Cholinergic and adrenergic Flashcards
Describe the nervous systemic pathways
Somatic NS
CNS to skeletal muscle
uses Ach neurotransmitter
Autonomic
Sympathetic
CNS - synapse - smooth muscle and cardiac uses NA and Ach neurotransmitter
CNS - adrenal medulla uses Ach neurotransmitter
Parasympathetic
CNS - synapse - smooth muscle and cardiac uses Ach neurotransmitter
Explain the autonomic nervous system and the different pathways
ANS is from CNS to smooth muscles and cardiac cells
Sympathetic ANS
Presynaptic activates nicotinic receptors by Ach
Post synaptic - adrenergic receptors - NA
Parasympathetic ANS
Presynaptic - nicotinic - Ach
Postsynaptic - muscarinic - Ach
Explain how the cholinergic system works
Biosynthesis of acetylcholine from choline by choline transferases
Ach incorporated into vesicles within synapse/ nerve terminal
Nerve signal opens Ca Channels = increased intracellular Ca = release of Ach
Acetyltransferases breaks down Ach
Choline taken back into nerve terminal
Describe the structure of Ach
Acetoxy contains ester functional group which is important for H-bonding
Methyl cannot be bigger - fits into hydrophobic pocket
Ethylene bridge - 4.4 for muscarinic, 5.9 for nicotinic
Quaternary nitrogen is important for ionic interactions
At least two methyl groups
Methacholine
Addition of methyl group on the ethylene bridge to protect carbonyl group from esterases
Carbachol
it is an Ach analogue that has an electronic protection
Replacement of CH3 to NH2
Lone EP of N interacts with neighbouring CO = less susceptible to hydrolysis
What is this structure
Bethanechol
Contains both steric shielding and electronic stabilisation
What are some clinical uses of Ach
Muscarinic agonist
Treament of glaucoma
Stimulating GIT and urinary tract AFTER surgery
Treatment of heart defects
Nicotinic
Treatment and management of myasthenia gravis
Atropine and hyoscine
Contains Ach structures but larger = can bind to outside of receptors but no effect occurs
Atropine to decrease GI motility
Hyoscine to treat motion sickness
Explain the structure of Ach antagonist
Tertiary or quaternary ammonium ion
can be bigger than methyl
Ethylene bridge
Acyl side must have very large groups = no activity
Can be aromatic or heteroaromatic
- overall shape must be Y or T shaped (branching)
Tubocurarine
Antagonist for Ach
Contains two positively charged N
No ester group
Decamethonium
Antagonist for Ach receptors
Contains two positively charged N
Suxamethonium
Antagonist for Ach receptors
Two acetylcholine linked together
Susceptible to hydrolysis
Pancuronium if R=Me
Vecuronium if R=H
Contains steroid skeleton and two acetylcholine skeletons
No ester bond = longer duration of action
Atracurium
Based on tubocurarine and suxamethonium structures
Can be inactivated by Hofmann elimination at physiological pH
Define acetylcholinesterase and anticholinesterases
Acetylcholinesterase (AChE): enzymes that hydrolyses Ach
Antiacetylcholinesterase (AChE inhibitors): inhibit AChE which as the same effect as cholinergic drugs
Explain the mechanism of hydrolysis
Carbamate
AChE inhibitor
Carbamate - amide + ester
Hydrophobic benzyl ring
Quaternary ammonium ion
Organophosphorus
AChE inhibitor
Irreversible inhibition
What is the adrenergic system
It is part of the peripheral NS
Innervates smooth muscle and cardiac muscles but stimulates fight or flight response
Uses adrenaline and noradrenaline as neurotransmitters
What are the adrenergic receptors
Alpha 1 and 2
Beta 1, 2 and 3
Both stimulated by A and NA
Alpha stimulates contraction of smooth muscles
Beta stimulates smooth and cardiac muscles
What is the main difference between A and NA
Both contains phenol with hydroxy attached to an symmetric carbon with H, OH and NHR
Adrenaline R = Me
Noradrenaline R = H
How is A and NA metabolised
Monoamine oxidase converts NHR into COH
Cathechol O methyltransferase converts 3-OH into 3-MeO
Explain the structure-activity relationship of catecholamines
OH group
M-phenol can be replaced as long as it can form H-bond
Amine
Ionic interaction
Must be protonated
Primary or secondary amine
Increase size of N-Alkyl
reduced potency for alpha
increased potency for beta
increase selectivity for beta
Alpha 1 selective blocker
MeO on benzyl ring
Isoprenaline
Selective beta agonist
R = 2 Methyl
Isoetharine
Selective beta 2 agonist
Contains Ethyl and R = 2 Methyl
Salbutamol
COOH on M-phenol
R = C4H9
Explain the structure-activity relationship of first generation beta blockers
R on NH = brancing and extension = fits hydrophobic pocket
NH = secondary amine = ionic bonding
OH - H bonding
O-C = H bonding
Rings - hydrophobic interactions
Secondary beta blockers
Selective for beta 1 receptors
Third generation beta blockers
More selective for beta 1 receptor
Extension and addition of groups to N
