AChE Inhibitors and Antagonists of Muscarinic Receptors

Question 1

What is the blood brain barrier? Why is it important?

Answer 1

The peripheral blood capillaries allow relatively free exchange of substances across and between cells
But the brain blood capillaries strictly limit transport of substances into the brain
The BBB is often the rate-limiting factor in determining permeation of therapeutic CNS drugs into the brain

Question 2

Describe the anatomy of the BBB

Answer 2

Tight junctions and an astrocyte sheath act a lipoid barrier to crossing for hydrophilic drugs
In some cases, the BBB is ineffective. Like brain infections which increases permeability. However many normally water soluble antibiotics that normally would not cross the BBB, can cross during the inflammation of a brain infection

Question 3

What are the different ways to cross the BBB?

Answer 3

The BBB can be crossed by using generally the same mechanisms as crossing biological membranes:
Passive diffusion can happen through aqueous channels - i.e., channels that are aqueous on the inside (not common)
Passive diffusion through lipid (this is the most important mechanism of absorption)
Some drugs can be taken up by endocytosis (rare)
Facilitated transport via transporters that transport endogenous compounds (e.g., amino acid transporters; this mechanism is important when a drug “looks” like endogenous compounds)

Question 4

What makes a molecule optimal for passive diffusion through the BBB

Answer 4

Mostly unionized at pH 7.4
Has molecular weight of less than 400
Has a log P within 1 and 4 (if the log P is too low, it will be too hydrophilic to partition into the lipid membrane and if the log P is too high, it will remain in the lipid membranes)

Question 5

What are pancuronium, atracurium and vencuronium?

Answer 5

Non-depolarizing neuromuscular blocking agents that are used in surgery to relax muscles. They are competitive antagonists of ACh receptors.

Question 6

What is succinylcholine?

Answer 6

A depolarizing neuromuscular blocking agent used in surgery to relax muscles that has a rapid onset and short duration of action. The mean that it can used and discontinued, and the effect will rapidly stop

Question 7

Why is it important to use depolarizing neuromuscular blocking agents?

Answer 7

With respect to the longer acting non-depolarizing neuromuscular blocking agents when the muscle blocking effect is no longer needed, there has to be a way to return muscle activity to normal as soon as possible so that the patient does not die of asphyxia when the ventilator is discontinued. Additionally, regaining consciousness while being paralyzed would be terrifying for the patient

Question 8

What is used in anesthesia to reverse the effects of non-depolarizing neuromuscular blocking agents?

Answer 8

Inhibitors of ACh (anticholinesterases or acetylcholinesterase inhibitors)

Question 9

Are anticholinesterases used with depolarizing neuromuscular blocking agents?

Answer 9

No!

Question 10

What anticholinesterases?

Answer 10

They inhibit acetylcholine esterase, which causes a buildup of ACh at the synapse. Excess ACh competes with non-depolarizing neuromuscular blockers. Because a non-depolarizing neuromuscular blocker is a competitive antagonist, its effects can be overcome by excess against i.e., ACh

Question 11

What are examples of anticholinesterases?

Answer 11

Edrophonium
Neostigmine
Pyridostigmine
Physostigmine

Question 12

Describe edrophonium

Answer 12

Binding is reversible and there is no covalent interaction with the enzyme. Its duration is short (a few minutes). It is used as a diagnostic test for myasthenia gravis. It is rarely used to reverse the effects of non-depolarizing neuromuscular blocking agents

Question 13

Describe neostigmine

Answer 13

Most commonly used anti cholinesterase in anaesthesia. Reversibly alkylates AChE rendering it inactive for about 30 minutes

Question 14

Describe pyridostigmine

Answer 14

Reversibly alkylates AChE. Longer onset than neostigmine and lasts for several hours. It is used to treat myasthenia gravis

Question 15

Describe physostigmine

Answer 15

Reversibly alkylates AChE. More lipid soluble than the other agents and can be absorbed from the GI tract. It can cross the BBB (exception to the rule: quaternary amines cannot cross BBB)

Question 16

What is myasthenia gravis?

Answer 16

Neuromuscular disorder characterized by remitting and relapsing muscle weakness that is aggravated by exercise and improve by rest. Any muscle can be affected but some are more likely than others.
It is an autoimmune disease characterized by production of antibodies to ACh receptors (AChR). Leads to decrease in receptor density at the NMJ. There are also morphological changes at the NMJ

Question 17

What are the morphological changes that occur at the NMJ due to a decrease in AChR density?

Answer 17

The fewer receptors, the greater distance between the nerve finer and receptors. There is less infolding at the NMJ. ACh needs to bind to most or all of the receptors to get depolarization and muscular contraction

Question 18

How can anticholinesterases be used to treat myasthenia gravis?

Answer 18

Can use anticholinesterases to treat myasthenia gravis. Increase ACh and NMJ restores muscular contraction upon nerve stimulus
Can use pyridostigmine (brane name: Mestinon) or other anticholinesterases that are orally abopsred, longer acting and do not cross the BBB

Question 19

Why is it important to properly dose anticholinesterases for the treatment of myasthenia gravis?

Answer 19

If there’s not enough, you won’t get 100% normal muscle function.
If there’s too much, the effects will decrease because of depolarizing neuromuscular block (cholinergic crisis)

Question 20

What are the side effects of anticholinesterases?

Answer 20

Salivation, sweating, decreased heart rate, increase GI motility, bronchospasm

Question 21

Describe the treatment of Alzheimer’s disease with anti-cholinesterases

Answer 21

A method treatment for Alzheimer’s disease is to inhibit AChE in the frontal cortex
Supposed to improve memory, learning and reasoning
Anticholinesterases are employed for this purpose but they cannot have a quaternary amine because they do not cross the blood-brain barrier

Question 22

What are some anticholinesterases used for the treatment Alzheimer’s?

Answer 22

Rivastigmine (brand name: Exelon)
Galantamine (brand name: Reminyl)
Donepezil (brand name: Aricept)

Question 23

Describe rivastigmine

Answer 23

This agent is similar to pyridostigmine and works the same way but there is not quaternary amine. After crossing the BBB, tertiary amine must ionize for activity so that it can bind anionic sites on AChE

Question 24

Describe galantamine

Answer 24

Has a tertiary amine that must be neutral to cross BBB but must ionize so it can bind to anionic sites on AChE once in the brain. It is a competitive and reversible inhibitor of AChE that does not alkylate the enzyme. Binds to enzymes like edrophonium

Question 25

Describe donepezil

Answer 25

Has a tertiary amine that must be neutral to cross BBB but must also ionize so it can bind to the anionic site on AChE. It is a competitive and reversible inhibitor of AChE that does not alkylate the enzyme. Like galantamine, it binds to enzymes like edrophonium

Question 26

Describe the AChE active site

Answer 26

There is a Asp-His-Ser catalytic triad which serves to make the alcohol of the serene a better nucleophile
There is an anionic binding site and an esteratic binding site in the active site for AChE

Question 27

What are organophoshpate anticholinesterases?

Answer 27

They have a phosphorous centre. There is a double bond oxygen or sulphur. There is an X group, and R and R1
The X group is usually a halogen, CN, alkylthio, or para-substituted phenol
The R and R1 group are usually short aliphatic O or S-alkyl chains (O-C3H7, O-CH3, or O-C2H5)

Question 28

What are examples of organophosphate anticholinesterases?

Answer 28

Sarin
Parathion
Malathion
All examples are highly hydrophobic and cross BBB easily

Question 29

Describe sarin

Answer 29

It is extremely potent and toxic. Its only use is as a nerve gas

Question 30

Describe parathion

Answer 30

It is an insecticide
It has a low activity as is; in insects, it is metabolized, replacing the S with O, making it very potent (humans do no do this)

Question 31

Describe malathion

Answer 31

Malathion is a safer insecticide than parathion because it is rapidly metabolized in higher organisms to inactive metabolites mono- and di-carboxylic acids (most important) and dimethyl-dithiophosphate

Question 32

Why are organophosphates nerve toxins?

Answer 32

They have the ability to increase ACh at the NMJ and synapse.
Eventually this leads to persistent activation of AChR, depolarizing neuromuscular block (think diaphragm) and death by asphyxia
The effects are very long acting because without treatment, organophosphates permanently inactivate AChE

Question 33

What are symptoms of organophosphate poisoning?

Answer 33

Similar side effects with regular anticholinesterases but more extreme
Pinpoint pupils, bronchospasm (laboured breathing, wheezing)
Decreased heart rate (weak pulse, low blood pressure)
Frothy salivation, profuse sweating
Increased GI motility, leading to spontaneous defecation and urination

Question 34

What is an aged enzyme?

Answer 34

An AChE modified by the phosphate of an organophosphate anticholinesterase. It is totally resistant to hydrolysis and permanently inactivated. This is lethal and there is not treatment

Question 35

What is 2-PAM?

Answer 35

Pralidoxime
It can bind to the anionic site to position itself for reaction
It can efficiently remove the initial phosphorylated enzyme (not the aged enzyme). It is the only treatment for organophosphate poisoning. It is often given with atropine but the 2-PAM is what save your life

Question 36

What are the three types of AChE inhibitors?

Answer 36

Those that competitively bind to the enzyme that are completely reversible and that do not covalently bind to the enzyme (donepezil, edrophonium, galantamine).
Those that covalently bind to the enzyme but DO NOT permanently inactivate it (neostigmine, pyridostigmine, physostigmine, rivastigmine).
Those that covalently bind to the enzyme and permanently inactivate it without treatment with 2-PAM (organophosphate anticholinesterases)

Question 37

What are muscarinic antagonists?

Answer 37

Muscarinic antagonists have affinity for the muscarinic receptors but have no intrinsic activity

Question 38

What is the effect of antimuscarinic drugs?

Answer 38

Different drugs are used for different purposes
Some are used for dilation of the pupil (mydriasis) prior to eye exams
Some are used for frequent urination or for abdominal pain that is caused by spasms of the GI
Because parasympathetic innervation of the lungs causes bronchoconstriction, muscarinic antagonists can cause bronchodilation. For that reason, some muscarinic antagonists are used for asthma and COPD

Question 39

What are examples of muscarinic antagonists?

Answer 39

Cyclopentolate (brand name: Cyclogyl)
Dicyclomine
Oxybutynin (brand name: Ditropan XL)
Tolterodine (brand name: Detrol LA)

Question 40

Describe cyclopentolate

Answer 40

Cyclopentolate is used as eye drops. It is often given prior to an eye examination to dilate the pupils (mydriasis)

Question 41

Describe oxybutynin and tolterodine

Answer 41

Oxybutynin and tolterodine are used for “over active bladder” or people who have excessive urinary frequency that does not have another cause. They are given as sustained release products hence the XL and LA

Question 42

What is atropine used for?

Answer 42

Atropine itself is not used much clinically
It is a component of belladonna and opium suppisotory
It is used for painful urethral spasm or intestinal cramping
Also given with 2-PAM for organophosphate anticholinesterase toxicity and sometimes with neostigmine after surgery when recovering from neuromuscular block

Question 43

What is hyoscyamine?

Answer 43

The is the purified S form of atropine (atropine is a racemic mixture). It is moro potent than the R form.

Question 44

What is benztropine?

Answer 44

Brand name: Cogentin
Many of the drugs used to treat schizophrenia are dopamine blockers. Dopamine is also needed in the brain in the substantial nigra to initiate movement. A movement disorder, Parkinson’s disease is marked by decreased dopamine in the substantial nigra. Some schizophrenics under treatment will get “Parkinson’s like” symptoms. In these cases, you can give benztropine to counteract these “Parkinsons like” symptoms

Question 45

What is scopolamine

Answer 45

Brand name: Transderm V
It is used to prevent motion sickness (although it can be used for any nausea). Comes as patches (transderm V) that are used for two days to provide continuous anti-nausea effect

Question 46

What is hyosine?

Answer 46

Brand name: Buscopan
It is used to stop spasms in the GI that produce abdominal pain. It is also known as butyl scopolamine. It is used as oral tablets 10 mg that are available without a prescription. The quaternary amine mean that is has a permanent positive charge because of this, very little drug is absorbed from the GI tract. The effect is therefore localized to the GI producing a minimum of systemic side effects

Question 47

What is ipratropium?

Answer 47

Brand name: Atroven
Given by inhalation MDI or nebulizer
Rarely used for asthma but can reduce bronchospasm (never given as mono therapy)
Often used for COPD
Has a quaternary amine; prevents crossing BBB (no CNS side effects). Also decreases systemic side effects (decreased systemic absorption from lungs)

Question 48

What is tiotropium?

Answer 48

Brane name: Spiriva
Formulated as a dry powder inhaler
Usually used to treat COPD (not asthma)
Advantage over ipratroprium is very long half life
Cannot be used for acute exacerbations of COPD

Question 49

What causes antimuscarinic side effects?

Answer 49

The generic structure for the structure-activity relationship for antimuscarinics suggests that many drugs that are otherwise targeted to other receptors may also be muscarinic antagonists (i.e., anti-histamines). Therefore, many drugs not otherwise thought to be muscarinic antagonists may have side effects that result from antimuscarinic activity.

Question 50

What are antimuscarinic side effects?

Answer 50

Dry mouth
Dilation of pupils
Difficulty with dark adaption (i.e., accommodating and sensitivity to light)
Blurred vision
Increased intraocular pressure
Hot, flushed, and dry skin
Tachycardia (increased HR)
Urinary retention
Constipation