Calcium channel blockers Flashcards
what are ion channels
proteins that form pores in the plasma membrane
these pores allow ions to go through
what determines direction of ion flow?
conc gradient
electrical gradient
what is membrane potential of K
K is high inside (155 mM) and low outside the cell (4 mM)
what is membrane potential of Na
Na is low inside (12 nM) and high outside the cell (145 mM)
what is membrane potential of Ca
Ca is very low inside (100 nM) and high outside the cell (1.5 mM)
contribution of specific ions to action potentials
structure of voltage gated channels
Closed form - helices are crossed, ions can’t get through
open form - inner helices bend away after ion binding happens to open channel
Cav1.1 type, location, function
L-type
skeletal muscle
voltage sensor in E/C coupling
Cav1.2 type, location, function
L-type
cardiac, smooth muscle
Ca2+ entry triggers contraction
Cav1.3 type, location, function
L-type
neurons, endocrine cells
trigger for hormone secretion
Cav2.1 type, location, function
P/Q-type
neurons
triggers neurotransmitter release at synapse
Cav2.2 type, location, function
N-type
neurons
triggers neurotransmitter release at synapse
Cav2.3 type, location, function
R-type
neurons
functions unknown
block of channels in VSM effect
vasodilation
decrease in BP
relief of angina pectoris
block of channels in cardiac muscle and SA/AV node effect
antiarrhythmic
vsm contraction moa
Ca2+ influx via Cav1.2 induces release of Ca from intracellular stores via RYR2 in SR
extracellular Ca is required for contraction of cardiac and smooth muscle
Beta adrenergic modulation of Ca2 channels
PKA phosphorylation of Cav1.2 increases Ca2 influx
increases contractility/force of contraction
increases AV nodal action potential conduction rate
what is required for contraction of cardiac and vsm but not for skeletal muscle
extracellular ca2
how does cardiac muscle contraction occur
Ca2+ ions released from sarcoplasmic reticulum binds to troponin C
Ca2 binding by troponin C causes displacement of tropomysin
displacement of tropomyosin allows myosin to bind actin –> leads to contraction
how does skeletal muscle contraction happen
mechanical coupling between Cav1.1 and RYR1
what are the clinical applications of CCBs
angina pectoris, arrhythmias, htn
what are the 3 distinct chemical classes of CCBs
Dihydropyridines
phenylalkylamines
benzothiazepines
Dihydropyridines structure activity
dihydropyridine ring
aryl group
chiral center
ester linked side chains
members of the dihydropyridines
what is clevidipine (cleviprex)
short acting DHP
what is clevidipine (cleviprex) half life
1 min (85-90%)
15 min (10-15%)
how is clevidipine given
IV to tx htn when PO admin of drugs not possible/desirable
what is clevidipine formulated from
lipids from soy and egg
what is the metabolism of clevidipine
cleaved by esterases
what does a + enantiomers DHP do
blocks current
aka interferes with opening of CBB
what does a - enantiomer DHP do
potentiates current
aka interferes with closing
what tissue is DHP more selective for
more selective and potent in relaxing smooth muscle (esp. coronary artery)
what is DHP tissue selectivity result of
aa differences in channel splice variants
differences in membrane potential properties
what is characteristic of DHP block
voltage dependence
binds to closed channels and prevent opening - tonic block
no frequency dependence
marked tonic block
what are clinical considerations for DHPs
vascular selectivity - marked decrease in peripheral resistance, decreased afterload, little effect on HR or force of contraction
DHPs reduce heart oxygen demand (efficacy for angina)
DHPs (except nifedipine) don’t depress cardiac function
DHPs may inhibit atherosclerosis
which DHPs are vasoselective
nisoldipine, felodipine, nicardipine, isradipine, amlodipine, nifedipine
which DHP exhibits selectivity for cerebral arteries
nimodipine - used in sub-arachnoid hemorrhage to prevent neuropathy
DHPs pk factors
all dhps are highly bound to serum proteins
all dhps undergo extensive first pass metabolism in liver
amlodipine has slow onset and long DOA
nifedipine risks
increased risk of subsequent MI
fast release nifedipine may increase risk of subsequent heart attack
verapamil (calan, isoptin) drug class
phenylalkylamine
verapamil clinical considerations
causes vasodilation, but less potent than DHPs
slows conduction through the SA and AV nodes
reflex tachycardia is blunted
where does verapamil bind
in the pore and blocks Ca2 influx
characteristics of verapamil block
channel has to be open for drug to enter pore - frequency dependent block…
…so marked freqency dependence
very little tonic block
diltiazem (cardizem) drug class
benzothiazepine
diltiazem clinical considerations
causes vasodilation
less potent than DHPs
slows conduction through SA and AV nodes
initial reflex tachycardia
diltiazem potency
inhibits heart less than verapamil, but more than DHPs
diltiazem block characteristics
some frequency dependent block of Ca2 channels
some tonic block
summary of cv effects
CCBs side effect profile
all classes have 5-10% of ankle edema
verapamil has >10% of constipation
DHPs have 10-20% of facial flushing
DHPs have 5-10% of tachycardia
