Drug Actions at Ion Channels Flashcards
What form do ion channels often take?
20 amino acids required to cross the lipid bilayer
In the form of an alpha helix
Ion channels usually contain 8 or more alpha helices
3 properties of ion channels
Selective for specific ions
Open and close in response to specific chemical, electrical or mechanical signals
Conduct ions across the plasma membrane
4 natural ligands that act at ligand gated ion channels
Acetylcholine
Serotonin
GABA
Glutamate
General properties of ligand-gated ion channels
Multimeric membrane glycoproteins Signal by altering membrane potential or by Ca entry Gating is very fast Central pore lines with alpha helices Ion selectivity Often have modulatory sites
3 superfamilies of ligand gated channels and how many subunits they have
Cys-loop receptors (pentamers)
Glutamate receptors (tetramers)
ATP (P2X) receptors (trimers)
4 examples of Cys-loop receptors
Nicotinic ACh
Serotonin
Gaba A and C
Glycine
Examples of Glutamate receptors
NMDA receptors
Non-NMDA receptors (AMPA-type and kainate-type)
How many molecules of ACh need to bind at it’s receptor?
5 subunits
At least 2 molecules need to bind between two subunits
How many transmembrane domains are there in each subunit for 1. Cys-loop 2. Glutamate 3. P2X receptors?
- 4
- 4 (one is only partial)
- 2
Nicotinic ACh receptor
Cationic receptor (Na)
Requires at least 2 ACh molecules to bind
Variable subunit composition
Pentameric
M2 alpha helices line the pore (1 from each subunit)
Ring of negative charge at the top attracts positive ions
Neutrally charged leucine ring in the middle forms block - needs to twist to open
Curare
Paralyzes you by stopping skeletal muscle movement
Competitive antagonist at the ACh receptor at the NMJ
Competitively and reversibly inhibit the nAChR
Acetylcholine lifecycle
Synthesized from choline and acetyl-coA
Packaged into vesicles
AP reaches terminal, voltage gated Ca channels open, Ca depolarization causes fusion of vesicles into synaptic cleft
Can bind on postsynaptic neuron or itself
Can be broken down by acetylcholine esterase
Pharmacophore
Part on a molecular structure that is responsible for the pharmacological or biological interaction that it undergoes
Myasthenia Gravis
Muscle weakness (ptosis) Caused by antibodies that block, alter or destroy receptors Gets worse with exercise because as muscles work more they get hotter and with the antibodies present they cause the receptor to internalize Treatment: cholinesterase inhibitors (not very selective though, will get too much ACh in lots of places, resulting in excess body fluids from the stimulation of parasympathetic NS)
Botulism
Caused by Clostridium botulinum
Flaccid paralysis
Neurotoxin interferes with the release of ACh at the NMJ
Interference is permanent, so to regain muscle function they must grow a new axon
Succinylcholine
Dimer of 2 ACh molecules
Binds to ACh receptors (particularly at the NMJ)
Causes flaccid paralysis (because Ca is still removed from the cell so the muscles relax)
Activates the receptor and uses up all the ACh
Prevents cells from repolarizing
GABA A receptor
Cys-Loop receptor
Anionic receptor (inhibitory - Cl causes hyperpolarization)
Variable subunit composition
Multiple allosteric sites (different pharmacological properties)
Pentameric
How do benzodiazepines vs barbiturates work?
Benzos: makes the channel easier to open - has to work with GABA
Barbs: increase the length of time that the channel stays open - at high doses can work without GABA
What makes the many benzodiazepines different?
Pharmacokinetics (how they are absorbed, transported, how long they last, time of onset)
Different subunit composition
A delta fibers
Myelinated (fast)
Small
Signal first pain and temperature
Responsible for the short sharp initial pain
C fibers
Non myelinated (slow)
Large
Signal second pain and temperature
Responsible for longer lasting dull pain
Local anesthetics
Bind reversibly to a specific receptor site within the pore of the Na+ channels in nerves
Can act on any part of the NS system and on every type of nerve fiber
How do local anesthetics block conduction?
By decreasing or preventing the large transient increase in the permeability of excitable membranes to Na+ that normally is produced by a slight depolarization of the membrane
Block the AP
2 types of linkages that separate the hydrophilic and hydrophobic portions of local anesthetics
Ester
Amide
The time for onset of local anesthesia is related to the…
Proportion of molecules that convert to the lipid-soluble structure when exposed to physiologic pH
Local anesthetics have high affinity for which conformations of the Na channel?
Open conformation (block Na influx) Inactivated conformation (refractory period)
Are most local anesthetics vasodilators or vasoconstrictors?
Vasodilators
Why do you need to give a vasoconstrictor with a local anesthetic?
So that they do not leave the site of action so quickly
Ex: give an alpha 1 agonist to keep at high concentrations locally
Problems with vasoconstrictors
Can delay wound healing or cause edema or necrosis
Increase O2 demand, leading to hypoxia
Cautious use in regions with limited collateral circulation or in some conditions such as diabetes
Where are
1. esters
2. amides
metabolized, and by what?
- plasma esterases
2. hepatic CYPs
Toxicity of local anesthetics
CNS toxicity possible for all
Can include light-headedness, sedation, nystagmus, or seizures
Can cause hypotension and arrythmias
Why do you add epinephrine when giving a local anesthetic?
To decrease the rate of absorption so it matches rate of metabolism
Reduces potential systemic toxicity
