Cholinergic Agonists + Antagonists

*The answer is C.* Botulinum toxin inhibits the release of acetylcholine vesicles. Therefore, there would be cycloplegia or the paralyzation of ciliary muscle. The ciliary muscle is relaxed and the zonule fibers are tensed and the lens is also tensed.

Several children at a summer camp were hospitalized with symptoms thought to be caused by ingestion of canned food contaminated with botulinum toxin. Botulinum toxin impairs all types of cholinergic neurotransmission. Which of the following symptoms or signs is consistent with the diagnosis of botulinum poisoning? A. Diarrhea B. Skeletal muscle spasm C. Cycloplegia D. Bronchospasm E. Hyperventilation

*The answer is A.*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.

"First-generation" (older) histamine H1 blockers such as diphenhydramine, phenothiazine anti-psychotic drugs (eg, chlorpromazine), and tricyclic antidepressants (eg, imipramine) have pharmacologic actions, side effects, toxicities, and contraindications that are very similar to those of which other drug? a. Atropine b. Bethanechol c. Isoproterenol d. Neostigmine e. Propranolol

*The answer is D.* Oxime cholinesterase "reactivators" are not indicated for non-organophosphate compounds. Carbamates lack phosphate groups, which are the chemical target for interaction by oximes. The other drug options listed are all indicated in the case of this type of poisoning.

A 2 year old child is brought into the emergency department by her parents suffering from signs and symptoms including altered mental status, drooling, sweating, nausea, diarrhea, urination, vomiting, pinpoint pupils, wheezing and apparent seizure-like jerking movements. The child's mother states that they found their child in their garage an hour ago next to an open container of Sevin ® , a commercial carbamate insecticide. What treatment option would be contraindicated (and ineffective) in the treatment of this patient? A. activated charcoal lavage B. atropine C. diazepam (benzodiazepine) D. pralidoxime

*The answer is B.* Tachycardia is a characteristic atropine overdose effect. Bradycardia is sometimes observed after small doses.

A 2-year-old child has been admitted to the emergency department. Antimuscarinic drug overdose is suspected. Probable signs of atropine overdose include which one of the following? (A) Gastrointestinal smooth muscle cramping (B) Increased heart rate (C) Increased gastric secretion (D) Pupillary constriction (E) Urinary frequency

*The answer is D.* Succinylcholine is the only "depolarizing" type skeletal muscle relaxant in clinical use. It has the most favorable rapid onset of action (intubation-level paralysis is achieved in < 60 secs). This makes it the drug of choice for situations requiring rapid skeletal muscle relaxation.

A 22-year-old patient involved in a DUI related car accident is brought into the Tulane ED by ambulance. Due to the patient's severe injuries and high risk for gastric aspiration, the ED physician decides to initiate a rapid sequence intubation to maintain and protect his airway prior to surgery. An intravenous line is placed in the patients arm, and the patient is given a bolus of propofol (general anesthetic), followed immediately by a bolus of a rapidly acting depolarizing neuromuscular blocking agent. Shortly thereafter, an endotracheal tube is inserted, and mechanical ventilation is initiated. The most likely drug given to produce skeletal muscle relaxation was: A. Atropine B. Ipratropium C. Neostigmine D. Succinylcholine E. Tubocurarine

*The answer is C.* Neostigmine is the prototypical indirect-acting cholinomimetic; it is a quaternary (charged) substance with poor lipid solubility; its duration of action is about 2-4 h. Physostigmine is similar but has good lipid solubility and significant CNS effects.

A 3-year-old child is admitted after taking a drug from her parents' medicine cabinet. The signs suggest that the drug is an indirect-acting cholinomimetic with little or no CNS effect and a duration of action of about 2-4 h. Which of the following is the most likely cause of these effects? (A) Acetylcholine (B) Bethanechol (C) Neostigmine (D) Physostigmine (E) Pilocarpine

*The answer is D.* Both ganglion blockers and muscarinic blockers can cause mydriasis, increase resting heart rate, blur vision, and cause dry mouth and constipation, because these are determined largely by parasympathetic tone. Postural hypotension, on the other hand, is a sign of sympathetic blockade, which would occur with ganglion blockers but not muscarinic blockers.

A 30-year-old man has been treated with several autonomic drugs for 4 weeks. He is now admitted to the emergency department showing signs of drug toxicity. Which of the following signs would distinguish between an overdose of a ganglion blocker versus a muscarinic blocker? (A) Blurred vision (B) Dry mouth, constipation (C) Mydriasis (D) Postural hypotension (E) Tachycardia

*The answer is B.* Because neostigmine acts on the enzyme cholinesterase, which is present at all cholinergic synapses, this drug increases acetylcholine effects at nicotinic junctions as well as muscarinic ones. Bethanechol, on the other hand, is a direct-acting agent that is selective for muscarinic receptors and has no effect on nicotinic junctions such as the skeletal muscle end plate.

A 30-year-old woman undergoes abdominal surgery. In spite of minimal tissue damage, complete ileus (absence of bowel motility) follows, and she complains of severe bloating. She also finds it difficult to urinate. Mild cholinomimetic stimulation with bethanechol or neostigmine is often effective in relieving these complications of surgery. Neostigmine and bethanechol in moderate doses have significantly different effects on which one of the following? (A) Gastric secretion (B) Neuromuscular end plate (C) Salivary glands (D) Sweat glands (E) Ureteral tone

*The answer is B.* Botulinum toxin inhibits the release of ACh from all cholinergic nerves.

A 33-year-old woman becomes poisoned after receiving an injection of illicitly prepared and overly concentrated botulinum toxin. What is the main neurochemical mechanism by which this Clostridium toxin causes its effects? a. Directly activates all muscarinic and nicotinic receptors b. Inhibits ACh release from all cholinergic nerves c. Prevents neuronal norepinephrine reuptaked. d. Releases norepinephrine via a nonexocytotic process e. Selectively and competitively blocks nicotinic receptors

*The answer is C.* This woman experiences symptoms on muscarinic receptors (salivary glands, eyes, and bladder) and nicotinic receptors (skeletal muscles).

A 37-year-old woman has blurred, double vision 8 hours after eating home-preserved peppers. Six hours later, she has dysphagia, dry mouth and eyes, progressive weakness of the arms and legs, and urinary retention. She is awake and alert. Which of the following is the most likely mechanism of these adverse effects? A. Antagonism of muscarinic receptors B. Antagonism of nicotinic receptors C. Inhibition of acetylcholine release D. Inhibition of cholinesterase activity E. Inhibition of G proteins

*The answer is C.* Acetylcholinesterase reactivator pralidoxime has to be given within 30 minutes of exposure to insecticide because of the effects of ''aging'' (i.e., strengthening of the alkylphosphoryl-serine bond formed between AChE and organophosphate). Physostigmine is a cholinesterase inhibitor that is occasionally used in atropine or scopolamine poisoning. Propranolol is a β-blocker used for hypertension as well as other indications. Phenylephrine is an α-agonist used for hypotensive emergencies. Pancuronium is a nondepolarizing inhibitor of acetylcholine that is used for muscle paralysis.

A 38-year-old farmer is brought to the ER by his wife with symptoms of sudden difficulty breathing, sweatiness, and anxiety. He was spraying insecticide when this happened. It has been 25 minutes since the symptoms started. The patient is emergently intubated and given atropine and another medication that acts to reactivate acetylcholinesterase. What medication is it? (A) Physostigmine (B) Propranolol (C) Pralidoxime (D) Phenylephrine (E) Pancuronium

*The answer is C.* Isoflurophate (DFP) is an acetylcholinesterase inhibitor, which will cause an increase in acetylcholine in the synaptic terminal. This will increase the blood pressure and cause bronchodilation.

A 42-year-old woman who is a chemist is brought to the emergency department because of a 1-hour history of severe abdominal cramps, nausea and vomiting, hypotension, bradycardia, sweating, and difficulty breathing due to bronchospasm and congestion. Exposure to which of the following is most likely? (A) Acrylamide (B) Cyanogen bromide (C) Isoflurophate (DFP) (D) Phentolamine (E) Propranolol

*The answer is E.* Edrophonium is a fast-acting and short-acting parenteral acetylcholinesterase inhibitor. If the patient is dealing with a cholinergic crisis, this means that there is excess ACh accumulating at the skeletal neuromuscular junction. If edrophonium is given to someone who already has excess ACh, the problems would be more severe because more ACh would be in the synapse.

A 43-year-old woman with diagnosed myasthenia gravis, and taking pyridostigmine daily, presents in the neurology clinic with profound skeletal muscle weakness. You are unsure whether she is experiencing a cholinergic crisis or a myasthenic crisis, so you administer a usually appropriate diagnostic dose of parenteral edrophonium. Assume the patient was actually experiencing a cholinergic crisis. What is the most likely response to the edrophonium? a. Hypertensive crisis from peripheral vasoconstriction b. Myocardial ischemia, 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

*The answer is A.* Although several of the listed drugs inhibit the activity of AChE, only edrophonium is sued in the diagnosis of myasthenia gravis. The drug has more rapid onset of action and a shorter duration of action.

A 48-year-old woman has a history of myasthenia gravis. She has been treated with an oral acetylcholinesterase (AChE) inhibitor for several years, and has done well until now. Today she presents in your clinic with muscle weakness and other signs and symptoms that could reflect either a cholinergic crisis (excess dosages of her maintenance drug) or a myasthenic crisis (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

*The answer is D.* The symptoms of cholinergic excess seen in this child are indicative of exposure to insecticides such as the organophosphate parathion, which cause irreversible inhibition of acetylcholinesterase. Other symptoms may include CNS excitation and stimulation of the skeletal NMJ, ultimately leading to paralysis of respiratory muscles—"DUMBBELSS." In addition to symptomatic support, management of AChE inhibitor poisoning involves the use of atropine and 2-PAM.

A 5-year-old child becomes ill while visiting relatives who have a farm in Arkansas. His symptoms include severe abdominal cramps with vomiting and diarrhea and profuse lacrimation and salivation. Pupillary constriction is marked. The most likely cause is exposure to A. herbicides B. antifreeze C. lead-based paint D. insecticides E. rat poison

*The answer is D.* The patient is exhibiting signs of cholinergic stimulation. Because he is a farmer, insecticide poisoning is a likely diagnosis. Thus, either intravenous or intramuscular doses of atropine are indicated to antagonize the muscarinic symptoms. Physostigmine and edrophonium are cholinesterase inhibitors and would exacerbate the problem. Norepinephrine would not be effective in combating the cholinergic stimulation. Trimethaphan, being a ganglionic blocker, would also worsen the condition.

A 50-year-old male farm worker is brought to the emergency room. He was found confused in the orchard and since then has lost consciousness. His heart rate is 45, and his blood pressure is 80/40 mm Hg. He is sweating and salivating profusely. Which of the following treatments is indicated? A. Physostigmine. B. Norepinephrine. C. Trimethaphan. D. Atropine. E. Edrophonium.

*The answer is E.* Pilocarpine (Salagen ®) is a naturally occurring muscarinic indicated for this condition. It will stimulate salivary glands, increasing the production of saliva.

A 52 year-old man undergoes radiotherapy to treat a tumor in his neck. A side effect of his treatment is the development of salivary gland hypofunction, with associated dry mouth. A drug that could be used to treat this patient's condition is: A. Atropine B. Diphenhydramine C. Ipratorpium D. Nicotine E. Pilocarpine

*The answer is A.* This is a drug of choice, especially in a patient who cannot tolerate an adrenergic agonist, which would dilate the bronchioles. Scopolamine's main effect is atropinic, and it is the most effective anti-motion sickness drug. Mecamylamine is a ganglionic blocker and completely inappropriate in this situation. Oxygen would improve aeration but would not dilate the bronchial musculature. Nicotine would exacerbate his condition.

A 75-year-old man who was a smoker is diagnosed with chronic obstructive pulmonary disease and suffers from occasional bronchospasm. Which of the following would be effective in treating him? A. Ipratropium aerosol. B. Scopolamine patches. C. Mecamylamine. D. Oxygen. E. Nicotine.

*The answer is A.* Benztropine, an antimuscarinic agent, is used as an adjunct for treatment of Parkinson disease. Reserpine is a norepinephrine uptake inhibitor occasionally used for treatment of hypertension. Doxazocin, an α-blocker, is used for benign prostatic hyperplasia. Timolol is a β-blocker used for glaucoma. Tubocurarine is a neuromuscular blocker used in anesthesia.

A 78-year-old man with Parkinson disease experiences worsening of his symptoms. He is already taking levodopa. Since the disease is characterized by degeneration of dopaminergic neurons, leading to the lack of inhibition of cholinergic neurons, the addition of which medication is likely to help alleviate the patient's symptoms? (A) Benztropine (B) Reserpine (C) Doxazocin (D) Timolol (E) Tubocurarine

*The answer is B.* Nicotine initially stimulates and then blocks nicotinic skeletal muscular (N 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 a ctivation by succi nyl choline initial stimulation followed by inhibition.) Initial ganglionic stimulation leads to vasoconstriction and hypertension, both of which are manifestations of sympathetic a ctivation. Bra dycardia may or may not occur; paras ympathetic ganglionic activation is likely to increase the predominant para sympathetic (bradycardic) tone on heart rate, but sympathetic a ctiva tion may cause the opposite effect. Initial stimulation of skeletal muscle NM receptors would a ccount for the tremor. As nicotine's blood levels rise we getautonomic ganglionicblockade, leading to hypotension and bradycardia. Subsequent blockade at the skeletal neuromus cular junction leads to muscle weakness and respira tory 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. More over, propranolol itself is sometimes use to manage skeletal muscle tre mor of certain etiologies. Scopolamine (e) is a muscarinic blocker with virtually no effects on skeletal muscle (nicotinic responses).

A child overdoses on a drug that affects both the autonomic and somatic nervous systems. As blood levels of the drug rise he experiences hypertension and tachycardia, accompanied by skeletal muscle tremor. Further elevations of blood levels of the drug cause all the expected signs and symptoms of autonomic ga nglionic blockade, plus weakness and eventual paralysis of skeletal muscle. Which drug did the child most likely ingest? a. Bethanechol b. Nicotine c. Pilocarpine d. Propranolol (or another β-adrenergic blocker) e. Scopolamine

*The answer is B.* Edrophonium is a very short-acting (reversible) AChE inhibitor that has been used in the diagnosis of myasthenia gravis. The drug is useful for distinguishing between muscle weakness attributable to excessive cholinergic receptor stimulation (usually due to overdose of a AChE inhibitor) and the symptoms of myasthenia (reflecting inadequate treatment). If symptoms improve with a single dose of edrophonium, then an increase in the dose of neostigmine or pyridostigmine is indicated. If symptoms worsen, then the dose of neostigmine should be reduced.

A colleague with myasthenia gravis wants you to assist him to the ER because he is experiencing muscle weakness and has found it difficult to titrate his drug dosage because he has had the "flu." You note that he has a slight temperature, shallow respirations, and a gray-blue skin pallor. What would be the most appropriate drug to give to your colleague at this time? A. Albuterol B. Edrophonium C. Propranolol D. Physostigmine E. Scopolamine

*The answer is E.* Respiratory failure, from neuromuscular paralysis or CNS depression, is the most important cause of acute deaths in cholinesterase inhibitor toxicity.

A crop duster pilot has been accidentally exposed to a high concentration of a highly toxic agricultural organophosphate insecticide. If untreated, the cause of death from such exposure would probably be (A) Cardiac arrhythmia (B) Gastrointestinal bleeding (C) Heart failure (D) Hypotension (E) Respiratory failure

*The answer is A.* Physostigmine is a cholinesterase inhibitor with a tertiary amine structure that can cross the blood-brain barrier. It is indicated for treating severe toxicity caused by "atropine-like" antimuscarinic compounds. Physostigmine is not a completely safe or harmless compound, so its use is typically reserved for severe cases of toxicity.

A patient comes in with anti-cholinergic toxidrome. If drug therapy were really necessary to treat a patient's symptoms (vs waiting for the drug effects to wear off), which option would be the best choice? A. Physostigmine B. Neostigmine C. Pralidoxime D. Scopolamine E. Tubocurarine

*The answer is B.* Edrophonium is a short-acting inhibitor of acetylcholinesterase (AChE) that is used to diagnose myasthenia gravis. It is a quaternary compound and does not enter the central nervous system. Donepezil, isoflurophate, and neostigmine are also AChEs but with longer actions. Donepezil is used in the treatment of Alzheimer disease. Echothiophate has some activity in treating open-angle glaucoma. Neostigmine is used in the treatment of myasthenia gravis but is not used in its diagnosis. Atropine is a cholinergic antagonist and, thus, would have the opposite effects.

A patient on a diagnostic test for myasthenia gravis would be expected to have improved neuromuscular function after being treated with: A. Donepezil. B. Edrophonium. C. Atropine. D. Echothiophate. E. Neostigmine.

*The answer is C.* These are among the classic signs and symptoms of atropine poisoning, which is also more generally known as the antimuscarinic or anticholinergic syndrome. The antimuscarinic drug-poisoned patient often can be described as: "Dry as a bone, blind as a bat, red as a beet, mad as a hatter" • Mydriasis, cycloplegia • Dry mouth • Tachycardia • Hot and flush skin, increased body temperature • Agitation and delirium

A patient presents in the Emergency Department in great distress and with the following signs and symptoms: Which drug most likely caused these signs and symptoms? A. AChE inhibitor B. α-adrenergic blocker C. Antimuscarinic D. β-adrenergic blocker E. Parasympathomimetic (muscarinic agonist) F. Peripherally acting (neuronal) catecholamine depletor

*The answer is C.* Homatropine is a short-acting semisynthetic derivative of atropine (antimuscarinic), which causes mydriasis and cycloplegia.

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 drug. 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 likely classified as, or worked most similar to, which prototype? a. Acetylcholine b. Epinephrine c. Homatropine d. Isoproterenol e. Pilocarpine f. Propranolol

*The answer is B.* Echothiophate iodide is a long-acting irreversible 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. Maximum reduction of intraocular pressure occurs within 24 hours, and the effect may persists for several days. The drug is water-soluble, which affords a practical advantage over the lipid-soluble isoflurophate.

A patient with a history of narrow-angle (angle-closure) glaucoma experience a sudden rise of intraocular pressure that is sufficiently severe. In addition to pain, there is an imminent risk of permanent vision loss. They require immediate treatment, one element of which is administration of echothiophate. A. Tyrosine hydroxylase - stimulated B. Acetylcholinesterase (AChE) - inhibited C. Catechol-O-methyltransferase (COMT) - inhibited D. Monoamine oxidase (MAO) - stimulated E. DOPA decarboxylase - stimulated

*The answer is D.* 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 organo phosphates. 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 αι adrenergic blocker. Although neostigmine d) is a cholinesterase inhibitor cholinesterase-inhibitory activity. Thus, use of pralidoxime for excesses of neostigmine (or other carbamate) doses would be both ineffective (mechanistically) and unnecessary s not an organophosphate (it is a carbamate), and spontaneously and relatively quickly hydrolyzed leading to loss of cholinesterase-inhibitory activity.

A patient with a recent drug poisoning is trans ported to the emergency department. 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

*The answer is D.* Pilocarpine can abort an acute attack of glaucoma, because it causes pupillary constriction to lower intraocular pressure. It binds mainly to muscarinic receptors and can enter the brain. It is not effective in inhibiting secretions.

A patient with an acute attack of glaucoma is treated with pilocarpine. The primary reason for its effectiveness in this condition is its: A. Action to terminate acetylcholinesterase. B. Selectivity for nicotinic receptors. C. Ability to inhibit secretions, such as tears, saliva, and sweat. D. Ability to lower intraocular pressure. E. Inability to enter the brain.

*The answer is C.* Ipratropium, a quaternary antimuscarinic drug, is FDA-approved for use as an inhaled bronchodilator for COPD. Its action involves blockage/antagonism of ACh-mediated bronchoconstriction, and it is often used adjunctively with albuterol, or other β2 agonist bronchodilators. A related drug is tiotropium. Albuterol = β2 agonist Diphenhydramine = H1 antagonist Pilocarpine = muscarinic agonist Vecruonium = NM receptor antagonist

A patient with chronic obstructive pulmonary disease (COPD, eg, emphysema, chronic bronchitis) is receiving an orally inhaled muscarinic receptor-blocking drug to maintain bronchodilation. What drug belongs to that class? a. Albuterol b. Diphenhydramine c. Ipratropium (or tiotropium) d. Pilocarpine e. Vecuronium

*The answer is A.* A ganglionic blocker will prevent all CV reflexes mediated through autonomic ganglia.

A severely hypertensive man suffering from a dissecting aortic aneurysm is given trimethaphan i.v. in order to rapidly lower his blood pressure. In addition to lowering of blood pressure, what other physiological effect would this drug produce? A. blunting of all baroreceptor reflexes B. bradycardia C. increased GI motility & diarrhea D. sweating E. urination

*The answer is C.* Organophosphates exert their effect by irreversibly binding to acetylcholinesterase (AChE) and, thus, can cause a cholinergic crisis. Administration of atropine will block the muscarinic sites, but it will not reactivate the enzyme, which will remain blocked for a long period of time. Therefore, it is essential to also administer pralidoxime as soon as possible to reactivate the enzyme before aging occurs. Administering pralidoxime alone will not protect the patient against the effects of acetylcholine resulting from AChE inhibition.

A soldier's unit has come under attack with a nerve agent. The symptoms exhibited are skeletal muscle paralysis, profuse bronchial secretions, miosis, bradycardia, and convulsions. The alarm indicates exposure to an organophosphate. What is the correct treatment? A. Do nothing until you can confirm the nature of the nerve agent. B. Administer atropine, and attempt to confirm the nature of the nerve agent. C. Administer atropine and 2-PAM (pralidoxime). D. Administer pralidoxime.

*The answer is E.* It is a quaternary carbamate-type cholinesterase inhibitor, and can be used to treat MG.

A year later Brian returns for a follow-up visit. His muscle weakness has become gradually more severe, to the point that he now requires some form of chronic treatment for relief of muscle weakness. A drug that would be a good choice for maintenance therapy, and would not cross the blood-brain barrier is: A. Edrophonium B. lycopyrrolate C. Nicotine D. Physostigmine E. Pyridostigmine

*The answer is A.* Atrial fibrillation and other arrhythmias are not responsive to antimuscarinic agents.

Accepted therapeutic indications for the use of antimuscarinic drugs include all of the following except (A) Atrial fibrillation (B) Motion sickness (C) Parkinson's disease (D) Postoperative bladder spasm (E) To antidote parathion poisoning

*The answer is B.* Muscarinic agonists cause accommodation and cyclospasm, the opposite of paralysis of accommodation (cycloplegia). In open-angle glaucoma, this results in increased outflow of aqueous and decreased intraocular pressure. These agents may cause bronchospasm but have no effect on neuromuscular transmission. They may cause diarrhea and are not used in its treatment. Muscarinic agonists may also cause sweating, but drug-induced sweating is of no value in the treatment of fever.

Actions and clinical uses of muscarinic cholinoceptor agonists include which one of the following? (A) Bronchodilation (asthma) (B) Improved aqueous humor drainage (glaucoma) (C) Decreased gastrointestinal motility (diarrhea) (D) Decreased neuromuscular transmission and relaxation of skeletal muscle (during surgical anesthesia) (E) Increased sweating (fever)

*The answer is B.* Postsynaptic muscarinic receptors on the heart (M2) are Gi protein coupled to inhibition of adenylyl cyclase and decreased formation of cAMP.

Activation of postsynaptic M2 receptors on the heart is associated with A. activation of adenylyl cyclase B. decrease in cAMP formation C. increase in IP3 and DAG D. inhibition of protein kinase C E. opening of Na+/K+ cation channels

*The answer is E.* The signs and symptoms experienced by this boy are highly suggestive of the ingestion of a compound with strong muscarinic receptorblocking actions. The leaves and seeds of jimsonweed (Datura stramonium) contain anticholinergic compounds, including atropine, hyoscyamine, and scopolamine—approximately 50 seeds may cause severe toxicity. In addition to symptomatic support, management of poisoning (or drug overdose) due to M blockers may involve use of the AChE inhibitor physostigmine.

An 11-year-old boy was brought to the ER by some of his friends because he "started going crazy" after eating seeds from a plant while "trying to get high." The boy was incoherent; his skin was hot and dry. His pupils were dilated and unresponsive to light. Blood pressure was 180/105, pulse 150, and rectal temp 40°C. The presumptive diagnosis was drug toxicity due to the ingestion of a compound similar to A. cannabis B. digoxin C. mescaline D. phencyclidine E. scopolamine

*The answer is A.* The historical basis for this question is that tinctures containing "belldonna alkaoids" (including atropine) were used by the women of ancient Rome as eye drops to dilate their pupils in order to make them appear more sexually aroused. Dilated pupils can be interpreted as a sign of allure and beauty - hence the frequent use of candle light for romantic dinners. (The word belladonna translates as "beautiful woman").

An older Italian woman who is "channeling" Livia Drusilla (first empress of ancient Rome) places some home made botanical eye drops in each eye before an upcoming date. Shortly thereafter her pupils become dilated & unresponsive to light. Later that evening she also discovers that she has extreme difficulty reading the restaurant menu. Regardless, her date finds her mysteriously attractive. What active ingredient did her eye drops most likely contain? A. Atropine B. Bethanechol C. Echothiophate E. Muscarine D. Pilocarpine

*The answer is C.* Pyridostigmine, a carbamate cholinesterase inhibitor, is believed to provide protection against soman by binding reversibly to cholinesterase, and competitively preventing soman from binding irreversibly. Once the effects of pyridostigmine wear off after a few hours, the cholinesterase that was previously inhibited by the carbamate is fully functional, and hopefully soman is no longer present.

As an officer in a US Marine combat unit, you are given orders to lead your troops into an area where there is a high probability of exposure to the nerve gas Soman. To protect you and your troops, you order them to take an oral medication approximately 8 hours before departure. This medication is: A. Atropine B. Echothiophate C. Pralidoxime D. Pyridostigmine E. Scopalamine

*The answer is C.* Botulinum toxin blocks calcium-dependent exocytosis of acetylcholine from storage vesicles, producing paralysis. Common sources of botulinum toxin include canned home goods and, in cases of infant botulism, honey. The condition is life threatening, and urgent care is necessary. Choline acetyltransferase is an enzyme catalyzing synthesis of acetylcholine from an acetate and choline. Sodium-dependent transport of choline can be blocked by hemicholinium. Enzyme acetylcholinesterase is responsible for catalyzing the hydrolysis of acetylcholine. Acetylcholine synapses at the ganglia of many neurons and tissues, and this step is not blocked by botulinum toxin.

Botulinum toxin causes paralysis by (A) Inhibiting choline acetyltransferase (B) Blocking transport of choline into neurons (C) Blocking release of acetylcholine from storage vesicles (D) Inhibiting acetylcholinesterase (E) Blocking the synapse at ganglia

*The answer is B.* Edrophonium is a quaternary alcohol that is a rapidly acting acting cholinesterase inhibitor with a 5-10 minute duration of action. It binds reversibly to the anionic site of cholinesterase. Historically, edrophonium (Tensilon #&178) has been used for the differential diagnosis of myasthenia gravis (the Tensilon test).

Brian is a 40 year-old patient with a previously diagnosed thymus gland disorder who presents with muscle weakness around the eyes (ptosis), as well as generalized muscle fatigue that gets worse with physical exertion. His symptoms are less severe after periods of rest. You suspect that he may have myasthenia gravis. To make a more definitive diagnosis, you run blood tests for elevated antibodies, and administer a drug that will likely produce a rapid transient reversal of his symptoms (e.g. improvement of his ptosis) if he indeed has myasthenia gravis. The drug you administer for your test is: A. Echothiophate B. Edrophonium C. Pralidoxime D. Succinylcholine E. Tubocurarine

*The answer is A.* In patients with malignant hyperthermia, a rare hereditary disorder, an impaired sarcoplasmic reticulum is unable to sequester calcium. The sudden release of calcium results in extensive muscle contraction that can be reduced with dantrolene.

Dantrolene is the drug of choice to treat malignant hyperthermia caused by succinylcholine because dantrolene (A) Blocks Ca2+ release from sarcoplasmic reticulum (B) Induces contraction of skeletal muscle (C) Increases the rate of succinylcholine metabolism (D) Inhibits succinylcholine binding to nicotinic receptors (E) Acts centrally to reduce fever

*The answer is E.* Trimethaphan is a ganglion blocker. It causes vasodilation.

During surgery the anesthesiologist administers trimethaphan, classified as an autonomic ganglionic blocker to an anesthetized patient. What would you expect in response to this drug? a. Bradycardia mediated by activation of the baroreceptor reflex b. Increased GI tract motility, possible spontaneous defecation c. Increased salivary secretions d. Miosis e. Vasodilation

*The answer is B.* Succinylcholine is a depolarizing neuromuscular blocker that is used in rapid sequence intubation, as well as other procedures. It quickly relaxes all muscles in the body, allowing a prompt intubation to prevent the reflux of gastric contents into the trachea. Baclofen is a centrally acting skeletal muscle relaxant used for spasticity. Neostigmine is an indirect-acting cholinergic agonist used for treatment of myasthenia gravis and reversal of neuromuscular blockade. Homatropine is an antimuscarinic agent used for induction of mydriasis for ophthalmologic examinations. Pralidoxime is an acetylcholinesterase reactivator used for organophosphate poisoning.

From the list below, choose the depolarizing neuromuscular blocker most likely to be used in ''rapid sequence intubation,'' a procedure that is done when the stomach contents have a high risk of refluxing and causing aspiration. (A) Baclofen (B) Succinylcholine (C) Neostigmine (D) Homatropine (E) Pralidoxime

*The answer is C.* Ganglion blockers (hexamethonium, mecamylamine) block NN receptors at autonomic ganglia and the adrenal medulla. As such, they can block all autonomic reflexes including those elicited by changes in blood pressure. They have no effect on nicotinic receptors at the neuromuscular junction (NM) or on the direct actions of drugs on the blood vessels or heart.

Ganglion blocking agents are of little clinical value today but they are important drugs to know for solving cardiovascular drug problems because they can block A. all muscarinic receptors B. all nicotinic receptors C. all autonomic reflexes D. the direct actions of drugs on blood vessels E. the direct actions of drugs on the heart

*The answer is D.* Succinylcholine is contraindicated in patients with either atypical pseudocholinesterase, or malignant hyperthermia. Succinylcholine is metabolised by pseudocholinesterase, and patients with genetic abnormalities related to pseudocholinesterase are unable to break down succinylcholine. Use of an ordinary dose of succinylcholine would produce a more intense and long-lasting blockade, if not other serious complications. A non-depolarizing skeletal muscle relaxant (that is not metabolised by pseudocholinesterase) should be used in this situation. Malignant hyperthermia can be triggered by both succinylcholine and halogenated general anesthetics (such as halothane or isoflurane). Non-halogenated general anesthetics (e.g. propofol or etomidate) would be safer alternatives. The other drugs listed (they all have names that ends in "rium" or "nium") are non-depolarizing skeletal muscle relaxants, which are not contraindicated in these situations.

John J is a 32 year-old man about to undergo surgery to remove his inflammed appendix. John has a family history of malignant hyperthermia, as well as a genetic disorder causing resulting in very low atypical pseudocholinesterase activity. Based upon his medical history, John's surgeon uses caution when selecting both the type of general anesthetic and skeletal muscle relaxant prior to starting the procedure. What skeletal muscle relaxant should John's surgeon avoid using? A. Atracurium B. Pancuronium C. Rocuronium D. Succinylcholine E. Vecuronium

*The answer is A.* The other drugs produce distinctly different toxicity (which you should review). The photo shown is that for Atropa belladonna or "deadly nightshade". It contains a number of "belladonna alkaloids" including atropine. Mikey's symptoms can be summarized as: "Blind as a Bat, Mad as a Hatter, Red as a Beet, Dry as a Bone, Hot as Hell (and possibly...Full as a Flask).

Mikey is a 5 year-old boy brought to the Emergency Department by his parents with an initial complaint of a ~24 hour recent history of odd behavior consisting of confusion, delusions & inappropriate laughter. A physical exam reveals that Mikey has a fever, elevated heart rate, dilated pupils, blurry vision, and an unusual pink flush color on his skin. His blood pressure is relatively normal. His parents mention that Mikey has seemed unusually thirsty, and has been drinking a large amount of water & Koolaid over the past 12 hours. Upon further questioning, Mikey mentions that he recently consumed some berries growing on a shrub in a post-Katrina abondoned lot near his home. Some left over berries from his pants pocket are shown below. Based upon Mikey's symptoms, the active ingredient(s) in these berries have properties similar to: A. Atropine B. Pilocarpine C. Reserpine D. Physostigmine E. Tyramine

*The answer is C.* Atropine-like antimuscarinics are CONTRAINDICATED in patients with NARROW (closed) ANGLE GLAUCOMA. As a result, it is wise to check for the presence of elevated intraocular pressure prior to administering "dilating" eye drops. Most cases of glaucoma are "unexpected". While narrow angle glaucoma is more rare than "open angle" glaucoma, it is still a risk factor that one can easily screen for.

Most patients 50 years and older are advised to have yearly eye exams. Part of the normal procedure for such eye exams involves administering eye drops to dilate the patient's pupils. What test would a good eye doctor perform prior to administering such eye drops? A. blood pressure & body weight B. credit history C. intraocular pressure D. temperature

*The answer is C.* Cholinesterase inhibition is typically associated with increased (never decreased) bowel activity. (Fortunately, many patients become tolerant to this effect.)

Mr Green has just been diagnosed with dysautonomia (chronic idiopathic autonomic insufficiency). You are considering different therapies for his disease. Pyridostigmine and neostigmine may cause which one of the following? (A) Bronchodilation (B) Cycloplegia (C) Diarrhea (D) Irreversible inhibition of acetylcholinesterase (E) Reduced gastric acid secretion

*The answer is B.* Any of the cholinesterase inhibitors (choices B, C, or E) would effectively correct myasthenic crisis. However, because cholinergic crisis (if that is what is causing the symptoms) would be worsened by a cholinomimetic, we choose the shortest-acting cholinesterase inhibitor, edrophonium.

Ms Brown has been treated for myasthenia gravis for several years. She reports to the emergency department complaining of recent onset of weakness of her hands, diplopia, and difficulty swallowing. She may be suffering from a change in response to her myasthenia therapy, that is, a cholinergic or a myasthenic crisis. Which of the following is the best drug for distinguishing between myasthenic crisis (insufficient therapy) and cholinergic crisis (excessive therapy)? (A) Atropine (B) Edrophonium (C) Physostigmine (D) Pralidoxime (E) Pyridostigmine

*The answer is C.* Muscarine is found in several types of mushrooms that grow wild in North America, including Clitocybe dealbata (the sweating mushroom) that is shown in the photo. Muscarinic effects can account for her SLUDE-like side effects.

Ms CM, a 65 year-old retired woman reports to the Tulane Emergency Department after becoming suddenly ill following her evening meal. Her presenting features include marked perspiration, excessive tear formation, nausea, drooling, pinpoint pupils & bradycardia. When asked about her recent history, she mentions having made a salad for dinner containing store-bought lettuce, tomatoes, vinegar & oil dressing, and some wild mushrooms that she hand-picked from the overgrown section of City Park (shown below). Assuming she is suffering from food poisoning, what active ingredient would best explain her signs & symptoms? A. Atropine B. Cocaine C. Muscarine D. Scopolamine

*The answer is D.* The release of nitric oxide activates guanylate cyclase, increasing guanosine 30,50-monophosphate (cyclic GMP) and sequestering calcium. This leads to a relaxation of vascular smooth muscle.

Muscarinic cholinoceptor agonists may cause vasodilation through the release of endothelial (A) Histamine (B) Norepinephrine (C) Acetylcholine (D) Nitric oxide

*The answer is E.* As an inhibitor of AChE, neostigmine exerts effects to enhance the actions of ACh at all innervated effector sites where ACh is a neurotransmitter. These include all ANS ganglia, PANS postganglionic neuroeffector junctions, and SANS innervation of thermoregulatory sweat glands. Pilocarpine activates M receptors and has no effects at conventional dose levels on nicotinic receptors such as those in ANS ganglia and the skeletal NMJ.

Neostigmine differs from pilocarpine in having effects on A. bladder tone B. bowel motility C. heart rate D. salivary glands E. skeletal muscle

*The answer is A.* Acetylcholine accumulation due to neostigmine inhibition of cholinesterase will reverse the action of the competitive neuromuscular blocking agents.

Neostigmine would be expected to reverse which one of the following conditions? (A) Paralysis of skeletal muscle induced by a competitive, nondepolarizing muscle relaxant (B) Paralysis of skeletal muscle induced by a depolarizing muscle relaxant (C) Cardiac slowing induced by stimulation of the vagus nerve (D) Miosis induced by bright light

*The answer is A.* Activation of the ACh receptor is attributed to depolarizing agents (succinylcholine). B, C, and D are true for nondepolarizing agents. Pancuronium may cause tachycardia and hypertension; rocuronium and vecuronium have favorable cardiovascular safety profiles.

Nondepolarizing neuromuscular blockers are associated with all of the following except: A. Initial activation of ACh receptor and depolarization of the motor end plate. B. Effects are reversed by acetylcholinesterase inhibitors. C. Intermediate to long duration of action. D. Bind but do not activate ACh receptor. E. Most of these agents have minimal cardiovascular effects.

*The answer is D.* Oxybutynin acts by binding to muscarinic receptors located on the detrusor muscle of the bladder, suppressing involuntary contraction of the muscle. Acetylcholinesterase inhibitors such as edrophonium are used for myasthenia gravis. Neuromuscular blockers such as succinylcholine are used for anesthesia. α1-Antagonists such as terazosin are used for benign prostatic hypertrophy. β2-Agonists such as terbutaline can be used to suppress premature labor.

Oxybutynin works by (A) Inhibiting acetylcholinesterase at muscarinic and nicotinic receptors (B) Causing a neuromuscular blockade (C) Antagonizing α1-adrenoceptors (D) Binding to muscarinic receptors (E) Activating β2-adrenoceptors

*The answer is D.* Choice (E) is not correct because the vagus slows the heart. Parasympathetic nerve stimulation does not cause vasodilation (most vessels do not receive parasympathetic innervation), so choice (C) is incorrect. Ganglion cells and the end plate contain nicotinic receptors, which are not affected by bethanechol, a direct-acting muscarinic agonist.

Parasympathetic nerve stimulation and a slow infusion of bethanechol will each: (A) Cause ganglion cell depolarization (B) Cause skeletal muscle end plate depolarization (C) Cause vasodilation (D) Increase bladder tone (E) Increase heart rate

*The answer is E.* The "-thion" organophosphates (those containing the P=S bond) are activated, not inactivated, by conversion to "-oxon" (PÓO) derivatives. They are less stable than halogenated hydrocarbon insecticides of the DDT type; therefore, they are less persistent in the environment. Parathion is more toxic than malathion. It is very lipid-soluble and rapidly absorbed through the lungs and skin. Pralidoxime has very high affinity for the phosphorus atom and is a chemical antagonist of organophosphates.

Parathion has which one of the following characteristics? (A) It is inactivated by conversion to paraoxon (B) It is less toxic to humans than malathion (C) It is more persistent in the environment than DDT (D) It is poorly absorbed through skin and lungs (E) If treated early, its toxicity may be partly reversed by pralidoxime

*The answer is C.* The muscarinic receptors of the parasympathetic nervous system maintain essential body functions such as digestion and waste elimination. The nicotinic receptors are a receptor for acetylcholine. It plays a major role in skeletal muscles, ganglia and synthesis of catecholamines in the adrenal medulla. α and β receptors are receptors for norepinephrine and epinephrine and activation of these receptors does not produce these effects.

Patient presents with salivation, lacrimation, urination and defecation as side effects of a medication. Which one of the following receptors mediates the actions of this drug? A. Nicotinic receptors. B. α Receptors. C. Muscarinic receptors. D. β Receptors.

*The answer is B.* Pilocarpine is a muscarinic cholinoceptor agonist.

Pilocarpine reduces intraocular pressure in patients with glaucoma because it (A) Activates nicotinic cholinoceptors (B) Activates muscarinic cholinoceptors (C) Selectively inhibits peripheral activity of sympathetic ganglia (D) Inhibits acetylcholinesterase

*The answer is E.* Atropine blocks the effects of increased acetylcholine resulting from cholinesterase inhibition. Physostigmine indirectly activates cholinoceptors; bethanechol and pilocarpine directly activate cholinoceptors. Propanolol is a β-adrenoceptor antagonist.

Poisoning with an insecticide containing an acetylcholinesterase inhibitor is best managed by administration of which one of the following agents? (A) Physostigmine (B) Bethanechol (C) Propranolol (D) Pilocarpine (E) Atropine

*The answer is B.* Plasma cholinesterase is responsible for the rapid inactivation of succinylcholine.

Prolonged apnea may occur following administration of succinylcholine to a patient with a hereditary deficiency of which of the following enzymes? (A) Glucose-6-phosphate dehydrogenase (B) Plasma cholinesterase (C) Monoamine oxidase (D) Cytochrome P4503A (E) Acetylcholinesterase

*The answer is A.* Nicotinic cholinoceptors are found in adrenal medullary chromaffin cells. At the other sites, acetylcholine activates muscarinic cholinoceptors.

Receptor actions of acetylcholine are mimicked by nicotine at which one of the following sites? (A) Adrenal medullary chromaffin cells (B) Urinary bladder smooth muscle cells (C) Iris circular (constrictor) muscle (D) Heart sinoatrial pacemaker cells

*The answer is B.* Botulinum toxin impairs all types of cholinergic transmission, including transmission at ganglionic synapses and somatic motor nerve endings. Botulinum toxin prevents discharge of vesicular transmitter content from cholinergic nerve endings. All of the signs listed except cycloplegia indicate increased muscle contraction; cycloplegia (paralysis of accommodation) results in blurred near vision.

Several children at a summer camp were hospitalized with symptoms thought to be due to ingestion of food containing botulinum toxin. Which one of the following signs or symptoms is consistent with the diagnosis of botulinum poisoning? (A) Bronchospasm (B) Cycloplegia (C) Diarrhea (D) Skeletal muscle spasms (E) Hyperventilation

*The answer is D.* In the vast majority of situations in which we give a patient a nondepolarizing (curare-like) neuromuscular-blocking drug (vecuronium in this case), we will also be given an acetylcholinesterase inhibitor (neostigmine). This is to reverse the competitive skeletal neuromuscular blockage.

Shortly after surgical wounds were closed and dressed, and right before the patient was transferred to the postanesthesia care unit (PACU) she received neostigmine. What was the reason for which it was given? a. Raise and support blood pressure during recovery b. Raise or otherwise control bradycardia upon recovery from anesthesia c. Restore normal neurotransmission in the brain, since it had been suppressed by the induction and anesthetic agents d. Reverse skeletal neuromuscular blockade/paralysis e. Suppress urinary bladder function to reduce the risk of postoperative bladder incontinence

*The answer is A.* Succinylcholine is a "depolarizing" type skeletal muscle relaxant, and intially stimulates skeletal muscle. Since there is a large mass of skeletal muscle in the body, this can cause some degree of hyperkalemia. This is not well tolerated in burn patients, who are already prone to having hyperkalemia. The use of succinylcholine in such patients can trigger the development of hyperkalemic rhabdomyolysis & cardiac arrest.

Succinylcholine has some significant side effects, one of which limits its use in patients suffering from major burns. This side effect is: A. Difficulty breathing B. Ganglionic blockade C. Histamine release D. Hyperkalemia E. Hypotension

*The answer is C.* Muscarinic receptors present in bronchiolar smooth muscle are of the M3 subtype coupled via Gq proteins to phospholipase C. Activation of this enzyme causes hydrolysis of phosphatidylinositol bisphosphate, with release of IP3 and DAG (the latter activates protein kinase C). Decreased formation of cAMP mediated via a Gi protein occurs with activation of M2 receptors such as those in the heart. Cation channel opening occurs in response to activation of nicotinic receptors.

The activation of muscarinic receptors in bronchiolar smooth muscle is associated with A. activation of adenylyl cyclase B. decrease in cAMP formation mediated by G-proteins C. increase in IP3 and DAG D. inhibition of protein kinase C E. opening of Na+/K+ cation channels

*The answer is E.* Pilocarpine, taken orally, has proven to be beneficial in this situation. All the others choices except scopolamine are cholinergic agonists. However, their ability to stimulate salivation is less than that of pilocarpine, and their other effects are more troublesome.

The drug of choice for treating decreased salivation accompanying head and neck irradiation is: A. Physostigmine. B. Scopolamine. C. Carbachol. D. Acetylcholine. E. Pilocarpine.

*The answer is E.* At usual therapeutic doses, succinylcholine causes rapid, brief, and noncompetitive depolarizing blockade of NM receptors on skeletal muscle. Even if skeletal muscle paralysis is maintained longer by continuous infusion of the drug, skeletal muscle function will return spontaneously - due to rapid metabolic inactivation of the drug by cholinesterases - without the need to administer any "reversal" drug.

The patient in the case presented here was not facing anyemergent or imminently life-threatening problems, so skeletal muscle paralysis and intubation were relatively straightforward procedures, not at all rushed. Now assume, hypothetically, that emergency intubation was required, and succinylcholine (SuCh) was used because of its very rapid onset of action. Assume further that slow infusion of SuCh was used to maintain paralysis throughout the procedure; blood levels of the drug were kept well in the therapeutic range; no curare-like (nondepolarizing) blocker was used; and the patient had no genetic or other factors that would affect the drug's pharmacokinetics or action. When the surgery is done, what drug would be given to reverse succinylcholine's effects? a. Atropine b. Bethanechol c. Neostigmine d. Physostigmine e. Nothing

*The answer is B.* These patients have a genetic deficiency of the nonspecific plasma cholinesterase that is required for the termination of succinylcholine's action. The other choices would not produce apnea.

The prolonged apnea sometimes seen in patients who have undergone an operation in which succinylcholine was used as a muscle relaxant has been shown to be due to: A. Urinary atony. B. Depressed levels of plasma cholinesterase. C. A mutation in acetylcholinesterase. D. A mutation in the nicotinic receptor at the neuromuscular junction. E. Weak histamine-releasing action.

*The answer is E.* Varenicline is a lipid-soluble partial agonist at nicotinic receptors and is used to reduce craving for tobacco in smokers.

Which of the following is a direct-acting cholinomimetic that is lipid-soluble and is used to facilitate smoking cessation? (A) Acetylcholine (B) Bethanechol (C) Neostigmine (D) Physostigmine (E) Varenicline

*The answer is A.* Thermoregulatory sweat glands are innervated only by the sympathetic nervous system. The pathway is unusual in that the postganglionic neuron releases acetylcholine. Thus, the receptors on sweat glands are muscarinic (M3). The term neurohumoral means "nerve-blood." The only site in the ANS where neurohumoral transmission occurs is the adrenal medulla, where sympathetic nerve activity elicits the release of catecholamines (mostly epinephrine) into the blood. Epinephrine cannot bind to muscarinic receptors.

Thermoregulatory sweat glands in the body utilize what type of pathway? A. Cholinergic nerves and muscarinic receptors B. Adrenergic nerves and alpha-1 receptors C. Adrenergic nerves and beta-2 receptors D. Cholinergic nerves and NM receptors E. Neurohumorally-released epinephrine

*The answer is E.* Drug X causes an increase in blood pressure that is blocked by a ganglion blocker but not by a muscarinic blocker. The pressor response is actually increased by pretreatment with atropine, a muscarinic blocker, suggesting that compensatory vagal discharge might have blunted the full response. This description fits a ganglion stimulant like nicotine but not epinephrine, since epinephrine's pressor effects are produced at α receptors, not in the ganglia.

Two new synthetic drugs (X and Y) are to be studied for their cardiovascular effects. The drugs are given to three anesthetized animals while the blood pressure is recorded. The first animal has received no pretreatment (control), the second has received an effective dose of a long-acting ganglion blocker, and the third has received an effective dose of a long-acting muscarinic antagonist. Drug X caused a 50 mm Hg rise in mean blood pressure in the control animal, no blood pressure change in the ganglion-blocked animal, and a 75 mm mean blood pressure rise in the atropine-pretreated animal. Drug X is probably a drug similar to (A) Acetylcholine (B) Atropine (C) Epinephrine (D) Hexamethonium (E) Nicotine

*The answer is A.* Drug Y causes a decrease in blood pressure that is blocked by a muscarinic blocker but not by a ganglion blocker. Therefore, the depressor effect must be evoked at a site distal to the ganglia. In fact, the drop in blood pressure is actually greater in the presence of ganglion blockade, suggesting that compensatory sympathetic discharge might have blunted the full depressor action of drug Y in the control animal. The description fits a direct-acting muscarinic stimulant such as acetylcholine (given in high dosage). Indirect-acting cholinomimetics (cholinesterase inhibitors) would not produce this pattern because the vascular muscarinic receptors involved in the depressor response are not innervated and are unresponsive to indirectly acting agents.

Two new synthetic drugs (X and Y) are to be studied for their cardiovascular effects. The drugs are given to three anesthetized animals while the blood pressure is recorded. The first animal has received no pretreatment (control), the second has received an effective dose of a long-acting ganglion blocker, and the third has received an effective dose of a long-acting muscarinic antagonist. The net changes induced by drug Y in these experiments are shown in the following graph. Drug Y is probably a drug similar to (A) Acetylcholine (B) Edrophonium (C) Hexamethonium (D) Nicotine (E) Pralidoxime

*The answer is B.* Urinary retention is a well known adverse effect of drugs that have antagonist effects on muscarinic receptors. In addition to the prototypic drug atropine, M blockers include drugs used in Parkinson disease, such as benztropine. Acetylcholine directly and AChE inhibitors (edrophonium, physostigmine) indirectly activate M receptors in the GU system, causing bladder contraction with voiding and incontinence. Activation of nicotinic receptors in ANS ganglia would lead to the stimulation of PANS functions.

Urination in the human subject is decreased by A. muscarinic agonists B. muscarinic antagonists C. AChase inhibitors D. Nicotinic agonists E. Spider venom

*The answer is E.* Bethanechol is a type of muscarinic receptor agonist that is used clinically to ameliorate urinary retention. Nicotinic blockers such as trimethaphan are rarely used in clinical practice because of the lack of selectivity. α-Agonists such as epinephrine can be used in management of acute bronchospasm (anaphylaxis). β1-Blockers do not have direct effects on bronchial smooth muscle. β2-Agonists such as albuterol are used for treatment of asthma.

What class of medications does bethanechol belong to? (A) Nicotinic blockers (B) α-Agonists (C) β1-Blockers (D) β2-Blockers (E) Muscarinic agonists

*The answer is D.* Edrophonium, which will increase muscle strength in untreated myasthenic patients, is the preferred acetylcholinesterase inhibitor (Tensilon test) because it has a short duration of action.

Which of the following drugs is used to diagnose myasthenia gravis? (A) Atropine (B) Neostigmine (C) Bethanechol (D) Edrophonium (E) Pralidoxime

*The answer B.* Muscarinic M1 and M3 receptors mediate increases in IP3 and DAG in target tissues (intestine, salivary glands). M2 receptors (heart) mediate a decrease in cAMP and an increase in potassium permeability. Antimuscarinic agents block these effects.

Which of the following is an expected effect of a therapeutic dose of an antimuscarinic drug? (A) Decreased cAMP (cyclic adenosine monophosphate) in cardiac muscle (B) Decreased DAG (diacylglycerol) in salivary gland tissue (C) Increased IP3 (inositol trisphosphate) in intestinal smooth muscle (D) Increased potassium efflux from smooth muscle (E) Increased sodium influx into the skeletal muscle end plate

*The answer is D.* Cholinomimetics cause smooth muscle contraction mainly through the release of intracellular calcium. This release is triggered by an increase in IP3 acting on receptors in the endoplasmic reticulum.

Which of the following is the primary second-messenger process in the contraction of the ciliary muscle when focusing on near objects? (A) cAMP (cyclic adenosine monophosphate) (B) DAG (diacylglycerol) (C) Depolarizing influx of sodium ions via a channel (D) IP3 (inositol 1,4,5-trisphosphate) (E) NO (nitric oxide)

*The answer is B.* The mydriatic effect of atropine can result in the narrowing of the canal of Schlemm leading to an increase in intraocular pressure. Physostigmine, pilocarpine, and echothiophate would cause miosis. Tropicamide produces mydriasis without increasing intraocular pressure because of its shorter duration of action.

Which of the following may precipitate an attack of open angle glaucoma if instilled into the eye? A. Physostigmine. B. Atropine. C. Pilocarpine. D. Echothiophate. E. Tropicamide.

*The answer is E.* Pralidoxime (PAM) is an actylcholinesterase reactivator.

Which of the following statements regarding pralidoxime (PAM) is TRUE? A. Pralidoxime is most effective in reactivating muscarinic acetylcholine receptors. B. Pralidoxime is most effective in reactivating nicotinic acetylcholine receptors. C. Pralidoxime exerts highly significant CNS effects. D. The endpoint for monitoring pralidoxime treatment is when patient's blood pressure returns to normal range. E. Pralidoxime reactivates acetylcholinesterase at a greatly accelerated rate.

*The answer is C.* Atropine has extensive duration of action in the eyes, which lasts about 12 days.

Which of the followings is the primary reason that atropine eye drops are NOT used in eye examinations ? A. Atropine causes miosis. B. Atropine causes excessive tearing. C. Atropine has extensive duration of action in the eyes. D. Atropine is extensively metabolized in the eyes. E. Atropine causes spasm of accommodation for near vision.

*The answer is B.* Bethanechol causes vasodilation by activating muscarinic receptors on the endothelium of blood vessels. This effect can be blocked by atropine.

Which one of the following drugs causes vasodilation that can be blocked by atropine? (A) Benztropine (B) Bethanechol (C) Botulinum (D) Cyclopentolate (E) Edrophonium (F) Neostigmine (G) Pralidoxime

*The answer is G.* Pralidoxime has a very high affinity for the phosphorus atom in organophosphate insecticides.

Which one of the following drugs has a very high affinity for the phosphorus atom in parathion and is often used to treat life-threatening insecticide toxicity? (A) Atropine (B) Benztropine (C) Bethanechol (D) Botulinum (E) Cyclopentolate (F) Neostigmine (G) Pralidoxime

*The answer is C.* Pilocarpine is present in several mushroom species including Amanita muscaria, the ingestion of which is associated with the stimulation of M receptors (parasympathomimetic effects). Activation of muscarinic receptors in the GI tract causes diarrhea. The activation by pilocarpine of M receptors present on vascular endothelial cells would lead to hypotension (not hypertension) via the release of NO. All of the other effects listed are typical of muscarinic antagonists.

Which one of the following effects is caused by the ingestion of mushrooms that contain pilocarpine? A. Tachycardia B. Bronchodilation C. Diarrhea D. Hypertension E. Hyperthermia

*The answer is A.* When an oxime is given before an organophosphate's "chemical aging" with cholinesterase (AChE) has developed, pralidoxime can reverse the binding of the organophophate (e.g. sarin) to AChE. Atropine can reverse the effect of excessive muscarinic stimulation. This drug combination is the most commonly recommended treatment for poisoning by organophosphate type cholinesterase inhibitors.

While on a medical mission in Syria, you are exposed to the nerve gas Sarin. Effective treatment typically involves the i.m. administration of: A. atropine + pralidoxime B. atropine + trimethaphan C. pilocarpine + pralidoxime D. tubocurarine + trimethaphan E. varenicline + tubocurarine

*The answer is D.* In "cholinesterase poisoning," we are dealing with overstimulation (from accumulated ACh) of both peripheral muscarinic and nicotinic receptors. Recall that atropine is a specific muscarinic blocker 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.

You give an "effective dose" of atropine to a person who was poisoned with an AChE inhibitor. What structure will continue to be overactivated by the excess ACh after the atropine is given? a. Airway smooth muscle b. S-A node of the heart c. Salivary and lacrimal glands d. Skeletal muscle e. Vascular smooth muscle

*The answer is A.* 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).

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 is very susceptible to motion sickness. What comorbidity would weigh against prescribing the drug because it is most likely 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)

*The answer is C.* Ipatropium is the active ingredient in Atrovent ®, a quaternary antimuscarinic agent indicated for reducing asthmatic brochoconstriction.

Your 23 year-old patient recently diagnosed with asthma cannot tolerate the CNS side effects of his inhaled albuterol (a beta-2 agonist bronchodilator). As an alternative, you recommend he try an inhaled quaternary antimuscarinic, and prescribe: A. Atropine B. Bethanechol C. Ipratropium D. Pyridostigmine E. arenicline

*The answer is B.* This is an FDA approved indication for bethanechol. It can increase the tone of the detrusor muscle sufficiently to initiate urination (micturation) and help empty the bladder.

Your 43 year-old patient is recovering from abdominal surgery and develops post-operative urinary retention. A drug that you could give orally to treat this condition is: A. Atropine B. Bethanechol C. Clonidine D. Scopolamine

*The answer is B.* Neostigmine is a quaternary drug that will not cross the BBB, and hence will not have unwanted CNS side effects (in contrast to physostigmine). It has been used (albeit "off label") for this type of non-obstructive bowel disorder, in a hospital setting.

Your 54 year-old patient undergoes intra-abdominal surgery for an appendicitis. During his post-operative recovery he develops constipation and abdominal discomfort due to a paralytic ileus (paralysis of the bowel) that can result from surgical manipulation of the intestines. From the list of options below, which would best treat his condition? A. Ipratropium B. Neostigmine C. Physostigmine D. Scopolamine E. Tubocurarine