calcium channel blockers-Hockman Flashcards
what determines direction flow?
concentration gradient
electrical gradient
ions can
flow in both directions through most ion channels
excitable cells have what kind of potential across membrane?
negative inward potential
-due to selective permeability of resting membrane to K+
K gradient
high INSIDE (155mM) low OUTSIDE (4mM)
Na gradient
low INSIDE (12mM) high OUTSIDE (145mM)
what maintains Na and K gradient
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
Ca gradient
very low inside the cell (100nM)
high outside (1.5mM)
-huge gradient
General voltage gated channel structure
- ) Spans the membrane: have transmembrane helices
- ) inverted Tepee conformation: closed, helices cross
- ) aqueous vestibule: water filled in middle of channel, to bind protons
- ) selectivity filter: G-Y-D motif (important for selectivity for dehydrated K).
calcium gated channel
- Selectivity filter
- gated
- calcium is what opens gate, by binding to structure MthK
difference between K and Ca channel?
gated region
- K-> cross helices
- Ca-> hinge gated region
target for Calcium channel blockers?
L type
what CCB are used for
- block channel in vascular smooth muscle: vasodilation
- decrease in BP
- relief in angina - block channels in cardiac muscle and SA/AV node:
- antiarrhythmic
skeletal muscle and CCB’s
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
skeletal muscle contraction
- 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
smooth muscle contraction
-put in later
cardiac muscle contraction
-put in later
clinical use of CCB
angina, arrh, HTN
3 classes of CCB
dihydropyridine
phenylalkylamines
benzothiazepines
dihydropyridine
dihydropyridine ring
aryl group
chiral center
ester linked side chains
dihydropyridine MOA
interference with gates
-bind to closed gates
(+)enantiomer interferes with opening, blocks current
(-)enantiomer interferes with closing, potentiates current
tissue selectivity of dihydropyridine
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
dihydropyridine block is
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)
why do dihydropyridines have higher affinity for vasculature than cardiac?
closer to opening states (C2 or C3)
-cardiac is mainly at C1
what does it mean that dihydropyridines are marked tonic block?
doesn’t depend on activity
-bind closed channels and prevent them from opening
