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Phar 752 Exam #1, 13 October 2005 Page 1 Name (Last, First) ___________________ Student ID #___________________ This test consists of 45 questions worth a total of 150 points (Questions #1-36 are 3 pts each; #37-45 are variable). There are a total of 16 pages. Check that your test is complete. Record your answers for questions #1-36 on a scantron sheet and turn in BOTH the printed exam and the scantron sheet. Use the following choices for answering questions 1 through 5. You may use any answer more than once: A. B. C. D. E. M1 M2 NN NM None of the above 1. ____ Activation of which cholinergic receptor subtype will increase blood pressure in a whole animal or person? (3 pts) 2. ____ Activation of which cholinergic receptor subtype mediates skeletal muscle contraction? (3 pts) 3. ____ Activation of which cholinergic subtype mediates smooth muscle contraction? (3 pts) 4. ____ 5. ____ Activation of which cholinergic receptor subtype mediates activation of protein kinase A (PKA) in smooth muscle? (3 pts) 6. ____ The sympathetic and parasympathetic nervous systems function in an oppositional manner in all of the following EXCEPT (3 pts) Activation of which cholinergic receptor subtype mediates the cardiac response of the baroreflex to increased blood pressure? (3 pts) A. B. C. D. E. control of heart rate control of bronchiol smooth muscle tone control of vascular smooth muscle tone control of peptic acid secretion control of urinary output Phar 752 Exam #1, 13 October 2005 Page 2 7. ____ One problematic side effect of trospium can be (3 pts) A. B. C. D. E. 8. ____ dizziness and motion sickness hallucinations postural hypotension incontinence dry mouth The primary benefit of the use of echothiophate or isofluorophate compared to other therapeutic agents in its drug class is (3 pts) A. B. C. D. E. 9. Name (Last, First) ___________________ Student ID #___________________ duration of action absorption from the GI decreased nicotinic effects decreased effects on secretions efficacy to induce mydriasis ____ Activation of acetylcholine-gated ion channels on post-ganglionic neurons will cause (3 pts) A. B. C. D. E. depolarization hyperpolarization an action potential special summation inhibition of neurotransmitter release 10. ____ The safest drug for patients with insufficient cardiac reserve would most likely be (3 pts) A. B. C. D. E. muscarine pilocarpine nicotine bethanechol civemiline Phar 752 Exam #1, 13 October 2005 Page 3 Name (Last, First) ___________________ Student ID #___________________ 11. ____ Scopolamine is preferred over ipratropium for its primary indication due to (3 pts) A. B. C. D. E. Fewer cardiac side effects Fewer effects on pulmonary secretions Fewer problems with urinary retention More permeability across the blood/brain barrier Fewer problems with hallucinations 12. ____ Non-depolarizing ganglionic blockers should have the most predictable effects on (3 pts) A. B. C. D. E. Blood pressure Heart rate GI motility Bronchodilation Salivation and sweating 13. ____ A child is treated with oxybutynin for nighttime enuresis. Which of the following additional factors would be of greatest concern in this case? (3 pts) A. B. C. D. E. Concurrent treatment with antibiotics Heart murmur Asthma Gastric reflux Excessive drooling 14. ____ Which of the following symptoms can distinguish between belladona (atropine) and toxic mushroom (muscarine) poisoning? (3 pts) A. B. C. D. E. Dermal flushing Skeletal muscle rigidity Excessive drooling Blurred vision None of the above Phar 752 Exam #1, 13 October 2005 Page 4 Name (Last, First) ___________________ Student ID #___________________ 15. ____ Botulin toxin is used to treat hyperhydrosis by (3 pts) A. B. C. D. E. poisoning and shrinking sweat glands blocking nicotinic receptors permanently activating Gi subunits coupled to muscarinic receptors blocking neuronal conductance blocking acetylcholine release 16. ____ Dantrolene is used to treat (3 pts) A. B. C. D. E. Malathion poisoning Myasthenia gravis Mushroom poisoning Malignant hyperthermia Muscarinic amnesia 17. ____ Parasympathetic relaxation of the bladder sphincter occurs through (3 pts) A. B. C. D. E. activation of M2 receptors on bladder sphincter smooth muscle activation of M2 receptors on sympathetic presynaptic neurons inhibition of M1 receptor on bladder sphincter smooth muscle inhibition of M2 receptors on bladder sphincter smooth muscle inhibition of M1 receptors on sympathetic presynaptic neurons 18. ____ Once an action potential is initiated, neuronal conductance can be blocked by (3 pts) A. B. C. D. E. toxics that block Ca++ channels toxins that block vesicle fusion with plasma membrane toxins that block acetylcholinesterase toxins that inhibit Na+ channels all of the above 19. ____ The GTPase activity of a heterotrimeric Gsubunit is required for (3 pts) A. B. C. D. E. Initial activation Effector stimulation Association with G protein coupled receptors Reassociation with G subunits Receptor desensitization Phar 752 Exam #1, 13 October 2005 Page 5 Name (Last, First) ___________________ Student ID #___________________ 20. ____ Tubocurare causes paralysis by (3 pts) A. B. C. D. E. blocking the acetylcholine binding site phase I blockade phase II blockade phase I followed by phase II blockade spinal blockade 21. ____ The most dangerous complication with succinylcholine use is (3 pts) A. B. C. D. E. abnormally extended duration of action in renal insufficiency abnormally extended duration of action in liver dysfunction chelation of calcium in muscle tissue excessive release of calcium in muscle tissue toxic combinations with antibiotics 22. ____ Paradoxially, nausea is listed as a side effect of scopolamine because A. B. C. D. E. it activates the chemoreceptor trigger zone it delays stomach emptying it increases peptic acid secretion it relaxes the pyloric sphincter at the top of the stomach nausea is a side effect for everything 23. ____ Bethanechol should be used post-surgery if a patient (3 pts) A. B. C. D. E. Does not show evidence of dementia Is not on antibiotics Did not receive inhalational anesthetics Was not intubated Has no evidence of bowel obstruction Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 6 24. ____ Which of the following is not a feature consistent with muscarinic agonist structural features? (3 pts) A. There should be a two-carbon unit between the oxygen atom and the nitrogen atom. B. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group. C. There should be an oxygen atom, preferably an ester-like or ether-like oxygen, capable of participating in a hydrogen bond. D. Substitution of a carbamate for the ester group can increase the duration of muscarinic action. E. The molecule must possess a primary or secondary amine capable of bearing a positive charge. 25. ____ Which is the approximate preferred conformation of acetylcholine for agonist action at the muscarinic receptor? (3 pts) (CH 3) 3N+ (CH 3) 3N+ H OCOCH 3 H H H H H H H H Synclinal (Gauche) A. B. C. D. E. (CH 3) 3N+ H OCOCH 3 Antiplanar Synclinal Antiplanar Anticlinal Synplanar None of the above H (CH 3) 3N+ OCOCH 3 H H H OCOCH 3 Anticlinal H H Synplanar Phar 752 Exam #1, 13 October 2005 Page 7 Name (Last, First) ___________________ Student ID #___________________ 26. ____ Which of the following is not consistent with the SAR for muscarinic antagonists? (3 pts) R1 R2 X-(CH 2) n-N R3 A. The R3 substituent in more potent antimuscarinics is a hydroxyl or a hydroxymethyl group. B. The N group is a tertiary amine or quaternary ammonium salt, with the alkyl substituents usually methyl, ethyl, or isopropyl. C. The distance between the X group and the amine nitrogen can vary from 2 to 4 carbons. D. The X substituent in the most potent anticholinergics is an ester. E. The size of the R1 and R2 groups should be no larger than a methyl group. 27. ____ What is the approximate half-life (t1/2) for hydrolysis of the modified serine intermediate of acetylcholinesterase shown below? (3 pts) A. B. C. D. E. 200 sec (microseconds) 15-30 sec 45 min 8 hours 24 hours O N H O Ser-AChE 28. ____ Muscarine and pilocarpine are natural products that have similar pharmacological actions, but only one is useful as a drug to treat glaucoma. What key structural difference supports the use of pilocarpine rather than muscarine? (3 pts) A. Muscarine lacks the ester group that is crucial for optimal activity. B. Pilocarpine is a tertiary amine that is readily absorbed in the eye, while muscarine is a quaternary ammonium compound with poor absorption. C. Pilocarpine has several chiral centers that lead to greater selectivity to receptors in the eye. D. Muscarine is much more highly lipophilic than pilocarpine, which results in broad systemic distribution of the compound, leading to undesired side effects. E. The lactone ring system in pilocarpine is resistant to hydrolysis, resulting in much longer duration of action than would be seen with muscarine. Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 8 29. ____ Some antipsychotic drugs are known to have peripheral anticholinergic effects. Based on structural features, which of the following antipsychotics would be most likely to display these antimuscarinic side effects? (3 pts) S O H3CH2C OH F N N N H3C Cl O N H A C B N O O H N CH3 H N O N D Cl O Cl N Cl CH3 N Cl E N N 30. ____ S Which non-depolarizing neuromuscular blocking agent is efficiently inactivated by plasma cholinesterase (pseudocholinesterase) cleavage? (3 pts) A. B. C. D. E. Pipecuronium Tubocurarine Mivacurium Rocuronium Succinylcholine 31. ____ Ketoconazole, a Cyp3A4 inhibitor, would be expected to increase the half-life of drugs metabolized by Cyp3A4, potentially requiring a reduction in dose to reduce unwanted effects. Which muscarinic receptor antagonist used to treat overactive bladder would be least likely to have a drug interaction if co-administered with ketoconazole? (3 pts) A. B. C. D. E. Tolterodine Oxybutynin Trospium Solifenacin None of the above Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 9 32. ____ Which of the phosphorylated AChE enzyme intermediates below corresponds to an aged enzyme? (3 pts) O O P P O O Ser O EtO AChE O O OEt A P Ser AChE O B Ser AChE C O O P H3CO O CH3 P O Ser O AChE O O Ser AChE O- D E 33. ____ Which competitive (non-covalent) inhibitor of AChE was rationally designed based on the crystal structure of AChE? This inhibitor binds at the narrow part of the AChE binding cavity/channel and has selectivity for AChE inhibition over butyrylcholinesterase inhibition. (3 pts) A. B. C. D. E. Donepezil Huperzine Physostigmine Rivastigmine Edrophonium Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 10 34. ____ All of the following muscarinic antagonists except one have been used to treat extrapyramidal symptoms associated with Parkinson’s disease. Which structure represents an antagonist that would NOT be effective? (3 pts) CH3 H3C N+ C H OH OH O N N B A D HO O H3C N N E H3C 35. ____ Which of the following structures represents an acetylcholinesterase inhibitor that acts by covalently modifying the AChE? (3 pts) O (H3C)2N H3CO O N H O H3CO B A H OH N+ CH3 CH3 H OH O H3CO H3C N C CH3 N+ CH3 D CH3 H3C NH H2N O E Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 11 36. ____ Which of the following muscarinic agonists does not undergo hydrolysis and would be expected to have the longest elimination half-life? (3 pts) O H3C CH3 O CH3 CH3 N+ CH3 H3CH2C CH3 H H2N O O A CH3 C B O S O CH3 O N N D O N H2N CH3 CH3 N+ CH3 O E CH3 CH3 N+ CH3 Phar 752 Exam #1, 13 October 2005 Page 12 Name (Last, First) ___________________ Student ID #___________________ Short Answer 37. (15 pts) Compare and contrast the cardiovascular (heart and blood pressure) effects of a muscarinic agonist and an antagonist, giving as much detail as possible into the molecular mechanisms for the action of each type of drug. Don't forget direct and indirect mechanisms and explain. Use of diagrams might be helpful. Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 13 38. (3 pts) Draw the structure of the plant natural product that selectively acts at nicotinic cholinergic receptors (correct stereochemistry, if present, is required). 39. (4 pts) On the structure of acetylcholine below, add two different structural changes, one that will: A) Increase selectivity for muscarinic over nicotinic receptors. And a second that will: B) Significantly increase the duration of action of acetylcholine. (Clearly indicate which change correlates to part A and which correlates to part B.) O H3C O CH3 CH3 N+ CH3 Phar 752 Exam #1, 13 October 2005 Page 14 Name (Last, First) ___________________ Student ID #___________________ 40. (4 pts) The following structure represents a drug that is currently in Phase III clinical trials. This molecule is a prodrug, which is modified in the body to produce the active agent. Draw the structure of the active species and indicate what type of pharmacological action the active species will have (agonist/antagonist; include specific receptor/enzyme selectivity). O O N HO 41. (2 pts) Explain why ipratropium is a better choice than atropine as an inhaled muscarinic antagonist to treat chronic obstructive pulmonary disorder (COPD). Base your answer on structural difference(s) between the two drugs. Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 15 42. (4 pts) What are the two major routes of inactivation for the neuromuscular blocking agent cisatracurium? For each route, indicate on the structure below what bond is broken to inactivate the drug. H3CO OCH3 N+ CH3 O H3C O H3CO N+ OCH3 H3CO O O OCH3 OCH3 H3CO 43. (4 pts) Malathion is an insecticide that is a prodrug – it requires activation to be a potent AChE inhibitor. Explain with words and/or structures why malathion is a relatively safe insecticide for use by humans. Include in your explanation both activation and inactivation pathways. S H3CO P CO2Et S OCH3 CO2Et Name (Last, First) ___________________ Student ID #___________________ Phar 752 Exam #1, 13 October 2005 Page 16 44. (4 pts) The structure of an acetylcholinesterase reactivator is shown below. Circle the portion of the molecule that acts as a strong nucleophile to regenerate the active AChE. Draw the structure of the modified reactivator that would result from regeneration of AChE from the phosphorylated enzyme depicted below. O N N+ OH P O CH3 H O CH3 Ser AChE 45. (2 pts) Although ambenonium is a non-covalent modifier (non-covalent inhibitor) of AChE, it still has a very long duration of action. Explain this phenomenon based on the structure of ambenonium?