Voltage-gated Ion Channel Drugs

Question 1

Ion channels are targets for…

Answer 1

Anesthetics
Heart failure drugs
Anti-arrhythmic drugs
Anti-hypertensives
Anti-convulsants
Anti-diabetics
Insecticides
Plant/animal toxins

Question 2

Excitatory ion channels

Answer 2

Na
Ca
(Depolarization)

Question 3

Inhibitory ion channels

Answer 3

K
Cl
(Hyperpolarization)

Question 4

Properties of voltage-gated ion channels

Answer 4

Ion selectivity
Large opening to small changes in voltage
Fast activation

Many variants - may be specific to particularly tissue/organ

Question 5

Types of voltage-gated Ca channels

Answer 5

N-type - neurons, release NT

L-type - cardiac cells, AP in cardiac cells

**Manipulated for drug specificity

Question 6

Ion current depends on …

Answer 6

Fraction of channels open

Driving force for ion movement (electrochemical potential)

Question 7

Inactivation of ion channels

Answer 7

Spontaneous closure (inactivation) —> intracellular domain of channel plugs the pore

Unplugged during repolarization

Question 8

Modulated receptor hypothesis

Answer 8

Channel proteins can exist in 3 (+?) functional states
> dependent on membrane potential

(I.e. closed, open, inactivated)

Question 9

Use/state dependence

Answer 9

Effect of drug depends on channel’s activity (state)

Question 10

Mechanism of use/state dependence

Answer 10

Drug may enter channel more readily when open

Drug may preferentially bind a particular state

Question 11

Actions of ion channel drugs

Answer 11

1. Block the channel (physical block or pore or prevent key intramolecular mvt)
2. change in gating behavior (change probability of gate opening)

Question 12

Voltage-gated Na channel drugs

Answer 12

Modulation of excitability

• local anesthetics block initiation/propogation of AP (block action of nocioceptors)

Question 13

Increasing conc of anesthetic (Na blocker) causes…

Answer 13

Increasing threshold for excitation
Slowing of impulse conduction
Decreased rate of rise of AP
Decreased amplitude of AP
Failure to generate AP

Question 14

Mechanism of Na-channel blocking local anesthetics

Answer 14

Physically plug membrane channel pore from inside

Question 15

Na-channel local anesthetic binds strongly to the…

Answer 15

Inactivated state

(Prolonging refractory period)

Question 16

pH dependence of Na channel blockers

Answer 16

Local anesthetics are weak bases

Non-ionized form penetrates membrane
Ionized form binds the channel

**needs to act from inside channel*
HIGHLY pH dependent

Question 17

Local anesthetic exhibit strong use dependence

Answer 17

Enter membrane through open channels
Bind more strongly to O and/or I state

Question 18

Class I antiarrhythmic drugs

Answer 18

Block voltage gated Na channels
Use dependence - bind strongly to O and/or I states - block high frequency excitations (tachy, premature beats)

Question 19

Binding rate of anti-arrhythmias

Answer 19

For drug that unbinds rapidly - strong activity at high rate of depolarization (tachy)

Not enough time to unbind > accumulation of block

Question 20

Lidocaine

Answer 20

Binds inactive state of Na channel

Unbinds rapidly - only tachycardic activity

Question 21

Quinidine

Answer 21

Binds open state
Unbinds slowly - block remains between beats; affects normal rates

Question 22

Grayanotoxins

Answer 22

Toxin in plants (rhododendron, Azalea)
Stabilized open conformation of Na channel

Toxic to grazing animals, MAD HONEY (raw honey from bees near these plants > human toxin)

Question 23

Increased intracellular Ca —>

Answer 23

Contraction in muscle cells

Secretion/release

Modulation of enzyme activity

Question 24

Cardiac muscle Ca channel opener

Answer 24

beta-adrenergic receptors in cardiac muscle

Question 25

Indirect mechanism of Ca channel openers

Answer 25

1. Activation of adenylyl cyclase —> phosporylation of Ca channels 2. Alpha subunit of G protein binds to Ca channels

Question 26

Classes of Ca channel antagonists

Answer 26

Phenylalkylamines (verapamil) Dihydropyridines (nifedipine) Benzothiazepines (diltiazem) **all act from inner side of channel

Question 27

Use dependence of Ca channel antagonists

Answer 27

Nifedipine > binds resting state Verapamil > binds open state Diltiazem > binds inactivated state **empirically determined

Question 28

Cardiovascular implications of Ca channel antagonism (dec inward current)

Answer 28

Decreases SA node pacemaker rate Decreased AV node conduction velocity Reduced cardiac muscle contractility Vascular smooth muscle relaxation

Question 29

Cardiac actions of Ca channel agonists

Answer 29

Slow SA/AV nodal conduction velocity (slow HR; nodal AP propagation depends on slow, inward current of Ca; terminate supraventricular tachycardias via partial AV block) Reduce force of contraction Verapamil/diltiazem have strong cardiac effects

Question 30

Vascular smooth muscle actions of Ca channel antagonists

Answer 30

Smooth muscle depends on Ca influx for resting tone/contraction Blocking Ca entry > generalized arteriolar dilation > drop in BP Nifedipine = most potent vasodilator (stronger affinity to Ca channel in VSMCs vs cardiac muscle cells)

Question 31

Unwanted effects of Ca channel agonists

Answer 31

Relaxation of off-target smooth muscle Headache/flushing (humans) Constipation AV block + negative inotropic effects

Question 32

Cantharidin

Answer 32

Blister beetle toxin > increases opening of Ca channels Blister beetles sometimes found in hay (esp alfalfa) Horses especially susceptible > die within 24-72 h Sheep/cattle often exposed, rarely ill