Drug interactions with receptors and ion channels: Drugs and ion channels Flashcards
Local anaesthetics
Target VGNa+C
Also function as antidysrhythmics
C and Aδ fibres (sensory, slow conduction velocity, small diameter) more susceptible to block than large diameter motor fibres.
Can exist as charged (BH+) or uncharged (B) forms. Uncharged form more readily penetrates sheath of nerve trunks & the axonal membrane. Charged form is believed to be the active dorm (except in the case of benzocaine)
In general, show use-dependence & voltage dependence
Procaine
LA, ester
Weak base, pKa 8-9- at physiological pH exists in both protonated & unprotonated forms.
Blocks channel best in charged form, but has to pass across to the inside of the cell (in uncharged form) to its site of block.
Benzocaine
LA, ester
Uncharged (does not exist in a chardeg form in the physiological pH range)- Acts via hydrophobic pathway within the membrane.
Does not show use dependence
Rate & extent of block are independent of pH.
However, block is faster in onset & offset than for procaine (the parent compound) at pH6.
Lidocaine (lignocaine)
LA, amide
Binds preferentially to inactivated VGNaC & stabilises this state
Weak base, pKa 8-9 - at physiological pH exists in both protonated & unprotonated forms.
Blocks channel best in charged form, but has to pass across to the inside of the cell (in uncharged form) to its site of block.
‘Fast-in, fast-out’. Shows use-dependence only at high rates of stimulation
Quinidine
‘Slow in-slow out’ LA
Shows use dependence at low rates of stimulation.
Tetrodotoxin
Toxin
Has a guanidinum group
Blocks Na+ channels from the outside
Does not show use-dependence
Use-dependence of LAs
Extent depends on the rate of entry into & dissociation from the LA binding site.
QX 314
quartenary LA
Almost ineffective when added to the outside of a squid giant axon, but a potent LA when perfused inside.
Voltage-dependence of LAs
For given pulse size, the initial rate of block per pulse is increased by giving a hyperpolarizing pre-pulse, and decreased by giving a depolarizing pre-pulse.
- i.e, the more channels opening during the pulse, the faster the block.
The more depolarising the test pulse, the faster the block.
- indicate that charges LAs have to get inside the channel to block it most effectively. A very positive test pulse increases the potential driving the LA into the channel.
Dihydropyridines (DHP)
Produce effects on cardiac & smooth muscle by modulating gating properties of the L-type Ca2+ channel
Highly lipid soluble, gain access to the channel through the lipid phase of the membrane.
Includes ‘calcium agonists’ and ‘calcium antagonists’
Cause peripheral & coronary vasodilatation- used in hypertension & angina
Bay K 8644
A DHP ‘calcium agonist’
Increase macroscopic Ca++ currents by favouring Mode 2 gating (v long openings, high opening probability) of L-type Ca2+ channels.
Nidedipine
A DHP ‘calcium antagonist’/ blocker
Reduce Ca2+ currents by favouring Mode 0 gating (channel does not open) of L-type Ca2+ channels
Verapamil
Ca2+ channel blocker
Also reduce DHP binding to channel (bind to a different site to the DHP binding site, but the sites interact)
Block shows much greater use-dependence & is more prolonged than that produced by DHPs
Preferentially block Ca2+ channels in cardiac muscle- used as antidysrhythmics
Diltiazem
A benzothiazepine
Ca2+ channel blocker
Also enhance DHP binding to channel (bind to a different site to the DHP binding site, but the sites interact)
Block shows much greater use-dependence & is more prolonged than that produced by DHPs
Preferentially block Ca2+ channels in cardiac muscle- used as antidysrhythmics
K+ channel openers (KCOs)
Examples
Clinical uses
A diverse group of compounds
e.g diazoxide, minoxidil, nicorandil
Cause hyperpolarization of cell membrane
Clinical uses - hypertension (cause relaxation of smooth muscle) - asthma - irritable bladder syndrome - male alopecia Target is probably the K[ATP] channel
