Drug Actions at Ion Channels

Question 1

What form do ion channels often take?

Answer 1

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

Question 2

3 properties of ion channels

Answer 2

Selective for specific ions
Open and close in response to specific chemical, electrical or mechanical signals
Conduct ions across the plasma membrane

Question 3

4 natural ligands that act at ligand gated ion channels

Answer 3

Acetylcholine
Serotonin
GABA
Glutamate

Question 4

General properties of ligand-gated ion channels

Answer 4

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

Question 5

3 superfamilies of ligand gated channels and how many subunits they have

Answer 5

Cys-loop receptors (pentamers)
Glutamate receptors (tetramers)
ATP (P2X) receptors (trimers)

Question 6

4 examples of Cys-loop receptors

Answer 6

Nicotinic ACh
Serotonin
Gaba A and C
Glycine

Question 7

Examples of Glutamate receptors

Answer 7

NMDA receptors

Non-NMDA receptors (AMPA-type and kainate-type)

Question 8

How many molecules of ACh need to bind at it’s receptor?

Answer 8

5 subunits

At least 2 molecules need to bind between two subunits

Question 9

How many transmembrane domains are there in each subunit for
1. Cys-loop
2. Glutamate
3. P2X 
receptors?

Answer 9

1. 4
2. 4 (one is only partial)
3. 2

Question 10

Nicotinic ACh receptor

Answer 10

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

Question 11

Curare

Answer 11

Paralyzes you by stopping skeletal muscle movement
Competitive antagonist at the ACh receptor at the NMJ
Competitively and reversibly inhibit the nAChR

Question 12

Acetylcholine lifecycle

Answer 12

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

Question 13

Pharmacophore

Answer 13

Part on a molecular structure that is responsible for the pharmacological or biological interaction that it undergoes

Question 14

Myasthenia Gravis

Answer 14

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)

Question 15

Botulism

Answer 15

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

Question 16

Succinylcholine

Answer 16

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

Question 17

GABA A receptor

Answer 17

Cys-Loop receptor
Anionic receptor (inhibitory - Cl causes hyperpolarization)
Variable subunit composition
Multiple allosteric sites (different pharmacological properties)
Pentameric

Question 18

How do benzodiazepines vs barbiturates work?

Answer 18

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

Question 19

What makes the many benzodiazepines different?

Answer 19

Pharmacokinetics (how they are absorbed, transported, how long they last, time of onset)
Different subunit composition

Question 20

A delta fibers

Answer 20

Myelinated (fast)
Small
Signal first pain and temperature
Responsible for the short sharp initial pain

Question 21

C fibers

Answer 21

Non myelinated (slow)
Large
Signal second pain and temperature
Responsible for longer lasting dull pain

Question 22

Local anesthetics

Answer 22

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

Question 23

How do local anesthetics block conduction?

Answer 23

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

Question 24

2 types of linkages that separate the hydrophilic and hydrophobic portions of local anesthetics

Answer 24

Ester

Amide

Question 25

The time for onset of local anesthesia is related to the…

Answer 25

Proportion of molecules that convert to the lipid-soluble structure when exposed to physiologic pH

Question 26

Local anesthetics have high affinity for which conformations of the Na channel?

Answer 26

Open conformation (block Na influx)
Inactivated conformation (refractory period)

Question 27

Are most local anesthetics vasodilators or vasoconstrictors?

Answer 27

Vasodilators

Question 28

Why do you need to give a vasoconstrictor with a local anesthetic?

Answer 28

So that they do not leave the site of action so quickly

Ex: give an alpha 1 agonist to keep at high concentrations locally

Question 29

Problems with vasoconstrictors

Answer 29

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

Question 30

Where are
1. esters
2. amides
metabolized, and by what?

Answer 30

1. plasma esterases

2. hepatic CYPs

Question 31

Toxicity of local anesthetics

Answer 31

CNS toxicity possible for all
Can include light-headedness, sedation, nystagmus, or seizures
Can cause hypotension and arrythmias

Question 32

Why do you add epinephrine when giving a local anesthetic?

Answer 32

To decrease the rate of absorption so it matches rate of metabolism
Reduces potential systemic toxicity