Calcium Channel Blockers Flashcards
Ion channels
What? proteins form pores in plasma membrane
membrane is extremely impermeable to charged ions due to lipophilicity
Categorized:
Gating: opening and closing mechanism
Voltage: membrane potential
Ligand: confirmation change upon ligand binding
Ion selectivity: K+ channels are very selective
ion channels are passive allowing ions to flow down electrochemical gradient with no energy input
What determines direction of flow?
Concentration gradient: flow from high to low concentration
Electrical gradient: ions flow from (+) to (-)
Membrane potential
Excitable cells have a negative inward potential across the membrane due to selective permeability of the resting membrane established by K+
Ion specific:
Potassium: high inside and low outside
Sodium: low inside and high outside
Calcium: very low inside and high outside
Desire a low intracellular Ca2+ to avoid activating calcium processes
Calcium is the key driver in muscle contraction
Type of calcium channel blocker
L-type Cav1.2: cardiac and smooth muscle–>Ca2+ triggering contraction
Effects of calcium channel blockers
Blocking channels in vascular smooth muscle: vasodilation
-decrease BP and relief in agina
Blocking channels on cardiac muscle: antiarrhythmic
Vascular smooth muscle contraction
Increase in extracellular Ca2+ is influx through the Cav1.2 channel down the concentration gradient and binds to RYR2 in the SR
This induces release of Ca2+ from intracellular stores from SR to cytoplasm
An increase in intracellular calcium allows for calcium to bind to calmodulin
Ca2+-calmodulin activates myosin LC kinase to cleave myosin LC to myosin PO4
Myosin LC-PO4 + actin allows for vascular smooth muscle contraction
EXTRACELLULAR CALCIUM IS REQUIRED
Cardiac muscle contraction
Increase in extracellular Ca2+ is influx through the Cav1.2 channel down the concentration gradient and binds to RYR2 in the SR
This induces release of Ca2+ from intracellular stores from SR to cytoplasm
An increase in intracellular calcium allows for calcium to bind to troponin C
Ca2-troponin C causes displacement of tropomyosin from the actin filament
Displacement of tropomyosin allows myosin to bind to actin allowing for contraction
EXTRACELLULAR CA2+ IS REQUIRED
Dihydropyridines
dihydropyridine ring
aryl group
chiral center
ester linked side chains
Nifedipine
no chiral center (symmetrical)
Immediate release formulations can lead to increase risk of MI
rapid decrease in BP can lead to reflex tachycardia
Isradipine
highest affinity
Felodipine
Amlodipine
slow onset, long duration allowing for minimal reflex tachycardia
Nisoldipine
Nimodipine
hydrophobic allowing for selectivity of cerebral arteries to treat subarachnoid hemorrhage indication
Nicardipine
