calcium channel blockers-Hockman

Question 1

what determines direction flow?

Answer 1

concentration gradient

electrical gradient

Question 2

ions can

Answer 2

flow in both directions through most ion channels

Question 3

excitable cells have what kind of potential across membrane?

Answer 3

negative inward potential

-due to selective permeability of resting membrane to K+

Question 4

K gradient

Answer 4

high INSIDE (155mM)
low OUTSIDE (4mM)

Question 5

Na gradient

Answer 5

low INSIDE (12mM)
high OUTSIDE (145mM)

Question 6

what maintains Na and K gradient

Answer 6

active transport Na out of and K into the cell and by channels that selectively permit K to run out of the cell at voltages near resting membrane potential

Question 7

Ca gradient

Answer 7

very low inside the cell (100nM)
high outside (1.5mM)
-huge gradient

Question 8

General voltage gated channel structure

Answer 8

1. ) Spans the membrane: have transmembrane helices
2. ) inverted Tepee conformation: closed, helices cross
3. ) aqueous vestibule: water filled in middle of channel, to bind protons
4. ) selectivity filter: G-Y-D motif (important for selectivity for dehydrated K).

Question 9

calcium gated channel

Answer 9

1. Selectivity filter
2. gated
   - calcium is what opens gate, by binding to structure MthK

Question 10

difference between K and Ca channel?

Answer 10

gated region

• K-> cross helices
• Ca-> hinge gated region

Question 11

target for Calcium channel blockers?

Answer 11

L type

Question 12

what CCB are used for

Answer 12

1. block channel in vascular smooth muscle: vasodilation
   - decrease in BP
   - relief in angina
2. block channels in cardiac muscle and SA/AV node:
   - antiarrhythmic

Question 13

skeletal muscle and CCB’s

Answer 13

mechanical coupling between Ca1.1 and RYR1

• extracellular Ca is not required
• drugs have a slight more affinity for Ca1.1
• CCB’s do not interfere with coupling

Question 14

skeletal muscle contraction

Answer 14

• physical coupling Ca1.1 and RYR1 on sacroplasmic reticular membrane-> conformation change drives release from Ca stores
• DUE TO CONFORMATION COUPLING-> release of Ca from sacroplasmic reticulum
• very fast

Question 15

smooth muscle contraction

Answer 15

-put in later

Question 16

cardiac muscle contraction

Answer 16

-put in later

Question 17

clinical use of CCB

Answer 17

angina, arrh, HTN

Question 18

3 classes of CCB

Answer 18

dihydropyridine
phenylalkylamines
benzothiazepines

Question 19

dihydropyridine

Answer 19

dihydropyridine ring
aryl group
chiral center
ester linked side chains

Question 20

dihydropyridine MOA

Answer 20

interference with gates
-bind to closed gates
(+)enantiomer interferes with opening, blocks current
(-)enantiomer interferes with closing, potentiates current

Question 21

tissue selectivity of dihydropyridine

Answer 21

more potent in relaxing smooth muscle-> especially coronary artery

• does NOT compromise cardiac function
• NOT ANTIARRHYTHMICS
  1. ) amino acid differences in channel splice variants
  2. differences in membrane potential properties

Question 22

dihydropyridine block is

Answer 22

voltage dependent

• affinity of drug for the channel is different at different voltages
• all closed states aren’t the same, multiple closed states
• binding with higher affinity the closer to opening (of closed states)

Question 23

why do dihydropyridines have higher affinity for vasculature than cardiac?

Answer 23

closer to opening states (C2 or C3)

-cardiac is mainly at C1

Question 24

what does it mean that dihydropyridines are marked tonic block?

Answer 24

doesn’t depend on activity

-bind closed channels and prevent them from opening

Question 25

clinical associations fir dihydropyridines

Answer 25

-do later

Question 26

phenylalkylamine

Answer 26

Verapamil

-causes vasodilation but less potent that DHP’s