Drug interactions with receptors and ion channels: Drugs and ion channels Flashcards Preview

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Flashcards in Drug interactions with receptors and ion channels: Drugs and ion channels Deck (22):
1

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

2

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.

3

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.

4

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

5

Quinidine

'Slow in-slow out' LA
Shows use dependence at low rates of stimulation.

6

Tetrodotoxin

Toxin
Has a guanidinum group
Blocks Na+ channels from the outside
Does not show use-dependence

7

Use-dependence of LAs

Extent depends on the rate of entry into & dissociation from the LA binding site.

8

QX 314

quartenary LA
Almost ineffective when added to the outside of a squid giant axon, but a potent LA when perfused inside.

9

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.

10

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

11

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.

12

Nidedipine

A DHP 'calcium antagonist'/ blocker
Reduce Ca2+ currents by favouring Mode 0 gating (channel does not open) of L-type Ca2+ channels

13

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

14

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

15

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

16

Orally-acting hypoglycaemic agents: the sulphonylureas

e.g tolbutamide, glibenclamide, glipizide

Act on the sulphonylurea receptor to close the K[ATP] channel -> depolarisation of the membrane of the pancreatic β cell -> triggers firing of VGCa2+ channels -> Ca2+ influx -> stimulates insulin release.

Treatment of Type II diabetes.
Ineffective in Type I diabetes as there are too few β cells

17

Tolbutamide

Sulphonylurea
Act on the sulphonylurea receptor to close the K[ATP] channel -> -> insulin release from pancreatic β cells

Type II diabetes

18

Glibenclamide

Sulphonylurea
Act on the sulphonylurea receptor to close the K[ATP] channel -> -> insulin release from pancreatic β cells

Type II diabetes

19

Minoxidil

K+ channel opener

20

Nicorandil

K+ channel opener

21

Diazoxide

K+ channel opener

22

Insulin

Injected as a replacement therapy in Type I diabetes