CCB

Question 1

Ion Channels

proteins that form ___ in the plasma membrane
categorized by:
- ___ opening and closing mechanism
- ion ___
- pharmacology

___ - allow ions to flow down their electrochemical gradient

Answer 1

pores
- gate
- selectivity

passive

Question 2

Ion Channels and the Electrochemical Gradient

• ions can flow in ___ directions through most ion channels
• ___ and ___ gradients determine direction of flow

Answer 2

both
- concentration, electrical

Question 3

Membrane Potential

excitable cells have a ___ inward potential across the membrane due to the selective permeability of the resting membrane to ___

Answer 3

negative, K+

Question 4

Membrane Potential

• ___ is high inside (155 mM) and low outside the cells (4 mM)
• ___ is low inside (12 mM) and high outside the cell (145 mM)
• ___ is very low inside (100 nM) and high outside the cell (1.5 mM)
• Nernst Equation: ?

Answer 4

K+
Na+
Ca2+

Question 5

Membrane Potential

membrane potential is set by ___ permeability at rest
- note that ___ charged ions do not cross the membrane

Answer 5

K
- negatively

Question 6

CCB

block channels in vascular smooth muscle: ___
- decrease in ___
- relief of ___

block of channels in cardiac muscle and SA/AV node: ___

Answer 6

vasodilation
- BP
- angina

antiarrhythmic

Question 7

voltage gated Ca2+ channel family

cardiac, smooth muscle, Ca2+ entry triggers contraction

Answer 7

L-type
Cav 1.2

Question 8

vascular smooth muscle contraction

Ca2+ influx via Cav 1.2 induces release of Ca2+ from ___ stores via ___ receptor in the SR

___ Ca2+ is required for contraction of cardiac and smooth muscle

Answer 8

• intracellular, ryanodine 2 (RYR2)
• extracellular

Question 9

B-adrenergic modulation Ca2+ channels

PKA phosphorylation of Cav1.2 increases Ca2+ ___
- increases contractility/force of contraction
- increases AV nodal action potential conduction rate

Answer 9

influx

Question 10

T or F: extracellular Ca2+ is required for contraction of cardiac and vascular smooth muscle (not skeletal)

Answer 10

True

Question 11

Cardiac Muscle Contraction

1) the Ca2+ ions released from the SR binds to ___
2) Ca2+ binding by ___ causes displacement of ___
3) displacement of ___ allows for ___ to bind actin
= CONTRACTION

Answer 11

• troponin C
• troponin C, tropomyosin
• tropomyosin, myosin

Question 12

Skeletal Muscle Contraction

Mechanical coupling between ___ and ___

• extracellular Ca is not required; therefore ___ do not interfere with coupling

Answer 12

• Cav1.1, RYR1
• CCB

Question 13

CCBs

clincal applications: angina pectoris, arrhythmia, HTN

Three distinct chemical classes
1) dihydropyridines
2) phenylalkylamines
3) benzothiazepines

Question 14

CCBs Dihydropyridines

dihydropyridine ring
aryl group
chiral center
ester linked side chains

Answer 14

Question 15

CCBs Dihydropyridines

Answer 15

• nifedipine (Procardia)
• isradipin (DynaCirc)
• felodipine (Plendil)
• amlodipine (Norvasc)
• nisoldipine (Sular)
• nimodipine (Nimotop)
• nicardipine (Cardene)
• clevidine (Cleviprex)

Question 16

CCBs Dihydropyridines - Clevidipine (Cleviprex)

• ___ acting
• given ___ when PO is not desirable
• formulated with lipids derived from ___ and ___

Answer 16

• short
• IV
• soy, egg

very rapid

Question 17

CCBs Dihydropyridines

MOA: (+) enantiomer ___ current , (-) enatiomer ___ current

• mechanism involves interference with ___
• (+) enantiomer interferes with ___
• (-) enantiomer interferes with ___

Answer 17

• blocks, potentiates
• gating
• opening
• closing

Question 18

CCBs Dihydropyridines

tissue selectivity - more potent in relaxing smooth muscle, esp. ___
- do not compromise cardiac function
- not ___
- selectivity result of amino acid differences in channel splice variants, differences in membrane potential properties

Answer 18

coronary artery
antiarrhythmics

Question 19

CCBs Dihydropyridines

characteristics of dihydropyridine block
- ___ dependence
- the ___ of drug for the channel is different at different voltages

Answer 19

voltage
affinity

Question 20

CCBs Dihydropyridines

binding site is allosteric ( ___ of the pore_
- DHP drugs bind to closed channels and prevent opening - ___ block

Answer 20

• outside
• tonic

Question 21

CCBs Dihydropyridines

• no ___ dependence
• marked tonic block

Answer 21

frequency

Question 22

CCBs Dihydropyridines - Clinical Considerations

• marked decrease in peripheral resisitance (dilation of ___ ; little affect on ___ )
• decreased ___
• little effect on HR or force of contraction
• ___ exhibits selectivity for cerebral arteries - is used in sub-arachnoid hemorrhage to prevent neuropathy
• reflex tachycardia secondary to vasodilation (except ___ )

Answer 22

• arterioles, venules
• afterload
• nimodipine
• amlodipine

Question 23

CCBs Dihydropyridines - Clinical Considerations

• reduce oxygen demand in heart - efficacy in ___
• do not depress cardiac function, except ___
• may inhibit ___
• all DHPs are highly bound to ___ ___ and undergo extensive first pass metabolism
• ___ has slow onset and long duration of action

Answer 23

angina
nifedipine
atherosclerosis
serum proteins
amlodipine

Question 24

T or F: prompt release nifedipine formulations may increase risk of subsequent heart attack

Answer 24

True
- rapid decrease in BP may lead to reflex sypathetic response tachycardia

Question 25

CCB - Phenylalkylamine

Verapamil
Clinical considerations
- causes ___ but less potent than ___
- slows conduction through ___ and ___ nodes (reducing HR and force of contraction)
- reflex tachycardia is ___
- inhibitory effect on heart is due to ___ dependent block
- binds in pore and blocks ___ influx; channel has to ___ for drug to enter the pore = ___ dependent block

Answer 25

• vasodilation, DHPs
• SA, AV
• blunted
• Ca2+, open, frequency

Question 26

CCB - Phenylalkylamine

characteristics of block
- marked ___ dependence
- very little ___ block

Answer 26

• frequency
• tonic

Question 27

CCB - benzothiazepine

diltiazem (Cadizem)
Clinical consideration
- less potent vasodilation than ___
- slows conduction through ___ and ___ nodes
- initial reflex ___
- diltiazem directly inhibits the heart less than ___ but more than ___
- exhibits ___ dependent block of Ca2+ channels

Answer 27

• DHP
• SA, AV
• tachycardia
• verapamil, DHPs
• frequency

Question 28

CCB - benzothiazepine

characteristics of block
- ___ tonic block
- ___ frequency dependence

Answer 28

some
some