Introduction to the PNS :Cholinergic therapeutics

Question 1

The PNS represents the output of the CNS and (usually) acts independently to regulate the body’s internal environment. what does the PNS consists of ?

Answer 1

1) Autonomic nervous system (ANS)
largely outside of voluntary control
2) Somatic (motor) nervous system (SNS)
- under conscious control

Question 2

state the function of the efferent and afferent nerves in the somatic nervous system.

Answer 2

1) Efferent nerves control movement by innervating skeletal muscle.
2) Afferent nerves respond to external stimuli e.g. pain-sensing (nociceptive) fibres.

Question 3

what does the ANS consist of?

Answer 3

1) Parasympathetic nervous system: Cranial-sacral output, synapse at ganglia close to innervated tissue.
2) Sympathetic nervous system: Thoracic-lumbar output, synapse at ganglia either side of vertebral column
- Ganglia distal to innervated tissue.
3) Enteric nervous system: neurones with cell bodies in the wall of the intestine which innervates GI tract, pancreas and gall bladder.

Question 4

describe the arrangement of neurons in the Autonomic Nervous System

Answer 4

The ANS is characterised by having 2 neurones outside the CNS:

1) preganglionic fibres arising from the CNS synapse onto postganglionic nerve in a ganglia.
2) Postganglionic neurones terminate at the effector.

Question 5

where is Acetylcholine released from in the ANS?

Answer 5

1) all preganglionic neurones of both parasympathetic and sympathetic nerves
2) all postganglionic parasympathetic neurones
= cholinergic transmission

Question 6

where is Noradrenaline (NA) released from in the ANS?

Answer 6

1) most postganglionic sympathetic neurones

= adrenergic (noradrenergic) transmission

Question 7

not all postganglionic transmission is due to ACh or NA. list some of the other neurotransmitters in the ANS

Answer 7

Non-adrenergic non-cholinergic (NANC) transmission:

1) classical neurotransmitters: catecholamines (dopamine): sympathetic neurones to kidney; indolamines (5-HT) and GABA: enteric neurones
2) Purinergic transmission (ATP): sympathetic neurones to blood vessels
3) Peptides: VIP, substance P, histamine
4) Nitric oxide

Question 8

outline where Cholinergic transmission occurs in the ANS

Answer 8

1) all postganglionic parasympathetic nerves release ACh to act on muscarinic acetylcholine receptors (mAChRs)
2) all motor nerves release ACh which act on nicotinic acetylcholine receptors (nAChRs)

Question 9

list the 5 different muscarinic ACh receptor subtypes and state their function and location.

Answer 9

1) M1 : Ganglia, CNS - excretion and secretion
2) M2: Cardiac CNS- cardiac inhibition
3) M3 : glands, smooth muscle, blood vessels- secretion, constriction, vasodilation
4) M4: CNS- enhanced movement
5) M5: CNS -N/A

Question 10

state the G-proten that each of the muscarinic ACh receptors are couppled to and the response.

Answer 10

1) M1,3,5 (odd) - Gαq : increase IP3

2) M2,4 (even) - Gαi/o response is to decrease cAMP

Question 11

state the agonists and antagonists for each of the muscarinic ACh receptor subtypes.

Answer 11

1) agonist: M1-5 can all be activated by the same agonists and so there is no specificity. agonists include: acetylcholine, carbachol, oxotremorine, pilocarpine..
2) M1-5 are all activated by atropine. (Atropine is a competitive antagonist of the muscarinic acetylcholine receptor)
- pirenzepine only activates M1
- darifenacin only activates M3

Question 12

Why is knowledge of receptor subtypes important?

Answer 12

1) selectivity
2) you get a different response depending on which receptor you target. M1,3,5 increase IP3. while M2,4 are inhibitory and decrease cAMP

Question 13

Actions of mAChR agonists lead to parasympathetic effects. list these parasympathetic effects

Answer 13

1) Bradycardia/reduced cardiac output
2) Vasodilation
3) Increases secretion (salivation, sweating)
4) Bronchoconstriction and bronchial secretion
5) Increased gut motility
6) Reduction of intraocular pressure (due to pupillary constriction)

Question 14

clinical uses of AChR agonists tend to be somewhat limited as it is usually desirable to suppress rather than accentuate parasympathetic activity. discuss some the therapeutic uses of mAChR agonists

Answer 14

1) Glaucoma is due increased intraocular pressure which can damage the eye’s optic nerve and lead to blindness. Pilocarpine used as eye drops to reduce intraocular pressure.
2. Urinary retention and constipation - Bethanechol has been used to relieve urinary retention and increase gut motility.

Question 15

list the actions of mAChR antagonists

Answer 15

1) Block secretion -salivation.
- bronchial secretion are reduced
2) Tachycardia - modest effect
3) Pupillary dilation and ciliary muscle paralysis
4) Inhibits gut motility
5) Paralysis of bladder
6) Smooth muscle (except gut) relaxation
7) CNS effects: excitatory

Question 16

list some of the side effects of using mAChR antagonists

Answer 16

1) can cause dry mouth
2) can lead to increase in intraocular pressure and blurred vision
3) constipation
4) urinary retention
5) disorientation, mood swings

Question 17

SLUDGE is caused by mAChR agonists and is the reason why therapeutics using these agents is limited
. What is SLUDGE?

Answer 17

1) Salivation: stimulation of the salivary glands
2) Lacrimation: stimulation of the lacrimal glands
3) Urination: relaxation of the internal sphincter muscle of urethra, and contraction of the detrusor muscles
4) Defecation: relaxation of the internal anal sphincter
5) Gastrointestinal upset: smooth muscle tone changes causing gastrointestinal problems, including diarrhea
6) Emesis: vomiting

Question 18

list some of the therapeutic uses of mAChR antagonists for the following:

1) Ophthalmic
2) Bronchodilation
3) Reduce intestinal motility

Answer 18

1) Ophthalmic : Tropicamide dilates pupils to aid eye examinations; atropine or cyclopentolate paralyse eye to treat inflammation
2) Bronchodilation: Orally inhaled , short-acting drugs such as ipratropium used in acute asthma episodes and longer-lasting, M1/M3-selective tiotropium used in chronic obstructive pulmonary disease (COPD)
3) Reduce intestinal motility : Atropine or dicycloverine act as smooth muscle relaxants to manage irritable bowel syndrome (IBS) and diverticular disease

Question 19

list some of the therapeutic uses of mAChR antagonists for the following:

1) Urinary incontinence
2) Cardiovascular
3) Nausea and vomitinG

Answer 19

1) Parasympathetic system controls bladder contraction, so antimuscarinics are used to prevent incontinence
- Tolterodine and oxybutynin in m/r can be taken once/day. Desirable drugs are selective M3 antagonist eg. darifenacin, solifenacin
2) Cardiovascular: Atropine used to treat bradycardia after myocardial infarction
3) Nausea and vomiting (CNS)- Hyoscine (e.g. Kwells®) given as transdermal patch or orally to treat motion sickness (acts on the ‘vomiting centre’ in the hind brain medulla)

Question 20

list some of the therapeutic uses of mAChR antagonists for the following:

1) Parkinson’s Disease
2) Anaesthesia

Answer 20

1) Parkinson’s Disease (CNS): In drug-induced PD, dopamine deficiency can cause excessive cholinergic activity eg. trihexyphenidyl hydrochloride
2) Anaesthesia: Pre-medication to inhibit salivation and bronchial secretion and to cause drowsiness eg. atropine or hyoscine
- During surgery to prevent vagal inhibition of the heart eg. atropine or glycopyrronium

Question 21

what is the biggest problem with mAChR antagonists ?

Answer 21

anticholinergic drugs all act as competitive antagonists, but are largely unselective and can cause dry mouth/blurred vision/constipation

Question 22

name the 3 Nicotinic ACh receptor subtypes and state their location.

Answer 22

1) muscle: located in (postsynaptic) NMJ
2) Ganglion: (postsynaptic) ganglia
3) CNS: pre and post-synaptic
- function for all 3 is excitation

Question 23

what are the agonists of Nicotinic ACh receptors?

Answer 23

1) acetylcholine for all 3 of them so its not good for selectivity
2) succinylcholine only agonises muscle
3) nicotine agonises ganglion and CNS

Question 24

Peripheral nAChRs present at autonomic ganglia and neuromuscular junctions (NMJs) and molecularly distinct. what are the problems with drugs which target these receptors?

Answer 24

1) drugs affecting ANS ganglia do not discriminate between sympathetic and parasympathetic nerves
2) Due to lack of discrimination between sympathetic and parasympathetic ganglia most nACh ligands are therapeutically undesirable
- however, nicotine is used to assist smoking cessation.

Question 25

outline the uses of Ganglion-blocking drugs

Answer 25

1) Cardiovascular: Effects largely due to block of sympathetic system: vasodilation causes fall
in blood pressure. Trimetaphan was used to produce hypotension in surgery
2) GastrointestinaI tract: Effects largely due to block of parasympathetic system: inhibition of motility
3) Genito-urinary system: Effects largely due to block of parasympathetic system: impairment of micturition

Question 26

list the two types of Neuromuscular blocking agents

Answer 26

1) Competitive antagonists of nAChRs - competitive blockers

2) Agonists which cause a depolarizing block of the muscle endplate - depolarizing blockers

Question 27

outline the used of competitive blockers and depolarizing blockers

Answer 27

1) competitive blockers: Widely used as muscle relaxants as an adjunct to anaesthesia e.g. pancuronium
2) depolarizing blockers: Used to cause paralysis during anaesthesia, e.g. succinylcholine

Question 28

outline the different ways we can interfere with cholinergic transmission at a synapse for therepeutic purposes.

Answer 28

1) Vesicle release on synapse: botulinum toxin
2) Carrier blockers block reuptake of choline etc: hemicholinium, vesamicol
3) Anticholinesterases: donepezil, rivastigmine and galantamine in Alzheimer’s disease
4) nicotinic ACh receptor and muscarinic
ACh receptor on postsynaptic cell can be blocked by:
- ipratropium (mAChR), darifenacin (mAChR)
- pancuronium (nAChR), suxamethonium (nAChR

Question 29

outline some non-receptor therapeutic targets of cholinergic transmission.

Answer 29

1) Acetylcholine synthesis and release:
- Vesamicol blocks ACh packaging into vesicles
- Hemicholinium blocks choline uptake
2) Acetylcholine release: Botulinum toxin type A blocks vesicle docking/release
3) Cholinesterase inhibitors (anticholinesterases)

Question 30

discuss the therapeutic applications of botulinum toxin

Answer 30

1) Muscle spasm: can result from stroke, cerebral palsy, , brain or spinal cord injury etc.
- focal dystonic spasms, spasmodic dystonia, pain
2) Migraine/headache treatment: Suggested that facial muscle contraction stimulates headache.
3) Excessive secretion: Botox® is used for the treatment of severe underarm sweating (hyperhidrosis) and salivation (drooling) that is not adequately managed with topical agents.

Question 31

Cholinesterase inhibitors are called anticholinesterases. list the 3 main classes of anticholinesterases

Answer 31

1) short-acting (eg. edrophonium)
2) medium-duration (eg. neostigmine and pyridostigmine)
3) irreversible (eg. ecothiopate)

Question 32

what are the Therapeutic uses of anticholinesterases?

Answer 32

1) Myasthenia gravis: Autoimmune disease leading to depletion of nAChRs at NMJ.
- Neostigmine or pyridostigmine used as they do cross blood/brain barrier
2) Dementia: eg. Alzheimer’s disease (AD) associated with a loss of cholinergic neurones in basal forebrain. Small improvement (~10%) seen with newer reversible, anticholinesterase drugs: donepezil, rivastigmine and galantamine,
3) Reversal of competitive neuromuscular block after anaesthesia: Edrophonium (transient action) and neostigmine

Question 33

outline the use of anticholinesterases in Alzheimer’s disease

Answer 33

1) Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease.
2) donepezil, galantamine and rivastigmine are now recommended as options for managing mild as well as moderate Alzheimer’s disease” NICE

Question 34

discuss the major therapeutic areas of interest in muscarinic ACh receptors and nicotinic ACh receptors

Answer 34

1) Major therapeutic interest is in muscarinic ACh receptor antagonists in the ANS. However, there is a lack of selectively and a number of side effects associated with these drugs
2) Major therapeutic interest is in nicotinic ACh receptor blockers (muscle relaxants) and non-receptor targets to affect cholinergic transmission in the SNS