10/19 Flashcards
ion channels definition
proteins that form pores in the plasma membrane
ion channels categorized by
gating (opening and closing) mechanism
ion selectivity
pharmacology
passive
allow ions to flow down their electrochemical gradient
ion flow is determined by
concentration gradient and electrical gradient
membrane potential overviw
excitable cells have a negative inward potential across the membrane due to the selective permeability of the resting membrane K+
K+ is high ___ and low ___
K+ is high inside (155 mM) and low outside the cell (4 mM)
Na+ is high ___ and low ___
Na+ is high outside the cell (145 mM) and low inside the cell (12 mM)
Ca is very low ___ and high ___
Ca is very low inside (100 nM) and high outside the cell (1.5 mM)
calcium can start to activate many pathways
need a ___ resting membrane potential
negative inward resting
type of channel expressed in cardiac smooth muscle
L-type, Cav1.2
this is the channel we want to block
CCBs block of channels in vascular smooth muscle:
vasodilation
-decrease BP
-relief of angina pectoris
block of channels in cardiac muscle and SA/AV node: antiarrhythmic
vascular smooth muscle contraction
Ca moves through (L type) channels, inc Ca conc., myosin LC kinase -> myosin LC -> phosphorylation + actin –> contraction
CCBs mechanism
if CCs are blocked, Ca can’t enter cell, Ca can’t be released from the SR, muscle can’t contract
CICR
- calcium influx (Cav1.2) induces release of Ca from intracellular stores vie RYR2 in the SR
- extracellular Ca is required for contraction of cardiac and smooth muscle (not skeletal)
cardiac smooth muscle contraction
Ca ions released from SR bind to troponin C, causes displacement of tropomyosin, allows myosin to bind actin -> CONTRACTION
skeletal muscle contraction
mechanical coupling between Cav1.1 RYR1, extracellular Ca is not required -> CCBs do not interfere with coupling
CCB clinical applications
HTN, angina pectoris, arrythmia
3 classes of CCBs
dihydropyridines, phenylalkylmines, benzothiapines
dihydropyridine members
nifedipine (Procardia), isradipine
amlodipine (Norvasc)
clevidipine = short acting, efficacy ends when drug is not being infused
dihydropyridines blockade mechanism
(+) enantiomer blocks current, intereferes w opening
(-) enantiomer potentiates current, interferes w closing
tissue selectivity of DHPs
more potent in relaxing smooth muscle
do not compromise cardiac function
not antiarrythmics
characteristics of DHP block
voltage-dependent
affinity depends of voltage
NOT frequency dependent
tonic block - closed channel block
clinical considerations from DHPs
vascular selectivity (decreases hearts work), reflex tachycardia secondary to vasodilation (except amlodipine), reduce oxygen demand of the heart (efficacy in angina), don’t depress cardiac function
phenylalkylamine
verapamil
verapamil clinical considerations
vas][odilator (less potent than DHPs), slows conduction through the SA/AV nodes (reduced HR and force of contraction), blunts reflex tachycardia
verapamil charactersitics of block
frequency dependent
very little tonic block (blocks open channels)
benxothiazepine
diltiazem
diltiazem clinical considerations
causes vasodilation (less potent than DHPs), slows conduction through SA/AV nodes, initial reflex tachycardia, exhibits frequency dependent block of Ca channels
CCB CV effect summary
verapamil: 2x dec HR, 2x dec AV cond, 2x dec myocard contract, 2x inc arteriol vasodil
DHPs: inc HR, 4x inc arteriol vasodil
Diltiazem: dec HR, dec AV cond, dec myocard contract, inc arteriol vasodil
CCBs SE profile
ankle edema present in all
DHPs: facial flushing and tachycardia
verapamil: constipation (>20%)
