Calcium Channel Blockers Flashcards
excitable cells have a ______ inward potential across the membrane due to ______ permeability of the resting membrane to K+
negative; selective
Every DHP except _______ is vasoselective
Nimodipine
Amlodipine has a _____ onset and _____ duration of action
slow ; long
What is the L type Cav1.2 channel location/function?
- cardiac
- smooth muscle / Ca2+ entry TRIGGERS contraction
***other types are also blocked
The block of calcium channels in vascular smooth muscle causes _______ which ________
vasodilation ; decrease in BP / relief of angina pectoris
For DHPs, ___________ is secondary to __________ (except amlodipine)
reflex tachycardia ; vasodilation
DHP binding site is ________
allosteric (outside of the pore)
Characteristics of frequency-dependent block
- marked frequency dependence
- very little tonic block
***when the channel opens, more and more of the drug can get in to block the pore
DHP drugs bind to _______ channels and prevent _______. This is known as a ______ block
closed ; opening ; TONIC (channel doesn’t have to open to allow drug access to its binding site)
Benzothiazepine causes _____ vasodilation than DHPs
LESS
How are ion channels categorized?
- gating
- ion selectivity
- pharmacology
What is an ion channel?
-proteins that form pores in the plasma membrane
Skeletal muscle contraction:
_________ coupling between ________ and ________
Extracellular Ca is ____ required because CCBs do not interfere with ___________
mechanical ; Cav1.1 ; RYR1 ; not ; coupling
DHP Pharmacokinetic Factors
- all DHPs are highly bound to serum PRTs
- all DHPs undergo extensive first pass metabolism in liver
Which CCB has the greatest tachycardia SE profile?
DHPs
Ca2+ induced Ca2+ release (CICR) causes _______
vascular smooth muscle contraction
Ions can flow in _____ directions through _____ ion channels
both; most
All CCB classes cause the ________ SE
ankle edema (peripheral edema)
Characteristics of DHP Block
- voltage-dependence
- affinity of drug for the channel is different at different voltages (there are multiple closed states)
- no frequency dependence
- marked tonic block
The block of calcium channels in cardiac muscle & SA/AV node is _________
antiarrhythmic
DHPs ______ oxygen demand in the _______ which is efficacious for _________
reduce ; heart ; angina
Which CCB has the greatest constipation SE profile?
verapamil
Example of phenylalkylamine CCB class
verapamil (calan, isoptin)
Benzothiazepine clinical considerations
- causes vasodilation LESS potent than DHPs
- slows conduction through the SA and AV nodes (due to reflex tachycardia)
- initial reflex tachycardia
Three distinct chemical classes of CCBs
- dihydropyridines
- phenylalkylamines
- benzothiazepines
Diltiazem exhibits ________-dependent block of Ca2+ channels
frequency
Verapamil binds in the pore and _______ Ca2+ influx. Channel has to _____ for drug to enter the pore. This is a ________-dependent block
blocks ; open ; frequency
The opening of ion-selective channels drives the ______________ toward the ______________ of the permanent ion
membrane potential ; equilibrium potential
Extracellular Ca is _______ for contraction of vascular smooth muscle
REQUIRED
Nimodipine exhibits selectivity for ___________
cerebral arteries
used in sub-arachnoid hemorrhage to prevent neuropathy
Clinical applications of Calcium Channel Blockers (CCBs)
- angina pectoris
- arrhythmias
- HTN
(nimodipine aids subarachnoid hemorrage)
Amlodipine (Norvasc) things to remember
- most common
- slow onset due to ester group
- slow onset prevents reflex tachycardia
Extracellular Ca is ____ required for contraction of skeletal muscle
NOT REQUIRED
MthK is a ___ gated ___ channel from bacteria
Ca2+ ; K+
this channel was crystallized in the presence of Ca2+. Showed the hinge points that open up the pathway for ions
Nifedipine might cause an ________ risk of ________ MI.
Prompt release nifedipine formulations may ______ the risk of subsequent heart attack
Mechanism: Rapid ______ in BP may lead to reflex sympathetic response = _______
increased ; subsequent ;
increase
decrease ; tachycardia
Ion channels are ________
passive
allow ions to flow down their electrochemical gradient
Order of direct CCB heart inhibition
Verapamil > Diltiazem > DHPs
Ksca is a ___ gated ___ channel from bacteria
H+ ; K+
Clevidipine (cleviprex) KEY THING
Given IV to treat HTN when PO administration of drugs is not possible/desirable
What determines direction of flow?
- concentration gradient (high to low)
- electrical gradient (we see this physiologically)
Members of the dihydropyridine (DHP) class
- nifedipine (procardia) PROTOTYPE
- isradipine (dynacirc) MOST POTENT
- felodipine (plendil)
- amlodipine (norvasc) MOST COMMON
- nisoldipine (sular)
- nimodipine (nimotop) GETS IN BRAIN, PREVENTS VASOCONSTRICTION
- nicardipine (cardene)
- clevidipine (cleviprex)
DHPs (except nifedipine) _____ depress _____ function
do not ; cardiac
Benzothiazepine CCB class example
Diltiazem (cardizem)
Which CCB has the greatest facial flushing SE profile?
DHPs (think vasodilation)
Cell membrane gradient is maintained by ___________ and ____________ into the cell and by channels that selectively permit K+ to run out of the cell at voltages near the ____________
active transport of Na out of ; K+ ; resting membrane potential
What is the order of events of contraction in vascular smooth muscle?
-Ca2+ channels (L-type) release Ca2+
(Calcium channel blockers work here)
- Intracellular Ca2+ stores are impacted
- Increase in intracellular Ca2+ concentration
- Increase in Ca2+ calmodulin
- Impacts myosin LC kinase
- Myosin LC (light chain) —> myosin LC-PO4 + actin
- CONTRACTION
Ca2+ induced Ca2+ release (CICR):
Ca2+ influx via Cav1.2 induces release of Ca2+ from ___________ stores via _____ in the SR
INTRACELLULAR ; RYR2 (ryanodine receptor 2)
Considerations for phenylalkylamine drug class
- causes vasodilation but less potent than DHPs
- slows conduction through SA and AV nodes (reducing heart rate and force of contraction)
- reflex tachycardia is blunted
- verapamil’s inhibitory effect on the heart is due to frequency dependent block
characteristics of benzothiazepine block
- some tonic block
- some frequency dependence
Clinical considerations for DHPs: Vascular selectivity
- marked decrease in peripheral resistance (dilation of arterioles; little effect on venules)
- decreased afterload
- little effect on heart rate or force of contraction
***reflex tachycardia is secondary to vasodilation (except amlodipine)
Nernst equation
Emem = (RT/F) ln (Kout/Kin) @ 37 degrees celcius, Emem = -98 mV
equation that determines the cell membrane potential
Blockage mechanism of dihydropyridines: Clues from a pair of enantiomers
+ enantiomer blocks current, interferes with opening
- enantiomer potentiates current, interferes with opening
For verapamil, reflex tachycardia is __________
blunted
Cardiac muscle contraction:
- Ca ions released from the sarcoplasmic reticulum bind to _______
- Ca binding by ________ causes _________ which allows myosin to bind actin and cause contraction
troponin C ; troponin C ; displacement of tropomyosin
Beta adrenergic modulation Ca2+ channels:
PKA phosphorylation of Cav1.2 _________ Ca2+ influx
increases
DHPs may ______ atherosclerosis
inhibit
Tissue selectivity of dihydropyridines (DHPs)
- more potent in relaxing smooth muscle (esp coronary artery)
- do not compromise cardiac function***
- not antiarrhythmics
- selectivity is the result of = amino acid differences in channel splice variants + differences in membrane potential properties
Dihydropyridine chemical class structural activity
- dihydropyridine ring***
- aryl group
- chiral center
- ester linked side chains
Beta adrenergic modulation Ca2+ channels:
What does the increase of Ca2+ as a result of PKA phosphorylation do?
- increases contractility/force of contraction
- increases AV nodal action potential conduction rate
Clevidipine (cleviprex) things to remember
- short acting DHP (maybe due to double esters)
- T1/2 = ~ 1 min (85 - 90%) , ~15 min (10 - 15%)
- ***Given IV to treat HTN when PO administration of drugs is not possible/desirable
- formulated with lipids derived from soy and egg
Ca is very _____ inside and ______ outside the cell
low (100 nM) ; high (1.5 mM)
cell works hard to keep the intracellular Ca 2+ levels low = Ca 2+ is a common signaling molecule
Ca2+ has the highest concentration gradient
Remember that DHPs _________ compromise cardiac function
DO NOT
DHPs have the most ________
arterial vasodilation
Membrane potential is set by ____ permeability at ____
K+ ; rest
- note that negatively charged ions do not cross the membrane
- when K+ is perfectly in balance, the membrane potential equals the equilibrium gradient
Ca2+ induced Ca2+ release (CICR)
Extracellular Ca2+ is ___________ for contraction of cardiac and smooth muscle
REQUIRED
