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

Calcium-gated K+ Channel from bacteria crystallized in the presence of Ca++

H+ gated K+ channel Either open or closed conformation

The _important\ member_ of the voltage-gated Ca2+ channel family, and what is its _location/function_? (\ important for CCB lecture)

Cav1.2 ( L-type ) Cardiac and smooth muscle Calcium entry triggers contraction

1. Dihydropyridines 2. Phenylalkylamines 3. Benzothiazepines

9 - Calcium channel blockers Flashcards by Chris Rodarte

What determines the direction of ion flow through a channel?

Concentration gradient

Electrical gradient*

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Excitable cells have what kind of potential, and why?

A negative inward potential across the membrane

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

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This molecule has high intracellular concentration

K+

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This molecule has low intracellular concentration

Na+

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This molecule has a very low intracellular concentration

Ca²⁺

(100nM Ca²⁺ vs 12mM of Na⁺)

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Nernst equation

E_mem = (^RT/_F) x ln (^[^{<strong>K+ Out</strong>]}/_{[<strong>K+ in</strong>]})

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Calcium concentrations inside and outside of the cell?

Intracellular = 100nM

Extracellular = 1.5 mM

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What is MthK?

Calcium-gated K+ Channel

from bacteria
crystallized in the presence of Ca++

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What is important for MthK function?

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

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What is Kcsa?

H+ gated K+ channel

Either open or closed conformation

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Voltage gated K+ channel in bacteria

K_VAP

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KvAP is a ___

tetramer

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

(*important for CCB lecture)

Ca_v1.2

(L-type)

Cardiac and smooth muscle
Calcium entry triggers contraction

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

Block channels in:

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

Cardiac muscle and SA/AV nodes = Antiarrhythmic

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What is CICR?

Calcium-induced Calcium release

Calcium influx via Ca_v1.2 (L-type) → Stimulates release from ryanodine receptor (RYR2) in Sarcoplasmic reticulum

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What is RYR2

What happens after this?

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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How do Calcium ions influence contraction

Bind to troponin C

→displacement of tropomyosin

→Myosin is able to bind Actin

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Skeletal muscle contraction mediated by which receptor?

Ca_v1.1 → RYR1

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Skeletal muscle and Cardiac muscle contraction differ how?

Skeletal muscle does not require extracellular Ca²⁺

Therefore CCB’s don’t interfere with coupling!

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3 Clinical applications for CCB

Angina

Arrhythmia

HTN

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Classes of CCB’s

Dihydropyridines
Phenylalkylamines
Benzothiazepines

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The binding sites for DHP, PAA, BZP are _________

linked, but not identical

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Blockade mechanism of DHPs

Study These Flashcards

Interferes with gate function

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

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

Major structural component of DHP’s

(others?)

Study These Flashcards

Dihydropyridine ring

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

DHP's structurally contain a

chiral center

Members of the DHP class

1. Amlodipine 2. Felodipine 3. Isradipine 4. Nifedipine\*

Which DHP has a significant sidegroup? What is the group, and what does it do?

Amlodipine Ester: plays a role in its **slow onset of action** = ↓ risk for **reflex tachycardia**

Other members of the DHP class of CCBs

Nisoldipine Nimodipine Nicardipine

Short acting DHP? Use? Metabolism?

_Clevidipine_ * I.V. treatment for HTN (when PO drugs not possible) * Formulated from soy/egg lipids Metabolism = esterases (rapid)

Tissue selectivity of DHP's

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

DHP's don't....

* compromise cardiac function * are NOT antiarrhythmics

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

_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*

DHP block does not display \_\_

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

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

↓↓ _Peripheral resistance_ ↓ _Afterload_ \*Little/no effect on *HR* or *inotropy*

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

Nifedipine

Cerebral artery-specific DHP

Nimodipine used in subarach hemorrhage to prevent neuropathy

Major AE of DHP's

_Reflex tachycardia_ Except **Amlodipine**

DHP's have efficacy in \_\_\_\_\_, and do not \_\_\_\_\_\_\_\_\_ Possibly \_\_\_\_\_\_\_\_

* _angina_ (reduce O2 demand) * do not _depress cardiac function_ * possibly _inhibit atherosclerosis_

PK factors for DHP's

Highly bound to serum proteins Extensive 1st pass metabolism in the liver

Most common DHP given

Amlodipine (it has slow onset and long duration of action)

PAA drug

Verapimil

Clinical consideration of verapimil

Causes vasodilation, but less potent than DHP

Verapimil vs DHP

Slows conduction rate through SA/AV nodes → reduces *HR* and *inotropy*

\_\_\_ is reduced in phenylalkylamine drugs

reflex tachycardia

Phenylalkylamine's inhibitory effect on the heart is due to

frequency-dependent block (\*Marked frequency dependence, little tonic block)

Benzothiazepine drug

Diltiazem

Diltiazem causes...

vasodilation (less potent than DHP)

Which drugs slow the conduction through the SA/AV nodes

**Diltiazem** (BTZ) and **Verapimil** (PAA)

Drugs that inhibit the heart from most to least

Most = Verapimil Middle = Diltiazem Least = DHP

Which drugs exhibit frequency dependent block of Ca²⁺ channels

Verapimil and Diltiazem

Characteristics of BTZ block

some tonic block some frequency dependence

Drug that causes the highest amount of arterole vasodilation

DHP

Verapamil major AE

Constipation (others are ankle edema, dizziness, flushing)

Major AE's for DHPs

Ankle edema Flushing Reflex tachycardia

Major diltiazem AE

Ankle edema

\_\_\_\_\_ formulations may increase risk of subsequent heart attach Mechanism?

Prompt-release nifedipine *Decrease in BP → reflex tachycardia (Sy response)*

9 - Calcium channel blockers Flashcards

(56 cards)