Acetylcholinesterase Inhibitors Flashcards
It’s therapeutic use is in the treatment of anti cholinergic toxicity (such as in atropine)
Physostigmine
If the name has -stigmine in it
Acetylcholinesterase inhibitors
What kind of amine is physostigmine
Tertiary amine, very lipid soluble, no charge, can go anywhere in the body
What is the downside to physostigmine
Can enter CNS and cause convulsions
What do we use for an atropine overdose?
Physostigmine
What is the primary use for pyridostigmine and neostigmine
For myasthenia gravis treatment
What are the reversible acetylcholinesterase inhibitors
Physostigmine, pyridostigmine, neostigmine, edrophonium, donepezil
Antibodies attack nicotinic (Nm) receptors at the NMJ
Myasthenia gravis
Acts to reverse no depolarize get blocking agents (rocuronium)
Pyridostigmine
Neostigmine
Pyridostigmine and neostigmine and the CNS
They are quaternary amines so have less potential to enter CNS and cause convulsions
Why is pyridostigmine or neostigmine a better choice for myasthenia gravis than physostigmine
Because physostigmine can reach the CNS and cause convulsions. It can definitely treat MG, but there’s not advantage to it. The other two dont reach CNS to cause convulsions so they are the best choice
It’s therapeutic use is to diagnose myasthenia gravis
Edrophonium
Why is edrophonium good for diagnosis MG
Has a short duration of action (10-20m) and IV injection leads to a rapid increase in muscle strength in those with MG. Inhibits Achase and increases Ach
Clinical presentation of myasthenia gravis
- ptosis
- difficulty chewing and swallowing
- anhydrosis
It’s therapeutic use is to treat mild to moderate Alzheimer’s
Donepezil
Oldest and most common drug to treat mild to moderate Alzheimer’s
Donepezil
Why do we use an Achase inhibitor to treat Alzheimer’s
Patients have a loss of neurons in the cortex and disproportionate loss of cholinergic neurons. Want to increase ACH as the primary therapeutic strategy
Examples of irreversible achase inhibitors
Sarin
Parathion
Malathion
What is sarin
- irreversible achase inhibitor
- nerve gas
- binds strongly with achase
- long 1/2 life
These are examples of organophosphate which are used as insecticides
Parathion and malathion
What is the danger of using an irreversible Achase inhibitor such as sarin, parathion, or malathion?
The binding of drug to achase is not easily reversed since it forms a covalent bond.
How do you get rid of an Achase inhibitor that is irreversibly bound?
With a chemical reactivator such as pralidoxime (PAM)
- this can break the bonds between the irreversible achase and achase inhibitor is given before chemical aging occurs.
- breaks the covalent bonds
Toxicity of Achase inhibitors
DUMBBEELSS
- diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (of CNS and skeletal muscles), emesis, lacrimation, salivation, sweating
- looks like excess parasympathetic plus sweating plus nicotinic effects
Receptors that are affected in Achase inhibitor toxicity
mostly M3s, some M2 and M1, also N activation
Treatment for an achase inhibitor overdoes
Atropine +/- pralidoxime
What does atropine do in the case of an Achase inhibitor overdose
- M blocker
- does not stop anything nicotinic!!
Why can someone still die from an achase inhibitor overdose even if they are started on atropine
Because the diaphragm is muscel which is innervated by Nm receptors. Atropine is an M blocker, and will not block the Nn receptor. If the diaphragm is paralyzed, you will die
When do you need to give pralidoxime with atropine in the case of an achase inhibitor overdose
Needed in extreme cases to target the Nm receptor on the diaphragm. Atropine will not block the Nm receptor so the pt could die
Chemical aging
- nerve gases change chemical structure after some time in the body
- pralidoxime has a hard time binding the enzyme to remove the nerve gas effectively
- have to act very quickly to get it taken care of
- atropine will relieve symptoms but wont get the diaphragm
Hyperthermia induced by anti muscarinic drugs; causes mainly by inhibition of sweating
Atropine fever
Marked cutaneous vasodilation of the arms and upper torso and head by anti muscarinic drugs; mechanism unknown
Atropine flush
A chemical antagonist that binds the phosphorus of organophosphates and displaces achase
Cholinesterase regenerator
Paralysis of accommodation
Cycloplegia
Flaccid skeletal muscle paralysis causes by persistent depolarization of the neuromuscular end plate
Depolarizing blockade
A drug that constricts the pupil
Miotic
Drug that dilates the pupil
Mydriatic
Flaccid skeletal muscel paralysis caused by blockade of the nicotinic end plate receptor
Nondepolarizing blockade
A chemical change in the organophosphate molecule that occurs after binding of the organophosphate to cholinesterase for a period of time; renders the enzyme-inhibitor complex less susceptible to regeneration by pralidoxime
Organophosphate aging
A drug that block the muscarinic receptors of autonomic effector tissue and reduces the effects of parasympathetic nerve stimulation
Parasympathetic
Selectivity of effect hat is achieved by local administration or special distribution of a drug, not by a receptor sensitivy
Pharmacokinetic selectivity
Classification for anti muscarinic agents
Selectivity for muscarinic receptor subtypes
-non-selective, will bind all M receptor subtypes
What is a common name for anti muscarinic agents?
Anything with “trop” or “scop” in the name
Belladonna alkaloid with high affinity for muscarinic receptors, can block M receptors in both the periphery and PNS
Atropine
Prototypical antimuscarinic drug
Atropine
Pharmacokinetics of atropine
- tertiary amine which makes it lipid soluble
- well distributed into the CNS and other organs
- short 1/2 life except in the eye
Mechanism of action of atropine
- competitive antagonist at muscarinic receptors
- can use physostigmine as antidote for overdose
Effects of muscarinic blockers on the blood vessels
Nothing will happen at the M3 receptors in the blood vessels since there is no physiologic function of them. There WILL be a response if patient is already taking an M agonist though, since those will be acting on the M3 receptors
Effects of muscarinic blockers on skeletal muscles
None, nicotinic
Clinical uses of atropine
Used to dilate pupils and to paralyze accommodation; duration is <72 hours
-not used a whole lot because of how long it lasts
What are the top muscarinic blockers for dilated eye exam
Atropine
Homatropine
Cyclopentalte
Tropicamide
Used for motion sickness and for Parkinson’s
Scopolamine
M blocker
What kind of drug is scopoloamine
M blocker
Why do we used scopolamine for Parkinson’s, when that is an issue with dopamine?
Parkinson’s is causes by loss of dopaminergic neurons, as a result there is an imbalance in NT where dopamine is too low and ACh is too high
-M blockers balance the two.
Motion sickness and M receptors
Stimulation of muscarinic receptors causes nausea and vomiting; in motion sickness, the main effect of muscarinic blockers is on the vestibular apparatus
Atropine for asthma and COPD
M blockers are good for asthma because they bronchodialte
Would you want to use an M blocker or an M agonist to treat asthma
Blocker
-want to bronchodilate the airway
What are some M antagonists that work on the bladder to reduce urgency
Tolterodine
Oxybutynin
What is urinary incontinence treated with
Muscarinic blockers
Toxicity of muscarinic antagonists
Dry as a bone Red as a beet Hot as a pistol Mad as a hatter Blind as a bat
Muscarinic antagonists and sweating
- Blockade of thermoregulatory mechanisms (sweating) may cause hyperthermia or “atropine fever”, this is potentially fatal in infants
- dry as a bone because sweating, salivation, and lacrimation are all significantly reduced or stopped
What effect do muscarinic antagonists have in the elderly
Acute angle-closure glaucoma because it decreases aqueous humor drainage
CNS effects of muscarinic blockers
Sedation, amnesiac, hallucinations
Cardiovascular effects of M blockers
Dilation of the cutaneous vessels of the periphery, also known as atropine flush and may be diagnostic of an overdose
Is atropine flush due to the effects of the drug?
Purely a compensation to increased temp because you are hot and cannot sweat, so blood vessels dilate. Drugs themselves NOT causing vasodilation
