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

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Flashcards in Lecture 8 (ACE Inhibitors and Antagonists of Muscarinic Receptors) Deck (105):
1

Blood-Brain Barrier (BBB)

-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

2

Briefly explain the anatomy of the BBB

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

-so normally water-soluble drugs cannot cross the BBB

3

Can the BBB fail/be ineffective?

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

4

How can things cross the BBB? (4)

-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)

5

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

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

6

Too low of logP = ?

compound to hydrophilic to partition into lipid membranes

7

Too high logP = ?

compound will remain in lipid membranes

8

Pancuronium, atracurium, tubocurarine, and vecuronium are all?

non-depolarizing (competitive) neuromuscular blocking agents

9

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

used in surgery to relax muscles

10

Succinylcholine is an example of a ?

depolarizing muscular blocking

11

What is succinylcholine used for?

used in surgery to relax muscles

12

Succinylcholine has _____ onset and ____ duration of action

rapid onset
short duration of action

13

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

AChE inhibitors

14

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

depolarizing

15

Anticholinesterase inhibits ____

AChE

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

16

What does the excess ACh at the synapse cause?

it causes ACh to compete with non-depolarizing neuromuscular blockers

17

Non-depolarizing neuromuscular blockers are _____ antagonists

competitive

18

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

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

19

List 4 Anticholinesterases (AChE inhibitors)

-edrophonium
-neostigmine
-pyridostigmine
-physostigmine

20

The binding of edrophonium is ______

reversible (no covalent interaction with the enzyme)

21

edrophonium has a _____ duration

short

22

Edrophonium is used as a diagnostic test for ?

myasthenia gravis

23

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

rarely

24

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

neostigmine

25

How does Neostigmine inhibit AChE?

reversibly alkylates AChE rendering it inactive for about 30 mins

26

________ - reversibly alkylates AChE

pyridostigmine

27

_______ - reversibly alkylates AChE as well

physostigmine

28

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

pyridostigmine

29

Pyridostigmine can be used to treat ?

myasthenia gravis

30

Physostigmine is more _____ _______ than other agents

lipid soluble

31

Physostigmine can be absorbed from the ?

GI tract

32

_______ can cross the BBB

physostigmine

33

Can quaternary amine anticholinesterases cross the BBB

no - they do not usually cross the BBB

34

What is myasthenia gravis?

-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

35

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

true man

36

How can you use AChE inhibitors to treat myasthenia gravis?

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

37

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

orally absorbed
longer acting
do not cross BBB

38

What is cholinergic crisis?

when you overdose AChE

39

AChE inhibitors can also treat ______ disease

Alzheimer's

40

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

frontal cortex

41

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

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

42

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

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

43

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

pyridostigmine

44

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

ionize

45

Galatamine has a ___ amine

tertiary

46

Tertiary amine must be _____ to cross BBB

neutral

47

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

ionize

48

Galantamine is ?

-competitive
-a reversible inhibitor of AChE that does not alkylate the enzyme
-rather it binds to the enzyme like edrophonium

49

Donepezil has a ____ amine

tertiary

50

Donepezil is ?

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

51

AChE active site has two sites: what are they?

anionic site
esteractic site

52

Describe AChE mechanism

-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

edrophonium is a ____ ______ for AChE

competitive antagonist
*it competes with ACh

54

Edrophonium binds to ____ site

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

Neostigmine has a _____ group

carbamoyl

56

Carbamoyl is much more stable to _____ than the acyl

stable

57

3 examples of organophosphate anticholinesterases

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

58

The 3 examples of organophosphate anticholinesterases are all highly _____

hydrophobic

*this means they can cross the BBB easily

59

Describe Sarin

-extremely potent and toxic
-used only as a nerve gas

60

Parathion has ___ activity as is

low

61

How does parathion become toxic to insects?

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

Malathion is also only activated in _____

insects

63

Why are organophosphate anticholinesterases (AChE inhibitors) toxins?

-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

Effects of organophosphate anticholinesterases (AChE inhibitors are ____ acting

long

65

Without treatment organophosphate anticholinesterases (AChE inhibitors can ?

permanently inactivate AChE

66

Symptoms of organophosphate poisoning?

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

67

How can you prevent dying after AChE inhibitor?

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

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

aged enzyme

69

aged enzyme is resistant to?

hydrolysis

70

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

AChE is permanently inactivated

*this is lethal
*no treatment
*you gon die

71

How can 2-PAM help?

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

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

72

There are 3 types of AChE inhibitors: explain them

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

Antimuscarinic = ?

muscarinic antagonists

74

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

ester

*it could also be ether oxygen or absent altogether

75

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

quaternary ammonium or tertiary amines

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

76

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

methyl, ethyl, propyl, or isopropyl

77

Possible effects of antimuscarinic drugs

-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

List 4 examples of muscarinic antagonists

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

79

Cyclopentolate is used as ?

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

80

Dicyclomine is used as?

used to stop spasms in the GI that produce abdominal pain

81

What are oxybutynin and tolerodine used for?

overactive bladder
-people who have excessive urinary frequency

82

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

shorter

83

MEMORIZE SAR FOR ANTIMUSCARINIC

OK
-see slide 28

84

Atropine is a _____ mixture

racemic

85

The S (- or l) form is more ____

potent

86

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

hyoscyamine

87

What is atropine used for?

-component of belladonna (dilate pupils)
-component of opium suppositories
-used for painful urethral spasm or intestinal cramping

88

Atropine is given with _____ for organophosphate anti cholinesterase toxicity

2-PAM

2-PAM to save your life

atropine to relieve symptoms like vomitng

89

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

neostigmine

90

Many of the drugs used to treat schizophrenia are ?

dopamine blockers

91

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

decreased dopamine in the substantia nigra

92

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

benztropine (cogentin)
-to contract these "parkinson like" symptoms

93

Scopolamine (Transform V) is used for?

to prevent motion sickness or for nausea

94

Form of Scopolamine (Transform V) ?

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

95

Hyoscine (Buscopan) is used for?

*also known as butylscopolamine

Used to stop spasms in the GI that produce abdominal pain

96

Form of Hyoscine (Buscopan)

oral tablets 10 mg (available without Rx)

97

Hyoscine (Buscopan) has a _____ amine

quaternary

98

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

-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

Ipratropium (Atrovent) is given as ?

inhalation from a MDI (metered dose inhaler)

100

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

no

101

Ipratropium (Atrovent) has a ______ amine

quaternary

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

102

Tiotropium (Spiriva) is formulated as ?

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

103

Tiotropium (Spiriva) is used to treat ?

COPD not asthma

104

What is an advantage of tiotropium over ipratropium?

very long half life

105

Antimuscarinic side effects?

-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