Introduction to the PNS :Cholinergic therapeutics Flashcards Preview

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Flashcards in Introduction to the PNS :Cholinergic therapeutics Deck (34):
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 ?

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

2

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

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

3

what does the ANS consist of?

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.

4

describe the arrangement of neurons in the Autonomic Nervous System

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.

5

where is Acetylcholine released from in the ANS?

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

6

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

1) most postganglionic sympathetic neurones
= adrenergic (noradrenergic) transmission

7

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

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

8

outline where Cholinergic transmission occurs in the ANS

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)

9

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

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

10

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

1) M1,3,5 (odd) - Gαq : increase IP3
2) M2,4 (even) - Gαi/o response is to decrease cAMP

11

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

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

12

Why is knowledge of receptor subtypes important?

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

13

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

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)

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

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.

15

list the actions of mAChR antagonists

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

16

list some of the side effects of using mAChR antagonists

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

17

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

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

18

list some of the therapeutic uses of mAChR antagonists for the following:
1) Ophthalmic
2) Bronchodilation
3) Reduce intestinal motility

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

19

list some of the therapeutic uses of mAChR antagonists for the following:
1) Urinary incontinence
2) Cardiovascular
3) Nausea and vomitinG

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)

20

list some of the therapeutic uses of mAChR antagonists for the following:
1) Parkinson’s Disease
2) Anaesthesia

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

21

what is the biggest problem with mAChR antagonists ?

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

22

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

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

23

what are the agonists of Nicotinic ACh receptors?

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

24

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

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.

25

outline the uses of Ganglion-blocking drugs

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

26

list the two types of Neuromuscular blocking agents

1) Competitive antagonists of nAChRs - competitive blockers
2) Agonists which cause a depolarizing block of the muscle endplate - depolarizing blockers

27

outline the used of competitive blockers and depolarizing blockers

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

28

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

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

29

outline some non-receptor therapeutic targets of cholinergic transmission.

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)

30

discuss the therapeutic applications of botulinum toxin

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.

31

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

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

32

what are the Therapeutic uses of anticholinesterases?

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

33

outline the use of anticholinesterases in Alzheimer's disease

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

34

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

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