Drugs Interacting With Ion Channels

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DRUGS THAT DIRECTLY INTERACT WITH ION CHANNELS

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- Lidocaine (lignocaine)

- They can physically block Na+ channels in nerves

- Physiological effect: local anaesthetic

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DRUGS THAT DIRECTLY INTERACT WITH LIGAND-GATED ION CHANNELS

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- Some drugs interact with receptors on ion channels and modify their transport function

- Eg: diazepam binds to benzodiazepine (BDZ) receptors on GABA-gated Cl- channels. This modifies Cl- transport --> sedative/anticonvulsant (reducing severity and frequency of seizures) effect

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WHY WE NEED ION CHANNELS

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- Ions are unable to penetrate lipid bilayer of cell membrane

- As ions are hydrophilic and part of the cell membrane is hydrophobic

- Ions can only get across with help of proteins (ion channels) which span the cell membrane

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TYPES OF ION CHANNELS

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- Protein molecules which interact to form water filled pores which span the cell membrane

- Allow movement of ions down concentration gradients

- Allow movement of ions down electrochemical gradients

- Switch between open and closed states known as 'gating'

- Voltage gated ion channels and ligand gated ion channels

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CHARACTERISATION OF ION CHANNELS

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1) Their selectivity for a particular ion species

2) Their gating properties (voltage/ligand/both)

3) Their location (intracellular/extracellular)

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SELECTIVITY OF ION CHANNELS

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- Generally selective for either anions or cations

- Cation channels may be selective for specific cations or non-selective and permeable to all cations

- Anions are less selective and generally permeable to Cl-

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VOLTAGE GATED ION CHANNELS

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- Modulate membrane excitability

- Involved in the generation of action potentials

- They open (activate) when cell membrane becomes depolarised

- Activation is short-lasting even when depolarisation is maintained - due to rapid channel inactivation

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MOST IMPORTANT VOLTAGE-GATED ION CHANNELS

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- Selective Na+ channels: Neuronal, skeletal, cardiac

- Selective Ca2+ channels: 5 types - L-type most important

- Selective K+ channels: 10 types (voltage or ligand gated)

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EXAMPLES OF DRUGS WHICH ACT ON VOLTAGE-GATED ION CHANNELS

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- Local anaesthetics (lidocaine): Block Na+ channels in nerves

- Some anticonvulsants (phenytoin): Block Na+ channels in brain (reduced spread of seizures, anti-epileptics)

- 'Class 1' antiarrhythmics (procainaminde, lidocain): Block Na+ channels in heart (resets premature heart beat)

- Calcium channel blockers (Verapamil): Block L-type Ca2+ channels in smooth muscle and heart (reduces force of contraction and blood pressure)

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LIGAND-GATED ION CHANNELS (LOCATION, STRUCTURE, MODULATES, COUPLINE, TIMESCALE, ACTIVATION)

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- Location: Cell membrane

- Structure: Oligomeric subunits surrounding a central pore

- Modulates: Ion channels

- Coupling: Direct

- Timescale: Milliseconds

- Activation: Binding of a ligand to receptor site on channel molecule

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EXTRACELLULAR LIGAND-GATED ION CHANNELS

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- Fast neurotransmitters such as glutamate, ACh and GABA bind to sites on outside of cell membrane

- Such receptors produce a response in milliseconds

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INTRACELLULAR LIGAND-GATED ION CHANNELS: IP3-gated Ca2+ channels

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- Intracellular channels

- Present on endoplasmic or sarcoplasmic reticulum of cells

- Receptor activated by IP3

- Activation releases Ca2+ from intracellular stores in response to Gq-protein-coupled receptor activation

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EXAMPLES OF DRUGS WHICH ACT ON LIGAND-GATED ION CHANNELS

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Mostly in the brain

- Benzodiazepines (Phenytoin): Act on GABA-gated Cl- channels (actions of GABA amplified, sedative effects, anticonvulsant)

- 5-HT3 receptor antagonists (Ondansetron): Block 5-HT3 receptors on 5-HT gated Ca2+ channels (reduces nausea)

- NMDA antagonists (ketamine): Block glutamate gated Na+/Ca2+ channels (produces anaesthesia)

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DIRECT DRUG INTERACTIONS OF ION CHANNELS

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A drug alters channel function via a direct action

Eg:

- Diazepam: direct action of Cl- channels by acting on BDZ receptors (no second messengers involved)

- Lidocain: physically blocks Na+ channels in nerves (no second messengers involved either)

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INDIRECT DRUG INTERACTIONS OF ION CHANNELS

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A drug alters channel function via interaction of second messenger systems:

Eg:

- Activation of intracellular Ca2+ channels after interaction of agonist with cell surface receptor

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GABA MODULATED CHLORIDE CHANNEL

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GABA (gamma-aminobutyric acid): predominant inhibitory neurotransmitter in brain. GABAa receptor gates Cl- channels

- GABA interacts with GABAa receptor

- Allows Cl- to enter cell

- Makes depolarisation difficult

- Stabilises brain tissues

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DRUGS CAN MODULATE ION CHANNEL FUNCTION BY INTERACTING WITH

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- A receptor site on ligand-gated channels. Eg. GABA acting on GABAa receptors to open Cl- channels

- Other parts of the channel molecule. Known as allosteric effect

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EXAMPLES OF ALLOSTERIC EFFECT DRUGS

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- Barbiturates and benzodiazepines (BDZs) (eg. diazepam): bind to other sites not the GABAa receptor, potentiate effects of GABA, make cell less excitable, used as sedatives/convulsants

- Picrotoxin also binds to other sites on Cl- channel (not GABAa receptor so non-competitive antagonism): inhibit effects of GABA by directly blocking the ion channel, make cells more excitabe causing convulsions

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BLOCKERS AND MODULATORS OF NERVES

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- Voltage-gated Na+ channels

- Blocker: Tetrodotoxin (puffer fish)

- Modulator: Veratridine (neuralgia: pain)

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BLOCKERS AND MODULATORS OF THE PANCREAS

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- ATP-sensitive K+ channels

- Blocker: Sulphonylureas (leading to release of (pro)insulin, useful for diabetics)

- Modulators: Chromokalin