Cholinergic Drugs

(Practice questions)
1) Which of the following statements regarding muscarinic agonists are correct? (Check all that apply) A) The maximal efficacy of muscarinic agonists is always 100% B) Activation of Nm receptors by these drugs in the eye leads to miosis C) Activation of M3 receptors by these drugs in the vessels leads to vasodilation D) All muscarinic agonists are rapidly hydrolyzed by cholinesterases E ) Penetration into brain by choline esters is negligible F) Myasthenia gravis is a recognized therapeutic indication of muscarinic agonists 2) Which of the following statements correctly pairs the acetylcholine effect with the postreceptor mechanism that mediates the effect? A) Decreased rhythmicity of SA node -< opening of ligand-gated Na+ channels B) Increased intestinal peristalsis -< release of NO C) Decreased force of myocardial contraction -<increased cAMP D) Bronchoconstriction -< increased IP3 and DAG E) Miosis -< decrease in IP3 and DAG 3)Which of the following are pharmacological effects of muscarinic agonists? (Check all that apply) A) Increased ventricular contractility B) Decreased A-V conduction C) Bronchodilation D) Decreased release of acetylcholine from cholinergic terminals E) Contraction of smooth muscle fibers in the erectile tissue of corpora cavernosa F) Peripheral vasodilation G) Increased release of acetylcholine from adrenal medulla 4) Which of the following is the most likely effect of muscarinic agonists upon the urinary system? A) Increased diuresis B) Increased tone of trigone of the bladder C) Increased tone of internal sphincter of the bladder D) Increased tone of the detrusor muscle E) Decreased peristalsis of ureters 5) Which of the following is the most likely effect of muscarinic agonists upon the gastrointestinal system?

A) Decreased pepsinogen secretion B) Increased tone of pylorus sphincter C) Relaxation of the external anal sphincter D) Contraction of the lower esophageal sphincter E) Decreased intestinal peristalsis 6) Muscarinic agonists are contraindicated, or should be used with caution, in which of the following disorders? (Check all that apply) A) Essential hypertension B) Gastrointestinal obstruction C) Raynauds disease D) Peripheral arteriosclerotic disease E) Biliary tract disease F) Hyperthyroidism 7) Which of the following statements regarding cholinesterase inhibitors is correct? (Check all that apply) A) Inhibition of cholinesterase by organophosphates may last up to 8 hours B) Xerostomia and constipation are common adverse effects of these drugs C) Sweating is a common adverse effects of these drugs D) These drugs are contraindicated in case of postoperative non obstructive ileus E) Reversible inhibitors are sometimes used in the therapy of glaucoma F) Central effects of organophosphates can be easily reversed by pralidoxime 8) Which of the following is the most common immediate cause of death from poisoning by irreversible cholinesterase inhibitors? A) Circulatory failure B) Convulsions C) Cardiac arrhythmias D) Respiratory paralysis E) Dehydration due to diarrhea and vomiting 9) Physostigmine can most effectively counteract which of the following drug-induced effects? A) Atropine-induced hallucinations B) Epinephrine-induced increase in blood pressure C) Prazosin-induced decrease in blood pressure D) Neostigmine-induced fasciculations E) Nicotine-induced tachycardia

10) The following table shows the effects of some autonomic drugs on the eye when they are administered locally in the conjunctival sac. Examine the table and identify which one of the drugs A, B, C, D, E, is most likely to be physostigmine. (+ = increased ; - = decreased ; 0 = negligible effect) Drug Pupillary diameter --- Lens curvature ---Ocular pressure A+0B-+C00D+-E+-+ 11) A 35-year-old farmer was brought to the emergency room complaining of severe abdominal cramps, vomiting and excess salivation. His skin was flushed, warm, and moist to the touch. He stated that he was working in his field with an organophosphate pesticide. Which of the following echanism best explains the cause of the flushed skin in this patient? A) Increased firing of efferent vagal fibers B) Activation of Nn receptors on autonomic ganglia C) Activation of M2 autoreceptors D) Inhibition of norepinephrine release from adrenergic terminals E) NO-induced increase in cGMP 12) A 67-year-old woman, recently diagnosed with open angle glaucoma, started a treatment with pilocarpine eye drops. Which of the following effects did most likely occur in this patient? A) Relaxation of ciliary muscle B) Decreased lens curvature C) Stretching of zonula fibers D) Impairment of far vision E) Contraction of radial muscle of iris 13) A 42-year-old man was brought to the emergency department because of severe vomiting and diarrhea which initiated about one hour after meal. The patient showed profuse salivation, lacrimation and wheezing. His skin was warm and moist, and pupils were miotic. Skeletal muscle movements were normal. Blood pressure was 80/50 mm Hg, pulse 46/min. Poisoning of this patient was most likely due to which of the following agents? A) Muscarine-containing mushrooms B) Nicotine-containing insecticide C) Organophosphate containing insecticide D) Atropine-containing mushrooms E) Carbamate-containing insecticide

14) A 63-year-old woman underwent total abdominal hysterectomy to remove an endometrial carcinoma. General anesthesia was induced with thiopental sodium, maintained with halothane and nitrous oxide, and supplemented with tubocurarine. Which of the following drugs did the patient most likely receive after the operation, in order to reverse the skeletal muscle paralysis? A) Physostigmine B) Edrophonium C) Neostigmine D) Bethanechol E) Pralidoxime 15) A 55-year-old man, recently diagnosed with myasthenia gravis, was treated with a cholinesterase inhibitor and with a second drug which should antagonize some of the adverse effects of the first one. Which of the following pairs of drugs were most likely given? A) Physostigmine and atropine B) Neostigmine and atropine C) Neostigmine and pralidoxime D) Donepezil and atropine E) Physostigmine and pralidoxime 16) A 45-year-old man was admitted to the emergency room because of extreme muscle weakness, ptosis, diplopia, difficulty in swallowing, speaking and breathing. The man, recently diagnosed with severe myasthenia gravis has been receiving neostigmine for the past three months. Which of the following responses to 2 mg edrophonium IV would indicate a cholinergic crisis? A) Increased muscle strength, no fasciculations B) Decreased muscle strength, fasciculations C) No change in muscle strength, no fasciculations D) Decreased muscle strength, no fasciculations E) Increased muscle strength, fasciculations 17) A 52-year-old diabetic woman presented to the emergency room with severe ocular pain and redness, decreased vision, colored halos, and nausea and vomiting. Ophthalmoscopy revealed anterior chamber inflammation and tonometry measured an intraocular pressure of 48 mm Hg in the right eye (normal 10-20). A diagnosis of acute glaucoma attack was made and two drugs were instilled into the conjunctival sac. Another drug was given by the same route 15 minutes later. Which of the following three drugs were most likely administered?

A) Timolol, apraclonidine and pilocarpine B) Homatropine, carbachol and timolol C) Scopolamine, dorzolamide and phenylephrine D) Homatropine, carbachol and dorzolamide E) Prazosin, physostigmine and mannitol 18) A 81-year-old woman underwent ocular surgery for cataract extraction. Upon completion of the surgery she received a drug that is able to lower the intraocular pressure by activating both Nn and M3 receptors. Which of the following drugs was most likely administered? A) Pilocarpine B) Timolol C) Bethanechol D) Carbachol E) Apraclonidine 19) A 54-year-old woman presented to the hospital because of a gradual onset of a scratchy sensation on both eyes and an extreme dryness of the mouth and lips. Lab exams showed elevated levels of antibodies against gamma-globulin. A diagnosis of Sjgrens syndrome was made and a drug was prescribed to relieve patients xerostomia. Which of the following drugs was most likely administered? A) Acetylcholine B) Phenylephrine C) Prazosin D) Donepezil E) Pilocarpine 20) A 63-year-old man underwent a surgical operation to remove a colonic carcinoma. Tree days after surgery he developed fever (103 F), abdominal distension and vomiting. Palpation showed tenderness over the entire abdomen, and auscultation revealed no bowel sound. Which of the following therapeutic measures is absolutely contraindicated in this case? A) Parenteral administration of an antipyretic B) Nasogastric intubation and suction C) Parenteral antibiotic therapy D) SC administration of neostigmine E) IV administration of fluid and electrolytes

Cholinergic Drugs
(Answers and explanations)
1) Answer: A C E By definition maximal efficacy of an agonist is the maximal effect an agonist can produce if the dose is taken at very high levels. An agonist (sometimes called full agonist) is a drug able to fully activate the effector system, when it binds to the receptor. A partial agonist is not able to fully activate the effector system even when it binds to all receptors of that system. Therefore the maximal efficacy of an agonist is b, by definition, 100% whereas the maximal efficacy of a partial agonist is less than 100%. All muscarinic agonist are full agonist drugs. Non innervated M3 receptors are located in the vascular endothelial cells. Their activation causes a release of nitric oxide, which in turn relaxes the vascular smooth muscle Choline esters are quaternary ammonium compounds. These compounds are not able to cross the blood brain barrier, because of their high water solubility. B) Nm receptors are located in the striatal muscle only. D) Muscarinic agonist like carbachol and bethanechol are resistant to hydrolysis by cholinesterase. F) Myasthenia gravis is a disease caused by an autoimmune-mediated loss of Nm receptors. Muscarinic agonist act on muscarinic receptors and therefore are of no value in this disease. 2) Answer: D Bronchoconstriction is due to activation of M3 receptors. M3 receptors are mainly excitatory and their activation increases the synthesis of IP3 and DAG. IP3 diffuses into cytoplasm ad releases stored Ca++ which triggers smooth muscle contraction. A) Decreased rhythmicity of SA node is due to the activation of M2 receptors. The postreceptor mechanism triggered by this activation is the opening of ligand-gated K+, not Na+, channels. B) Increased intestinal peristalsis is due to activation of M3 receptors. M3 receptor activation in endothelial cells, not in intestinal smooth muscle cells, releases NO. C) All cholinergic actions in the heart are mediated by the activation of M2 receptors. The postreceptor mechanism triggered by this activation is the opening of ligandgated K+channels.

E) Miosis is due to contraction of the sphincter muscle of iris. The receptors involved are M3 and the postreceptor mechanism is an increase, not a decrease ,of IP3 and DAG. 3) Answer: B D F Activation of M2 receptors in the heart leads to a decrease in AV conduction. Activation of presynaptic M2 receptor on cholinergic terminals leads to a decrease of acetylcholine release. Activation of non innervated M3 receptors in the vascular endothelium lead to the release of nitric oxide which in turn causes vasodilation. A, C) Muscarinic agonists actually cause a slight decrease, not increase, of ventricular contractility and elicit bronchoconstriction, not bronchodilation. E) Smooth muscle fibers in the erectile tissue of corpora cavernosa are relaxed, not contracted, by M3 receptor activation that releases nitric oxide in those structure. This action allows a rapid arterial blood into corpora cavernosa of the penis, so causing erection. 4) Answer: D
M. Babbini, MD, PhD Cholinergic Drugs

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By activating M3 receptors muscarinic agonists increase the tone and contractility of the detrusor muscle of the bladder. A) Diuresis refers to the urine formation by the kidney. Muscarinic agonists are not diuretic agents. B, C)The trigone and the external sphincter of the bladder are relaxed (not contracted) by parasympathetic activation, and the receptors involved are not cholinergic. With drugs that are pure muscarinic agonists, this relaxation is indirect (local reflexes are stimulated by the increased detrusor tone). E) Ureters peristalsis is increased, not decreased, by activation of M3 receptors. 5) Answer: D Activation of M3 receptors by muscarinic agonists contracts the lower esophageal sphincter. This sphincter normally remains tonically constricted, so preventing the reflux of stomach content into the esophagus, but can be relaxed by several causes including antimuscarinic drugs

A) Activation of M3 receptors in the peptic cells of the stomach actually increases pepsinogen secretion. B) The tone of all sphincters (except the lower esophageal sphincter) of gastrointestinal tract is decreased, not increased by parasympathetic activation. C) The external anal sphincter is composed of a striated voluntary muscle and therefore not sensitive to parasympathetic activation. E) Activation of M3 receptors by muscarinic agonists actually increases intestinal peristalsis. 6) Answer: B E F Muscarinic drugs are contraindicated when the strength or integrity of the gastrointestinal wall is questionable. Increased muscular activity of the gastrointestinal tract or biliary tract may prove harmful, worsening the underlying condition and risking perforation. Muscarinic drugs are contraindicated in hyperthyroidism since they can precipitate atrial flutter or fibrillation (it is worth to remember that cholinergic impulses decrease intraatrial refractoriness). A, C, D) Muscarinic drugs dilate the arterial vessels and therefore are not contraindicated in diseases that are caused by constriction of those vessels. 7) Answer: C E increase the availability of acetylcholine in the synaptic cleft of cholinergic terminals an therefore have both muscarinic and nicotinic effects. Muscarinic effects include stimulation of secretion of sweat glands Cholinesterase inhibitors (i.e. physostigmine) may be used in the therapy of glaucoma when other drugs (beta-blockers, alpha-2 agonist etc.) have not given satisfactory results. A) Organophosphates are irreversible inhibitors of cholinesterase. The inhibition of the enzyme is permanent, in most cases. B) These drug actually cause salivation and diarrhea. D) These drugs are not contraindicated (in fact they are sometimes used) in case of non obstructive ileus. F) Pralidoxime is a cholinesterase regenerator that does not cross the blood brain barrier. Therefore it can only counteract the peripheral effects of organophosphates.
M. Babbini, MD, PhD Cholinergic Drugs

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8) Answer: D Death due to poisoning by irreversible cholinesterase inhibitors is primarily caused by respiratory paralysis. Actions that contribute to this effect are laryngospasm, bronchoconstriction, increased tracheobronchial secretions, paralysis of intercostal muscles and diaphragm, and central respiratory depression. A, B, C, E) All these symptoms can occur in the acute intoxication by these drugs, but they are rarely the primary cause of death. 9) Answer: A Physostigmine increases the availability of acetylcholine in the synaptic cleft of cholinergic terminal. Atropine and acetylcholine compete each other for the occupancy of muscarinic receptors and physostigmine can also counteract the central symptoms of atropine overdose, since it can enter the brain. B) Physostigmine can decrease the blood pressure (even if this effect is not pronounced) by inducing vasodilation and decrease of cardiac output, whereas epinephrine increases the blood pressure by opposite effect. The two drugs can antagonize each other but they act on different receptors and therefore the antagonism is functional (also called physiological) , not pharmacological. A pharmacological antagonism is more effective than a physiological antagonism in most cases. C, D, E) all these effect are actually enhanced, not antagonized, by physostigmine. 10) Answer: B Physostigmine is a reversible cholinesterase inhibitor which increases the amount ov acetylcholine in the synaptic cleft. Acetylcholine-induced activation of M3 receptors causes contraction of the sphincter muscle of iris ( so decreasing pupillary diameter) and contraction of the ciliary muscle (so increasing lens curvature and). Ocular pressure is decreased because the contraction of the ciliary muscle opens the pores of the trabecular meshwork, so facilitating the outflow of the aqueous humor into the Schlemms canal A) These effects would be caused by an alpha-2 agonist ,like apraclonidine.

C) These effects would be caused by a beta-blocker like timolol. D) These effects would be caused by epinephrine E) These effects would be caused by an antimuscarinic drug , like scopolamine. 11) Answer: E The signs and symptoms of the patients are consistent with the diagnosis of organophosphate poisoning and are all due to an excessive amount of acetylcholine at the synaptic cleft of cholinergic terminals. The arteriolar vasodilation that causes the flushed skin is mainly due to the acetylcholine induced activation of non innervated M3 receptors which in turn trigger the release of NO. NO acts by increasing the synthesis of cGMP which is a powerful smooth muscle relaxant. A) By activating Nn receptors on autonomic ganglia acetylcholine can increase the firing of efferent vagal fibers, but this cannot explain the flushed skin (in fact this activation increases the firing of sympathetic fibers too). B) (see explanation above) C) Activation of presynaptic M2 receptors actually causes a decrease of acetylcholine release
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from cholinergic terminals. D) Acetylcholine can inhibit the release of norepinephrine from adrenergic terminals (by activating M2 receptors) but this is not the main action that causes the flushed skin. 12) Answer: D By activating M3 receptors pilocarpine triggers the contraction of ciliary muscle, which in turn increases lens curvature. The lens is therefore accommodated for near vision and far vision is impaired. A, B) (see explanation above) C) The contraction of ciliary muscle actually relaxes zonula fibers. E) The radial muscle of iris receives only sympathetic innervation. Parasympathetic activation cannot change the contractility of this muscle. 13) Answer: A The signs and symptoms of the patients are consistent with the diagnosis of muscarine poisoning. High concentrations of muscarine are present in various species of Inocybe and

Clitocybe mushrooms and poisoning is not exceptional because of the habit to consume wild mushrooms. The symptoms of muscarine intoxication start within one hour after the ingestion and are all attributable to activation of muscarinic receptors. B) Nicotine poisoning results from the activation, and later the blockade, of Nn and Nm receptors. Activation of Nn receptors in ganglia and adrenal medulla causes increase in sympathetic firing and increased release of norepinephrine. Early signs include cold sweat, rapid and irregular pulse and hypertension, followed by hypotension and collapse. Moreover the activation of Nm receptors at the motor end plate would cause muscle paralysis due to depolarization blockade. C) Poisoning by organophosphates causes all symptoms due to activation of muscarinic receptors, but in addition there are also symptoms due to activation of nicotinic receptors (ie. skeletal muscle paralysis due to depolarization blockade). D) Some mushroom species contain atropine. The symptoms of atropine poisoning are due to blockade of muscarinic receptors, so are the opposite of those exhibited by the patient. E) Carbamate insecticides are reversible cholinesterase inhibitors. Symptoms of poisoning by these agents are the same as the symptoms of poisoning by organophosphates. 14) Answer: C Reversible cholinesterase inhibitors are currently used to reverse the paralysis induced by nondepolarizing neuromuscular blocking drugs, like tubocurarine. This drug block Nm receptors at the motor end plate while acetylcholine activates these receptors. The two drugs competitively antagonize each other and an increase availability of acetylcholine at the motor end plate can therefore reverse the muscle paralysis induced by tubocurarine. Neostigmine is the preferred drug since it does not enter the brain and it is therefore free of central adverse effects. A) Pysostigmine is not indicated since it can cross the blood brain barrier. B) Edrophonium is not indicated since it has a very short duration of action (its half-life is 1-10 min)

C, E) These drugs do not act at Nm receptors.

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15) Answer: B Neostigmine is a drug of choice for myasthenia gravis. The drug increases the availability of acetylcholine at the motor end plate and it can also activate directly Nm receptors. Both actions contributes to the therapeutic effect of improvement of skeletal muscle strength. Neostigmine increases the availability of acetylcholine at all cholinergic synapses and can therefore elicits muscarinic effects, mainly in the gastrointestinal tract. In order to block these unwanted effects atropine is often given concurrently. A, D) These cholinesterase inhibitors are not used in myasthenic patients since they enter the brain and can cause central adverse effects. C, E) Pralidoxime is a cholinesterase regenerator used only in case of poisoning by organophosphates. 16) Answer: B Myasthenic patients under treatment with cholinesterase inhibitors may exhibit decrease muscle strength, because of an excessive concentration of acetylcholine that causes depolarization blockade of the motor end plate. This is called cholinergic crisis. On the other hand, these patients may also exhibit decrease muscle strength because of a sudden exacerbation of the disease. This is called myasthenic crisis. Edrophonium can be used to distinguish between the two syndromes. In fact ,in case of cholinergic crisis edrophonium administration will produce no relief or worsen the syndrome. (a decrease in muscle strength) whereas in case of myasthenic crisis the drug will improve the syndrome (an increase in muscle strength). Moreover an edrophonium-induced decrease of muscle strength is accompanied by fasciculations (brief muscle contractions before the paralysis) since acetylcholine activates nicotinic receptors, whereas an increase in muscle strength is not accompanied by fasciculations. A, C, D , E) (see explanation above) 17) Answer : A

An acute glaucoma attack is usually the first symptom of an acute angle-closure glaucoma, a disease associated with a closed anterior chambre angle. When this occurs intraocular pressure raises because the normal drainage of aqueous humor from the eye is prevented by the obstruction of peripheral iris. An acute glaucoma attack is a medical emergency, because vision can be lost quickly. The production of the aqueous humor must be decreased and therefore a topical beta-blocker and an alpha-2 agonist are immediately administered. Then pilocarpine is given to increase aqueous humor outflow ( cholinergic drugs alone are generally ineffective when the intraocular pressure is > 40 mm Hg). B, C, D) Scopolamine and homatropine are contraindicated in angle-closure glaucoma since they induce mydriasis which increase the risk of closing the anterior chamber. E) Prazosin is ineffective in glaucoma. Mannitol is not given topically, but IV, and is used to lower the intraocular pressure only if the response to the first treatment is inadequate. 18) Answer: D Carbachol is currently used to lower intraocular pressure after cataract extraction. This is accomplished by contracting the ciliary muscle, which in turn opens the pores of the trabecular meshwork, so facilitating the outflow of the aqueous humor into the Schlemms canal. Ciliary muscle receives mainly a parasympathetic innervation and the receptors on the muscle membrane are M3. By activating those receptors as well as the Nn receptors on
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parasympathetic ganglia carbachol can enhance significantly the parasympathetic activity. A, ) C) Pilocarpine an bethanechol can lower intraocular pressure by activating M3 receptors but are devoid of significant activity on Nn receptors. B, E) Timolol and apraclonidine can reduce aqueous humor production but have negligible effect on aqueous humor outflow. 19) Answer: E Sjgrens syndrome is a diffuse connective tissue disease in which lymphocytes infiltrate

mucosal and other tissues. Lymphocytic infiltration in salivary glands causes gland atrophy. Saliva diminishes, resulting in extreme dryness of the mouth and lips. If glands are not severely atrophied, pilocarpine can be used to stimulate salivary production. A) Acetylcholine is not used for systemic therapy, because of its very short duration of action. B, C, D) These drugs have little effects on salivary production. 20) Answer: D. The signs and symptoms of the patient strongly suggest the diagnosis of adynamic ileus, due to intraperitoneal infection (see the high grade fever). Ileus means paralysis of the gut. When this paralysis is due only to a lack of autonomic neurotransmission (as in most cases of postoperative ileus), a drug that increases the levels of acetylcholine can help to restore the motor activity of the gut. On the other hand, when the paralysis is due to obstruction or inflammation of the gut, cholinergic drugs are absolutely contraindicated since to increase the gut motility in these conditions can exacerbate the inflammation and lead to the perforation of the intestine. A, B, C, E) All these therapeutic measures are indicated in case of ileus due to intraperitoneal infection. Cholinergic Drugs (answer key) 1) ACE 2) D 3) BDF 4) D 5) D 6) BEF 7) CE 8) D 9) A 10) B 11) E 12) D 13) A 14) C 15) B 16) B 17) A

18) D 19) E 20) D