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Hemicholinium
- Blocks choline transporter into nerve terminal
- No clinical use
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What acetylates choline?
cholineacetyltransferase (cytoplasmic)
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What is choline uptake dependent on?
Extracellular sodium concentration
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Triethylcholine
- Competitive substrate for choline
- Can be acetylated (by cholineacetyltransferase) and released in place of choline
- False transmitter - doesn't activate cell
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Vesamicol
- Blocks the transporter which carries ACh into vesicles
- Non-competitive and reversible
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beta-Bungarotoxin
(mechanism)
- Blocks ACh release
- Acts through a phospholipase A2
- Localises to the membrane by a K+ channel binding moiety
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Botulinum Toxin
- Blocks ACh release (SNAREs!)
- Enters via vesicle activity
- Can cause respiratory failure
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alpha-Latarotoxin
- Causes massive ACh release
- Binds to neurexins (TM proteins)
- Can cause depolarisation by inhibiting K+ channels, because it makes latrophilin form ion pores that allow calcium entry
- Can cause respiratory failure
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BuChE
- Butyrylcholinesterase aka Pseudocholinesterase
- Not very specific (no anionic binding site)
- Can break down procaine
- made in liver and found in plasma
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Location of AChE
- Presynaptic: soluble to prevent build up outside vesicles
- Synaptic cleft: localised to basement membrane (collagenous tail to heparan sulphate proteoglycan)
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Mechanism of action of AChE
- 3 subunits: collagen tail, disulphide bonds to tetramers
- tail localises AChE to heparan sulphate proteoglycan in basement membrnae
- serine hydrolase: serine hydroxyl (Ser203 and His447) in esteratic site is a receptor for the acetyl moeity, which is cleaved. the hydroxyl is then hydrolysed to regenerate the enzyme and release acetic acid
- anionic site: Glu334 forms an ionic bond with the choline head group (BuChE doesn't have this, so is less specific eg also breaks down procaine)
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3 different AChRs and their subunit compositions
- Striated muscle: (a1)2, B1, d, E [fetal has gamma instead of E]
- Brain: (a4)2(B2)3 or (a7)5
- Autonomic ganglion: (a3)2(B4)3
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Differences between NAChR blockers in different locations
- Trimetaphan: comp antagonist at GANGLIONIC NAChR only
- a-bungarotoxin: irreversible antagonist at NMJ and (a7)5 brain only
- atracurium and pancuronium: comp antagonist at NMJ only
- suxamethonium and decamethonium: depolarising block at NMJ only
- d-tubocurarine: non-selective NAChR antagonist
- Mecamylamine: non-comp antagonist (non-selective)
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Edrophonium
use?
- Reversible inhibitor of AChE
- Quaternary ammonium - charged, cannot enter CNA
- Binds to active site via an electrostatic interaction
- Used to diagnose myasthenia gravis (causes a temp increase in the muscle tension that can be developed by the patient)
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Tacrine
use?
- Reversibly inhibits AChE and BuChE
- Uncharged - can enter CNS
- Developed for use in Alzheimer's disease
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Donepezil
- Reversibly inhibits AChE
- Can enter CNS, has relatively few peripheral side effects
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Neostigmine
mechanism
use
- Medium, reversible inhibitor of AChE
- Carbamic acid ester of choline; binds to esteratic site and carbamoylates AChE
- Hydrolysis is much slower with a carbamoylated rather than acetylacted serine
- IV to reduce curare-type muscular blockade after surgery
- Orally to treat myasthenia gravis
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Pyridostigmine
mechanism?
use?
- Medium, reversible inhibitor of AChE
- Carbamic acid ester of choline; binds to estaric site and carbamoylates AChE
- Hydrolysis is much slower with a carbamoylated rather than acetylacted serine
- Longer alsting than neostigmine
- Used to treat myasthenia gravis
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Physostigmine
mechanism?
use?
- Medium, reversible inhibitor of AChE
- Carbamic acid ester of choline; binds to estaric site and carbamoylates AChE
- Hydrolysis is much slower with a carbamoylated rather than acetylacted serine
- Topical treatment of glaucoma
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Dyflos
mechanism?
use?
- Irreversible serine hydrolase (AChE) inhibitor
- Organophosphorus compounds form a strong covalent bond between their phosphorus atom and the serine residue at the esteratic site
- Used to treat glaucoma
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Malathion
mechanism?
use?
- Irreversible serine hydrolase (AChE) inhibitor
- Organophosphorus compounds form a strong covalent bond between their phosphorus atom and the serine residue at the esteratic site
- Used to treat head lice (active ingredient maloxide)
- Insect CYP450s are more efficient at activating it by replacing its sulphur atom with oxygen; and mammalian plasms carboxylesterases can detoxify it better
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Nerve gases
- Sarin, Tabun, Soran
- irreversibly inhibits AChE
- Penetrate skin
- acute and chronic toxic effects
- long term exposure: demyelination
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Pralidoxime
mechanism?
- Reverses inhibition of AChE by organophosphorus agents, and therefore restores normal AChE function
- Phosphorylated serine of the inhibited AChE is transferred to the strongly nucleophilic oxime group
- Can only occur a few hours after inhibition as the enzyme/inhibitor complex undergoes ageing, making the bond no longer susceptible to nucleophilic attack
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Nicotine
phases?
- Depolarising block of NAChR
- Agonist (more potent at ganglion than at NMJ)
- Phase 1: Na channels: cannot stimulate electrically ('antidromic stimulation')
- Phase 2: desensitisation of NAChR: can stimulate electrically, but not via stimulation of the preganglionic nerve ('orthodromic stimulation'): because when NAChR desensitises and closes, the membrane repolarises, allowing the VGNaC to return to their resting state
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Trimetaphan
use?
- Competitive antagonist for ganglionic form of NAChR
- Controlled lowering of BP in surgery to give a 'bloodless field'
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Mecamylamine
- Non-competitive antagonist for NAChR
- Blocks channel
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Hexamethonium
- Non-competitive antagonist for ganglionic NAChR
- Use-dependent channel blockade
- Increasing chain length changes selectivity: ganglion - short, NMJ - long (decamethonium, suxamethonium)
- Antidepressant activity
- Was used for hypertension, but (a) blocked both parasymp and symp activity, and (b) has a double positive charge so requires frequent injections
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d-Tubocurarine
- Nicotine receptor antagonist
- Relatively non-selective between nmj and ganglion at clinical doses
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Atracurium
- Competitive antagonist at nmj (non-depolarising)
- Quaternary ammonium - not orally active
- Blocks EPP in response to nerve impluse/directly applied ACh
- Ester: broken doen by spontaneous hydrolysis and plasma esterases
- Used for muscle relaxation in surgery - affects fast more than slow - good for resp
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What is tetanic fade?
- block of pre-synaptic nicotinic autoreceptors that give positive feedback to maintain transmitter release
- means that tetanus in response to high frequency stimulation is not maintained
- blocked by atracurium and pancuronium (comp antagonist at MNJ)
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Pancuronium
- Competitive antagonist at NMJ (non-depolarising)
- Longer lasting, not hydrolysable (unlike ester atracurium)
- Used for muscle relaxation in surgery - affects fast more than slow - good for resp
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Decamethonium
Depolarising neuromuscular blocking agent
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Suxamethonium (succinylcholine)
Use
- Depolarising neuromuscular blocking agent
- Ester: Short acting due to breakdown by BuChE
- Used for intubation
- 0.1-0.2% of population have an enzyme activity deficiency which can lead to prolonged action: risk of cardiac arrythmia
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Phases of nmj block
- Decamethonium and suxamethonium
- Phase I: the drugs bind to the NMJ NAChR, opening them and causing depolarisation. Anticholinesterases deepen the blockade by causing more depolarisation, but their effects can be opposed by non-depolarising blockers.
- Phase II: the NAChR is desensitised, the membrane is repolarised. Anticholinesterases can reverse the blockade by making the non-desensitied NAChRs more likely to be stimulated.
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M1 receptors
location
mechanism
- Gq/11 -> IP3 and DAG -> PKC and Ca release
- Peripheral and central neurons
- Reduced PIP2 in membrane: K conductance inhibited -> late epsp in autonomic ganglion
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M2 receptors
- alphai - >decreased cAMP and decreased phosphorylation of VGCC -> reduced Ca entry -> decreased release of transmitter and decreased heart cell excitability
- beta-gamma subunit opens GIRK (K+ channel) in pacemaker cells of SA and AV node -> hyperpolarisation -> reduced pacemaker rate
- May be a similar pathway in neurons: VGCC inhibition separate from decreased activity caused by reduced cAMP
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M3 receptors
- Gq/11 -> IP3 and DAG -> PKC and Ca release
- Exocrine glands, sweat glands, oxyntic cells, smooth muscle
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Bethanechol
use?
- Mucarinic agonist
- Used systemically for urinary retention
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Pilocarpine
- Muscarinic agonist
- Topical for glaucoma, absorbed through cornea
- Contracts ciliary muscle -> improved aqueous humour drainage
- Lasts ~ 1 day
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Carbachol
Muscarinic agonist
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Methacholine
- Muscarinic agonist
- 2 isomers, neither hydrolysed by BuChE
- + is a substrate for AChE and is ~200x more potent than - at muscarinic receptors
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Atropine
Non-selective muscarinic antagonist
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Hyoscine
Non-selective muscarinic antagonist
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Pirenzipine
use?
- M1 antagonist
- Decreases gastric acid secretion (maybe by an effect on local ganglion rather than on M3 receptors on oxyntic cells)
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Tripitamine
M2 antagonist
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Acute and chronic toxic effects of irreversible anticholinesterases
- Acute: widespread cholinergic overactivity -> convulsions, respiratory distress, bradycardia, hypotension, bronchoconstriction...
- Chronic: demyelination (inhibition of an esterase (not AChE) involved in myelin processing)
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Evidence AChEsterases do no work directly on the receptor (2)
- Slow onset of action (AChE agonists very fast)
- Effect reduced/absent in denervated preparations or systems where ACh release has been blocked (eg botulinum, beta-bungarotoxin)
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Darifenacin
use?
- M3 antagonist
- Decreases bladder activity
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