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PHRM 825 > Cholinergic Agonist 4: Cholinesterase Inhibitors > Flashcards

Cholinergic Agonist 4: Cholinesterase Inhibitors Flashcards

1
Q

What are the reversible indirect acting cholinergic agonist (AChE inhibitors)?

A

Edrophonium

Physostigmine

Neostigmine

These are also clinically used.

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2
Q

What are the irreversible indirect acting cholinergic agonist (AChE inhibitors)?

A

Organophosphates

These are poisons.

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3
Q

What are the three chemicals that can block acetylcholine neruotransmission?

A

Hemicholinium which has no clinical use and can inhibit sodium-dependent choline transporter (CHT) blocking the whole process.

Vesamicol which has no clinical use can inhibit the vesicle-associated transporters (VAT) causing ACh buildup in presynaptic neuron.

Botox (botulinum toxin) can block the fusion of vesicles with the surface membrane preventing the release of ACh.

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4
Q

Where is acetylcholines action terminated?

A

Through the enzyme acetylcholinesterase.

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5
Q

What are the 2 types of cholinesterases?

A

Acetylcholinesterases which are located in the synapse and highly selective for ACh.

Plasma cholinesterase which are located in plasma and less selective for substrates. They include ACh, succinylcholine and local anesthetics (procaine).

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6
Q

What is important to know about AChE?

A

Fastest turnover rate of mammalian enzymes.

Uses hydrolysis (requires H2O) to break up acetylcholine.

There are three amino acid residues that form a catalytic triad called the esteric site.

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7
Q

What is acetylcholine broken down into?

A

acetic acid and choline

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8
Q

What are the two types of sites on AChE and their attraction?

A

Esteratic site: covalent bonding

Anionic site:electrostatic attraction

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9
Q

In the esteratic site of AChE, what are the 3 amino acid residues?

A

Glutamate: acidic AA with negative charge

Histine: basic AA with positive charge

Serine: polar AA

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10
Q

In the anionic site of AChE, what are the 2 amino acid residues?

A

Phenylalanine: aromatic, nonpolar AA

Tryptophan: aromatic, nonpolar AA

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11
Q

Where would an AChE inhibitor interfere in the breakdown of ACh?

A
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12
Q

What are the muscarinic receptors?

A

M1

M2: heart

M3: smooth muscles and exocrine glands

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13
Q

What are the nicotinic receptors?

A

Nn: autonomic ganglia

Nm: skeletal muscle

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14
Q

What is the classification of the reversible cholinesterase inhibitors?

A

Alcohol: Edrophonium

Carbamates: Physostigmine, Neostigmine and Pyridostigmine

Others: Donepezil (Aricept) ALZ

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15
Q

What is the classification of the irreversible cholinesterase inhibitors?

A

Organophosphates:

Echothiophate - glaucoma

Sarin - nerve gas/chemical warfare

Malathion - pesticide for head lice

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16
Q

What is important about tetra-alkyl ammonium ions?

A

Bind to anionic site and block ACh binding
-reversible and non covalent

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17
Q

What is important about quaternary ammonium alcohol?

A

Edrophonium (Tensilon) is an example.

Bind to anionic side and blocks ACh binding
-reversible and non covalent

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18
Q

What is important about carbamates?

A

Quaternary or tertiary ammonium groups
-reversible and causes covalent modifications to AChe therefore more slowly hydrolyzed than ACh.

19
Q

What are the structures of the carbamate cholinesterase inhibitors?

A

Neostigmine (Prostigmin) has a tertiary ammonium, ester and core structure of Edrophonium.

Pyridostigmine (Mestinon) has the tertiary ammonium and ester of Neostigmine but aromatic ring has methyl group.

Physostigmine (Antilirium) has central benzene ring with ester and tertiary amine on the left and 2 nitrofuran rings on the right both tertiary as well.

20
Q

What are the 3 AChE inhibitors with a quaternary amine and their clinical use?

A

Edrophonium: Used for myasthenia gravis (MG) - skeletal muscle weakness due to loss of skeletal muscle nicotinic receptors due to autoimmune disease
-very short acting (mins)

Pyridostigmine: Used for MG
-reversal of nondepolarizing neuromuscular blockade
-pretreatment for potential nerve gas (sarin) exposure

Neostigmine: Used for MG
-reversal of nondepolarizing neuromuscular blockade
-post op urinary retention

21
Q

What are the problems of AChE inhibitors with a quaternary amine?

A

Excessive cholinergic receptor activation

22
Q

Why is physostigmine an exception?

A

It can cross the BBB acting as an antidote to antimuscarinic poisoning.

Stigmines are more slowly hydrolyzed than ACh.

Problem: excessive cholinergic receptor activation.

23
Q

What is important to know about the organophosphates cholinesterase inhibitors?

A

THEY HAVE A PHOSPHATE GROUP hince the name.

Irreversible causing covalent modifications to AChE.

Used in treatment of glaucoma.

Most OGPs are toxic.

24
Q

What are the clinical useful organophosphates?

A

Isofluorophate, DFP (Floropryl): has a central phosphate group bound to 3 oxygens and a fluorine. 2 isopropyl groups.

Echothiophate (Phospholine Iodide): choline group with sulfur instead of ester and phosphate group.

25
Q

What is important to know about echothiophate?

A

inhibits AChE: long acting essentially irreversible

Originally used for glaucoma to increase ACh and enhance muscarinic activation and outflow of AH.

Not currently used due to better drugs and caused excessive cholinergic receptor activation.

26
Q

What are the two nerve gases and what is important about them?

A

Both cause irreversible and causes covalent modifications to AChE

Sarin: very similar to isofluorophate but exchange 1 isopropyl for methyl group

Soman: 3 carbon chain with ether and phosphate group.

27
Q

What are the two insecticides and what is important about them?

A

Both irreversible, causes covalent modifications to AChE and rapidly inactivated in mammals through carboxyesterase.

Malathion: 3 carbon branches with 2 sulfur molecules on right

Diazinon: central pyrimidine with phosphate group on right.

28
Q

Why is malathion deadly to insects but not humans?

A

Insects have CYT P450 that converts malathion to malaoxon which is toxic.

29
Q

Why do organophosphates selectively affect the cholinergic system?

A

They covalently bind directly to the serine AA residue and water can’t reverse hydrolyze.

Over time it can’t be detoxified.

30
Q

What is the antidote for AChE poisoning?

A

2- PAM (Pralidoxime chloride)
-will hydrolyze and creates leaving group allowing for action to return

Antidote for nerve gas or pesticide poisoning.

Needs to be given with in few hours of exposure to be most effective.

31
Q

What do you commonly give pralidoxime with? Why?

A

Atropine which is a muscarinic receptor antagonist.

It will block access to muscarinic receptors.

32
Q

What happens in alzheimer’s disease?

A

The protein Beta amyloid precursor protein leads to a toxic form Beta amyloid 42 that promotes apoptosis.

Leads to loss of cholinergic neurons in brain.

33
Q

What is the first drug created to treat ALZ?

A

Donepezil (Aricept). for all stages

It will bind to the anionic side of AChE and block ACh binding.
-reversible and non covalent

Cholinergic effect is enhancing cognitive ability.

Doesn’t slow the progress of dieases.

34
Q

What is important to know about Rivastigmine (Exelon)

A

Carbamate AChE inhibitor.

Enhances cognitive ability by increasing cholinergic function.

Loses effectiveness as ALZ progresses

Has central benzene ring with carbamate on top.

35
Q

What are the side effects of Rivastigmine (Exelon)?

A

Nausea, vomiting, anorexia and weight loss.

There is a newer long acting carbamate called Eptastigmine

36
Q

What is important about Galantamine (Razadyne)?

A

Extracted from daffodil bulbs.

Loses effectiveness as disease progresses.

Inhibitor of P450 enzymes (3A4 and 2D6) leading to increased galantamine bioavailability.

37
Q

Why is Memantine(Namenda) special?

A

NMDA receptor antagonist.

Therefor it may slow the progress of ALZ approved for moderate to severe disease.

Better side effects.

38
Q

What are cholinergic agonist side effects?

A

Diarrhea
Urination
Miosis (pupil contraction)
Bradycardia
Bronchoconstriction
Emesis (vomiting)
Lacrimation (tears)
Salivation + Sweating

39
Q

What are the at risk populations for cholinergic agonist?

A

Those with asthma, coronary insufficiency or peptic ulcer.

Cardiovascular and respiratory.

40
Q

What does SLUD stand for

A

Salivation
Lacrimation
Urination
Defecation

Also increased sweating, decreased HR, miosis, CNS activation.

41
Q

What does SLUD stand for?

A

Salivation
Lacrimation
Urination
Defecation

Also increased sweating, decreased HR, miosis, CNS activation.

42
Q

How do you treat SLUD?

A

If reversible use Atropine which is a cholinergic receptor antagonist.

If irreversible AChE inhibitor use 2-PAM

43
Q

What are the contraindications for parasympathomimetic drugs?

A

Asthma/COPD
-using drug would increase bronchoconstriction

Coronary deficiency
-using drug would lower heart rate lower

Peptic ulcer
-using drug would increase acid secretion

Obstruction of the urinary or GI tract
-using drug would increase contraction

Epilepsy
-M1 receptors and can permeate like pilocarpine and physostigmine

PHRM 825 (13 decks)

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