Voltage gated channels

• 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 (pK_a: 8-9): needs high pH outside (uncharged) to pass through membrane, low pH (charged) inside in order in inactivate channel

• High pH outside: LAs are uncharged (lidocaine and procaine weak bases pK_a 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

• 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

• 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

ester LA

LA

• 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?)

LA, slow in, slow out - shows use dependence at low frequencies, used for supraventricular tachycardia

• LA, blocks Na channels from outside
• binds to Glu residue: Cys in heart confers resistance
• no use dependence.
• contains guanidium groups

• LA, blocks Na channels from outside
• binds to Glu residue: Cys in heart confers resistance
• no use dependence
• contains guanidium groups

• 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)

• 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)

• DHP
• Ca channel blocker: favour mode 0 (channel does not open at all)

• DHP
• Ca channel opener: favour mode 2 (very long openings)

• phenylalkylamine
• Ca channel blocker (more prolonged and use-dependent than DHPs)
• decreases DHP binding
• preferential for cardiac muscle: antidysrythmic

• benzothiazepine
• Ca channel blocker (more prolonged and use-dependent than DHPs)
• enhances DHP binding
• preferential for cardiac muscle: antidysrythmic

• benzimidazoyl tetraline
• blocks both L and T type Ca channels
• binds to alpha-1 subunit

• sulphonylurea
• K_ATP channel blocker -> depolarises membrane of pancreatic beta cell -> firing of VGCC
• stimulates insulin release

• sulphonylurea
• K_ATP channel blocker -> depolarises membrane of pancreatic beta cell -> firing of VGCC
• stimulates insulin release

• K_ATP channel opener
• Inhibit ATP binding to channel (ATP causes channel to close)
• Increased efflux of K
• smooth muscle relaxation (hypertension, asthma, IBS, male alopecia)

• K_ATP channel opener
• Inhibit ATP binding to channel (ATP causes channel to close)
• Increased efflux of K
• smooth muscle relaxation (hypertension, asthma, IBS, male alopecia)

• K_ATP channel opener
• Inhibit ATP binding to channel (ATP causes channel to close)
• Increased efflux of K
• treats baldness