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Med Chem > Lecture 8 (ACE Inhibitors and Antagonists of Muscarinic Receptors) > Flashcards

Lecture 8 (ACE Inhibitors and Antagonists of Muscarinic Receptors) Flashcards

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1
Q

Blood-Brain Barrier (BBB)

A
  • peripheral blood capillaries allow relatively free exchange of substances across/between cells
  • but brain blood capillaries strictly limit transport of substances into the brain
  • The BBB is often the rate-limiting factor in determine permeation of therapeutic CNS drugs into the brain
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2
Q

Briefly explain the anatomy of the BBB

A

Tight junctions and astrocyte sheath act as a lipoid barrier to crossing for hydrophilic drugs

-so normally water-soluble drugs cannot cross the BBB

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3
Q

Can the BBB fail/be ineffective?

A

Yes - ex. brain infections can increase permeability
Many normally water soluble antibiotics that normally would not cross the BBB can cross during the inflammation of a brain infection

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4
Q

How can things cross the BBB? (4)

A
  • passive diffusion through aqueous channels (not common)
  • passive diffusion through lipid (most important mechanism of absorption)
  • some drugs can be taken up by endocytosis
  • facilitated transport (via transporters that transport endogenous compounds)
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5
Q

Passive diffusion through the BBB is the most optimal if the molecule is:

A

-mostly unionized at pH 7.4
-has molecular weight < 400
-has log P within this range:
1 < logP < 4

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6
Q

Too low of logP = ?

A

compound to hydrophilic to partition into lipid membranes

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7
Q

Too high logP = ?

A

compound will remain in lipid membranes

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8
Q

Pancuronium, atracurium, tubocurarine, and vecuronium are all?

A

non-depolarizing (competitive) neuromuscular blocking agents

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9
Q

What are non-depolarizing (competitive) neuromuscular blocking agents used for?

A

used in surgery to relax muscles

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10
Q

Succinylcholine is an example of a ?

A

depolarizing muscular blocking

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11
Q

What is succinylcholine used for?

A

used in surgery to relax muscles

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12
Q

Succinylcholine has _____ onset and ____ duration of action

A

rapid onset

short duration of action

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13
Q

_____ _________ are used in anesthesia to reverse the effects of non-depolarizing neuromuscular blocking agnets

A

AChE inhibitors

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14
Q

AChE inhibitors are never used with _____ neuromuscular blocking agents such as succinylcholine

A

depolarizing

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15
Q

Anticholinesterase inhibits ____

A

AChE

*if AChE is being inhibited, then there will be an increase of ACh at the synapse

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16
Q

What does the excess ACh at the synapse cause?

A

it causes ACh to compete with non-depolarizing neuromuscular blockers

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17
Q

Non-depolarizing neuromuscular blockers are _____ antagonists

A

competitive

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18
Q

Because non-depolarizing neuromuscular blockers are competitive antagonists then it’s effects can be overcome by ?

A

excess agonist (i.e. ACh in this case)

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19
Q

List 4 Anticholinesterases (AChE inhibitors)

A
  • edrophonium
  • neostigmine
  • pyridostigmine
  • physostigmine
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20
Q

The binding of edrophonium is ______

A

reversible (no covalent interaction with the enzyme)

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21
Q

edrophonium has a _____ duration

A

short

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22
Q

Edrophonium is used as a diagnostic test for ?

A

myasthenia gravis

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23
Q

Is edrophonium used to reverse the effects of non-depolarizing neuromuscular blocking agents?

A

rarely

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24
Q

______ is the most commonly used anti cholinesterase (AChE inhibitor) in anesthesia

A

neostigmine

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25
Q

How does Neostigmine inhibit AChE?

A

reversibly alkylates AChE rendering it inactive for about 30 mins

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26
Q

________ - reversibly alkylates AChE

A

pyridostigmine

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27
Q

_______ - reversibly alkylates AChE as well

A

physostigmine

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28
Q

______ has a longer onset that neostigmine and lasts for several hours

A

pyridostigmine

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29
Q

Pyridostigmine can be used to treat ?

A

myasthenia gravis

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30
Q

Physostigmine is more _____ _______ than other agents

A

lipid soluble

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31
Q

Physostigmine can be absorbed from the ?

A

GI tract

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32
Q

_______ can cross the BBB

A

physostigmine

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33
Q

Can quaternary amine anticholinesterases cross the BBB

A

no - they do not usually cross the BBB

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34
Q

What is myasthenia gravis?

A
  • remitting and relapsing muscle weakness
  • improved with rest
  • aggravated by exercise
  • production of antibodies to ACh receptors
  • leads to a decrease in receptor density at the NMJ

*destruction of ACh receptors

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35
Q

T or F: you can use AChE inhibitors to treat myasthenia gravis

A

true man

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36
Q

How can you use AChE inhibitors to treat myasthenia gravis?

A

it will increase ACh at NMJ and restores muscular contraction upon nerve stimulus

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37
Q

You want to use AChE inhibitors that are ____ absorbed, _____ acting, and do not cross ____

A

orally absorbed
longer acting
do not cross BBB

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38
Q

What is cholinergic crisis?

A

when you overdose AChE

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39
Q

AChE inhibitors can also treat ______ disease

A

Alzheimer’s

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40
Q

When treating Alzheimer’s disease, you want to inhibit AChE in the _____ ______

A

frontal cortex

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41
Q

You cannot give an AChE inhibitor that is a quaternary amine because??

A

it would not be able to cross the BBB and reach the frontal cortex in the brain

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42
Q

What are 3 examples of AChE inhibitors used to treat alzheimer’s

A

1 - Rivastigmine (Exelon)
2 - Galantine (Reminyl)
3 - Donepezil (Aricept)

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43
Q

Rivastigmine is similar to ______ and works the same way except there is no quaternary amine (so it can cross the BBB)

*this one has a tertiary amine

A

pyridostigmine

44
Q

After rivastigmine crosses BBB, the tertiary amine must _____ for activity so that it can bind anionic site on AChE

A

ionize

45
Q

Galatamine has a ___ amine

A

tertiary

46
Q

Tertiary amine must be _____ to cross BBB

A

neutral

47
Q

Tertiary amine must _____ after crossing BBB in order to bind to anionic site on AChE

A

ionize

48
Q

Galantamine is ?

A
  • competitive
  • a reversible inhibitor of AChE that does not alkylate the enzyme
  • rather it binds to the enzyme like edrophonium
49
Q

Donepezil has a ____ amine

A

tertiary

50
Q

Donepezil is ?

A
  • competitive
  • a reversible inhibitor of AChE that does not alkylate the enzyme
  • rather it binds to the enzyme like edrophonium and galantamine
51
Q

AChE active site has two sites: what are they?

A

anionic site

esteractic site

52
Q

Describe AChE mechanism

A
  • bunch of rearrangements
  • water comes in and creates the acyl enzyme intermediate
  • i think the ester bond of ACh is being broken or “removes acetyl group”
53
Q

edrophonium is a ____ ______ for AChE

A

competitive antagonist

*it competes with ACh

54
Q

Edrophonium binds to ____ site

A

anionic

  • there is no covalent interaction with enzyme, just sits there and occupies the space that ACh would
  • if we had enough ACh we could overcome the antagonist because it is a competitive antagonist
55
Q

Neostigmine has a _____ group

A

carbamoyl

56
Q

Carbamoyl is much more stable to _____ than the acyl

A

stable

57
Q

3 examples of organophosphate anticholinesterases

A

1 - sarin - nerve gas
2 - parathion - insecticide
3 - malathion - insecticide

58
Q

The 3 examples of organophosphate anticholinesterases are all highly _____

A

hydrophobic

*this means they can cross the BBB easily

59
Q

Describe Sarin

A
  • extremely potent and toxic

- used only as a nerve gas

60
Q

Parathion has ___ activity as is

A

low

61
Q

How does parathion become toxic to insects?

A

it gets metabolized in insects replacing S with O and making it much more potent.

-it is not a risk to humans as we do not perform the replacement

62
Q

Malathion is also only activated in _____

A

insects

63
Q

Why are organophosphate anticholinesterases (AChE inhibitors) toxins?

A
  • they have the ability to increase ACh at the NMJ and synapse
  • eventually this leads to persistent activation of ACh receptors which depolarizes neuromuscular block and death by asphyxia (oxygen deprivation/suffocation)
64
Q

Effects of organophosphate anticholinesterases (AChE inhibitors are ____ acting

A

long

65
Q

Without treatment organophosphate anticholinesterases (AChE inhibitors can ?

A

permanently inactivate AChE

66
Q

Symptoms of organophosphate poisoning?

A

-pinpoint pupils
-bronchospasm
-decreased HR
-frothy salivation
-profuse sweating
-increased GI motility
(parasympathetic symptoms)

67
Q

How can you prevent dying after AChE inhibitor?

A

if you get rapid treatment of 2-PAM (pralidoxime) - it will remove organophosphate from enzyme and produce a free enzyme so you won’t die

68
Q

you need to get 2-PAM before you have ??

A

aged enzyme

69
Q

aged enzyme is resistant to?

A

hydrolysis

70
Q

if you get the aged enzyme (charged phosphate modified enzyme) it is totally resistant to hydrolysis and ??

A

AChE is permanently inactivated

  • this is lethal
  • no treatment
  • you gon die
71
Q

How can 2-PAM help?

A

it can efficiently remove the initial phosphorylated enzyme (NOT THE AGED ENZYME)

*2-PAM is the only treatment for organophosphate poisoning.

72
Q

There are 3 types of AChE inhibitors: explain them

A

1-competitively bind to the enzyme that are completely reversible and do not covalently bind to the enzyme
ex. donepezil, edrophonium, galantine

2-those that covalently bind to the enzyme but DO NOT permanently inactivate it
ex. neostigmine, pyridostigmine, physostigmine, rivastigmine

3-those that covalently bind to the enzyme and permanently inactive it without treatment with 2-PAM
ex. organophosphate anticholinesterases

73
Q

Antimuscarinic = ?

A

muscarinic antagonists

74
Q

For maximum potency, the X substituent on a muscarinic antagonist should be?

A

ester

*it could also be ether oxygen or absent altogether

75
Q

For maximum potency, the N substituent on muscarinic antagonist should be?

A

quaternary ammonium or tertiary amines

*but they have to be able to have a + charge to bind to the receptor

76
Q

Subsitutents on the N of a muscarinic antagonist are usually ??

A

methyl, ethyl, propyl, or isopropyl

77
Q

Possible effects of antimuscarinic drugs

A
  • some are used for dilation of the pupil prior to an eye exam
  • used for frequent urination or abdominal pain that is caused by spasms in the GI
  • can cause bronchodilation

(sympathetic symptoms)

78
Q

List 4 examples of muscarinic antagonists

A

cyclopentolate (Cyclogyl)
dicyclomine
oxybutynin (Ditropan XL)
tolterodine (Detrol LA)

79
Q

Cyclopentolate is used as ?

A

eye drops

-given prior to eye exam to dilate pupils (mydriasis)

80
Q

Dicyclomine is used as?

A

used to stop spasms in the GI that produce abdominal pain

81
Q

What are oxybutynin and tolerodine used for?

A

overactive bladder

-people who have excessive urinary frequency

82
Q

Drugs with ___ half-lives are put in sustained release form

A

shorter

83
Q

MEMORIZE SAR FOR ANTIMUSCARINIC

A

OK

-see slide 28

84
Q

Atropine is a _____ mixture

A

racemic

85
Q

The S (- or l) form is more ____

A

potent

86
Q

If the S form of atropine is purified it is called ______

A

hyoscyamine

87
Q

What is atropine used for?

A
  • component of belladonna (dilate pupils)
  • component of opium suppositories
  • used for painful urethral spasm or intestinal cramping
88
Q

Atropine is given with _____ for organophosphate anti cholinesterase toxicity

A

2-PAM

2-PAM to save your life

atropine to relieve symptoms like vomitng

89
Q

Atropine is also sometimes given with ______ after surgery when recovering from neuromuscular block

A

neostigmine

90
Q

Many of the drugs used to treat schizophrenia are ?

A

dopamine blockers

91
Q

The movement disorder, Parkinson’s disease is marked by ?

A

decreased dopamine in the substantia nigra

92
Q

Some schizophrenics under treatment will get “parkinson’s like” symptoms. In this case, what can you give?

A

benztropine (cogentin)

-to contract these “parkinson like” symptoms

93
Q

Scopolamine (Transform V) is used for?

A

to prevent motion sickness or for nausea

94
Q

Form of Scopolamine (Transform V) ?

A

comes as patches that are used for 3 days to provide continuous anti-nausea effect

95
Q

Hyoscine (Buscopan) is used for?

*also known as butylscopolamine

A

Used to stop spasms in the GI that produce abdominal pain

96
Q

Form of Hyoscine (Buscopan)

A

oral tablets 10 mg (available without Rx)

97
Q

Hyoscine (Buscopan) has a _____ amine

A

quaternary

98
Q

What does the quaternary amine on Hyoscine (Buscopan) mean?

A
  • it means that is has a permanent positive charge
  • because of this, very little drug is absorbed from the GI tract

*therefore the drug is localized to the Gi producing very minimal systemic side effects

99
Q

Ipratropium (Atrovent) is given as ?

A

inhalation from a MDI (metered dose inhaler)

100
Q

Can Atrovent ever be given as a mono therapy for asthma?

A

no

101
Q

Ipratropium (Atrovent) has a ______ amine

A

quaternary

  • prevents crossing BBB so no CNS side effects
  • also decreases systemic side effects (decreased systemic absorption from lungs)
102
Q

Tiotropium (Spiriva) is formulated as ?

A

a dry powder inhaler

-comes in capsules and you poke a hole in the capsule and then inhale the contents of the capsule

103
Q

Tiotropium (Spiriva) is used to treat ?

A

COPD not asthma

104
Q

What is an advantage of tiotropium over ipratropium?

A

very long half life

105
Q

Antimuscarinic side effects?

A
  • dry mouth
  • pupil dilation
  • difficulty with dark adaption
  • blurred vision
  • increased intraocular pressure
  • hot, flushed, and dry skin
  • tachycardia (increase HR)
  • urinary retention
  • constipation
  • blocking parasympathetic system
  • having sympathetic-like symptoms

Med Chem (11 decks)

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