Calcium Channel Blockers Flashcards by Brittany Galloway

excitable cells have a ______ inward potential across the membrane due to ______ permeability of the resting membrane to K+

negative; selective

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Every DHP except _______ is vasoselective

Nimodipine

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Amlodipine has a _____ onset and _____ duration of action

slow ; long

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What is the L type Cav1.2 channel location/function?

cardiac
smooth muscle / Ca2+ entry TRIGGERS contraction

***other types are also blocked

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The block of calcium channels in vascular smooth muscle causes _______ which ________

vasodilation ; decrease in BP / relief of angina pectoris

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For DHPs, ___________ is secondary to __________ (except amlodipine)

reflex tachycardia ; vasodilation

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DHP binding site is ________

allosteric (outside of the pore)

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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

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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)

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Benzothiazepine causes _____ vasodilation than DHPs

LESS

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How are ion channels categorized?

gating
ion selectivity
pharmacology

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What is an ion channel?

-proteins that form pores in the plasma membrane

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Skeletal muscle contraction:

_________ coupling between ________ and ________

Extracellular Ca is ____ required because CCBs do not interfere with ___________

mechanical ; Cav1.1 ; RYR1 ; not ; coupling

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DHP Pharmacokinetic Factors

all DHPs are highly bound to serum PRTs

- all DHPs undergo extensive first pass metabolism in liver

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Which CCB has the greatest tachycardia SE profile?

DHPs

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Ca2+ induced Ca2+ release (CICR) causes _______

vascular smooth muscle contraction

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Ions can flow in _____ directions through _____ ion channels

both; most

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All CCB classes cause the ________ SE

ankle edema (peripheral edema)

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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

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The block of calcium channels in cardiac muscle & SA/AV node is _________

antiarrhythmic

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DHPs ______ oxygen demand in the _______ which is efficacious for _________

reduce ; heart ; angina

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Which CCB has the greatest constipation SE profile?

verapamil

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Example of phenylalkylamine CCB class

verapamil (calan, isoptin)

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Benzothiazepine clinical considerations

causes vasodilation LESS potent than DHPs
slows conduction through the SA and AV nodes (due to reflex tachycardia)
initial reflex tachycardia

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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

Calcium Channel Blockers Flashcards

(65 cards)