Cholinergic and adrenergic

Question 1

Describe the nervous systemic pathways

Answer 1

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

Question 2

Explain the autonomic nervous system and the different pathways

Answer 2

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

Question 3

Explain how the cholinergic system works

Answer 3

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

Question 4

Describe the structure of Ach

Answer 4

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

Question 5

Answer 5

Methacholine

Addition of methyl group on the ethylene bridge to protect carbonyl group from esterases

Question 6

Answer 6

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

Question 7

What is this structure

Answer 7

Bethanechol

Contains both steric shielding and electronic stabilisation

Question 8

What are some clinical uses of Ach

Answer 8

Muscarinic agonist
Treament of glaucoma
Stimulating GIT and urinary tract AFTER surgery
Treatment of heart defects

Nicotinic
Treatment and management of myasthenia gravis

Question 9

Answer 9

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

Question 10

Explain the structure of Ach antagonist

Answer 10

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)

Question 11

Answer 11

Tubocurarine

Antagonist for Ach

Contains two positively charged N
No ester group

Question 12

Answer 12

Decamethonium

Antagonist for Ach receptors

Contains two positively charged N

Question 13

Answer 13

Suxamethonium

Antagonist for Ach receptors

Two acetylcholine linked together
Susceptible to hydrolysis

Question 14

Answer 14

Pancuronium if R=Me
Vecuronium if R=H

Contains steroid skeleton and two acetylcholine skeletons

No ester bond = longer duration of action

Question 15

Answer 15

Atracurium

Based on tubocurarine and suxamethonium structures

Can be inactivated by Hofmann elimination at physiological pH

Question 16

Define acetylcholinesterase and anticholinesterases

Answer 16

Acetylcholinesterase (AChE): enzymes that hydrolyses Ach

Antiacetylcholinesterase (AChE inhibitors): inhibit AChE which as the same effect as cholinergic drugs

Question 17

Explain the mechanism of hydrolysis

Answer 17

Question 18

Answer 18

Carbamate

AChE inhibitor

Carbamate - amide + ester
Hydrophobic benzyl ring
Quaternary ammonium ion

Question 19

Answer 19

Organophosphorus

AChE inhibitor

Irreversible inhibition

Question 20

What is the adrenergic system

Answer 20

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

Question 21

What are the adrenergic receptors

Answer 21

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

Question 22

What is the main difference between A and NA

Answer 22

Both contains phenol with hydroxy attached to an symmetric carbon with H, OH and NHR

Adrenaline R = Me
Noradrenaline R = H

Question 23

How is A and NA metabolised

Answer 23

Monoamine oxidase converts NHR into COH

Cathechol O methyltransferase converts 3-OH into 3-MeO

Question 24

Explain the structure-activity relationship of catecholamines

Answer 24

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

Question 25

Answer 25

Alpha 1 selective blocker

MeO on benzyl ring

Question 26

Answer 26

Isoprenaline

Selective beta agonist
R = 2 Methyl

Question 27

Answer 27

Isoetharine

Selective beta 2 agonist
Contains Ethyl and R = 2 Methyl

Question 28

Answer 28

Salbutamol

COOH on M-phenol
R = C4H9

Question 29

Explain the structure-activity relationship of first generation beta blockers

Answer 29

R on NH = brancing and extension = fits hydrophobic pocket

NH = secondary amine = ionic bonding

OH - H bonding

O-C = H bonding

Rings - hydrophobic interactions

Question 30

Secondary beta blockers

Answer 30

Selective for beta 1 receptors

Question 31

Third generation beta blockers

Answer 31

More selective for beta 1 receptor

Extension and addition of groups to N