Calcium Channel Blockers

Question 1

Ion channels

Answer 1

ions are charged, membrane made up of lipid bilayers, impermeable to ions, so need channels –> proteins that form pores in the plasma membrane, allow ions to go through
categorized by: gating (opening and closing) mechanism - voltage gated and ligan gated; ion selectivity; pharmacology
passive: allow ions to flow down their electrochemical gradient

Question 2

Ion channels and the electrochemical gradient

Answer 2

ions can flow in both direction through most ion channels
what determines direction of flow: concentration gradient and electrical gradient

Question 3

Know the intracellular/extracellular distribution of Na+, K+, and Ca2+ in excitable cells

Answer 3

excitable cells have a negative inward potential across the membrane due to the selective permeability of the resting membrane to K+
K+ is high inside and low outside the cell
Na+ is low inside and high outside the cell
gradient maintained by active transport of Na+ out of and K+ into the cell, and by channels that selectively permit K+ to run out of the cell at voltages near the resting membrane potential - resting membrane potential largely set by permeability of cell to K+
Ca2+ is very low inside and high outside the cell - want to keep intracellular Ca2+ low at rest b/c it is a key driver for muscle contraction, neurotransmitter release, hormone release

Question 4

Contribution of specific ions to action potentials

Answer 4

opening of ion-selective channels drives the membrane potential toward the equilibrium potential of the permeant ion
influx of Na+ leads to depolarization; Ca2+ helps maintain resting potential at (+) level, opens slowly and stays open for long time; K+ slower activating K+ channel

Question 5

Structure of voltage-gated channels

Answer 5

Kcsa- a H+ gated K+ channel from bacteria
2 transmembrane helices made up of amino acids; ions squeeze through selectivity filter, very narrow passage, ion gets rehydrated in aqeuous pore
MthK- a Ca2+ gated K+ channel from bacteria
open when bound to Ca2+; inner helices bend away from eachother in response to Ca2+ binding; crystallized in presence of Ca2+
bacterial voltage-gated K+ channel KvAP - at resting membrane potentials, voltage sensor pulled in, negative inward; at depolarized potentials that lead to activation of voltage-gated channels, sensor moves outward

Question 6

Understand the role of voltage-gated calcium channels in cardiac, vascular, and skeletal muscle

Answer 6

voltage-gated Ca2+ channel family: L-type is the target for the Ca2+ channel blockers; family is Cav1.2; location/function: cardiac, smooth muscle/Ca2+ entry triggers contraction of vascular smooth muscle
block of channels in vascular smooth muscle: vasodilation, decrease in BP and relief of angina pectoris
block of channels in cardiac muscle and SA/AV node: antiarrhythmic

Question 7

Vascular smooth muscle contraction

Answer 7

Ca2+ induced Ca2+ release
Ca2+ influx via Cav1.2 induces release of Ca2+ from intracellular stores via RYR2 (ryanodine receptor 2), this is a ligand gated channel, in the SR
extracellular Ca2+ is required for contraction of cardiac and smooth muscle

Question 8

Beta-adrenergic modulation Ca2+ channels

Answer 8

PKA phosphorylation of Cav1.2 increases Ca2+ influx leading to increases in contractility/force of contraction, and increases AV nodal action potential conduction rate

Question 9

Cardiac muscle contraction

Answer 9

Ca2+ ions released from sarcoplasmic reticulum binds to troponin C –> Ca2+ binding by troponin C causes displacement of tropomyosin –> displacement of tropomyosin allows myosin to bind actin –> contraction

Question 10

Skeletal muscle contraction

Answer 10

mechanical coupling between Cav1.1 and RYR1, interact with each other indirectly through protein intermediates
extracellular Ca2+ is not required
CCBs do not interfere with coupling

Question 11

Know the three chemical classes of calcium channel blockers and recognize members of each class by their names and chemical structures

Answer 11

dihyropyridines, phenylalkylamines, benzothiazepines
clinical applications: angina pectoris, arrhythmia, hypertension

Question 12

Dihydropyridines

Answer 12

structure activity: dihydropyridine ring (not aromatic), aryl group, chiral center, ester linked side chains

Question 13

Members of the dihydropyridine class

Answer 13

nifedipine - no chiral center, symmetrical
isradipine - highest affinity for Ca2+ channel
felodipine - good vascular selectivity
amlodipine - ether group gives slow onset and long duration of action; minimal reflex tachycardia
nisoldipine - more hydrophilic
nimodipine - pretty hydrophobic
nicardipine - more hydrophilic

Question 14

Clevidipine

Answer 14

short acting DHP; rapid reduction in BP
given IV to treat HTN when PO admin not possible/desirable
works rapidly but also breaks down quickly to inactivate metabolite
broken down by esterases –> cleave off butryic acid group –> cleave into inactive acid and formaldehyde

Question 15

Blockade mechanism of DHPs

Answer 15

(+) enantiomer blocks current
(-) enantiomer potentiates current
bind to the same binding site
mechanism involves interference with gating: (+) enantiomer interferes with opening, (-) enantiomer intereferes with closing

Question 16

Understand the pharmacodynamics and tissue selectivity of the 3 different classes of calcium channel blockers

Answer 16

tissue selectivity of DHPs: selective for relaxing vascular smooth muscle
phenylalkylamines: also causes vasodilation, but less potent than DHPs; slows conduction through the SA and AV nodes

Question 17

tissue selectivity of DHPs

Answer 17

high degree for selectivity of relaxing vasculature smooth muscle
more potent in relaxing smooth muscle - esp coronary artery
do not compromise cardiac function, not antiarrhythmics
tissue selectivity the result of: amino acid differnces in channel splice variants, differences in membrane potential properties
observed in functional (cell intact) but not binding asays

Question 18

Characteristics of DHP block

Answer 18

voltage dependence of binding
affinity of drug for the channel is different at different voltages
drug more potent at more (+) values
no frequency dependence; marked tonic block

Question 19

DHP binding site

Answer 19

allosteric (outside of the pore)
DHP drugs bind to closed channels and prevent opening - tonic block (molecules can enter and bind to the pore in its closed state)

Question 20

Clinical considerations for DHPs

Answer 20

vascular selectivity - marked decrease in peripheral resistance (dilation of arterioles; little affect on venules); decreased afterload, little effect on heart rate or force of contraction
vasoselective: nisoldipine, felodipine, nicardipine, isradipine, amplodipine, nifedipine
nimodipine exhibits selectively for cerebral arteries (used in hemorrhage to prevent neuropathy)
reflex tachycardia secondary to vasodilation (except amlodipine due to slow onset of action)

Question 21

Clinical considerations for DHP cont

Answer 21

DHPs reduce oxygen demand in heart - efficacy in angina
DHPs (except nifedipine) don’t depress cardiac function
DHPs may inhibit atherosclerosis

Question 22

DHPs PK factors

Answer 22

all DHPs highly bound to serum proteins; undergo extensive first pass metabolism in liver; amlodipine has slow onset and long duration of action

Question 23

Nifedipine

Answer 23

increased risk of subsequent MI, only the rapid release formulations
MOA: rapid decrease in BP may lead to reflex sympathetic response - tachycardia (rapid vadodilation, put pt into ischemic state)

Question 24

Phenylalkylamine: verapamil clinical considerations

Answer 24

causes vasodilation, less potent than DHPs
slows conduction through SA and AV nodes (reducing HR and force of contraction)
reflex tachycardia is blunted (bc also inhibiting channels in the heart)
inhibitory effect on heart due to frequency dependent block

Question 25

Verapamil binding

Answer 25

binds in the pore and blocks Ca2+ influx
channel has to open for drug to enter the pore - frequency dependent block

Question 26

Characteristics of phenylalkylamine block

Answer 26

marked frequency dependence
very little tonic block

Question 27

Explain the basis for frequency-dependent block and its role in calcium channel blocker tissue selectivity

Answer 27

have to open channel for drug to get into pore; channel not opening, drug not binding; accumulation of blocked channels with more depolarization of the channels

Question 28

Benzothiazepine: diltiazem clinical considerations

Answer 28

causes vasodilation, less potent than DHPs; slows conduction through the SA and AV nodes; initial reflex tachycardia
directly inhibits the heart less than verapamil, but more than DHPs
exhibits frequency dependent block of Ca2+ channels

Question 29

Characteristics of benzothiazepine block

Answer 29

some tonic block, some frequency block

Question 30

Verapamil cardiovascular effects

Answer 30

decrease HR, decrease AV conduction, decrease myocardial contraction, increase arteriole vasodilation

Question 31

DHPs cardiovascular effects

Answer 31

increase HR, increase arteriole vasodilation

Question 32

Diltiazem cardiovascular effects

Answer 32

decrease HR, decrease AV conduction, decrease myocardial contraction, increase aterial vasodilation

Question 33

Know the unique aspects of nimodipine and amlodipine action relative to other dihydropyridines

Answer 33

Nimodipine: exhibits selectivity for cerebral arteries, reestablishes blood flow in areas bleeding in the brain; prevents neuropathy; pretty hydrophobic, relax vasculature smooth muscle to restore blood flow
amlodipine: has slow onset and long duration of action due to its ether group (minimal reflex tachycardia)

Question 34

Know the side-effect profile of the three classes of calcium channel blockers

Answer 34

all have ankle edema
verapamil: constipation
DHPs: facial flushing, tachycardia

Question 35

Cav1.3 use

Answer 35

selectivity for treatment of drug addiction

Question 36

Cav2.1 use

Answer 36

selectivity for treatment of familial hemiplegic migraine, some types of ataxia

Question 37

Cav2.2 use

Answer 37

selectivity for treatent of refractory chronic pain (conus magus shell)