Where are the three types of muscarinic receptors found in the body?
M1: Postganglionic neurons of autonomic gangliaM2: Heart, primarily smooth muscleM3: Glands, smooth muscle, endothelium
Where are the two types of nicotinic receptors found in the body?
N1/Nn: postganglionic neurons of autonomic ganglia (including adrenal medulla)N2/Nm: neuromuscular junction of skeletal muscles
What are the cholinergic receptor subtypes, and what are these subtypes based on?
Muscarinic and nicotinic, based on selectivity for muscarine or nicotine
What type of receptors are nicotinic receptors?
nicotinic receptors are ligand-gated ion channels
What is the mechanism of action for nicotinic receptors?
2 ACh molecules bind to receptor and cause the Na+ channel to open, which in turn triggers an EPSP.
What type of receptors are muscarinic receptors?
7 transmembrane domain receptors coupled to G proteins
ACh and other cholinergic drugs mimic stimulation of the ______ nervous system via ______ receptors.
Why does ACh have no real therapeutic application?
It has limited therapeutic use because of its diffuse action and its rapid breakdown by cholinesterase.
T or F: Synthetic choline esters and natural alkaloids are both examples of cholinergic drugs.
Which natural alkaloids are selective for muscarinic receptors? Nicotinic receptors?
Muscarinic: muscarine and pilocarpineNicotinic: nicotine and varenicline
Name as many of the normal physiological functions of the parasympathetic nervous system as you can.
decrease heart rate, decrease blood pressure, activation of GI movements, emptying of bladder and rectum, activation of mucosal cells and salivary and lacrimal glands, constriction of bronchi, constriction of pupil and lens
The rate of ACh synthesis is controlled by the rate of _____.
Which enzyme catalyzes ACh synthesis?
Choline acetyltransferase (ChAT)
Which two enzymes can catalyze the hydrolysis of ACh?
Acetylcholinesterase (AChE) and plasma cholinesterase (aka pseudocholinesterase and butyrylcholinesterase)
Name the four directly-acting muscarinic receptor agonists (aka cholinomimetics).
acetylcholine, methacholine, carbachol, bethanechol
Which of the cholinomimetics are susceptible to cholinesterase? Which are unaffected by cholinesterase?
Acetylcholine and methacholine are susceptible to cholinesterase, while carbachol and bethanechol are not
Why are carbachol and bethanechol longer acting than the other cholinomimetics?
duration of action of cholinergic agonists is based primarily on susceptibility to cholinesterase; carbachol and bethanechol are not effectively hydrolyzed by cholinesterase.
Where is acetylcholinesterase primarily found?
high concentrations are found at cholinergic synapses, neuromuscular junctions, and in RBCs
Where is plasma cholinesterase primarily found?
plasma and liver, with limited expression in other tissues
Which enzyme hydrolyzes ingested esters from plant sources and ACh that escapes from cholinergic synapses?
Name the four competitive inhibitors of cholinesterases
edrophonium, neostigmine, pyridostigmine, physostigmine
T or F: cholinesterase inhibitors are agonists of the parasympathetic nervous system that operate through direct stimulation.
F; cholinesterase inhibitors indirectly stimulate the parasympathetic nervous system by prolonging the activity of ACh in the synapse
Name the three major types of noncompetitive cholinesterase inhibitors.
Organophosphate (O-P) derivatives, insecticides, and nerve gases
O-P insecticides react first with _______, while O-P nerve gases react first with _______.
O-P insecticides react first with plasma cholinesterase while O-P nerve gases react first with AChE.
Which enzyme inactivates the neuromuscular blocker succinylcholine?
Name the three chemical categories of cholinesterase inhibitors.
simple alcohols with quarternary ammonium group, carbamates, and organophosphates
Name the simple alcohol cholinesterase inhibitor
Name the carbamate cholinesterase inhibitors
neostigmine, physostigmine, pyridostigmine, and carbaryl
Which class of cholinesterase inhibitors is irreversible and longer-acting, competitive or noncompetitive?
noncompetitive is irreversible and long-acting, while competitive is reversible and short-acting
Name the organophosphate cholinesterase inhibitors
DFP (diisopropylfluorophosphate) and echothiophate
Explain the two step process in which ACh is hydrolyzed by AChE.
1) ACh bound to AChE is partially hydrolyzed to choline + acetylated AChE2) the acetylated AChE is then hydrolyzed to acetate + AChE
Study this too.
What is the standard two-step therapy used to treat O-P intoxication?
treatment with 1) atropine and 2) pralidoxime (2-PAM)
What is the function of atropine in treating O-P intoxication?
Antagonizing O-P actions by binding competitively to muscarinic receptors
What does Pralidoxime do to combat O-P intoxication?
pralidoxime reactivates AChE that has been inhibited by O-P intoxication
T or F: Pralidoxime combats O-P intoxication through reactivation of inhibited and aged AChE.
F, pralidoxime can only reactivate inhibited AChE, not aged AChE
Why are drugs that stimulate the cholinergic system used to treat acute closed angle glaucoma?
cholinergic agonists reduce intraocular pressure by causing the ciliary body to contract, allowing for better drainage of aqueous humor from the anterior chamber of the eye
What effect do cholinergic stimulants have on the GI and urinary tract? what types of conditions are they used to treat?
Cholinergic drugs increase the smooth muscle activity of the GI and Urinary tract, and so they are used to treat all conditions in which there is a depression (eg ileus, urinary retention, etc)
What type of drugs are used to treat myasthenia gravis?
What are some common undesireable effects of cholinergic agonists?
flushing, sweating, abdominal cramps, difficulty with visual accomodation, salivation