Voltage gated channels

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Author:
mfawcett
ID:
185239
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Voltage gated channels
Updated:
2012-11-25 06:28:17
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LA MODA local anaesthetic voltage gated channel channels
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voltage gated channels
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  1. lidocaine
    • amide LA
    • binds preferentially to and stabilises inactivated (h gate shut) form of channel
    • shows use dependence at high frequencies - most effective in ischaemic tissue, used in ventricular arrythmia
    • inactivation curve shifted to hyperpolarised potentials: at any given membrane potential, a greater % of channels are inactivated than if lidocaine was not present
    • weak base (pKa: 8-9): needs high pH outside (uncharged) to pass through membrane, low pH (charged) inside in order in inactivate channel
  2. Explain effect of pH
    • High pH outside: LAs are uncharged (lidocaine and procaine weak bases pKa 8-9): can pass through membrane
    • Low pH inside: LAs are charged: can inactivate channel
    • Benzocaine does not exist in a charged form in physiological pH
    • QX 314 (permanently charged quaternary LA) ineffective when outside a squid axon, potent LA when perfused inside
  3. Explain use-dependence
    • LAs show a faster rate of onset and offset if the channels are opening frequently
    • extent depends on rate of entry into and dissociation from LA binding site
    • 'fast in, fast out' LA eg lidocaine shows use dependence only at high rates of stimulation
    • 'slow in, slow out' eg quinidine shows use dependence at low rates of stimulation
  4. Explain voltage-dependence
    • The initial rate of block per pulse is increased if a hyperpolarising pre-pulse is given, but decreased if a depolarising pre-pulse is given
    • (the more channels opening during the pulse (more are already open with a depolarising prepulse), the faster the block)
    • The more depolarising the test pulse, the faster the block
  5. procaine
    ester LA
  6. tetracaine
    LA
  7. benzocaine
    • ester LA, uncharged at physiological pH - no voltage or use dependence
    • block is faster in onset and offset than procaine at pH 6
    • implies there is a hydrophobic pathway showing no use dependence (possibily within membrane?)
  8. quinidine
    LA, slow in, slow out - shows use dependence at low frequencies, used for supraventricular tachycardia
  9. tetrodotoxin
    • LA, blocks Na channels from outside
    • binds to Glu residue: Cys in heart confers resistance
    • no use dependence.
    • contains guanidium groups
  10. saxitoxin
    • LA, blocks Na channels from outside
    • binds to Glu residue: Cys in heart confers resistance
    • no use dependence
    • contains guanidium groups
  11. dihydropyridines
    • affect L type Ca channel,
    • highly lipid soluble: gain access to channel through lipid phase of membrane
    • bind to a1 subunit
    • vascular selectivity
    • inc nifedine, nitrendipine, nimodipine (block) and Bay K 8644 (open)
  12. Modes of L type Ca channels
    • 0: channel does not open at all
    • 1: channel openings occur in burts separated by long closed intervals
    • 2: very long openings
    • DHPs switch channel between gating modes (blockers favour 0, openers favour 2)
  13. nifedipine
    • DHP
    • Ca channel blocker: favour mode 0 (channel does not open at all)
  14. Bay K 8644
    • DHP
    • Ca channel opener: favour mode 2 (very long openings)
  15. verapamil
    • phenylalkylamine
    • Ca channel blocker (more prolonged and use-dependent than DHPs)
    • decreases DHP binding
    • preferential for cardiac muscle: antidysrythmic
  16. diltiazem
    • benzothiazepine
    • Ca channel blocker (more prolonged and use-dependent than DHPs)
    • enhances DHP binding
    • preferential for cardiac muscle: antidysrythmic
  17. mibefradil
    • benzimidazoyl tetraline
    • blocks both L and T type Ca channels
    • binds to alpha-1 subunit
  18. tolbutamide
    • sulphonylurea
    • KATP channel blocker -> depolarises membrane of pancreatic beta cell -> firing of VGCC
    • stimulates insulin release
  19. glibencamide
    • sulphonylurea
    • KATP channel blocker -> depolarises membrane of pancreatic beta cell -> firing of VGCC
    • stimulates insulin release
  20. cromakalim
    • KATP channel opener
    • Inhibit ATP binding to channel (ATP causes channel to close)
    • Increased efflux of K
    • smooth muscle relaxation (hypertension, asthma, IBS, male alopecia)
  21. diazoxide
    • KATP channel opener
    • Inhibit ATP binding to channel (ATP causes channel to close)
    • Increased efflux of K
    • smooth muscle relaxation (hypertension, asthma, IBS, male alopecia)
  22. minoxidil
    • KATP channel opener
    • Inhibit ATP binding to channel (ATP causes channel to close)
    • Increased efflux of K
    • treats baldness

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