expensive cruise and i s very susceptible to motion s i What comorbidity would weigh against prescribing the drug because i t i s most l ikely to pose adverse effects—or be truly contraindicated?

A	Angle-closure (narrow-angle) glaucoma
B	Bradycardia
C	History of allergic reactions to uncooked shellfish
D	Resting blood pressure of 112/70
E	Hypothyroidism, mild
F	Parkinson disease (early onset, not currently treated)

Question 4 Explanation: 

With any antimuscarinic drug—and scopolamine certainly is one— narrow-angle glaucoma (which accounts for about 10% of all glaucomas) is the biggest concern (assuming no other relevant comorbidities). The drug might provoke significant rises of intraocular pressure as it further reduces aqueous humor drainage, causing not only pain but vision problems that might be severe or permanent. Bradycardia (b) is not a concern; if anything, usual doses of scopolamine may increase heart rate a bit. Should the patient eat some shellfish or other allergy-provoking food (c), the incidence or severity diarrhea might be reduced or prevented altogether by the scopolamine, due to its effects on longitudinal muscles in the gut (inhibited) and on sphincters (activated). A resting blood pressure of 112/70 or thereabouts (d) is not at all uncommon or worrisome, and not likely to be changed at all by the drug. Hypothyroidism (e) typically is associated with slight bradycardia; again, no likely problem with scopolamine. And if our patient had mild Parkinson disease (f), we might actually, eventually, see a little improvement with this drug. Recall, one strategy to manage parkinsonism—which is basically a central imbalance between dopamine and ACh, the latter appearing to be acting in relative excess—is to block central muscarinic receptors (with such drugs as benztropine or trihexyphenidyl; see CNS chapter).

Question 5

A child overdoses on a drug that affects both the autonomic and somatic nervous As blood levels of the drug ri se he experiences hypertension and tachycardia, accompanied by skeletal muscle tremor. Further elevations of blood levels of the drug cause all the expected s igns and symptoms of autonomic ganglionic blockade, plus weakness and eventual paralysis of skeletal muscle. Which drug did the child most l ikely ingest?

A	Bethanechol
B	Nicotine
C	Pi locarpine
D	Propranolol (or another β-adrenergic blocker)
E	Scopolamine

Question 5 Explanation: 

Nicotine initially stimulates and then blocks nicotinicskeletal muscular (NM) and nicotinic-neural (NN; in autonomic ganglia and on adrenal medullary cells) cholinergic receptors. (Both effects involve depolarization of the target cells, and in many ways it is comparable to the depolarizing blockade of skeletal muscle activation by succinylcholine —initial stimulation followed by inhibition.) Initial ganglionic stimulation leads to vasoconstriction and hypertension, both of which are manifestations of sympathetic activation. Bradycardia may or may not occur; parasympathetic ganglionic activation is likely to increase the predominant parasympathetic (bradycardic) tone on heart rate, but sympathetic activation may cause the opposite effect. Initial stimulation of skeletal muscle N M receptors would account for the tremor. As nicotine’s blood levels rise we get autonomic ganglionic blockade, leading to hypotension and bradycardia. Subsequent blockade at the skeletal neuromuscular junction leads to muscle weakness and respiratory depression caused by interference with the function of the diaphragm and intercostals. Bethanechol (a) and pilocarpine (c) are cholinomimetics that, at usual blood levels, exert their primary effects as direct agonists on muscarinic receptors for ACh, not on nicotinic receptors. β-Blockers (d) would not cause hypertension or tachycardia. Indeed, overdoses would change blood pressure and heart rate in the other direction. Moreover, propranolol itself is sometimes use to manage skeletal muscle tremor of certain etiologies. Scopolamine (e) is a muscarinic blocker with virtually no effects on skeletal muscle (nicotinic responses)

Question 6

Many cl inical studies have shown that propranolol will lower blood pressure to varying degrees in nearly every patient with essential hypertension (ie, high BP of unknown etiology or identifiable causes, such as pheochromocytoma or vasopressor drug overdose). What i s the most likely and physiologically most important mechanism for propranolol’s pressure-lowering effect?

A	Induced a baroreceptor reflex that reduces vasoconstriction usually caused by activation of the sympathetic nervous system
B	Inhibited catecholamine release from adrenergic nerves and the adrenal medulla (suprarenal medulla)
C	Reduced heart rate and left ventricular contractility
D	Reduced total peripheral resistance via direct vasodilator actions involving nitric oxide synthesis in endothelial cells
E	Stimulated renin release, ultimately leading to enhanced synthesis of vasodilator chemicals such as bradykinin

Question 6 Explanation: 

ecall that the basic “equation” for blood pressure is: and since CO = heart rate × stroke volume (HR × SV), then Propranolol is, of course, a nonselective (β1 and β2) β-adrenergic blocker that lacks any α-blocking or other vasodilator effects (eg, due to nitric oxide generation), regardless of the dose. So to answer the question, given the above equation, you simply ask which one or more of the variables —HR, SV, or TPR—is reduced by a nonselective β-blocker. The answer, of course, is both HR and SV. Rapid parenteral administration of propranolol or another β-blocker in the same class will lower blood pressure, and if that occurs quickly enough (eg, with rapid- and brief-acting β-blocker esmolol) and blood pressure falls by a sufficient magnitude, a baroreceptor reflex (answer a) will be activated. This reflex sympathetic activation will lead to increased peripheral vasoconstriction, since α-adrenergic receptors are not blocked by propranolol or any other β-blockers except for labetalol or carvedilol (therefore answer a is incorrect), but this will not lead to reflexmediated increases of either HR or SV. No β-blocker has the ability to inhibit catecholamine release, whether from adrenergic nerves or from the adrenal (suprarenal) medulla (b). As noted above, there is no mechanism by which a β-blocker such as propranolol will lower TPR (d). (Labetalol and carvedilol can, by a-blockade; and nebivolol does by a nitric-oxide mediated mechanism.) Finally, β-blockers reduce renin release (a β1- mediated effect) from the kidneys’ juxtaglomerular apparatus, and so answer e is incorrect.

Question 7

A 35-year-old man who weighs 150 pounds and i s 5 feet 10 inches tall i s transported to the emergency department in severe He complains of episodes of severe, throbbing headaches, profuse diaphoresis, and palpitations. Eighteen months ago his physician told him he i s healthy except for essential hypertension, but he refused medication and has not seen a health care provider for the last year and a half. He denies use of any drugs, whether prescription or over-the-counter, legal or otherwise. Assessment reveals that he i s  tachycardic and has an i rregular pulse (occasional premature ventricular beats are noted on his ECG). Heart rate    at rest i s approximately 130 beats/min, sometimes more. His resting blood pressure i s 200/140 mm Hg. These cardiovascular findings are shown in the figure below. The fi rst year house officer who i s caring for this patient knows that all the orally effective β-adrenergic blockers are approved for use to treat essential hypertension, and concludes that prompt lowering of blood pressure i s essential for this patient. Therefore, he orders intravenous administration of propranolol (at the arrow, above), and a large dose of the drug s ince  the  symptoms  seem severe. Unknown to  the  physician i s the fact that the patient’s s igns and symptoms are due to a pheochromocytoma (epinephrine-secreting tumor of the adrenal/suprarenal medulla). What i s the most l ikely ultimate outcome of administering this β-blocker (or any other β-blocker that lacks α-blocking or other vasodilator activity), supplemented with no other medication?  

A	Heart failure, cardiogenic shock, death
B	Long-lasting normalization of heart rate, contractility, and blood pressure
C	Normalization of blood pressures but persistence of tachycardia Restoration of normal s inus rate and rhythm, but no change of blood
D	Restoration of normal s inus rate and rhythm, but no change of blood pressure from predrug levels
E	Sudden and s ignificant ri se of systolic blood pressure and heart rate

Question 7 Explanation: 

The figure, below, approximates what is likely to happen following administration of a β- blocker to a patient with a pheochromocytoma.To answer this question correctly you must integrate your basic knowledge of both autonomic pharmacology and cardiovascular physiology. With a pheochromocytoma we have what might be described as “massive” amounts of catecholamines—mainly epinephrine—being released from the tumor into the bloodstream. Germane to our problem, then, is excessive stimulation of cardiac rate, contractility, impulse conduction, and automaticity (β1); intense vasoconstriction (α); and vasodilation in some vascular beds (β2). Nonetheless, while the patient I’ve described is not at all healthy, he is still alive before we give the β-blocker. But what happens after we give the β-blocker is critical. The β-blocker does nothing to block the α-mediated vasoconstriction, so in terms of only vascular effects BP will remain very high. If you wish to opine that blocking β2-mediated vasodilation will raise BP a bit, that’s fine; I’ve shown that in the figure above. (Remember: Usually effective doses of a β-blocker will either lower BP [most common response], or not affect it at all, in patients with essential hypertension. If pressure rises in response to a β-blocker, suspect pheochromocytoma.) Nonetheless, there will not be a sudden and significant rise or normalization of BP and/or cardiac function (b, c, d). Likewise, heart rate will not rise significantly (e); it can’t: the β1 receptors necessary for that to occur are blocked. Next you must recall that the inotropic state of the heart (ie, of the left ventricle, LV) is critical. This is critical because LV peak systolic pressure must exceed aortic pressure in order to establish the LV-aortic pressure gradient to expel blood into the aorta, and propel blood throughout the circulation. If aortic diastolic pressure exceeds LV peak systolic pressure, blood will not flow out of the heart. But until we give the β-blocker, the heart can maintain (for a while) its function thanks to catecholamine-mediated stimulation. But when we give just a β-blocker to the pheochromocytoma patient we have done little if anything to lower the already high aortic pressure, and simultaneously have inhibited cardiac contractility, rate, and other key parameters. The function of the heart as a pump is suppressed. It now faces a very high aortic pressure, and ultimately it fails. Cardiac output falls, the patient develops cardiogenic shock, and is then likely to die. This is why, when treating hypertension associated with a pheochromocytoma, we give an α-blocker first. Blood pressure will fall. We then deal with the excessive cardiac stimulation (which may be intensified, via the baroreceptor reflex, in response to a sudden and significant BP fall) by giving a suitable β-blocker immediately thereafter.

Question 8

A patient with chronic obstructive pulmonary disease (COPD, eg, emphysema, chronic bronchitis) i s receiving an orally inhaled muscarinic receptor-blocking drug to maintain What drug belongs to that class?

A	Albuterol
B	Diphenhydramine
C	Ipratropium (or tiotropium)
D	Pi locarpine
E	Vecuronium

Question 8 Explanation: 

Ipratropium, a quaternary (and so poorly absorbed) antimuscarinic drug, is FDA-approved for use as an inhaled bronchodilator for COPD. Its action involves blockade/antagonism of ACh-mediated bronchoconstriction, and it is often used adjunctively with albuterol or other β2 agonist bronchodilators. A related drug is tiotropium. Albuterol (a) is an inhaled bronchodilator for asthma or COPD, but it works, of course, as a β2-adrenergic agonist. Diphenhydramine (b) hasbronchodilator activity (by blocking both histamine H1 and muscarinic receptors), but it is not given by inhalation; moreover, for ambulatory patients with asthma the mucus-thickening effects of muscarinic receptor blockade can do more harm than good. Vecuronium (e) is a curare-like skeletal neuromuscular blocker (competitive antagonist of ACh at NM receptors) and is used mainly for causing intentional skeletal muscle paralysis during surgry to suppress spontaneous ventilation in some ICU patients on a ventilator. Pilocarpine (d) is a muscarinic agonist, used mainly for causing miosis (constricting the pupil[s] of the eye[s]) in some patients with angle-closure glaucoma. Pilocarpine will cause bronchoconstriction—an effect that may be harmful, if not fatal, for patients with COPD or asthma.

Question 9

You give an “effective dose” of atropine to a person who was poisoned with an AChE What structure  will continue to be overactivated  by the excess ACh after the atropine i s given?

A	Airway smooth muscle
B	S-A node of the heart
C	Salivary and lacrimal glands
D	Skeletal muscle
E	Vascular smooth muscle

Question 9 Explanation: 

In “cholinesterase poisioning” we are dealing with overstimulation (from accumulated ACh) of both peripheral muscarinic and nicotinic receptors. Recall that atropine is a specific muscarinic receptor blocker, and the muscarinic receptors are the ones found on such structures as smooth muscle, cardiac nodal tissue, and exocrine glands. In contrast, the cholinergic receptor on skeletal muscle is nicotinic, so skeletal muscle isn’t affected by atropine. If one receives a lethal dose of a cholinesterase inhibitor, he or she may be a little more comfortable (less defecation, urination, respiratory tract mucus hypersecretion and bronchoconstriction, and all that, after the atropine is given), but they are still likely to die from skeletal muscle (NM nicotinic) overstimulation and then paralysis. Paralysis of the diaphragm and intercostals muscles are the most lethal consequences

Question 10

The house officer considers prescribing nadolol for a 53-year-old What preexisting condition (comorbidity) would most l ikely contraindicate safe use of this drug?

A	Angina pectoris, chronic-stable (effort-induced)
B	Asthma
C	Essential hypertension
D	Heart failure, mild
E	Sinus tachycardia

Question 10 Explanation: 

You probably learned that nadolol is a β-blocker, and perhaps that it’s a nonselective (β1/β2) blocker with a rather long duration of action and half-life. If not, you should have been able to recognize that since the generic name ends in “-olol” it is, indeed, some kind of β-blocker. You should also know that asthma is one of the main contraindications for β-blocker administration. β-Adrenergic blockade results in an increase in airway resistance (by antagonism of bronchodilation mediated by epinephrine) that can be fatal in some asthmatic patients. Nadolol, and all the other orally effective β-blockers, are approved for treating chronic-stable angina (a) and essential hypertension (c). They are critical elements in contemporary therapy of heart failure (d; except when it is severe and cardiac output is profoundly depressed); and have beneficial effects to control heart rate in such conditions as sinus tachycardia (e)

Question 11

A variety of ophthalmic drugs, working by several main mechanisms of action, are useful for managing chronic open-angle Which one reduces intraocular pressure by decreasing the formation of aqueous humor, rather than by changing the s i ze of the pupil(s)?

A	Echothiophate
B	Isoflurophate
C	Neostigmine
D	Pi locarpine
E	Timolol

Question 11 Explanation: 

When applied topically to the eye, both the direct-acting cholinomimetic agents (eg, pilocarpine) and those that act by inhibition of AChE (eg, echothiophate, isoflurophate, and physostigmine) cause miosis by constricting the pupil. In patients with narrow-angle (angle closure) glaucoma, this effect provides greater drainage of the aqueous humor through the trabecular meshwork and the canal of Schlemm and a reduction in resistance to outflow of the aqueous humor. Certain β-adrenergic blocking agents (eg, timolol and levobunolol), applied to the eye(s), are also very useful in treating chronic wide-angle glaucoma. These drugs appear to act by decreasing the secretion (or formation) of aqueous humor by antagonizing the effect of circulating catecholamines on β-adrenergic receptors in the ciliary epithelium. Echothiophate (a), isoflurophate (b), and neostigmine (e) are acetylcholinesterase inhibitors and all constrict the pupil. Pilocarpine (d) is muscarinic receptor agonist; it, too, causes miosis.

Question 12

It’s fair to say that epinephrine, norepinephrine, and acetylcholine play the most important roles as endogenous agonists for the various receptors under control of the peripheral nervous However, dopamine also plays a small but important therapeutic role, particularly when administered IV at low doses. What other peripheral effects can dopamine cause at usual therapeutic doses?

A	Bronchodilation via relaxation of airway smooth muscles
B	Direct activation of pressure receptors (eg, baroreceptors) in response to blood pressure changes triggered by other agonists
C	Direct activation of the juxtaglomerular apparatus, release of aldosterone
D	Inhibition of epinephrine release from chromaffin cells (eg, cells of the adrenal/suprarenal medulla).
E	Regulation of renal blood flow via control of renal arterial tone

Question 12 Explanation: 

Infusing low doses of dopamine rather preferentially activates D 1 receptors, raises vascular smooth muscle cAMP levels, and causes vasodilation in the kidneys and mesentery. (Clinicians often refer to these as “renal doses” because, in such conditions as low cardiac output the drug is given not only as a cardiac stimulant but also to increase renal blood flow and urine output.) The outcome of the increased renal blood flow is increased glomerular filtration and sodium excretion. A similar D1/cAMPmediated effect also occurs in the renal tubules (particularly the proximal tubules and the medullary region of the thick ascending limb in the Loop of Henle). This inhibits a Na+ -K+ -ATPase, which further increases renal sodium loss by inhibiting sodium reabsorption.

Question 13

Guanadrel i s an antihypertensive drug: i t reduces arteriolar constriction, and in doing so lowers BP by reducing the amount of NE in peripheral adrenergic Lowered blood pressure i s not accompanied by reflex tachycardia, and in fact a reduction of heart rate  from predrug levels i s the more common outcome. The main ocular effect of guanadrel i s miosis. The widespread abolition of sympathetic influences throughout the body often causes diarrhea and urinary frequency. Based on this description, to which prototypic drug i s guanadrel most s imilar in terms of i ts ultimate qualitative autonomic effects, and in terms of overall mechanism of action?

A	Acetylcholine
B	Atropine
C	Epinephrine
D	Isoproterenol
E	Norepinephrine
F	Propranolol
G	Reserpine

Question 13 Explanation: 

The qualitative and mechanistic effects of guanadrel are very similar to those of reserpine. Both drugs cause what has been described as a “chemical sympathectomy,” gradually but eventually markedly reducing sympathetic (adrenergic) influences on all the usual target structures and thereby exposing or unmasking opposing parasympathetic influences. (The resulting syndrome has been called “parasympathetic predominance” since adrenergic influences are removed, leaving PNS tone on a host of structures unopposed and now exposed.) For example, in the presence of guanadrel miosis, diarrhea and urination develop; and arterioles dilate and blood pressure falls (because there’s little/no norepinephrine to be released, since it has been depleted from adrenergic nerve endings). Heart rate does not increase reflexly (via the baroreceptor reflex mechanism) for two main reasons. First, heart rate cannot rise because after a sufficient duration of treatment there is little or no NE to be released. The second reason for no baroreceptor reflex is that guanadrel (and reserpine) cause BP to fall so slowly that the baroreceptors simply do not respond to any BP changes. Indeed, heart rate falls markedly during treatment. Reserpine causes its effects mainly by interfering with intraneuronal storage of NE, exposing the neurotransmitter to metabolic inactivation by MAO and ultimately depleting the NE. Guanadrel releases NE directly, and gradually, eventually leading to a state of intraneuronal NE depletion with signs and symptoms very similar to those caused by reserpine. None of the other drugs listed will have any effects on the levels of NE in adrenergic nerves. Acetylcholine (a), the physiologic agonist for both muscarinic and nicotinic receptors, will cause many of the responses described for guanadrel, but, again, does not do so by reducing catecholamine levels in adrenergic neurons. It’s also worth noting that ACh is not classified—and certainly not used—as an antihypertensive drug. The peripheral autonomic effects of atropine (b) administration would be the opposite of those described for guanadrel. Usual parenteral doses of epinephrine (c; α and β1 and β2 agonist) or norepinephrine (e; α and β1 agonist) tend to raise blood pressure and peripheral resistance (the effects clearly are dose-dependent), and if there were any changes in pupil size it would be manifest as mydriasis due to activation of α-receptors on iris dilator muscle cells. Isoproterenol (d; β1 and β2 agonist with no direct effects on α receptors) may raise BP by increasing cardiac output (via increased heart rate and stroke volume). Propranolol (f), the prototypic β1 and β2 antagonist, certainly is an antihypertensive drug, but it and other β-blockers do not affect intraneuronal NE levels; do not cause any change in pupil size (ie, neither mydriasis nor miosis); and do not typically unmask parasympathetic influences on such structures as the gut and urinary tract musculature.

Question 14

An “effective” dose of a drug i s given and the following responses occur:

• Stimulates heart rate and, apparently, left ventricular stroke volume
• Dilates some blood vessels but constricts none
• Dilates the bronchi (relaxes airway smooth muscles)
• Raises blood glucose levels
• Neither dilates nor constricts the pupil of the eye What drug i s capable of causing all these responses?

A	Atropine
B	Epinephrine
C	Isoproterenol
D	Norepinephrine
E	Phenylephrine

Question 14 Explanation: 

Piece things together. Some tip-offs to help arrive at the correct answer: no effect on the size of the pupil, so rule out any drug that has effects on the “parasympathetic” side, whether as an agonist or antagonist (here, atropine), and rule out any drug with α effects. (As noted above, no β-receptors control the size of the pupil of the eye.) Does isoproterenol fit all the other criteria/properties? Yes. And none of the other choices have all the stated properties, only some of them.

Question 15

It i s common to include small amounts of epinephrine (EPI) in solutions of local anesthetics that will be administered by infiltration (injection around sensory nerve endings), as when a skin laceration needs What i s the most l ikely reason for, or outcome of, including the EPI?

A	To antagonize the otherwise intense and common vasoconstrictor and hypertensive effects of the anesthetic
B	To counteract cardiac depression caused by the anesthetic
C	To prevent anaphylaxis in patients who are allergic to the anesthetic
D	To reduce the ri sk of toxicity caused by systemic absorption of the anesthetic
E	To shorten the duration of anesthetic action

Question 15 Explanation: 

There are several reasons for and outcomes of adding a vasoconstrictor (usually epinephrine) to some local anesthetics given by infiltration. The vasoconstrictor confines the local anesthetic to the desired site of action (basically the site of administration) by reducing local blood flow and the rate of anesthetic entry into the bloodstream. It is the bloodstream (or, more precisely, it is the presence of anesthetic in the systemic circulation) that delivers the drug to sites where signs and symptoms of toxicity occur. Slow down anesthetic absorption rates and the drug will enter the circulation slowly enough that it can be metabolized (inactivated) fastenough to prevent accumulation to toxic levels. That is, we reduce the risk of systemic toxicity with added vasoconstrictor. Another outcome of including a vasoconstrictor is to prolong (and certainly not shorten) the duration of local anesthetic effect. That occurs also because reduced local blood flow keeps the anesthetic in the vicinity of sensory nerves longer (since the anesthetic is not being removed as quickly by blood flow). More on this issue will be presented in the CNS questions. But for now: Local anesthetics (except cocaine) can cause vasodilation (not vasoconstriction; a), but unless the local anesthetic dosages are quite high (toxic), the vasodilation is not intense; hypotension is uncommon with usual dosages. Likewise, cardiac depression can occur, but again that is a manifestation of overdose. We don’t routinely include epinephrine in a local anesthetic to combat or prevent these cardiac-depressant problems (b), and the amount of epinephrine found in these preparations is far too low to do anything meaningful to remedy these adverse responses should they occur. Likewise, the amounts of vasoconstrictor are far too low to prevent (or treat) anesthetic-induced anaphylaxis (c)—a reaction that requires only a few molecules of antigen to occur. So what the vasoconstrictor does is essentially cause a pharmacologic tourniquet, reducing regional blood flow that otherwise would quickly “wash away” the anesthetic. This essentially confines the anesthetic to the desired site longer (not shorter; e) than otherwise, and decreases the potential systemic reactions (d). Some local anesthetics cause vasodilation, which allows more compound to escape the tissue and enter the blood. Two final notes: In plastic surgery, otolaryngologic surgery (nose, throat) and many other types of surgery, the direct vasoconstrictor effects of EPI, administered as part of a mixture of the anesthetic and epinephrine, not only antagonize the local vasodilator effects of a local anesthetic, but also cause direct vasoconstriction in the region—a local hemostatic effect that limits blood loss in yet another way. It is also important to note that epinephrine (or other vasoconstrictors) should not be used in or as a supplement to parenteral local anesthetics being used to relieve or prevent pain in “end organs”—fingers, toes, penis, tip of the nose, earlobes, etc. Such structures have relatively discrete blood supplies, and blocking blood flow to distal tissues can lead to ischemia and tissue damage.

Question 16

In your third year of medical school, you are conducting a study on s imilarities and differences between two prototypic drugs, phentolamine and prazosin, as they affect cardiovascular You selected two identical twins to ensure their pharmacogenetic make-up, and so their responses to drugs, i s as nearly identical as possible. One twin will get the phentolamine, the other gets prazosin. Their cardiovascular parameters at baseline (rest) are identical and normal, and everything else that might have an impact on their drug responses i s normal and, well, identical. They aren’t taking any other drugs. One twin gets an IV injection of phentolamine. His mean blood pressure falls 20 mm Hg in 20 seconds. The other gets an IV injection of prazosin at an equally effective dose in terms of the blood pressure response. His mean BP falls by an identical amount, 20 mm Hg, over the same time period, 20 seconds. Which is the most likely difference you will find in the responses of these two lads, one who got phentolamine and the other who got an equivalent pressure-lowering dose of prazosin?

A	Phentolamine will trigger a greater baroreceptor-mediated reflex increase of heart rate and contractility than the prazosin will
B	Prazosin will lead to a bigger reflex positive inotropic and chronotropic response than phentolamine.
C	Prazosin will block all reflex cardiac responses because i t also has strong β-blocking activity.
D	Prazosin will lead to a greater ri se of cardiac output than phentolamine by selectively blocking norepinephrine-mediated
E	VasodilationPhentolamine will reduce left ventricular afterload, prazosin will raise i t.

Question 16 Explanation: 

First you need to know that prazosin and phentolamine are α-adrenergic blockers. Then you need to know upon which α-adrenergic receptors they act, and what responses they elicit. Phentolamine is a nonselective α-adrenergic blocker, acting at both α1 (postsynaptic) and α2 (presynaptic) receptors. Prazosin selectively blocks α1 receptors. Activating the postsynaptic receptors, on vascular smooth muscle cells, causes contraction (vasoconstriction); block those receptors and vasodilation (ie, the fall of blood pressure we noted) occurs. Both phentolamine and prazosin do this. The blood pressure fall upon drug administration is of a sufficient magnitude (20 mm Hg), and occurs sufficiently quickly (20 seconds or less), that the baroreceptor reflex is activated. This leads to increased sympathetic “outflow” to the periphery as part of the body’s attempt to maintain the cardiovascular status quo. Sympathetic stimulation of vascular smooth muscle normally will cause vasoconstriction, but since the α-adrenergic receptors that must be activated to cause it are blocked (by phentolamine or prazosin), vasoconstriction will not occur (or be very much reduced). Increased baroreceptor-mediated sympathetic stimulation of the heart also occurs, and neither phentolamine nor prazosin blocks the β1 receptors on which released NE exerts its cardiac-stimulating effects. But what else occurs at the adrenergic neuroeffector junctions, such as at the heart? Normally, some of the released NE acts on the presynaptic α-receptors. The result of that interaction is a physiologic “turning off” or feedback-inhibition of further NE release in response to each action potential. Phentolamine blocks the presynaptic α-receptors, thereby blocking what amounts to the ability of released NE to suppress further NE release. The consequence of this? Significant increases in the amount of NE released into the synapse, and prolonged presence of NE in the synapse, and significantly increased cardiac stimulation. Prazosin, however, does not block the presynaptic α-receptors, and in doing so does not interfere with the normal feedback-inhibitory effects of released NE. And the obvious difference? Much less intense reflex cardiac stimulation with prazosin than that with phentolamine—not the opposite (b). Prazosin and phentolamine have no β-blocking activity (c). Neither drug blocks NE-mediated vasodilation (d). And neither will reduce LV afterload (e): as noted in the question, both drugs lowered arterial pressure and so afterload is obviously decreased too.

Question 17

A 48-year-old woman has a history of myasthenia She has been treated with an oral acetylcholinesterase (AChE) inhibitor for several years, and has done well until now. Today she presents in your cl inic with muscle weakness and other s igns and symptoms that could reflect either a cholinergic cris i s (excess dosages of her maintenance drug) or a myasthenic cris i s (insufficient treatment). You will use a rapidly acting parenteral acetylcholinesterase inhibitor to help make the differential diagnosis. Which drug would, therefore, be most appropriate to use?

A	Edrophonium
B	Malathion
C	Physostigmine
D	Pralidoxime
E	Pyridostigmine

Question 17 Explanation: 

Although several of the listed drugs inhibit the activity of AChE, only edrophonium is used in the diagnosis of myasthenia gravis. The drug has a more rapid onset of action (1 to 3 minutes following intravenous administration) and a shorter duration of action (approximately 5 to 10 minutes) than pyridostigmine. This fast acting/short duration profile is precisely what we want in this situation. We can quickly get our diagnostic answer, yet not have to deal too long with adverse responses (such as ventilatory paralysis) if the patient was experiencing a cholinergic crisis (excessive doses of their oral cholinesterase inhibitor) and we’ve now worsened the situation by inhibiting the metabolic inactivation of ACh even more with our diagnostic medication. (The short duration and the need for parenteral administration preclude use of edrophonium as a practical drug for long-term treatment of myasthenia gravis.) Malathion (b) is used topically to treat head lice and is never used internally (intentionally). Pyridostigmine (e) is used orally for maintenance therapy of myasthenia gravis. Physostigmine (c) is indicated for treatment of glaucoma (given topically), and is also a valuable parenteral drug for treating toxicity of anticholinergic drugs such as atropine. They are all cholinesterase inhibitors. Pralidoxime (d) is a “cholinesterase reactivator” and is used adjunctively (with atropine) in the treatment of poisonings caused by “irreversible” cholinesterase inhibitors, such as the “nerve gases” used as bioweapons and some commercial insecticides.

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Part 1 | Part 2 | Part 3 | Part 4 

II. Preview all questions below

1.A patient with a history of narrow-angle (angle-closure) glaucoma experiences a sudden ri se of intraocular pressure that i s  sufficiently In addition to pain there i s an imminent ri sk of permanent vis ion loss. They require immediate treatment, one element of which i s administration of echothiophate. What enzyme i s affected by this autonomic drug?

1. Tyrosine hydroxylase—stimulated
2. Acetylcholinesterase (AChE)—inhibited
3. Catechol-O-methyltransferase (COMT)—inhibited
4. Monoamine oxidase (MAO)—stimulated
5. DOPA decarboxylase—stimulated

2. A patient has essential hypertension, and lab tests would show that their ci rculating catecholamine and plasma renin levels are unusually The chosen therapeutic approach for this patient i s to give a s ingle drug that blocks both α- and β-adrenergic receptors, thereby reducing blood pressure by reducing both cardiac output and total peripheral resistance (systemic vascular resistance). What drug i s most capable of doing that?

1. Labetalol
2. Metoprolol
3. Nadolol
4. Pindolol
5. Timolol

3. A man who has been “surfing the Web” in search of an aphrodisiac or some other agent to enhance “sexual prowess and performance” discovers He consumes the drug in excess and develops symptoms of toxicity that require your intervention. You consult your preferred drug reference and learn that yohimbine i s a selective α₂-adrenergic antagonist that acts mainly in the brain’s medullary “cardiovascular control center.” What would you expect as a response to this drug?

1. Bradycardia
2. Bronchoconstriction
3. Excessive secretions by exocrine glands (salivary, lacrimal, etc)
4. Reduced cardiac output from reduced left ventricular contractility
5. Rise of blood pressure

4. You plan to prescribe scopolamine, as a transdermal drug delivery system (skin patch), for a patient who will be leaving for an expensive cruise and i s very susceptible to motion s i What comorbidity would weigh against prescribing the drug because i t i s most l ikely to pose adverse effects—or be truly contraindicated?

1. Angle-closure (narrow-angle) glaucoma
2. Bradycardia
3. History of allergic reactions to uncooked shellfish
4. Resting blood pressure of 112/70 Hypothyroidism, mild
5. Parkinson disease (early onset, not currently treated)

5. A child overdoses on a drug that affects both the autonomic and somatic nervous As blood levels of the drug ri se he experiences hypertension and tachycardia, accompanied by skeletal muscle tremor. Further elevations of blood levels of the drug cause all the expected s igns and symptoms of autonomic ganglionic blockade, plus weakness and eventual paralysis of skeletal muscle. Which drug did the child most l ikely ingest?

1. Bethanechol
2. Nicotine
3. Pi locarpine
4. Propranolol (or another β-adrenergic blocker)
5. Scopolamine

6. Many cl inical studies have shown that propranolol will lower blood pressure to varying degrees in nearly every patient with essential hypertension (ie, high BP of unknown etiology or identifiable causes, such as pheochromocytoma or vasopressor drug overdose). What i s the most likely and physiologically most important mechanism for propranolol’s pressure-lowering effect?

1. Induced a baroreceptor reflex that reduces vasoconstriction usually caused by activation of the sympathetic nervous system
2. Inhibited catecholamine release from adrenergic nerves and the adrenal medulla (suprarenal medulla)
3. Reduced heart rate and left ventricular contractility
4. Reduced total peripheral resistance via direct vasodilator actions involving nitric oxide synthesis  in endothelial cells
5. Stimulated renin release, ultimately leading to enhanced synthesis of vasodilator chemicals such as bradykinin

7. A 35-year-old man who weighs 150 pounds and i s 5 feet 10 inches tall i s transported to the emergency department in severe He complains of episodes of severe, throbbing headaches, profuse diaphoresis, and palpitations. Eighteen months ago his physician told him he i s healthy except for essential hypertension, but he refused medication and has not seen a health care provider for the last year and a half. He denies use of any drugs, whether prescription or over-the-counter, legal or otherwise.

Assessment reveals that he i s  tachycardic and has an i rregular pulse (occasional premature ventricular beats are noted on his ECG). Heart rate    at rest i s approximately 130 beats/min, sometimes more. His resting blood pressure i s 200/140 mm Hg. These cardiovascular findings are shown in the figure below.

The fi rst year house officer who i s caring for this patient knows that all the orally effective β-adrenergic blockers are approved for use to treat essential hypertension, and concludes that prompt lowering of blood pressure i s essential for this patient. Therefore, he orders intravenous administration of propranolol (at the arrow, above), and a large dose of the drug s ince  the  symptoms  seem severe. Unknown to  the  physician i s the fact that the patient’s s igns and symptoms are due to a pheochromocytoma (epinephrine-secreting tumor of the adrenal/suprarenal medulla).

What i s the most l ikely ultimate outcome of administering this β-blocker (or any other β-blocker that lacks α-blocking or other vasodilator activity), supplemented with no other medication?

1. Heart failure, cardiogenic shock, death
2. Long-lasting normalization of heart rate, contractility, and blood pressure
3. Normalization of blood pressures but persistence of tachycardia
4. Restoration of normal s inus rate and rhythm, but no change of blood pressure from predrug levels
5. Sudden and s ignificant ri se of systolic blood pressure and heart rate

8. A patient with chronic obstructive pulmonary disease (COPD, eg, emphysema, chronic bronchitis) i s receiving an orally inhaled muscarinic receptor-blocking drug to maintain What drug belongs to that class?

1. Albuterol
2. Diphenhydramine
3. Ipratropium (or tiotropium)
4. Pi locarpine
5. Vecuronium

9. You give an “effective dose” of atropine to a person who was poisoned with an AChE What structure  will continue to be overactivated  by the excess ACh after the atropine i s given?

1. Airway smooth muscle
2. S-A node of the heart
3. Salivary and lacrimal glands
4. Skeletal muscle
5. Vascular smooth muscle

10. The house officer considers prescribing nadolol for a 53-year-old What preexisting condition (comorbidity) would most l ikely contraindicate safe use of this drug?

1. Angina pectoris, chronic-stable (effort-induced)
2. Asthma
3. Essential hypertension
4. Heart failure, mild
5. Sinus tachycardia

11. A variety of ophthalmic drugs, working by several main mechanisms of action, are useful for managing chronic open-angle Which one reduces intraocular pressure by decreasing the formation of aqueous humor, rather than by changing the s i ze of the pupil(s)?

1. Echothiophate
2. Isoflurophate
3. Neostigmine
4. Pi locarpine
5. Timolol

12. It’s fair to say that epinephrine, norepinephrine, and acetylcholine play the most important roles as endogenous agonists for the various receptors under control of the peripheral nervous However, dopamine also plays a small but important therapeutic role, particularly when administered IV at low doses. What other peripheral effects can dopamine cause at usual therapeutic doses?

1. Bronchodilation via relaxation of airway smooth muscles
2. Direct activation of pressure receptors (eg, baroreceptors) in response to blood pressure changes triggered by other agonists
3. Direct activation of the juxtaglomerular apparatus, release of aldosterone
4. Inhibition of epinephrine release from chromaffin cells (eg, cells of the adrenal/suprarenal medulla).
5. Regulation of renal blood flow via control of renal arterial tone

13. Guanadrel i s an antihypertensive drug: i t reduces arteriolar constriction, and in doing so lowers BP by reducing the amount of NE in peripheral adrenergic Lowered blood pressure i s not accompanied by reflex tachycardia, and in fact a reduction of heart rate  from predrug levels i s the more common outcome. The main ocular effect of guanadrel i s miosis. The widespread abolition of sympathetic influences throughout the body often causes diarrhea and urinary frequency. Based on this description, to which prototypic drug i s guanadrel most s imilar in terms of i ts ultimate qualitative autonomic effects, and in terms of overall mechanism of action?

1. Acetylcholine
2. Atropine
3. Epinephrine
4. Isoproterenol
5. Norepinephrine
6. Propranolol
7. Reserpine

14. An “effective” dose of a drug i s given and the following responses occur:

• Stimulates heart rate and, apparently, left ventricular stroke volume
• Dilates some blood vessels but constricts none
• Dilates the bronchi (relaxes airway smooth muscles)
• Raises blood glucose levels
• Neither dilates nor constricts the pupil of the eye What drug i s capable of causing all these responses?

1. Atropine
2. Epinephrine
3. Isoproterenol
4. Norepinephrine
5. Phenylephrine

15. It i s common to include small amounts of epinephrine (EPI) in solutions of local anesthetics that will be administered by infiltration (injection around sensory nerve endings), as when a skin laceration needs What is the most l ikely reason for, or outcome of, including the EPI?

1. To antagonize the otherwise intense and common vasoconstrictor and hypertensive effects of the anesthetic
2. To counteract cardiac depression caused by the anesthetic
3. To prevent anaphylaxis in patients who are allergic to the anesthetic
4. To reduce the ri sk of toxicity caused by systemic absorption of the anesthetic
5. To shorten the duration of anesthetic action

16. In your third year of medical school, you are conducting a study on s imilarities and differences between two prototypic drugs, phentolamine and prazosin, as they affect cardiovascular You selected two identical twins to ensure their pharmacogenetic make-up, and so their responses to drugs, i s as nearly identical as possible. One twin will get the phentolamine, the other gets prazosin.

Their cardiovascular parameters at baseline (rest) are identical and normal, and everything else that might have an impact on their drug responses i s normal and, well, identical. They aren’t taking any other drugs.

One twin gets an IV injection of phentolamine. His mean blood pressure falls 20 mm Hg in 20 seconds.

The other gets an IV injection of prazosin at an equally effective dose in terms of the blood pressure response. His mean BP falls by an identical amount, 20 mm Hg, over the same time period, 20 seconds.

Which is the most likely difference you will find in the responses of these two lads, one who got phentolamine and the other who got an equivalent pressure-lowering dose of prazosin?

1. Phentolamine will trigger a greater baroreceptor-mediated reflex increase of heart rate and contractility than the prazosin will.
2. Prazosin will lead to a bigger reflex positive inotropic and chronotropic response than phentolamine.
3. Prazosin will block all reflex cardiac responses because i t also has strong β-blocking activity.
4. Prazosin will lead to a greater ri se of cardiac output than phentolamine by selectively blocking norepinephrine-mediated
5. VasodilationPhentolamine will reduce left ventricular afterload, prazosin will raise i t.

17. A 48-year-old woman has a history of myasthenia She has been treated with an oral acetylcholinesterase (AChE) inhibitor for several years, and has done well until now. Today she presents in your cl inic with muscle weakness and other s igns and symptoms that could reflect either a cholinergic cris i s (excess dosages of her maintenance drug) or a myasthenic cris i s (insufficient treatment). You will use a rapidly acting parenteral acetylcholinesterase inhibitor to help make the differential diagnosis. Which drug would, therefore, be most appropriate to use?

1. Edrophonium
2. Malathion
3. Physostigmine
4. Pralidoxime
5. Pyridostigmine