Cholinergic transmission drugs

Card Set Information

Author:
mfawcett
ID:
180329
Filename:
Cholinergic transmission drugs
Updated:
2013-04-19 11:14:29
Tags:
MODA pharmacology acetylcholine choline nicotinic muscarinic drug drugs
Folders:

Description:
Drugs acting on cholinergic transmission
Show Answers:

Home > Flashcards > Print Preview

The flashcards below were created by user mfawcett on FreezingBlue Flashcards. What would you like to do?


  1. Hemicholinium
    • Blocks choline transporter into nerve terminal
    • No clinical use
  2. What acetylates choline?
    cholineacetyltransferase (cytoplasmic)
  3. What is choline uptake dependent on?
    Extracellular sodium concentration
  4. Triethylcholine
    • Competitive substrate for choline
    • Can be acetylated (by cholineacetyltransferase) and released in place of choline
    • False transmitter - doesn't activate cell
  5. Vesamicol
    • Blocks the transporter which carries ACh into vesicles
    • Non-competitive and reversible
  6. beta-Bungarotoxin
    (mechanism)
    • Blocks ACh release
    • Acts through a phospholipase A2
    • Localises to the membrane by a K+ channel binding moiety
  7. Botulinum Toxin
    • Blocks ACh release (SNAREs!)
    • Enters via vesicle activity
    • Can cause respiratory failure
  8. 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
  9. BuChE
    • Butyrylcholinesterase aka Pseudocholinesterase
    • Not very specific (no anionic binding site)
    • Can break down procaine
    • made in liver and found in plasma
  10. Location of AChE
    • Presynaptic: soluble to prevent build up outside vesicles
    • Synaptic cleft: localised to basement membrane (collagenous tail to heparan sulphate proteoglycan)
  11. 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)
  12. 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
  13. 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)
  14. 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)
  15. Tacrine
    use?
    • Reversibly inhibits AChE and BuChE
    • Uncharged - can enter CNS
    • Developed for use in Alzheimer's disease
  16. Donepezil
    • Reversibly inhibits AChE
    • Can enter CNS, has relatively few peripheral side effects
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. Nerve gases
    • Sarin, Tabun, Soran
    • irreversibly inhibits AChE
    • Penetrate skin
    • acute and chronic toxic effects
    • long term exposure: demyelination
  23. 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
  24. 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
  25. Trimetaphan
    use?
    • Competitive antagonist for ganglionic form of NAChR
    • Controlled lowering of BP in surgery to give a 'bloodless field'
  26. Mecamylamine
    • Non-competitive antagonist for NAChR
    • Blocks channel
  27. 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
  28. d-Tubocurarine
    • Nicotine receptor antagonist
    • Relatively non-selective between nmj and ganglion at clinical doses
  29. 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
  30. 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)
  31. 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
  32. Decamethonium
    Depolarising neuromuscular blocking agent
  33. 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
  34. 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.
  35. 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
  36. 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
  37. M3 receptors
    • Gq/11 -> IP3 and DAG -> PKC and Ca release
    • Exocrine glands, sweat glands, oxyntic cells, smooth muscle
  38. Bethanechol
    use?
    • Mucarinic agonist
    • Used systemically for urinary retention
  39. Pilocarpine
    • Muscarinic agonist
    • Topical for glaucoma, absorbed through cornea
    • Contracts ciliary muscle -> improved aqueous humour drainage
    • Lasts ~ 1 day
  40. Carbachol
    Muscarinic agonist
  41. Methacholine
    • Muscarinic agonist
    • 2 isomers, neither hydrolysed by BuChE
    • + is a substrate for AChE and is ~200x more potent than - at muscarinic receptors
  42. Atropine
    Non-selective muscarinic antagonist
  43. Hyoscine
    Non-selective muscarinic antagonist
  44. Pirenzipine
    use?
    • M1 antagonist
    • Decreases gastric acid secretion (maybe by an effect on local ganglion rather than on M3 receptors on oxyntic cells)
  45. Tripitamine
    M2 antagonist
  46. 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)
  47. 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)
  48. Darifenacin
    use?
    • M3 antagonist
    • Decreases bladder activity

What would you like to do?

Home > Flashcards > Print Preview