(PM3B) Cholinergic Therapeutics Flashcards
Where does cholinergic transmission occur?
In the autonomic nervous system
What is the peripheral nervous system?
Output of CNS
Acts independently to regulate body’s internal environment
(1) Autonomic nervous system – ANS
(2) Somatic (motor) nervous system – SNS
What type of nerves control movement?
Efferent nerves of somatic (motor) nervous system
Innervate skeletal muscle
What type of nerves respond to external stimuli?
Afferent nerves of somatic (motor) nervous system
e.g. nociceptive fibres (pain-sensing)
What systems are in the autonomic nervous system (ANS)?
(1) Sympathetic nervous system
– Thoracic-lumbar output
– Synapase at ganglia either side of vertebral column
– Ganglia are distal to innervated tissue
(2) Parasympathetic nervous system
– cranial-sacral output
– Synapse at ganglia close to innervated tissue
(3) Enteric nervous system
– Neurones with cell bodies in intestine wall
– innervates GIT, pancreas, and gall bladder
Name some structures in the sympathetic nervous system.
- eye
- salivary glands
- heart
- lungs
- adrenal medulla
- liver
- GIT
- bladder
- genitalia
- blood vessels
- sweat glands
Name some structures in the parasympathetic nervous system.
- eye
- lacrimal gland
- salivary glands
- heart
- lungs
- upper GIT
- lower GIT
- bladder
- genitalia
What neurones are outside of the CNS in the autonomic nervous system?
(1) Preganglionic fibres
- arise from CNS synapse
- releases acetylcholine (ACh)
- cholinergic transmission
(2) Postganglionic nerve
- in ganglia
- terminate at the effector
- most release noradrenaline (NA)
- adrenergic transmission
Which type of neurones in the autonomic nervous system are responsible for cholinergic transmission?
Preganglionic fibres
Which type of neurones in the autonomic nervous system are responsible for adrenergic transmission?
Postganglionic nerves
How does the CNS act on skeletal muscle?
Binding of acetylcholine to nicotinic receptors
How does the CNS act on blood vessels?
Release of acetylcholine and binding to nicotinic receptors
Leads to release of noradrenaline
How does the CNS act on sweat glands?
Release of acetylcholine and binding to nicotinic receptors
Least to release of further acetylcholine and binding to muscarinic receptors
How does the CNS act on the adrenal medulla?
Release of acetylcholine and binding to nicotinic receptors
How does the CNS act on the salivary glands?
Release of acetylcholine and binding to nicotinic receptors
Least to release of further acetylcholine and binding to muscarinic receptors
Which nerves release ACh?
All postganglionic parasympathetic nerves
- to act on mAChRs
All motor nerves
- to act on nAChRs
Where are M1 receptors located?
Ganglia in CNS
Where are M2 receptors located?
Cardiac
CNS
Where are M3 receptors located?
Glands + smooth muscle + blood vessels
Where are M4 receptors located?
CNS
Where are M5 receptors located?
CNS
What is the function of M1 receptors?
Excitation + secretion
What is the function of M2 receptors?
Cardiac + CNS inhibition
What is the function of M3 receptors?
Secretion
Contraction
Vasodilatation
What is the function of M4 receptors?
Enhanced movement
What is the function of M5 receptors?
Unknown
Which G protein does an M1 receptor act on?
G-alpha q
Which G protein does an M2 receptor act on?
G-alpha- i/o
Which G protein does an M3 receptor act on?
G-alpha q
Which G protein does an M4 receptor act on?
G-alpha- i/o
Which G protein does an M5 receptor act on?
G-alpha q
What is the response following binding of an M1 receptor?
Increased IP3
What is the response following binding of an M2 receptor?
Decreased cAMP
What is the response following binding of an M3 receptor?
Increased IP3
What is the response following binding of an M4 receptor?
Decreased cAMP
What is the response following binding of an M5 receptor?
Increased IP3
What is the effect of binding to a muscarinic receptor eliciting an effect on a G-alpha q G protein?
Increased IP3
What is the effect of binding to a muscarinic receptor eliciting an effect on a G-alpha i/o G protein?
Decreased cAMP
Name some agonists of muscarinic receptors.
(1) Acetylcholine
(2) Carbachol
(3) Oxotremorine
(4) Pilocarpine
(5) Bethanechol
What are some antagonists of an M1 receptor?
(1) Atropine
(2) Pirenzepine
What are some antagonists of an M2 receptor?
Atropine
What are some antagonists of an M3 receptor?
(1) Atropine
(2) Darifenacin
What are some antagonists of an M4 receptor?
Atropine
What are some antagonists of an M5 receptor?
Atropine
What are some general effects of muscarinic receptor agonists?
(1) Bradycardia/ reduced cardiac output
(2) Vasodilation
(3) Increased secretion
- salivation
- lacrimation
- sweating
(4) Bronchoconstriction + increased bronchial secretion
(5) Increased gut motility
(6) Reduction of intraocular pressure
- a result of pupillary constriction
When is an mAChR agonist used in glaucoma?
A mitotic (pilocarpine) used to reduce intraocular pressure
Action lasts ~1 day
When is an mAChR agonist used in urinary retention?
Bethanechol
To relieve urinary retention
When is an mAChR agonist used in constipation?
Bethanechol
Increase gut motility
What is the acronym SLUDGE in regard to mAChRs?
S = salivation L = lacrimation U = urination (relaxation of internal sphincter + contraction of detrusor muscles) D = defecation G = gastrointestinal upset E = emesis (vomiting)
What is emesis?
Vomiting
Why is therapeutic use of mAChRs limited?
Causes SLUDGE
What are some actions of mAChR antagonists?
(1) Block secretion
- salivary
- lacrimal
- sweating
- bronchial
(2) Tachycardia
(3) Pupillary dilation
(4) Inhibition of gut motility
(5) Bladder paralysis
(6) Smooth muscle relaxation (except gut)
(7) Excitatory CNS effects
What can blocked secretion, due to use of mAChR antagonists, lead to?
Dry mouth
What can pupillary dilation, due to use of mAChR antagonists, lead to?
Increased intraocular pressure
What can inhibition of gut motility, due to use of mAChR antagonists, lead to?
Constipation
What can paralysis of the bladder, due to use of mAChR antagonists, lead to?
Urinary retention
What can the excitatory effects on the CNS, due to use of mAChR antagonists, lead to?
Disorientation
Mood swings
When are mAChR antagonists used for ophthalmic purposes?
(1) Tropicamide
- to dilate pupils (mydriasis)
- to aid eye examinations
(2) Atropine/ cyclopentolate
- to paralyse the eye
- to treat inflammation
When are mAChR antagonists used for bronchodilation purposes?
(1) Ipratropium
- orally inhaled aerosol
- short-acting
- half-life 2-4 hours
- acute asthma
(2) Tiotropium
- orally inhaled aerosol
- half-life ~10 hours
- long-acting
- COPD
When are mAChR antagonists used for reducing intestinal motility?
(1) Atropine/ dicycloverine
- smooth muscle relaxant
- anti-spasmodic agents
- management of IBS
- management of diverticular disease (presence of pouches in wall of intestine)
When are mAChR antagonists used for treating urinary incontinence?
(1) Tolterodine/ oxybutynin
- treatment of OAB (overactive bladder)
- extended-release formulation OD
Ideally want a selective M3 antagonist such as darifenacin/ solifenacin
When are mAChR antagonists used for cardiovascular purposes?
(1) Atropine
- bradycardia
- after MI
When are mAChR antagonists used for nausea and vomiting?
(1) Hyoscine
- transdermal patch
- orally
- treatment of motion sickness
- acts on ‘vomiting centre’ of hind brain medulla
When are mAChR antagonists used for Parkinson’s disease?
(1) Trihexyphenidyl hydrochloride
- treatment of dopamine deficiency
- due to overactivity of cholinergic transmission
When are mAChR antagonists used for anaesthesia?
(1) Atropine/ hyoscine
- inhibition of salivation/ bronchial secretion
- cause drowsiness
(2) Atropine/ glycopyrronium
- during surgery
- prevent vagal inhibition of the heart
What is the function of nicotinic receptor subtypes?
Excitation
Where are nicotinic receptors in muscle located?
Postsynaptic
Neuromuscular junction (NMJ)
Where are nicotinic receptors in ganglia located?
Postsynaptic ganglia
Where are nicotinic receptors in CNS located?
Pre- and post- synaptic
What are some agonists of nicotinic receptors located in muscle?
(1) Acetylcholine
(2) Succinylcholine
What are some agonists of nicotinic receptors located in ganglia?
(1) Acetylcholine
(2) Nicotine
What are some agonists of nicotinic receptors located in the CNS?
(1) Acetylcholine
(2) Nicotine
What are some antagonists of nicotinic receptors located in muscle?
(1) Tubocurare
(2) Pancuronium
What are some antagonists of nicotinic receptors located in ganglia?
(1) Trimetaphan
(2) Hexamethonium
What are some antagonists of nicotinic receptors located in the CNS?
Mecamlylamine
Why are most nicotinic acetylcholine ligands therapeutically undesirable?
Lack of selectivity between sympathetic + parasympathetic ganglia
What effects do the ganglion-blocking drugs trimetaphan and hexamethonium have?
(1) Cardiovascular
- block of sympathetic system
- vasodilation causes fall in BP
- trimetaphan used to induce hypotension in surgery
(2) GIT
- block of parasympathetic system
- inhibition of motility
(3) Genito-urinary system
- block of parasympathetic system
- impairment of micturition (urination)
How do neuromuscular blocking agents work?
(1) Competitive antagonists
- widely used as muscle relaxants
- adjunct to anaesthesia
- e.g. pancuronium, vecuronium, atracurium
(2) Agonists which cause a depolarising block of muscle endplate (depolarising blockers)
- to cause paralysis during anaesthesia
- e.g suxamethonium (succinylcholine)
What are the stages of cholinergic transmission?
(1) Acetyl CoA + choline produce ACh in the presence of CAT
(2) ACh is packaged into vesicles and released into synaptic cleft
(3) Binds to mAChR or nAChR on postsynaptic membrane to elicit a cellular effect
What happens to excess ACh in the synaptic cleft?
(1) Broken down into choline + acetate by acetylcholinesterase
(2) Endocytosis of choline + acetate
Name a drug that prevents vesicle release in cholinergic transmission.
Botulinum toxin
Name some therapeutic acetylcholinesterases.
(1) Donepezil
(2) Galantamine
(3) Rivastigmine
What is the function of vesamicol?
Block packaging of ACh into vesicles
What is the function of hemicholinium?
Blocks choline reuptake
What is the function of botulinum toxin type A?
Blocks vesicle docking/ release
Causes dry mouth/ blurred vision
Can lead to respiratory paralysis
What are some therapeutic applications of botulinum toxin?
(1) Muscle spasm
- focal dystonic spasms (writer’s cramp)
- spasmodic dystonia
- pain associated with continual muscle contraction
(2) Migraine/ headache
- facial muscle contractions causing headaches
(3) Excessive secretion
- severe underarm sweating
- severe salivation
- when not managed effectively with topical agents
- can be effective for 6-10 months
What amino acid binding sites are present in cholinesterase?
(1) Histidine - catalytic (active) site
(2) Serine
(3) Glutamate - allosteric (anionic) site
What are the main classes of anticholinesterase?
(1) Short-acting
- e.g. edrophonium
(2) Medium-duration
- e.g. neostigmine/ pyridostigmine
(3) Irreversible
- e.g. ecothiopate
What is the mechanism of action of neostigmine?
Inhibits cholinesterase
Binds to serine of cholinesterase
What is myasthenia gravis?
Autoimmune disease
Leads to depletion of nAChRs at NMJ
Use of neostigmine/ pyridostigmine as they are able to cross BBB
What are some therapeutic uses of anticholinesterases?
(1) Myasthenia gravis
(2) Dementia
(3) Reversal of competitive neuromuscular block after anaesthesia
Why are anticholinesterases used for treatment of dementia?
Alzheimer’s is associated with loss of cholinergic neurones in basal forebrain
Donepezil, rivastigmine + galantamine used to treat mild-moderate AD
What anticholinesterases are used for reversal of competitive neuromuscular block after anaesthesia?
(1) Edrophonium - transient action
(2) Neostigmine
