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Pharm Exam 3 > 9 - Calcium channel blockers > Flashcards

9 - Calcium channel blockers Flashcards

1
Q

What determines the direction of ion flow through a channel?

A

Concentration gradient

Electrical gradient*

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2
Q

Excitable cells have what kind of potential, and why?

A

A negative inward potential across the membrane

due to the selective permeability of the resting membrane to K+

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3
Q

This molecule has high intracellular concentration

A

K+

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4
Q

This molecule has low intracellular concentration

A

Na+

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5
Q

This molecule has a very low intracellular concentration

A

Ca2+

(100nM Ca2+ vs 12mM of Na+)

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6
Q

Nernst equation

A

Emem = (RT/F) x ln ([<strong>K+ Out</strong>]/[<strong>K+ in</strong>])

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7
Q

Calcium concentrations inside and outside of the cell?

A

Intracellular = 100nM

Extracellular = 1.5 mM

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8
Q

What is MthK?

A

Calcium-gated K+ Channel

  • from bacteria
  • crystallized in the presence of Ca++
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9
Q

What is important for MthK function?

A

Bending outward of the helices in the gate portion of the channel

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10
Q

What is Kcsa?

A

H+ gated K+ channel

  • Either open or closed conformation
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11
Q

Voltage gated K+ channel in bacteria

A

KVAP

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12
Q

KvAP is a ___

A

tetramer

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13
Q

The important* member of the voltage-gated Ca2+ channel family, and what is its location/function?

(*important for CCB lecture)

A

Cav1.2

(L-type)

  • Cardiac and smooth muscle
  • Calcium entry triggers contraction
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14
Q

CCB’s act on what two tissues? What are each of their effects?

A

Block channels in:

Vascular smooth muscle = Vasodilation (↓BP, angina relief)

Cardiac muscle and SA/AV nodes = Antiarrhythmic

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15
Q

What is CICR?

A

Calcium-induced Calcium release

Calcium influx via Cav1.2 (L-type) → Stimulates release from ryanodine receptor (RYR2) in Sarcoplasmic reticulum

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16
Q

What is RYR2

What happens after this?

A

ryanodine receptor

when trigger calcium enters, it causes release of intracellular stores of calcium in SR

→ Increase intracellular [Ca2+]

→ form Ca2+-Calmodulin complex

→ Phosphorylate Myosin Light Chain Kinase

→→ Contraction

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17
Q

How do Calcium ions influence contraction

A

Bind to troponin C

→displacement of tropomyosin

→Myosin is able to bind Actin

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18
Q

Skeletal muscle contraction mediated by which receptor?

A

Cav1.1 → RYR1

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19
Q

Skeletal muscle and Cardiac muscle contraction differ how?

A

Skeletal muscle does not require extracellular Ca2+

Therefore CCB’s don’t interfere with coupling!

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20
Q

3 Clinical applications for CCB

A

Angina

Arrhythmia

HTN

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21
Q

Classes of CCB’s

A
  1. Dihydropyridines
  2. Phenylalkylamines
  3. Benzothiazepines
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22
Q

The binding sites for DHP, PAA, BZP are _________

A

linked, but not identical

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23
Q

Blockade mechanism of DHPs

A

Interferes with gate function

(+) enantiomer = Blocks current (stops opening of channel)

(-) enantiomer = Potentiates current (stops closing of channel)

24
Q

Major structural component of DHP’s

(others?)

A

Dihydropyridine ring

(Aryl group at 4’ position & Ester-linked side chains)

25
Q

DHP’s structurally contain a

A

chiral center

26
Q

Members of the DHP class

A
  1. Amlodipine
  2. Felodipine
  3. Isradipine
  4. Nifedipine*
27
Q

Which DHP has a significant sidegroup?

What is the group, and what does it do?

A

Amlodipine

Ester: plays a role in its slow onset of action

= ↓ risk for reflex tachycardia

28
Q

Other members of the DHP class of CCBs

A

Nisoldipine

Nimodipine

Nicardipine

29
Q

Short acting DHP?

Use?

Metabolism?

A

Clevidipine

  • I.V. treatment for HTN (when PO drugs not possible)
  • Formulated from soy/egg lipids

Metabolism = esterases (rapid)

30
Q

Tissue selectivity of DHP’s

A

More potent in relaxing smooth muscle

(especially coronary arteries)

Tissue selectivity is d/t:

  1. amino acid differences in channel splice variants
  2. differences in membrane potential properties
31
Q

DHP’s don’t….

A
  • compromise cardiac function
  • are NOT antiarrhythmics
32
Q

The degree of channel blockade from DHP’s depends on what?

A

Voltage

Requires FAR lower concentration at a membrane potential of -15mV than it does at a resting voltage of -80mV

(0.36 nM @ 15mV vs 730 nM @ -80mV)

Therefore ↓↓ effect on vascular muscle than in cardiac muscle

33
Q

DHP block does not display __

A

Frequency dependence

**Marked tonic block

  • After administration of PAA drugs, channel still functions and declines normally
  • After DHP given, the channels were bound in the closed position so the function is reduced immediately after removal of the drug
34
Q

What are the clincal considerations for DHP’s in terms of vascular selectivity?

A

↓↓ Peripheral resistance

↓ Afterload

*Little/no effect on HR or inotropy

35
Q

What is the DHP with the lowest degree of vascular specificity?

A

Nifedipine

36
Q

Cerebral artery-specific DHP

A

Nimodipine

used in subarach hemorrhage to prevent neuropathy

37
Q

Major AE of DHP’s

A

Reflex tachycardia

Except Amlodipine

38
Q

DHP’s have efficacy in _____, and do not _________

Possibly ________

A
  • angina (reduce O2 demand)
  • do not depress cardiac function
  • possibly inhibit atherosclerosis
39
Q

PK factors for DHP’s

A

Highly bound to serum proteins

Extensive 1st pass metabolism in the liver

40
Q

Most common DHP given

A

Amlodipine

(it has slow onset and long duration of action)

41
Q

PAA drug

A

Verapimil

42
Q

Clinical consideration of verapimil

A

Causes vasodilation, but less potent than DHP

43
Q

Verapimil vs DHP

A

Slows conduction rate through SA/AV nodes

→ reduces HR and inotropy

44
Q

___ is reduced in phenylalkylamine drugs

A

reflex tachycardia

45
Q

Phenylalkylamine’s inhibitory effect on the heart is due to

A

frequency-dependent block

(*Marked frequency dependence, little tonic block)

46
Q

Benzothiazepine drug

A

Diltiazem

47
Q

Diltiazem causes…

A

vasodilation (less potent than DHP)

48
Q

Which drugs slow the conduction through the SA/AV nodes

A

Diltiazem (BTZ) and Verapimil (PAA)

49
Q

Drugs that inhibit the heart from most to least

A

Most = Verapimil

Middle = Diltiazem

Least = DHP

50
Q

Which drugs exhibit frequency dependent block of Ca2+ channels

A

Verapimil and Diltiazem

51
Q

Characteristics of BTZ block

A

some tonic block

some frequency dependence

52
Q

Drug that causes the highest amount of arterole vasodilation

A

DHP

53
Q

Verapamil major AE

A

Constipation

(others are ankle edema, dizziness, flushing)

54
Q

Major AE’s for DHPs

A

Ankle edema

Flushing

Reflex tachycardia

55
Q

Major diltiazem AE

A

Ankle edema

56
Q

_____ formulations may increase risk of subsequent heart attach

Mechanism?

A

Prompt-release nifedipine

Decrease in BP → reflex tachycardia (Sy response)

Pharm Exam 3 (11 decks)

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