The Quizzes about Autonomic and Somatic Nervous System Pharmacology – Part 4

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The Peripheral Nervous Systems: Autonomic and Somatic Nervous System Pharmacology- Part 4

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Question 1

“First-generation” (older) histamine H₁ blockers such as diphenhydramine, phenothiazine antipsychotic drugs (eg, chlorpromazine), and tri - cyclic antidepressants (eg, imipramine) have pharmacologic actions, s ide effects, toxicities, and contraindications that are very s imilar to those of which other drug?

A	Atropine
B	Bethanechol
C	Isoproterenol
D	Neostigmine
E	Propranolol

Question 1 Explanation: 

These drugs all possess antimuscarinic (atropine-like) actions that often are sufficiently strong to cause all the side effects and adverse responses associated with atropine itself. Likewise, it is prudent to assume they share all the contraindications and precautions associated with atropine and that managing severe overdoses of those drugs or drug groups will resemble (and need to be treated) in quite the same way as those of the prototype antimuscarinic. That would include the potential need to administer physostigmine, the acetylcholinesterase inhibitor that plays an important role in managing atropine poisoning. Note that of all the drugs with atropine-like actions, diphenhydramine (and, to a somewhat lesser extent the other first-generation antihistamines) are available over-the-counter. Although you may do your best to avoid prescribing drugs with atropine-like actions for patients who should not receive them, atropine-like problems can arise in patients who self-prescribe these nonprescription medications. Clearly, the effects of bethanechol (muscarinic agonist) and neostigmine (acetylcholinesterase inhibitor) are the opposite of those you’d expect to see with atropine (muscarinic receptor blocker). You might argue that isoproterenol (β1 and β2 agonist) causes some effects (eg, tachycardia) that you would expect with atropine. True. However, despite any similarities in appearance, the mechanism is quite different, the spectrum of all effects caused by the drug is different, and certainly most contraindications and toxic manifestations are very different. Propranolol (prototype nonselective β-blocker) is radically different from atropine in nearly every important way

Question 2

A 6-year-old i s transported to the Emergency Department by a parent, who says the boy took a large amount of an allergy The sole active ingredient in the product the parent mentions i s diphenhydramine, and i t i s clear the child i s experiencing toxicity from an overdose. The intern, fresh out of medical school, orders parenteral administration of neostigmine, and the medication order i s not questioned. What adverse effect of the diphenhydramine will persist following neostigmine administration?

A	Bronchoconstriction and wheezing
B	Delirium, hallucinations, and other CNS manifestations of toxicity
C	Profuse secretions from lacrimal, mucus, and sweat glands
D	Skeletal muscle tremor or fasciculations
E	Tachycardia

Question 2 Explanation: 

The major signs and symptoms of diphenhydramine toxicity are attributable to its strong antimuscarinic (atropine-like) effects in both the peripheral and central nervous systems. Neostigmine— unlike the preferred antidote, physostigmine—is a quaternary compound and does not enter the CNS. Thus, delirium, hallucinations, and other CNS manifestations of diphenhydramine poisoning will persist. Physostigmine is the preferred antidote specifically because it is not a quaternary (ionized) at physiologic pH, and will readily cause desired antidotal effects in the CNS as well as in the periphery. Bronchoconstriction and wheezing (a) are not expected outcomes of diphenhydramine toxicity; the antimuscarinic effects of the drug will cause bronchodilation by blocking the bronchoconstrictor influences of endogenous ACh. Likewise, toxic (or even therapeutic) blood levels of diphenhydramine will inhibit—not stimulate—exocrine gland secretions (c). Excesses of diphenhydramine (or atropine itself) will have no significant effects on skeletal muscle activation (d) because these drugs only affect muscarinic receptors; skeletal muscle activation by ACh involves nicotinic receptors. Overdoses of diphenhydramine or any other drugs with strong peripheral muscarinic receptor-blocking effects certainly will cause tachycardia by blocking muscarinic receptor activation of the sino-atrial node. That effect can be reversed by acetylcholinesterase inhibitors, even those that work only in the peripheral nervous systems, such as neostigmine. You won’t encounter too many patients overdosed on atropine itself, but you’ll see many people suffering toxicity from older antihistamines (eg, diphenhydramine), older (tricyclic or tetracyclic) antidepressants (eg, imipramine), some of the centrally acting antimuscarinics that are used for parkinsonism (eg, benztropine and trihexyphenidyl); scopolamine (used for motion sickness), and most of the phenothiazine antipsychotics (eg, chlorpromazine). Owing to the often strong antimuscarinic side effects of these drugs, treating overdoses of any of them probably will involve managing what amounts to “atropine poisoning”—and many other problems too. (You may not know this, but perhaps it will have some meaning or help jog your memory: the trade name for physostigmine is Antilirium. Recall that one of the hallmark CNS signs of atropine/antimuscarinic poisoning is delirium. Hence, “anti-lirium” makes sense.)

Question 3

In between your M1 and M2 years you are volunteering in a hospital in a very poor part of the Their drug selection i s l imited. A patient presents with acute cardiac failure, for which your preferred drug i s dobutamine, given intravenously. However, there i s  none available. Which other drug, or combination of drugs, would be a suitable alternative, giving the pharmacologic equivalent of what you want the dobutamine to do? (All these drugs are available in parenteral formulations.)

A	Dopamine (at a very high dose)
B	Ephedrine
C	Ephedrine plus propranolol
D	Norepinephrine plus phentolamine
E	Phenylephrine plus atropine

Question 3 Explanation: 

Dobutamine behaves, for all practical purposes, as a selective β1 agonist. Norepinephrine is a β1 agonist that also activates α-adrenergic receptors effectively. However, when it is administered with phentolamine (prototype α-blocker) its spectrum of activity is, qualitatively, identical to that of dobutamine. High doses of dopamine (a) cause positive inotropic and chronotropic effects, but also release neuronal norepinephrine and probably activate α-adrenergic receptors directly (causing unwanted vasoconstriction). These vasoconstrictor effects would negate vasodilator effects due to stimulation of dopamine D1 receptors found in some arterioles; and of D2 receptors found on some ganglia, and in the cardiovascular control center of the CNS.Ephedrine (b) weakly activates all adrenergic receptors and also leads to norepinephrine release. Overall, its effects are quite similar to those produced by norepinephrine itself. Regardless, the intensity peripheral adrenergic responses for a usual therapeutic dose of ephedrine usually are less intense than those norepinephrine. And if one administers ephedrine with propranolol (c), the prototypic nonselective (β1 and β2) blocker, ephedrine’s remaining actions amount to selective α-adrenergic activation (ie, phenylephrine-like)—not at all like dobutamine, and not at all what we want in this situation. Phenylephrine (α-agonist) plus atropine (muscarinic antagonist) (e) causes effects that in no way resemble those of dobutamine or the norepinephrine-phentolamine combination. From a cardiovascular perspective, this combination would give us a rise of blood pressure due to peripheral vasoconstriction. The vasoconstriction would elicit a baroreceptor reflex tantamount to withdrawing sympathetic tone and increasing opposing parasympathetic tone. However, the presence of atropine would blunt parasympathetic-mediated cardiac slowing. The overall and combined effect on heart rate of reduced sympathetic tone to the SA node, and concomitant blockade of ACh-mediated cardiac slowing (also an effect on the SA node) can vary. However, it would be reasonable to predict a slight increase of rate over predrug rates. Nonetheless, there would not be a positive inotropic response, which is what would occur with either dobutamine or a norepinephrine-phentolamine combination.

Question 4

In general, structures that are affected by sympathetic influences respond to both sympathetic neural activation and to the hormonal component, epinephrine released from the adrenal Which structure/function i s unique in that i t responds to epinephrine, but not norepinephrine, and has no direct sympathetic neural control?

A	Airway (tracheal, bronchiolar) smooth muscle: relaxation
B	Atrioventricular node: increased automaticity and conduction velocity
C	Coronary arteries: constriction
D	Iri s of the eye: dilation (mydriasis)
E	Renal juxtaglomerular apparatus: renin release

Question 4 Explanation: 

With only one major exception (eccrine sweat glands), the neurotransmitter released by postganglionic sympathetic nerves (adrenergic nerves) to activate their targets is norepinephrine (NE). NE is a “good” agonist for only α- and β1-adrenergic receptors, but not β2. In contrast, epinephrine (EPI; from the adrenal medulla) is a very efficacious agonist for both classes of adrenergic receptors and their main subtypes, including β2. Of the responses listed in the question, only airway smooth-muscle relaxation is a process that involves (depends on) autonomic activation of β2-adrenergic receptors. There is no innervation of these muscles, and so no NE to be released. Even if NE were injected, its lack of β2-agonist activity would render it ineffective as a bronchodilator. A-V nodal automaticity and conduction (b) are increased, in terms of sympathetic influences, by β1 receptors, which can be activated by either or both NE and EPI. The same applies to the coronary vasculature, which constricts in response to α-adrenergic receptor activation by either or both NE or EPI. (If the answer choice were coronary vasodilation involving sympathetic influences, then only EPI would be a correct answer, since sympathetic coronary vasodilation involves β2 receptors.) Either NE or EPI will cause mydriasis (d), which is an α-mediated response. Finally, sympathetically influenced renin release from the juxtaglomerular apparatus involves β1 activation, which can be caused by either NE or EPI. Note: You may have learned something like “if it’s a sympathetic response involving the heart, the receptor involved is β1.” Well, that’s usually true, but now you see that sympathetic mediated coronary vascular smooth muscle relaxation—a response that occurs “in the heart”—involves β2 receptors. (α-Adrenergic receptor activation in the coronaries causes vasoconstriction, just as occurs in the periphery.) You may have also learned “if a β1 receptor is involved, the response is occurring (only) in the heart.” Again, the statement is usually true, but juxtaglomerular cell renin release is obviously occurring outside the heart, but it is a β1-mediated response nonetheless.

Question 5

Adrenergic nerves to the heart are  activated, leading to  a  reflex increase of heart rate  and cardiac contractility, in response to  a  sudden and s ignificant fall of blood pressure. Those sympathetic nerves release norepinephrine (NE). What i s the main physiologic mechanism by which the actions of the released NE are terminated?

A	Diffusion away from postsynaptic receptors
B	Hydrolysis by nonspecific deaminases
C	Metabolic inactivation by MAO
D	Metabolic inactivation by catechol-O-methyltransferase
E	Reuptake into the adrenergic nerve from which the NE was released

Question 5 Explanation: 

In short, the answer is “reuptake.” A norepinephrine transporter plays the main role in terminating the activity of neuronally (physiologically) released NE. This transporter is blocked by cocaine and tricyclic antidepressants (eg, imipra-mine). Diffusion of released NE from the synaptic space, leading to metabolism by such enzymes as COMT (d), is overall a minor process in terms of the physiologic inactivation of the effects of NE. Metabolic inactivation by MAO (c) requires reuptake of the catecholamines into the neuron, since the MAO that degrades catecholamines is located intraneuronally (and intramitochondrially).

Question 6

The figure below shows several responses measured in a  subject (healthy; receiving no other drugs) at rest (before) and after receiving a  dose of an unknown Note: The blood pressures shown can be considered mean blood pressure; the  fall caused by the  unknown was  mainly due to a fall of diastolic pressure. Which drug most l ikely caused the observed responses?

A	Atropine
B	Isoproterenol
C	Neostigmine
D	Phenylephrine
E	Propranolol

Question 6 Explanation: 

To me, the tip-off that helps get to the correct answer, isoproterenol, is to focus (no pun intended) on the fact that the unknown drug did not change the size of the pupil of the eye. Of all the main autonomic receptor types, adrenergic and cholinergic, only the β-receptors play no role in regulating the size of the pupil. That narrows things down to isoproterenol or propranolol. Propranolol might lower BP (particularly in a hypertensive patient), but it would not raise heart rate or dilate the bronchi. Only isoproterenol fits the bill. And the other answers? Atropine (a) might raise heart rate, it is not likely to lower BP, and it will relax airway smooth muscle cells and increase bronchiolar diameter, but it would cause mydriasis, which we don’t see in the results presented in the diagram. Neostigmine (c) would slow heart rate, perhaps lower BP (probably not), and constrict the airways and pupils. Phenylephrine (d) would raise BP, and if the BP rise is sufficiently high and quick, reflexly lower heart rate (baroreceptors). It would do nothing to airway diameter, but would cause mydriasis.

Question 7

A 59-year-old man has a history of emphysema from 40 years of cigarette smoking; hypercholesterolemia that i s being managed with atorvastatin; and Stage 2 essential hypertension for which he i s taking He presents in cl inic today with his main new complaints: nocturia, urinary frequency, and an inability to urinate forcefully and empty his bladder. Following a complete work-up, the physician arrives at a diagnosis of benign prostatic hypertrophy (BPH). We start daily therapy with tamsulosin. What i s the most l ikely s ide effect the patient may experience from the tamsulosin, and about which he should be forewarned?

A	Bradycardia
B	Increased ri sk of statin-induced skeletal muscle pathology
C	Orthostatic hypotension
D	Photophobia and other painful responses to bright l ights
E	Wheezing or other exacerbations of the emphysema

Question 7 Explanation: 

Tamsulosin is a selective α1-adrenergic blocker, much like prazosin (note the “-osin” at the end of the generic names—that’s a certain tip-off to the drug’s general class), and presumably its affinity is greater for α-receptors on smooth muscles in the prostate (hence, its use for BPH, due to relaxation of smooth muscles there) than for those in the peripheral vasculature. Nonetheless, its pharmacologic profile is most similar to that of prazosin, which can be considered the prototypic α1-selective adrenergic blocker that is mainly used to treat hypertension because it competitively blocks vasoconstriction caused by α-agonists such as epinephrine and norepinephrine. (Remember: Drugs with a generic name that ends in “-osin” or “-zosin” are selective α1-adrenergic blockers: eg, tamsulosin, prazosin, terazosin, doxazosin.) So, of the answers listed above, orthostatic hypotension is the most likely side effect. Among the many classes of adrenergic drugs, bradycardia (a) would most likely be caused by a β-blocker (or lesser prescribed drugs such as reserpine, a catecholamine depletor), or a muscarinic agonist or cholinesterase inhibitor, and certainly not by a drug that has no direct cardiac effects and is more likely to elicit reflex cardiac stimulation secondary to reduced blood pressure. There are no known interactions between α-blockers and atorvastatin or related drugs, whether involving skeletal muscle pathology and dysfunction (b) or other adverse responses that a statin might cause. Photophobia (d) is an exceedingly unlikely problem: it is usually caused by drugs that cause mydriasis (eg, α-adrenergic agonists or antimuscarinics), and if anything tamsulosin is likely to prevent the mydriasis that is a common cause of photophobia. Exacerbations of emphysema (e), whether due to bronchoconstriction or other causes, is unlikely too. From an autonomic perspective, epinephrine is the main bronchodilator substance (via β2 activation), ACh is the main autonomic bronchoconstrictor (via muscarinic activation). Tamsulosin affects neither.

Question 8

A patient walks out of the ophthalmologist’s office and into bright sunlight after a comprehensive eye exam, for which he received a topical ophthalmic The drug has not only dilated his pupils, but also impaired his ability to focus his eyes up-close. The drug this patient received was most l ikely classified as, or worked most s imilar to, which prototype?

A	Acetylcholine
B	Epinephrine
C	Homatropine
D	Isoproterenol
E	Pi locarpine
F	Propranolol

Question 8 Explanation: 

There are a couple of ways you could have arrived at this answer, even if you did not learn specifically about homatropine being a shorter-acting, semisynthetic derivative of atropine, the prototypic antimuscarinic drug. For one thing, the drug’s generic name, homatropine, should immediately lead you to thinking about an antimuscarinic drug. Now, consider major autonomic innervation of the eye. The sympathetic nervous system, via α-adrenergic receptors, controls mainly the size of the pupil of the eye; there is very little influence on the ciliary muscle or other structures that control accommodation. (β-Adrenergic influences play no role in controlling pupil size or tone of the ciliary muscle.) The parasympathetic branch of the ANS, and its influences on muscarinic receptors, can alter both pupil size and accommodation—precisely what we have here. So, we can rule out any “sympathetic” drug, agonist or antagonist, as a correct answer. Thus, we reject epinephrine (b), an α- and β-agonist that would cause mydriasis; isoproterenol (d), the β1/2 agonistand propranolol (f), the β1/2 blocker, that affect neither pupil size nor accommodation. We reject ACh (a); this muscarinic agonist would cause miosis and facilitates accommodation. The same applies to pilocarpine (e). This leaves us with homatropine (c). So you could arrive at this correct answer either by the process of elimination, or by making an educated guess (correctly, of course) that homatropine is an atropine-like (antimuscarinic) drug

Question 9

You’ve received approval from the Institutional Review Board to study the in vi tro (ti ssue bath) responsiveness of i solated human arteriolar segments (obtained during surgery) to a variety of pharmacologic and other The ti ssue samples are 1 cm-long “cylinders” of otherwise-normal (but now denervated) arterioles obtained from the lower legs of patients undergoing amputation surgery. The setup allows you to perfuse the vessels with a solution that will keep the ti ssue functionally and structurally intact for many hours; to monitor and change perfusion pressure (mm Hg; analogous to “blood pressure” in the intact organism) and perfusate flow (mL/min); and to assess the effects of various vasoactive drugs on the system. You add ACh to the perfusate to give a concentration identical to the plasma concentration of ACh that causes “expected responses” in an intact human. Under this experimental setup, adding ACh causes a ri se of perfusion pressure and a decrease of flow, both of which basically reflect vasoconstriction. What i s the most l ikely explanation for these findings?

A	ACh released norepinephrine from the endothelium, which caused vasoconstriction
B	Atropine was added to the ti ssue bath before adding the ACh
C	Botulinum toxin was added to the bath before adding the ACh
D	The vascular endothelium has been damaged or removed (denuded)
E	This response i s precisely what we’d expect with injection of ACh into the intact human

Question 9 Explanation: 

ACh, in vivo or in vitro, causes its vasodilator response via an action on the endothelium, where the muscarinic receptors are located. The vasodilator response ultimately depends on endothelial cell formation of nitric oxide (NO), which in the case of ACh is a process that requires endothelial cell integrity. When the endothelium is damaged or removed (d; the most likely case described here), the direct effect of ACh on vascular smooth muscle is contraction (constriction of arterioles). Atropine, the prototype muscarinic antagonist, will prevent ACh-mediated vasodilation of intact arterioles (b), with intact endothelium, by blocking the interaction between ACh and endothelial cell muscarinic receptors, but it will not cause vasoconstriction when the endothelium is intact (it is important here to distinguish between preventing vasodilation and causing vasoconstriction). Botulinum toxin (c) prevents ACh release from cholinergic nerves, but in our experimental setup that is irrelevant because the in vitro preparation is devoid of innervation, and ACh is added directly to the tissue bath. Moreover, even if the smooth muscle preparation were innervated, botulinum toxin would not convert the usual vasodilator response to ACh into a vasoconstrictor one.

Question 10

A 33-year-old woman becomes poisoned after receiving an injection of i l l i ci tly prepared and overly concentrated botulinum What i s the main neurochemical mechanism by which this Clostridium toxin causes i ts effects?

A	Directly activates all muscarinic and nicotinic receptors
B	Inhibits ACh release from all cholinergic nerves
C	Prevents neuronal norepinephrine reuptake
D	Releases norepinephrine via a nonexocytotic process
E	Selectively and competitively blocks nicotinic receptors

Question 10 Explanation: 

Botulinum toxin, the cause of botulism, inhibits release of ACh from all cholinergic nerves, particularly those in the autonomic and somatic/motor nervous systems. (Take a look at the schematic of the peripheral nervous systems on pages 50 and 81 to refresh your memory about where these sites are.) It has no agonist (a) activity on any cholinergic receptors, nor an ability to block nicotinic (e) or muscarinic receptors. The toxin has no direct effects on adrenergic nerves (other than preventing their physiologic activation by ACh, normally released by preganglionic sympathetic nerves. Thus, NE reuptake is not affected (c; recall that cocaine and tricyclic antidepressants do inhibit NE reuptake); nor is NE released (d) as occurs with, say, amphetamines.

Question 11

A 43-year-old woman with diagnosed myasthenia gravis, and taking pyridostigmine daily, presents in the  neurology cl inic with profound skeletal muscle You are unsure whether she i s experiencing a cholinergic cris i s or a myasthenic cris i s , so you administer a usually appropriate diagnostic dose of parenteral edrophonium. Assume the patient was actually experiencing a cholinergic cris i s . What i s the most l ikely response to the edrophonium?

A	Hypertensive cris i s from peripheral vasoconstriction
B	Hypertensive cris i s from peripheral vasoconstriction Myocardial i schemia, and angina, from drug-induced tachycardia and coronary vasoconstriction
C	Premature ventricular contractions from increased ventricular automaticity
D	Prompt improvement of skeletal muscle tone and function
E	Ventilatory distress or failure

Question 11 Explanation: 

Edrophonium is a fast- and short-acting parenteral acetylcholinesterase inhibitor—one of the relatively few therapeutic AChE inhibitors with a generic name that doesn’t end in “-stigmine.” The question states that we are dealing with a patient experiencing a cholinergic crisis. That means, of course, that she has received either relatively or absolutely excessive doses of the oral cholinesterase inhibitor (eg, pyridostigmine, neostigmine, etc) used to manage her myasthenia gravis. Because of the dosage excess, and the excess ACh accumulating at the skeletal neuromuscular junctions (owing to reduced metabolic inactivation of the neurotransmitter), her skeletal muscles are weakened and fatigued from what amounts to overstimulation of nicotinic receptors by the ACh. This skeletal muscle hypofunction involves not only muscles in the extremities, but also the diaphragm and intercostals that must function normally for adequate ventilation. So, when we give a cholinesterase inhibitor to patients like the one described above, who is already experiencing excessive cholinergic effects, further (over)activation of the diaphragm and intercostals may be sufficient to cause ventilatory distress or total ventilatory failure. This is a main reason why the “edrophonium test” is so dangerous should the underlying problem actually be the cholinergic crisis, and why edrophonium is preferred to other ACh esterase inhibitors because it has a very short duration of action (highly desirable should adverse effects occur). Edrophonium is not at all likely to trigger a hypertensive crisis (a). It and other drugs in its class, or direct muscarinic agonists (eg, bethanechol) for that matter, have no vasoconstrictor activity (when vascular endothelial cells are intact). Cholinesterase inhibitors are far more likely to lower heart rate (via indirect muscarinic receptor activation secondary to inhibited ACh hydrolysis at the S-A node) than stimulate it (b); and just as the drug causes no peripheral vasoconstriction, it causes no coronary vasoconstriction. Ventricular automaticity is likely to decrease further, not increase (c), in response to increased muscarinic activation. Edrophonium will not improve skeletal muscle tone and function (d) if the problem is a cholinergic crisis; that is the expected response, however, if the patient has a myasthenic crisis (reflecting inadequate dosages of the cholinesterase inhibitor used for maintenance therapy). Note: For many patients with myasthenia gravis, and who are being treated with an oral cholinesterase inhibitor, you should be able to differentiate between a myasthenic and a cholinergic crisis without resorting to the “edrophonium test.” You simply need to assess your patient carefully, and apply some basic autonomic pharmacology knowledge. In either crisis, the main common features are skeletal muscle fatigability, weakness, or paralysis due to inadequate (myasthenic crisis) or excessive (cholinergic crisis) activation of nicotinic receptors on skeletal muscle. With a myasthenic crisis, the primary problems are confined to skeletal muscle function (and secondary consequences of that, such as inadequate ventilation). Things usually present quite differently, however, if the underlying problem is a cholinergic crisis. Remember that cholinesterase inhibitors do not act only at skeletal neuromuscular junctions. They also act at all cholinergic synapses in the peripheral nervous systems: at all the postganglionic parasympathetic nerve “endings” and at the synapses between postganglionic sympathetic fibers and sweat glands—inhibiting ACh metabolism there, and leading to signs and symptoms of muscarinic activation in addition to nicotinic/skeletal muscle effects. Thus, in patients who are experiencing a cholinergic crisis many or most of the signs and symptoms typically associated with parasympathetic (muscarinic) activation will occur, and they will be useful to you in making the differential diagnosis if you look and listen carefully: miosis and excessive lacrimation; salivation; bradycardia (and possibly A-V block determined by an ECG); wheezing or other manifestations of bronchoconstriction and/or increased airway mucus secretions; gut and bladder hypermotility (eg, defecation, urinary frequency or incontinence, increased bowel sounds); and diaphoresis. See some of these in addition to skeletal muscle dysfunction and you should be thinking cholinergic crisis and placing myasthenic crisis further down on your list of possible diagnoses.

Question 12

A patient takes a massive overdose of diphenhydramine, suffering not only s ignificant CNS depression but also numerous and serious peripheral autonomic s ide By what mechanism did diphenhydramine exert i ts untoward peripheral autonomic actions?

A	Activation of both β1 and β2 adrenoceptors
B	Blockade of α-adrenergic receptors
C	Competitive antagonism of ACh actions on muscarinic receptors
D	Massive, direct overactivation of ganglionic nicotinic receptors
E	Sudden release of epinephrine from the adrenal medulla (suprarenal medulla)

Question 12 Explanation: 

The peripheral autonomic actions of diphenhydramine (an ethanolamine-type “first-generation” histamine H1 antagonist) are very similar to those of atropine, the prototypic competitive muscarinic receptor antagonist. These effects are seen with both therapeutic doses (eg, dry mouth, blurred vision, and occasionally urinary retention or constipation) and with toxicity. In life-threatening cases physostigmine, the “antidote for atropine poisoning,” may be a valuable adjunct. Diphenhydramine, and other H1 blockers for that matter, have no direct effects either as agonist (a) or antagonist (b) on adrenergic receptors; and no nicotinic receptor-activating activity, whether in autonomic ganglia (d) or at the adrenal medulla (suprarenal gland; e)

Question 13

A patient with a recent drug poisoning i s transported to the emergency The physician correctly orders administration of pralidoxime as part of the comprehensive emergency treatment plan. Which best describes who the patient was?

A	A 13-year-old boy who to took an overdose of methylphenidate for his ADD/ADHD.
B	A 43-year-old who took an overdose of neostigmine, prescribed for her myasthenia gravis, in a suicide attempt.
C	A 6-year-old who got into the family medicine cabinet and took 10 “adult doses” of her dad’s prazosin.
D	A farm/field worker accidentally doused with insecticide from an overflying crop-duster plane.
E	An asthma patient who accidentally gave himself an intravenous injection of epinephrine in an attempt to self-treat a developing anaphylactic reaction.

Question 13 Explanation: 

Pralidoxime is classified as a “cholinesterase reactivator” and is used specifically, and adjunctively, for managing poisoning with the long-acting (“irreversible”) organophosphate cholinesterase inhibitors that are found in some insecticides; and “nerve gases” such as soman, sarin, and VX. Pralidoxime, an oxime, has very high affinity for phosphorus in the organophosphates. If given early enough in the poisoning it will prevent or reverse the binding of the organophosphate to, and long-term inhibition of, the active binding site on the cholinesterase. The need for early pralidoxime administration is critical: if it is delayed too long the enzyme will “age,” yielding a largely permanent and irreversible enzyme configuration.Methylphenidate (a) is an indirect-acting (norepinephrine-releasing or amphetamine-like) sympathomimetic; pralidoxime has no effect on its actions, nor on the actions of epinephrine (b) or prazosin (e), a selective α1 adrenergic blocker. Although neostigmine (d) is a cholinesterase inhibitor it is not an organophosphate (it is a carbamate), and it is spontaneously and relatively quickly hydrolyzed leading to loss of cholinesterase-inhibitory activity. Thus, use of pralidoxime for excesses of neostigmine (or other carbamate) doses would be both ineffective (mechanistically) and unnecessary.

Question 14

To facilitate a certain eye exam you want to cause mydriasis, but not alter normal control of All of the following drugs are available as topical ophthalmic formulations. Which one will dilate the pupil without altering accommodation?

A	Atropine
B	Epinephrine
C	Homatropine
D	Isoproterenol
E	Pi locarpine
F	Timolol

Question 14 Explanation: 

Start with a fundamental review of autonomic innervation of the eye insofar as control of pupil size, and effects on the ciliary muscle (which affects accommodation—the ability of the lens of the eye to thicken so we can see close-up). The sympathetic nervous system, via α-adrenergic receptor activation, has the ability to cause mydriasis. Activate those receptors and the pupil dilates; or block the opposing parasym-pathetic influences (via muscarinic receptor blockade) and the same thing happens, since there’s a relatively comparable influence of both branches of the autonomic nervous system on pupil size. However, there is little resting influence of the sympathetic nervous system (or adrenergic receptors) on the tone of the ciliary muscle. That is mainly a parasympatheticdependent phenomenon that indirectly affects the shape of the lens of the eyes and, so, the point of sharp focus. And, for all practical purposes, β-receptor activation has no influence on pupil size or accommodation. Now, classify the drugs by their sites and mechanisms of action. Eliminate atropine (a) as a possible answer choice. By blocking all ocular effects of normal parasympathetic innervation (muscarinic blockade), it will both dilate the pupil and impair accommodation. The same applies to homatropine (c), a drug that is, for all practical purposes, atropinelike. Pilocarpine (e), a muscarinic agonist, will constrict the pupil of the eye and impair cholinergic mechanisms involved in focusing of the lens. Isoproterenol (d) activates all β-adrenergic receptors, timolol (f) blocks them all; and as I said, β-receptors are not relevant in terms of pupil size or accommodation. This leaves us with epinephrine: it has both α-adrenergic and β-adrenergic activating activity, and no cholinergic/muscarinic activity. It will dilate the pupil and not significantly affect accommodation.

Question 15

A 26-year-old woman has rhinorrhea, excessive lacrimation, and ocular congestion from a bout with the common Diphenhydramine provides symptomatic relief. What i s the most l ikely mechanism by which this drug relieved her symptoms?

A	α-adrenergic activation (agonist, vasoconstrictor)
B	β-adrenergic blockade
C	Calcium channel blockade
D	Histamine (H2) receptor blockade
E	Muscarinic receptor blockade

Question 15 Explanation: 

You may have chosen d (histamine H2 receptor blocker) as your answer to this question. However, H2 receptors are mainly involved in regulating gastric acid secretion, not typical responses to seasonal allergies. What if I had given “Histamine H1 receptor blockade” as an answer choice? Although diphenhydramine blocks H1 receptors quite well, histamine plays a relatively minor role in the symptoms of rhinovirus infections (in contrast with a much more important role in, say, seasonal allergies). As a result, blocking the effects of histamine on H1 receptors per se does not account for most of the symptom relief in the common cold. The drying up of nasal secretions afforded by diphenhydramine in this instance is due to the drug’s rather intense muscarinic receptor-blocking (atropine-like) actions. The antihistamines (first-generation drugs such as diphenhydramine or second-generation ones such as loratadine) lack any antagonist or agonist activity on α-adrenergic receptors (a) or on β-adrenergic receptors (b); and have no direct or major effect on calcium channels (d)

Question 16

You have treated dozens of patients with acute hypotension from various causes, including overdoses of antihypertensive drugs, all of which can cause Your usual approach to restoring blood pressure, and one that has worked well every time before, i s to inject x mg of phenylephrine intravenously. Today a patient with severe drug-induced hypotension presents in the Emergency Department. He has been taking this drug for many months. He i s not volume-depleted, nor hemorrhaging. You give the phenylephrine at the same dose and by the same route as you always have. It causes no change of blood pressure. Which drug did the patient most l ikely take and overdose on?

A	Atenolol
B	Bethanechol
C	Prazosin
D	Propranolol
E	Reserpine

Question 16 Explanation: 

Phenylephrine raises blood pressure by activating α- adrenergic receptors on vascular smooth-muscle cells. Prazosin competitively blocks those receptors, and when present at sufficiently high doses (as might occur with an acute, severe overdose) may eliminate the vasopressor response to even higher than usual doses of phenylephrine. β- Blockers (atenolol, propranolol) have no α-blocking activity and so won’t reduce the vasopressor response to phenylephrine. Nor will bethanechol, which causes vasodilation by activating muscarinic receptors for ACh. And reserpine? See the answer to Question 104.

Question 17

This i s a strange day for you in the ED. Now you have to treat another normovolemic patient with acute drug-induced hypotension, and give the usually correct and effective dose of This time the drug causes a vasopressor response that i s far greater than you’ve ever encountered when giving the very same dose: systolic pressure ri ses dramatically, i f not dangerously. What drug did the patient most l ikely take?  

A	Atenolol
B	Bethanechol
C	Prazosin
D	Propranolol
E	Reserpine

Question 17 Explanation: 

Reserpine treatment of sufficient duration (because its effects develop slowly) depletes neuronal norepinephrine. This accounts for the lowered blood pressure with therapeutic doses or frank hypotension with overdoses. One consequence of this, long-term, is development of adrenergic receptor supersensitivity because the receptors just aren’t being activated as they should. And a consequence of that, in turn, there will be heightened (and sometimes extreme) responses to a given dose of adrenergic agonists that can activate their receptors (α or β) directly, including the phenylephrine you administered. (That is, the dose-response curve for direct-acting adrenergic agonists is “shifted to the left” after long-term reserpine treatment.) Atenolol (a) and propranolol (d) are β-blockers. Although atenolol preferentially blocks β1 receptors, while propranolol (and most other β- blockers) affect both β1 and β2, neither drug will alter the expected vascular responses to an α-agonist such as phenylephrine. Prazosin (c) competitively antagonizes the effects of an α-agonist. Bethanechol (b) is a muscarinic agonist; if effective concentrations of the drug were in the circulation at the same time as phenylephrine was given, its effects would physiologically antagonize the pressor responses to the vasoconstrictor.

Question 18

A patient who will be new to your practice makes an appointment for their fi rst vis i t. Your nurse asks them to bring in all their current prescribed medications and any OTC drugs they take They comply. One OTC drug i s a popular brand-name product that contains doxylamine as i ts sole active ingredient. Which property or characteristic best describes this drug?

A	Likely to lower heart excessively
B	May be a cause of diarrhea that the patient says he often gets
C	Should not be used by patients with prostatic hypertrophy or angle-closure glaucoma
D	Tends to raise blood pressure through a typical catecholamine-like vasoconstrictor (α-adrenergic) mechanism
E	Used during the day, helps them keep awake and alert via a weak amphetamine-like action in the CNS

Question 18 Explanation: 

First off, I think you should know that the main active ingredient in OTC sleep aids (other than those advertised as “natural” supplements such as melatonin, vitamins, etc) is a sedating antihistamine: doxylamine or, more likely, diphenhydramine. Doxylamine is extremely similar to diphenhydramine, the prototype first-generation (older) “antihistamine”—a competitive H1 receptor antagonist. Chemically, they are in the ethanolamine class and are used not only for allergy relief, but also for sedation and sleep. If one wanted to stay awake and alert (e) these certainly would not be drugs that achieve that goal; moreover, they don’t have any amphetamine-like catecholamine-releasing activity. These drugs also block muscarinic receptors—and quite effectively to boot. So the answer to this question boils-down to “What best describes the actions or effects of atropine?” As you should know, atropine or drugs with similar antimuscarinic actions should not be used by patients with prostatism or angle-closure (narrowangle) glaucoma. Given the antimuscarinic effects, if therapeutic doses do anything to heart rate it will be an increase, not a decrease (a) since chronotropic effects of ACh on the S-A node are inhibited. ACh normally increases gut motility, facilitates micturition by stimulating the bladder’s trigone and detrusor, and relaxes sphincters in the GI and urinary tracts. Blocking those influences on the gut would tend to cause constipation, not diarrhea (b). Blood pressure will not rise because of catecholamine-like vasoconstriction; these drugs have no α-adrenergic (or any other) agonist activity. Note: Once again I wrote a question about an ostensibly “miscellaneous” drug, so why did I ask about doxylamine? I did so not to be picky, but because doxylamine (and more so diphenhydramine) are widely used; can cause problems for certain people; and are available OTC, which means your patient can take them without your advice, consent, or knowledge

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Part 1 | Part 2 | Part 3 | Part 4 

II. Preview all questions below

1.“First-generation” (older) histamine H₁ blockers such as diphenhydramine, phenothiazine antipsychotic drugs (eg, chlorpromazine), and tri – cyclic antidepressants (eg, imipramine) have pharmacologic actions, s ide effects, toxicities, and contraindications that are very s imilar to those of which other drug?

1. Atropine
2. Bethanechol
3. Isoproterenol
4. Neostigmine
5. Propranolol

2. A 6-year-old i s transported to the Emergency Department by a parent, who says the boy took a large amount of an allergy The sole active ingredient in the product the parent mentions i s diphenhydramine, and i t i s clear the child i s experiencing toxicity from an overdose. The intern, fresh out of medical school, orders parenteral administration of neostigmine, and the medication order i s not questioned. What adverse effect of the diphenhydramine will persist following neostigmine administration?

1. Bronchoconstriction and wheezing
2. Delirium, hallucinations, and other CNS manifestations of toxicity
3. Profuse secretions from lacrimal, mucus, and sweat glands
4. Skeletal muscle tremor or fasciculations
5. Tachycardia

3. In between your M1 and M2 years you are volunteering in a hospital in a very poor part of the Their drug selection i s l imited. A patient presents with acute cardiac failure, for which your preferred drug i s dobutamine, given intravenously. However, there i s  none available. Which other drug, or combination of drugs, would be a suitable alternative, giving the pharmacologic equivalent of what you want the dobutamine to do? (All these drugs are available in parenteral formulations.)

1. Dopamine (at a very high dose)
2. Ephedrine
3. Ephedrine plus propranolol
4. Norepinephrine plus phentolamine
5. Phenylephrine plus atropine

4. In general, structures that are affected by sympathetic influences respond to both sympathetic neural activation and to the hormonal component, epinephrine released from the adrenal Which structure/function i s unique in that i t responds to epinephrine, but not norepinephrine, and has no direct sympathetic neural control?

1. Airway (tracheal, bronchiolar) smooth muscle: relaxation
2. Atrioventricular node: increased automaticity and conduction velocity
3. Coronary arteries: constriction
4. Iri s of the eye: dilation (mydriasis)
5. Renal juxtaglomerular apparatus: renin release

5. Adrenergic nerves to the heart are  activated, leading to  a  reflex increase of heart rate  and cardiac contractility, in response to  a  sudden and s ignificant fall of blood pressure. Those sympathetic nerves release norepinephrine (NE). What i s the main physiologic mechanism by which the actions of the released NE are terminated?

1. Diffusion away from postsynaptic receptors
2. Hydrolysis by nonspecific deaminases
3. Metabolic inactivation by MAO
4. Metabolic inactivation by catechol-O-methyltransferase
5. Reuptake into the adrenergic nerve from which the NE was released

6. The figure below shows several responses measured in a  subject (healthy; receiving no other drugs) at rest (before) and after receiving a  dose of an unknown Note: The blood pressures shown can be considered mean blood pressure; the  fall caused by the  unknown was  mainly due to a fall of diastolic pressure.

Which drug most l ikely caused the observed responses?

1. Atropine
2. Isoproterenol
3. Neostigmine
4. Phenylephrine
5. Propranolol

7. A 59-year-old man has a history of emphysema from 40 years of cigarette smoking; hypercholesterolemia that i s being managed with atorvastatin; and Stage 2 essential hypertension for which he i s taking He presents in cl inic today with his main new complaints: nocturia, urinary frequency, and an inability to urinate forcefully and empty his bladder. Following a complete work-up, the physician arrives at a diagnosis of benign prostatic hypertrophy (BPH). We start daily therapy with tamsulosin. What i s the most l ikely s ide effect the patient may experience from the tamsulosin, and about which he should be forewarned?

1. Bradycardia
2. Increased ri sk of statin-induced skeletal muscle pathology
3. Orthostatic hypotension
4. Photophobia and other painful responses to bright l ights
5. Wheezing or other exacerbations of the emphysema

8. A patient walks out of the ophthalmologist’s office and into bright sunlight after a comprehensive eye exam, for which he received a topical ophthalmic The drug has not only dilated his pupils, but also impaired his ability to focus his eyes up-close.

The drug this patient received was most l ikely classified as, or worked most s imilar to, which prototype?

1. Acetylcholine
2. Epinephrine
3. Homatropine
4. Isoproterenol
5. Pi locarpine
6. Propranolol

9. You’ve received approval from the Institutional Review Board to study the in vi tro (ti ssue bath) responsiveness of i solated human arteriolar segments (obtained during surgery) to a variety of pharmacologic and other The ti ssue samples are 1 cm-long “cylinders” of otherwise-normal (but now denervated) arterioles obtained from the lower legs of patients undergoing amputation surgery.

The setup allows you to perfuse the vessels with a solution that will keep the ti ssue functionally and structurally intact for many hours; to monitor and change perfusion pressure (mm Hg; analogous to “blood pressure” in the intact organism) and perfusate flow (mL/min); and to assess the effects of various vasoactive drugs on the system.

You add ACh to the perfusate to give a concentration identical to the plasma concentration of ACh that causes “expected responses” in an intact human.

Under this experimental setup, adding ACh causes a ri se of perfusion pressure and a decrease of flow, both of which basically reflect vasoconstriction.

What i s the most l ikely explanation for these findings?

1. ACh released norepinephrine from the endothelium, which caused vasoconstriction
2. Atropine was added to  the  ti ssue bath before adding the ACh
3. Botulinum toxin was added to  the  bath before adding the ACh
4. The vascular endothelium has been damaged or removed (denuded)
5. This response i s precisely what we’d expect with injection of ACh into the intact human

10. A 33-year-old woman becomes poisoned after receiving an injection of i l l i ci tly prepared and overly concentrated botulinum What i s the main neurochemical mechanism by which this Clostridium toxin causes i ts effects?

1. Directly activates all muscarinic and nicotinic receptors
2. Inhibits ACh release from all cholinergic nerves
3. Prevents neuronal norepinephrine reuptake
4. Releases norepinephrine via a  nonexocytotic process
5. Selectively and competitively blocks nicotinic receptors

11. A 43-year-old woman with diagnosed myasthenia gravis, and taking pyridostigmine daily, presents in the  neurology cl inic with profound skeletal muscle You are unsure whether she i s experiencing a cholinergic cris i s or a myasthenic cris i s , so you administer a usually appropriate diagnostic dose of parenteral edrophonium. Assume the patient was actually experiencing a cholinergic cris i s . What i s the most l ikely response to the edrophonium?

1. Hypertensive cris i s from peripheral vasoconstriction
2. Myocardial i schemia, and angina, from drug-induced tachycardia and coronary vasoconstriction
3. Premature ventricular contractions from increased ventricular automaticity
4. Prompt improvement of skeletal muscle tone and function
5. Ventilatory distress or failure

12. A patient takes a massive overdose of diphenhydramine, suffering not only s ignificant CNS depression but also numerous and serious peripheral autonomic s ide By what mechanism did diphenhydramine exert i ts untoward peripheral autonomic actions?

1. Activation of both β1 and β2 adrenoceptors
2. Blockade of α-adrenergic receptors
3. Competitive antagonism of ACh  actions  on muscarinic receptors
4. Massive, direct overactivation of ganglionic nicotinic receptors
5. Sudden release of epinephrine from the adrenal medulla (suprarenal medulla)

13. A patient with a recent drug poisoning i s transported to the emergency The physician correctly orders administration of pralidoxime as part of the comprehensive emergency treatment plan. Which best describes who the patient was?

1. A 13-year-old boy who to took an overdose of methylphenidate for his ADD/ADHD.
2. A 43-year-old who took an overdose of neostigmine, prescribed for her myasthenia gravis, in a suicide attempt.
3. A 6-year-old who got into the family medicine cabinet and took 10 “adult doses” of her dad’s prazosin.
4. A farm/field worker accidentally doused with insecticide from an overflying crop-duster plane.
5. An asthma patient who accidentally gave himself an intravenous injection of epinephrine in an attempt to self-treat a developing anaphylactic reaction.

14. To facilitate a certain eye exam you want to cause mydriasis, but not alter normal control of All of the following drugs are available as topical ophthalmic formulations. Which one will dilate the pupil without altering accommodation?

1. Atropine
2. Epinephrine
3. Homatropine
4. Isoproterenol
5. Pi locarpine
6. Timolol

15. A 26-year-old woman has rhinorrhea, excessive lacrimation, and ocular congestion from a bout with the common Diphenhydramine provides symptomatic relief. What i s the most l ikely mechanism by which this drug relieved her symptoms?

1. α-adrenergic activation (agonist, vasoconstrictor)
2. β-adrenergic blockade
3. Calcium channel blockade
4. Histamine (H₂) receptor blockade
5. Muscarinic receptor blockade

16. You have treated dozens of patients with acute hypotension from various causes, including overdoses of antihypertensive drugs, all of which can cause Your usual approach to restoring blood pressure, and one that has worked well every time before, i s to inject x mg of phenylephrine intravenously. Today a patient with severe drug-induced hypotension presents in the Emergency Department. He has been taking this drug for many months. He i s not volume-depleted, nor hemorrhaging. You give the phenylephrine at the same dose and by the same route as you always have. It causes no change of blood pressure. Which drug did the patient most l ikely take and overdose on?

1. Atenolol
2. Bethanechol
3. Prazosin
4. Propranolol
5. Reserpine

17. This i s a strange day for you in the ED. Now you have to treat another normovolemic patient with acute drug-induced hypotension, and give the usually correct and effective dose of This time the drug causes a vasopressor response that i s far greater than you’ve ever encountered when giving the very same dose: systolic pressure ri ses dramatically, i f not dangerously. What drug did the patient most l ikely take?

1. Atenolol
2. Bethanechol
3. Prazosin
4. Propranolol
5. Reserpine

18. A patient who will be new to your practice makes an appointment for their fi rst vis i t. Your nurse asks them to bring in all their current prescribed medications and any OTC drugs they take They comply. One OTC drug i s a popular brand-name product that contains doxylamine as i ts sole active ingredient. Which property or characteristic best describes this drug?

1. Likely to lower heart excessively
2. May be a cause of diarrhea that the patient says he often gets
3. Should not be used by patients with prostatic hypertrophy or angle-closure glaucoma
4. Tends to raise blood pressure through a typical  catecholamine-like vasoconstrictor (α-adrenergic) mechanism
5. Used during the day, helps them keep awake and alert via a weak amphetamine-like action in the CNS