Cholinergic Agonists and Antagonists Flashcards
What are the functions of the M1 muscarinic receptor?
Activates myenteric plexus
What are the functions of the M2 muscarinic receptor?
Decreases HR and contraction via opening of the K channels
What are the functions of the M3 muscarinic receptor?
Pupillary constriction
Bronchoconstriction
Increase GI motility
Contract bladder detrusor
Stimulate salivary secretion
What are the muscarinic receptors?
M1
M2
M3
What are the nicotinic receptors?
Nn
Nm
What is the Nn receptor?
Neuronal nicotinic receptor
What is the Nm receptor?
Muscle cell nicotinic receptor
What receptor does nicotine bind?
Nn
What is the effect of nicotine?
Diffuse activation of central and peripheral nicotinic receptors
Nicotine indication
Limited to preparations for smoking cessation often in a transdermal patch
Nicotine Toxicity
Effects include irritation at site of administration and dyspepsia
What does succinylcholine stimulate?
Succinylcholine sticks on the Nm receptor for a
long period of time and that leads to prevention
of action potential conduction by blocking the Nm receptor
Succinylcholine indication
Used clinically as a muscle relaxant during intubation or electro convulsive shock therapy
Succinylcholine Contraindications
Familial hyperthermia
Skeletal muscle myopathies
What are the types of muscarinic agonists?
Quaternary nitrogen analogs
Tertiary amine alkaloids
Synthetic analogs
What does ACh stimulate?
Binds to both nicotinic and muscarinic receptors of the autonomic nervous system, the CNS and the neuromuscular junction.
ACh indication
It is rapidly hydrolyzed by acetyl- and plasma cholinesterases. Therefore, it has no therapeutic use.
What does methacholine stimulate?
Primarily muscarinic effects on smooth muscle, glands and heart
Methacholine indication
Used to diagnose bronchial hyperactivity in patients suspected of having asthma
Methacholine Toxicity
Bronchiolar constriction
Methacholine Contraindications
Contraindicated in pts given β-blockers since antidote to overdose is β-agonist.
What does carbachol stimulate?
Muscarinic and nicotinic activity
Is carbochol easily hydrolyzed by AChE?
Resistant to hydrolysis by AchE
Carbachol indication
Miotic agent for ocular surgery and glaucoma
Used as an intraocular injection to reduce pressure after cataract surgery
Carbachol Toxicity
Side effects are related to excessive muscarinic and nicotinic receptor activation i.e., bronchoconstriction, reduced cardiac conduction
Bethanechol targets
Muscarinic selectivity
Bethanechol hydrolysis
It is resistant to hydrolysis by cholinesterases
What is the effect of bethanechol?
It has selective action on muscarinic receptors of GI tract and urinary bladder and minimizes the cardiac effects.
Bethanechol indication
Post-op urinary retention
Neurogenic bladder atony
Bethanechol Toxicity
Bradycardia
Bronchoconstriction
Bethanechol Contraindications
Asthma
Peptic ulcer
Bradycardia
What are the quaternary nitrogen analogs?
Methacholine
Carbachol
Bethanechol
Muscarine targets
Pure muscarinic activity
Muscarine hydrolysis
Resistant to hydrolysis (no ester moiety)
Muscarine indication
No therapeutic use
What is muscarine poisoning treated with?
Muscarinic poisoning causes profound parasympathetic activation, and is treated with atropine, a muscarinic receptor antagonist
Pilocarpine targets
Pure muscarinic activity
Pilocarpine and BBB
Crosses the BBB and has CNS effects
Pilocarpine indication
Dry mouth due to head and neck radiotherapy
Sjogren’s syndrome
Open angle glaucoma
Acute and chronic angle-closure glaucoma
Pilocarpine Toxicity
Excess muscarnic activation (slowed AV conduction), Hypotension
Excessive salivation
Bronchoconstriction
Pilocarpine Contraindications
Administer with care to patients taking β-blockers due to exacerbation of conduction slowing.
Acetylcholinesterase
Acetylcholinesterase catalyzes the hydrolysis of acetylcholine
What are indirect cholinergic agonists?
Inhibition of cholinesterase protects acetylcholine from hydrolysis, and leads to the accumulation of endogenous acetylcholine and increased cholinergic activity. Thus, cholinesterase inhibitors act indirectly as cholinergic agonists.
What is regional function of acetylcholinesterase?
Hydrolysis of acetylcholine liberated in synaptic cleft or in neuroeffector transmission.
What is the regional function of butyl cholinesterase?
Plasma, non-specific esterase. Does hydrolyze certain exogenous drugs, e.g., succinylcholine.
Neostigmine and BBB
Contains a quaternary nitrogen, and thus poorly penetrates blood brain barrier.
What is the effect of neostigmine?
Inhibits acetylcholinesterase and has direct stimulatory effect on nicotinic receptors at the skeletal muscle endplate
Neostigmine indication
Myasthenia graves
Used to reverse neuromuscular blockade
Neostigmine Toxicity
Side effects due to excessive Ach action at peripheral muscarinic and nicotinic receptors
Neostigmine Contraindications
Intestinal obstruction
Edrophonium targets
Inhibits cholinesterases and stimulates nicotinic receptors
Edrophonium onset and duration of effect
Has a very rapid onset of action, and a very short duration of action (10-15 min)
Edrophonium indication
Diagnosis of myasthenia gravis
Differential diagnosis of too little or too much AchE inhibitor in myasthenia gravis
Edrophonium Toxicity
Bradycardia
Edrophonium Contraindications
Intestinal blockade
Urinary obstruction
How does treatment with edrophonium allow for differential diagnosis in myasthenia gravis?
Treatment with short acting cholinesterase inhibitor reduces symptoms if muscle weakness is due to disease progression. It will worsen symptoms if due to cholinesterase toxicity.
Physostigmine and BBB
Readily crosses the BBB
Physostigmine onset and duration
Inactivated by plasma cholinesterases but takes a long time with duration of action up to 2 hours
Physostigmine indication
Antidote for muscarinic antagonist poisoning
Physostigmine Toxicity
Side effects related to increased Ach
at muscarinic or nicotinic receptors.
Convulsions, respiratory and CV depression
Physostigmine Contraindications
Asthma
Cardiac insufficiency
Gut obstruction
Donezipil indication
Alzheimer’s Disease
Donezipil target
Inhibits only acetylcholinesterase and is reversible inhibitor in the CNS
What are the irreversible cholinesterase inhibitors?
Organophosphates phosphorylate cholinesterases which exhibits severe toxicity.
What are the signs of organophosphate toxicity?
(DUMBBELS)
D Diarrhea
U Urination
M miosis
B bradycardia
B bronchorrea
E emesis
L lacrimation
S Salivation
How is atropine used in the treatment of organophosphates?
It protects from systemic muscarinic effects
How does pralidoximine treat organophosphate poisoning?
Reactivation of the alkylphosphorylated acetylcholinesterase with Pralidoxime Chloride (2-PAM)
Echothiophate targets
Irreversible acetycholinesterase inhibitor
Echothiophate indication
Produce long term miosis in the treatment of open angle
glaucoma
Echothiophate Toxicity
Blurred vision
Brow ache
Echothiophate duration
Long half life and once a day administration is enough
What are the competitive muscarinic antagonists?
Atropine
Scopolamine
Glycopyrrolate
Atropine target
Muscarinic antagonist
Atropine indication
Organophosphate poisoning
Induction of mydriasis and cycloplegia (though long duration of action)
Reverse bradycardia of vagal origin
Reverse gastrointestinal hypermotility
Bladder spasms (urgency) associated with cystitis
Scopolamine target
Muscarinic antagonist
Scopolamine indication
Used in preparation for surgical anesthesia to minimize
secretion
To treat nausea and vomiting associated with motion sickness and chemotherapy induced nausea
Scopolamine Toxicity
Anti-muscarinic actions
Scopolamine Contraindications
Narrow angle glaucoma
Glycopyrrolate target
Muscarinic antagonist
Glycopyrrolate indication
Its antimuscarinic activity is used to prevent overstimulation of the gut during reversal of neuromuscular blockade
Glycopyrrolate Toxicity
Heat stroke due to inability to sweat in heat
What are the signs of atropine poisoning?
Dry mouth
Hot
Dilated pupils
Tachycardia
Increased BP
Nervousness
