9 - Calcium channel blockers Flashcards
What determines the direction of ion flow through a channel?
Concentration gradient
Electrical gradient*
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+
This molecule has high intracellular concentration
K+
This molecule has low intracellular concentration
Na+
This molecule has a very low intracellular concentration
Ca2+
(100nM Ca2+ vs 12mM of Na+)
Nernst equation
Emem = (RT/F) x ln ([<strong>K+ Out</strong>]/[<strong>K+ in</strong>])
Calcium concentrations inside and outside of the cell?
Intracellular = 100nM
Extracellular = 1.5 mM
What is MthK?
Calcium-gated K+ Channel
- from bacteria
- crystallized in the presence of Ca++
What is important for MthK function?
Bending outward of the helices in the gate portion of the channel
What is Kcsa?
H+ gated K+ channel
- Either open or closed conformation
Voltage gated K+ channel in bacteria
KVAP
KvAP is a ___
tetramer
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
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
What is CICR?
Calcium-induced Calcium release
Calcium influx via Cav1.2 (L-type) → Stimulates release from ryanodine receptor (RYR2) in Sarcoplasmic reticulum
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
How do Calcium ions influence contraction
Bind to troponin C
→displacement of tropomyosin
→Myosin is able to bind Actin
Skeletal muscle contraction mediated by which receptor?
Cav1.1 → RYR1
Skeletal muscle and Cardiac muscle contraction differ how?
Skeletal muscle does not require extracellular Ca2+
Therefore CCB’s don’t interfere with coupling!
3 Clinical applications for CCB
Angina
Arrhythmia
HTN
Classes of CCB’s
- Dihydropyridines
- Phenylalkylamines
- Benzothiazepines
The binding sites for DHP, PAA, BZP are _________
linked, but not identical
Blockade mechanism of DHPs
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?)
Dihydropyridine ring
(Aryl group at 4’ position & Ester-linked side chains)
DHP’s structurally contain a
chiral center
Members of the DHP class
- Amlodipine
- Felodipine
- Isradipine
- 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:
- amino acid differences in channel splice variants
- 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)
