Drugs Targeting Nicotinic and Muscarinic Receptors Flashcards
Describe cholinergic receptors
All cholinergic receptors bind ACh for activity
There are different types of cholinergic receptors, they are differentiated by their differing affinities for two agonists: nicotine and muscarine
Nicotinic: nicotinic ganglionic (also nicotinic neuronal) and nicotinic cholinergic (this is part of the somatic nervous system)
Muscarinic: there are at least 5 subtypes of muscarinic receptors and all are GPCRs
What happens with depolarization and neuromuscular junctions (NMJs)
Depolarization at the NMJ initiates an action potential, which propagates muscular contraction via nearby voltage gated sodium channels
What do depolarizing NMJ blockers do?
Depolarizing neuromuscular blockers (succinylcholine, decamethoium) initially can cause an action potential and propagate muscular contraction. But continued stimulus results in an increase in the resting membrane potential. Over time, continuous stimulation of Nm receptors increases the resting membrane potential resulting in the nearby voltage gated sodium channels becoming refractory and no muscular contraction is propagated
How does a non depolarizing neuromuscular block work?
It is caused by competitive antagonism of the Nm receptor (d-tubocurarine and pancuronium)
What are the uses of succinylcholine and pancuronium?
Although they work via different mechanism, both are used clinically to induce muscle relaxation during surgery
Succinylcholine is rapidly hydrolyzed by esterase’s to inactive metabolites and is used when it is desirable to have tight control of blockade such as electroconvulsive therapy ECT for refractory depression
Pancuronium is used for muscle relaxation during longer surgery procedures due to its longer duration of action
What are examples of Ng selective antagonists?
Trimetaphan
Hexamethonium
Not used clinically anymore due to too many side effects
M1 receptors: what type of G alpha protein do they interact with? What are the tissue locations? What are the cellular effects? What are their functions?
They interact with G alpha q proteins
They are in the CNS (cortex, hippocampus), ganglia, parietal cells
They increase IP3 and DAG, they increase intracellular calcium and they decrease potassium outflow. This results in excitation
Functions: CNS excitation (memory), gastric acid secretion, GI motility
M2 receptors: what type of G alpha protein do they interact with? What are the tissue locations? What are the cellular effects? What are their functions?
They interact with G alpha i proteins
They are found in the cardiac tissue (atria and conducting tissue) and neural tissue (presynaptic terminals)
They decrease cAMP, intracellular calcium and increase potassium outflow. Results: inhibition
Function: cardiac inhibition, decreased heart rate, decreased force of contraction, presynaptic inhibition and neural inhibition
M3 receptors:what type of G alpha protein do they interact with? What are the tissue locations? What are the cellular effects? What are their functions?
They interact with G alpha q proteins
They are found in the smooth muscle and the vascular endothelium
They increase IP3 and DAG, intracellular calcium and decrease potassium outflow. Results: stimulation
Function: smooth muscle contraction
Describe the conformational flexibility of acetylcholine
There is significant conformational flexibility in the ACh molecule
It can adopt several conformations, some favour binding to nicotinic while others favour muscarinic receptors
We can make restricted analogues and modify parts of the ACh structure to determine what parts of ACh are important for binding and what conformation ACh adopts when it binds to each receptor
Why is ACh rapidly hydrolyzed by AChE?
Internal ion-dipole interaction with ACh increases polarization of carbonyl double bond. This carbonyl is a strong electrophile. At is very susceptible to hydrolysis
This is in part why it is rapidly hydrolyzed by AChE
What is the difference between ACh and carbachol?
Delocalized electrons decrease the electrophilic nature of the carbonyl carbon. It resists hydrolysis by ACh
What is the difference between ACh and methacholine?
Methyl-group is added as a “steric shield”, which reduces access to carbonyl carbon by nucleophiles. It also streakily inhibits binding to AChE
What is methacholine used for?
Used as a test for asthma called methacholine challenge test
What is bethanechole used for?
Used to increase urinary output
Often after surgery or in prostatic hypertrophy that does not respond to conventional treatments like tamsulosin
