Lecture 8 (ACE Inhibitors and Antagonists of Muscarinic Receptors) Flashcards
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
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
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
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)
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
Too low of logP = ?
compound to hydrophilic to partition into lipid membranes
Too high logP = ?
compound will remain in lipid membranes
Pancuronium, atracurium, tubocurarine, and vecuronium are all?
non-depolarizing (competitive) neuromuscular blocking agents
What are non-depolarizing (competitive) neuromuscular blocking agents used for?
used in surgery to relax muscles
Succinylcholine is an example of a ?
depolarizing muscular blocking
What is succinylcholine used for?
used in surgery to relax muscles
Succinylcholine has _____ onset and ____ duration of action
rapid onset
short duration of action
_____ _________ are used in anesthesia to reverse the effects of non-depolarizing neuromuscular blocking agnets
AChE inhibitors
AChE inhibitors are never used with _____ neuromuscular blocking agents such as succinylcholine
depolarizing
Anticholinesterase inhibits ____
AChE
*if AChE is being inhibited, then there will be an increase of ACh at the synapse
What does the excess ACh at the synapse cause?
it causes ACh to compete with non-depolarizing neuromuscular blockers
Non-depolarizing neuromuscular blockers are _____ antagonists
competitive
Because non-depolarizing neuromuscular blockers are competitive antagonists then it’s effects can be overcome by ?
excess agonist (i.e. ACh in this case)
List 4 Anticholinesterases (AChE inhibitors)
- edrophonium
- neostigmine
- pyridostigmine
- physostigmine
The binding of edrophonium is ______
reversible (no covalent interaction with the enzyme)
edrophonium has a _____ duration
short
Edrophonium is used as a diagnostic test for ?
myasthenia gravis
Is edrophonium used to reverse the effects of non-depolarizing neuromuscular blocking agents?
rarely
______ is the most commonly used anti cholinesterase (AChE inhibitor) in anesthesia
neostigmine
How does Neostigmine inhibit AChE?
reversibly alkylates AChE rendering it inactive for about 30 mins
________ - reversibly alkylates AChE
pyridostigmine
_______ - reversibly alkylates AChE as well
physostigmine
______ has a longer onset that neostigmine and lasts for several hours
pyridostigmine
Pyridostigmine can be used to treat ?
myasthenia gravis
Physostigmine is more _____ _______ than other agents
lipid soluble
Physostigmine can be absorbed from the ?
GI tract
_______ can cross the BBB
physostigmine
Can quaternary amine anticholinesterases cross the BBB
no - they do not usually cross the BBB
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
T or F: you can use AChE inhibitors to treat myasthenia gravis
true man
How can you use AChE inhibitors to treat myasthenia gravis?
it will increase ACh at NMJ and restores muscular contraction upon nerve stimulus
You want to use AChE inhibitors that are ____ absorbed, _____ acting, and do not cross ____
orally absorbed
longer acting
do not cross BBB
What is cholinergic crisis?
when you overdose AChE
AChE inhibitors can also treat ______ disease
Alzheimer’s
When treating Alzheimer’s disease, you want to inhibit AChE in the _____ ______
frontal cortex
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
What are 3 examples of AChE inhibitors used to treat alzheimer’s
1 - Rivastigmine (Exelon)
2 - Galantine (Reminyl)
3 - Donepezil (Aricept)
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
After rivastigmine crosses BBB, the tertiary amine must _____ for activity so that it can bind anionic site on AChE
ionize
Galatamine has a ___ amine
tertiary
Tertiary amine must be _____ to cross BBB
neutral
Tertiary amine must _____ after crossing BBB in order to bind to anionic site on AChE
ionize
Galantamine is ?
- competitive
- a reversible inhibitor of AChE that does not alkylate the enzyme
- rather it binds to the enzyme like edrophonium
Donepezil has a ____ amine
tertiary
Donepezil is ?
- competitive
- a reversible inhibitor of AChE that does not alkylate the enzyme
- rather it binds to the enzyme like edrophonium and galantamine
AChE active site has two sites: what are they?
anionic site
esteractic site
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”
edrophonium is a ____ ______ for AChE
competitive antagonist
*it competes with ACh
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
Neostigmine has a _____ group
carbamoyl
Carbamoyl is much more stable to _____ than the acyl
stable
3 examples of organophosphate anticholinesterases
1 - sarin - nerve gas
2 - parathion - insecticide
3 - malathion - insecticide
The 3 examples of organophosphate anticholinesterases are all highly _____
hydrophobic
*this means they can cross the BBB easily
Describe Sarin
- extremely potent and toxic
- used only as a nerve gas
Parathion has ___ activity as is
low
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
Malathion is also only activated in _____
insects
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)
Effects of organophosphate anticholinesterases (AChE inhibitors are ____ acting
long
Without treatment organophosphate anticholinesterases (AChE inhibitors can ?
permanently inactivate AChE
Symptoms of organophosphate poisoning?
-pinpoint pupils
-bronchospasm
-decreased HR
-frothy salivation
-profuse sweating
-increased GI motility
(parasympathetic symptoms)
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
you need to get 2-PAM before you have ??
aged enzyme
aged enzyme is resistant to?
hydrolysis
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
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.
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
Antimuscarinic = ?
muscarinic antagonists
For maximum potency, the X substituent on a muscarinic antagonist should be?
ester
*it could also be ether oxygen or absent altogether
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
Subsitutents on the N of a muscarinic antagonist are usually ??
methyl, ethyl, propyl, or isopropyl
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)
List 4 examples of muscarinic antagonists
cyclopentolate (Cyclogyl)
dicyclomine
oxybutynin (Ditropan XL)
tolterodine (Detrol LA)
Cyclopentolate is used as ?
eye drops
-given prior to eye exam to dilate pupils (mydriasis)
Dicyclomine is used as?
used to stop spasms in the GI that produce abdominal pain
What are oxybutynin and tolerodine used for?
overactive bladder
-people who have excessive urinary frequency
Drugs with ___ half-lives are put in sustained release form
shorter
MEMORIZE SAR FOR ANTIMUSCARINIC
OK
-see slide 28
Atropine is a _____ mixture
racemic
The S (- or l) form is more ____
potent
If the S form of atropine is purified it is called ______
hyoscyamine
What is atropine used for?
- component of belladonna (dilate pupils)
- component of opium suppositories
- used for painful urethral spasm or intestinal cramping
Atropine is given with _____ for organophosphate anti cholinesterase toxicity
2-PAM
2-PAM to save your life
atropine to relieve symptoms like vomitng
Atropine is also sometimes given with ______ after surgery when recovering from neuromuscular block
neostigmine
Many of the drugs used to treat schizophrenia are ?
dopamine blockers
The movement disorder, Parkinson’s disease is marked by ?
decreased dopamine in the substantia nigra
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
Scopolamine (Transform V) is used for?
to prevent motion sickness or for nausea
Form of Scopolamine (Transform V) ?
comes as patches that are used for 3 days to provide continuous anti-nausea effect
Hyoscine (Buscopan) is used for?
*also known as butylscopolamine
Used to stop spasms in the GI that produce abdominal pain
Form of Hyoscine (Buscopan)
oral tablets 10 mg (available without Rx)
Hyoscine (Buscopan) has a _____ amine
quaternary
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
Ipratropium (Atrovent) is given as ?
inhalation from a MDI (metered dose inhaler)
Can Atrovent ever be given as a mono therapy for asthma?
no
Ipratropium (Atrovent) has a ______ amine
quaternary
- prevents crossing BBB so no CNS side effects
- also decreases systemic side effects (decreased systemic absorption from lungs)
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
Tiotropium (Spiriva) is used to treat ?
COPD not asthma
What is an advantage of tiotropium over ipratropium?
very long half life
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
