(From Dr. Nardell’s ANS Physiology Handout, by Brian Buschman)
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Choline esters act on M1, M2 and M3 receptors. Carbachol is one choline ester that works primarily on the muscarinic receptors but also functions on nicotinic receptors a little. Bethanechol is another choline ester but it’s effects are largely limited to the muscarinic receptors. The major advantage of bethanechol is that since it’s limited to muscarinic receptors it will only produce it’s effects on the sympathetic system and not on the ganglia and somatic motor end plates also.
Choline esters act on the CV, GI, GU and the eye to a large degree. They are good drugs to use because they are not easily degraded by ACh esterase like ACh would be if administered pharmacologically. Since they are not degraded their mechanism of inactivation is by kidney excretion.
Their effects are normal parasympathetic responses to all parts of the body. This does bring concern when administered to asthmatic patients for the obvious reason of bronchioconstriction. They do not enter the CNS. Administration is tricky because they cannot be given IV or IM because that would cause excessive local reaction near the site of administration. Bethanechol is given either pro-oral or sub-q which carbachol is given topically on the conjunctiva. I remember that carbachol is on the conjunctiva because both start with C and also carbachol has ganglionic activity so it can cause more problems systemically so you want to administer it as local as possible. Because of this you don’t want to ingest it but would rather apply topically to the conjunctiva for things like glaucoma.
One additional difference between bethanechol and carbachol is that carbachol is only slightly antagonized by atropine but bethanechol is very antagonized by atropine. With atropine OD I guess you could give carbachol.
Adverse effects of cholinergic drugs can be remembered by the mnemonic, DUM BELS.
D – defecation
U – urination
M – miosis
B – bronchioconstriction
E – electrical changes
L – lacrimation
S – salivation/secretion
They are really just a bunch of parasympathetic things that can be bad.
Bethanechol is used clinically to treat post-op paralytic ileus (GI), urinary retention (GU) and glaucoma. (In glaucoma the choline ester, bethanechol, is used to reopen the channels while the soon to be seen adrenergics will help decrease aqueous humor production.)
Both pilocarpine and muscarine act almost exclusively on M1, M2 and M3 receptors with effects similar to choline esters. They also have DUM BELS as their adverse effects but also enter the CNS so extra adverse effects include headache, tremor, arousal and excitation.
They have very few therapeutic uses. There are none for muscarine and pilocarpine is only used for the treatment of open-angle glaucoma.
Another way to stimulate a cholinergic response is to inactivate ACh-esterase thereby leaving the ACh around for a longer time. The drugs come as either reversible or irreversible.
The reversible class of cholinesterase inhibitors are called carbamates and have a T˝ of minutes to hours. The include endrophonium, physostigmine, neostigmine and tacrine.
Organophosphates are the irreversible ACh-esterase inhibitors. There is a process called aging whereby the organophosphate first binds to ACh-esterase and then after a time it irreversibly destroys the molecule. During this time of aging the process can be blocked by the anti-aging drug, pralidoxime or obidoxine. Reversible cholinesterase inhibitors include isoflurophate and echothiophate.
Effects of cholinesterase inhibitors are similar to choline agonists but are strange because they do play a large role in ganglionic function until bethanechol since ACh is the NT for both nicotinic and muscarinic receptors. This means there is a degree of stimulation of both the sympathetic and parasympathetics but mainly the parasympathetics. At low doses it can cause increase skeletal muscle contraction (first for muscles of fine motor in the fingers) and bradycardia with no or slight BP decrease. At higher doses it causes fasciculations, Nm blockage and marked bradycardia and hypotension (due to vasodilatation).
Oral bioavailability is high and in general organophosphates enter through any route including direct absorption through the skin (a gas mask doesn’t block nerve gas). Except for neostigmine they enter the CNS.
Adverse effects are DUM BELS plus the associated fasciculations.
This can be figured out logically by thinking about how more ACh would interact with respect to the action of the other drug. Non-depolarizing neuromuscular blockers and antimuscarinics are antagonized. Depolarizing neuromuscular blockers and cholinesterase inhibitors act synergistically.
Glaucoma is treated with cholinergic drugs (pilocarpine & carbachol) to open the channels of Schlemm to allow the aqueous humor to drain. Glaucoma is caused by their closure and the buildup of pressure of the aqueous humor.
They are also used to treat various diseases that are associated with a loss of parasympathetic function.
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