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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
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Exam #1, 13 October 2005
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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 Gi 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 Gsubunit 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
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Exam #1, 13 October 2005
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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 #___________________
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Exam #1, 13 October 2005
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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
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Exam #1, 13 October 2005
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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
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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
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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
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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?