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Therapeutics II > Calcium Channel Blockers > Flashcards

Calcium Channel Blockers Flashcards

1
Q

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

A

negative; selective

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2
Q

Every DHP except _______ is vasoselective

A

Nimodipine

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3
Q

Amlodipine has a _____ onset and _____ duration of action

A

slow ; long

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4
Q

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

A
  • cardiac
  • smooth muscle / Ca2+ entry TRIGGERS contraction

***other types are also blocked

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5
Q

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

A

vasodilation ; decrease in BP / relief of angina pectoris

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6
Q

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

A

reflex tachycardia ; vasodilation

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7
Q

DHP binding site is ________

A

allosteric (outside of the pore)

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8
Q

Characteristics of frequency-dependent block

A
  • 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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9
Q

DHP drugs bind to _______ channels and prevent _______. This is known as a ______ block

A

closed ; opening ; TONIC (channel doesn’t have to open to allow drug access to its binding site)

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10
Q

Benzothiazepine causes _____ vasodilation than DHPs

A

LESS

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11
Q

How are ion channels categorized?

A
  • gating
  • ion selectivity
  • pharmacology
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12
Q

What is an ion channel?

A

-proteins that form pores in the plasma membrane

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13
Q

Skeletal muscle contraction:

_________ coupling between ________ and ________

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

A

mechanical ; Cav1.1 ; RYR1 ; not ; coupling

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14
Q

DHP Pharmacokinetic Factors

A
  • all DHPs are highly bound to serum PRTs

- all DHPs undergo extensive first pass metabolism in liver

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15
Q

Which CCB has the greatest tachycardia SE profile?

A

DHPs

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16
Q

Ca2+ induced Ca2+ release (CICR) causes _______

A

vascular smooth muscle contraction

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17
Q

Ions can flow in _____ directions through _____ ion channels

A

both; most

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18
Q

All CCB classes cause the ________ SE

A

ankle edema (peripheral edema)

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19
Q

Characteristics of DHP Block

A
  • 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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20
Q

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

A

antiarrhythmic

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21
Q

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

A

reduce ; heart ; angina

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22
Q

Which CCB has the greatest constipation SE profile?

A

verapamil

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23
Q

Example of phenylalkylamine CCB class

A

verapamil (calan, isoptin)

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24
Q

Benzothiazepine clinical considerations

A
  • 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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25
Q

Three distinct chemical classes of CCBs

A
  • dihydropyridines
  • phenylalkylamines
  • benzothiazepines
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26
Q

Diltiazem exhibits ________-dependent block of Ca2+ channels

A

frequency

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27
Q

Verapamil binds in the pore and _______ Ca2+ influx. Channel has to _____ for drug to enter the pore. This is a ________-dependent block

A

blocks ; open ; frequency

28
Q

The opening of ion-selective channels drives the ______________ toward the ______________ of the permanent ion

A

membrane potential ; equilibrium potential

29
Q

Extracellular Ca is _______ for contraction of vascular smooth muscle

A

REQUIRED

30
Q

Nimodipine exhibits selectivity for ___________

A

cerebral arteries

used in sub-arachnoid hemorrhage to prevent neuropathy

31
Q

Clinical applications of Calcium Channel Blockers (CCBs)

A
  • angina pectoris
  • arrhythmias
  • HTN

(nimodipine aids subarachnoid hemorrage)

32
Q

Amlodipine (Norvasc) things to remember

A
  • most common
  • slow onset due to ester group
  • slow onset prevents reflex tachycardia
33
Q

Extracellular Ca is ____ required for contraction of skeletal muscle

A

NOT REQUIRED

34
Q

MthK is a ___ gated ___ channel from bacteria

A

Ca2+ ; K+

this channel was crystallized in the presence of Ca2+. Showed the hinge points that open up the pathway for ions

35
Q

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 = _______

A

increased ; subsequent ;

increase

decrease ; tachycardia

36
Q

Ion channels are ________

A

passive

allow ions to flow down their electrochemical gradient

37
Q

Order of direct CCB heart inhibition

A

Verapamil > Diltiazem > DHPs

38
Q

Ksca is a ___ gated ___ channel from bacteria

A

H+ ; K+

39
Q

Clevidipine (cleviprex) KEY THING

A

Given IV to treat HTN when PO administration of drugs is not possible/desirable

40
Q

What determines direction of flow?

A
  • concentration gradient (high to low)

- electrical gradient (we see this physiologically)

41
Q

Members of the dihydropyridine (DHP) class

A
  • 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)
42
Q

DHPs (except nifedipine) _____ depress _____ function

A

do not ; cardiac

43
Q

Benzothiazepine CCB class example

A

Diltiazem (cardizem)

44
Q

Which CCB has the greatest facial flushing SE profile?

A

DHPs (think vasodilation)

45
Q

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 ____________

A

active transport of Na out of ; K+ ; resting membrane potential

46
Q

What is the order of events of contraction in vascular smooth muscle?

A

-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
47
Q

Ca2+ induced Ca2+ release (CICR):

Ca2+ influx via Cav1.2 induces release of Ca2+ from ___________ stores via _____ in the SR

A

INTRACELLULAR ; RYR2 (ryanodine receptor 2)

48
Q

Considerations for phenylalkylamine drug class

A
  • 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
49
Q

characteristics of benzothiazepine block

A
  • some tonic block

- some frequency dependence

50
Q

Clinical considerations for DHPs: Vascular selectivity

A
  • 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)

51
Q

Nernst equation

A

Emem = (RT/F) ln (Kout/Kin) @ 37 degrees celcius, Emem = -98 mV

equation that determines the cell membrane potential

52
Q

Blockage mechanism of dihydropyridines: Clues from a pair of enantiomers

A

+ enantiomer blocks current, interferes with opening

- enantiomer potentiates current, interferes with opening

53
Q

For verapamil, reflex tachycardia is __________

A

blunted

54
Q

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
A

troponin C ; troponin C ; displacement of tropomyosin

55
Q

Beta adrenergic modulation Ca2+ channels:

PKA phosphorylation of Cav1.2 _________ Ca2+ influx

A

increases

56
Q

DHPs may ______ atherosclerosis

A

inhibit

57
Q

Tissue selectivity of dihydropyridines (DHPs)

A
  • 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
58
Q

Dihydropyridine chemical class structural activity

A
  • dihydropyridine ring***
  • aryl group
  • chiral center
  • ester linked side chains
59
Q

Beta adrenergic modulation Ca2+ channels:

What does the increase of Ca2+ as a result of PKA phosphorylation do?

A
  • increases contractility/force of contraction

- increases AV nodal action potential conduction rate

60
Q

Clevidipine (cleviprex) things to remember

A
  • 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
61
Q

Ca is very _____ inside and ______ outside the cell

A

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

62
Q

Remember that DHPs _________ compromise cardiac function

A

DO NOT

63
Q

DHPs have the most ________

A

arterial vasodilation

64
Q

Membrane potential is set by ____ permeability at ____

A

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
65
Q

Ca2+ induced Ca2+ release (CICR)

Extracellular Ca2+ is ___________ for contraction of cardiac and smooth muscle

A

REQUIRED

Therapeutics II (12 decks)

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