Calcium Channel Blockers Flashcards
Three ways that ion channels are classified
Gating mechanism
Ion Selectivity
Pharmacology
Ion channels allow ions to flow…
down their chemical and/or electrical gradient
How is membrane potential maintained?
Active transport of Na out and K into the cell
Average K inside a cell? outside a cell?
155 mM
4mM
Average Na inside a cell? Outside a cell?
12mM
145 mM
Average Ca inside a cell? Outside a cell?
100nM
1.5 mM
What is Kcsa?
an H+ gated K+ channel from bacteria
The MthK Ca gated K channel from bacteria showed that…
The gating processes causes outward bending of iner helices
Structure on the inside and outside of the mthK calcium channel?
Outside – Selectivity filter
Inside – Gate
In the channel he explained to us (KvAP), what are the roles of S4, S5, S6
S4 is charged, so it moves aroudn in response to potential change in the serum. If negative, it moved inward, pulls S4 down, pushes S5 in, closing the channel. If positiv, S4 goes up, S5 is pulled out, and S6 can now open.
The type of Calcium channel we give a shit about?
What is it’s location and function?
The L-type Cav1.2
Cardiac, Smooth muscle/ Ca entry triggers contraction
Calcium channels blockers are used to….
Vasodilate
(Decrease BP, relieve angina pectors)
Also, acts as an anti-arrythmetic
How does vascular smooth muscle contraction work?
Ca influx via Cav1.2 induces release of Ca in intracellular stores via RYR2. NEEDS extracellular Ca
What does released intracellular Ca do in vascular smooth muscle?
Ca –> Calmodulin –> myosin LC kinase –> myosin LC PO4 + Actin = Contraction
What happens in cardiac muscle contraction
Ca ions released from SR bind troponin C, displacing tropomyosin, allowing for myosin binding and contraction
Skeletal muscle contraction requires what two receptors
Cav1.1, RYR1
These are the two mechanically coupled ones
Clinical applications of Calcium Channel Blockers?
Angina Pectoris, Arrythmia, HTN
Three chemical classes of Ca Channel Blockers
Dihydropyridines
Phenylalkylamines
Benzothiazepines
What did we learn about Dihydropyridines from their enantiomers
The opposite enantiomners have opposite effects on current. This implies that the mechanism involved interference with gating.
Which Dihydropyridine enantiomer did what?
+ enantiomer interferes with opening
- enantiomer interferes with closing
Seven main classes of Dihydropyridines?
Nifedipine Isradipine Felodipine Amlodipine Nisoldipine Nimodipine Nicardipine
Important details for Clevidipine?
Short acting Dihydropyridine. (Half life of about a minute)
Given IV to treat HTN when PO administration isn’t possible
Tissue selectivity of Dihydropyridines?
More potent with relaxing smooth muscle, don’t compromise fxn
Not antiarrythmetics
Important characteristic of a Dihydropyridine block?
Voltage dependence (the affinity of the drug for the channel is different at different voltages). NO frequency block, marked TONIC BLOCK
What unique about Nimodipine?
Selectivity for cerebral arteries
Used in subarachnoid hemorrhage to prevent neuropathy
Which calcium channel blocker avoids reflex tachycardia?
Amlodipine
Clinical considerations of using Dihydropyridines?
Reduce Oxygen Demand of the Heart (helps angina)
Don’t depress cardiac fxn (except nifedipine)
May inhibit atherosclerosis
Pharmokinetic factors associated with Dihydropyridines?
Highly bound to serum proteins
Extensive first pass metabolism in liver
Amlopidine has slow onset and long duration
Classic example of a phenylalkylamine?
Verapamil
Clinical considerations of phenylalkylamines?
Vasodilation (but less than DHPs)
Slows nodal conduction, downing HR and contraction)
Blunted Reflex Tachy
FREQUENCY DEPENDENT BLOCK
Where does phenylalkylamine bind?
Plug in the drain style
Classic example of a benzothiazepine?
Diltiazem
benzothiazepine clinical considerations?
Vasodilation, less potent than DHPs
Slows nodal conduction
Initial reflex tachycardia
Type of block exhibited by benzothiazepine?
Frequency dependent block
BUT ALSO
Some tonic block
Summary. Verapamil, DHPs, Diltiazem.
Compare HR?
Verapamil – Big Drop
DHP – rises a bit (reflex tachy)
Diltiazem – drops a bit (because freq. dep.)
Summary. Verapamil, DHPs, Diltiazem.
Compate AV conduction changes.
DHPS don’t mess with it.
Verapamil slows it more than Diltiazem.
Summary. Verapamil, DHPs, Diltiazem.
Myocardial contraction.
DHPS don’t mess with it.
Verapamil decreases it more than Diltiazem.
Summary. Verapamil, DHPs, Diltiazem.
Arteriol. Vasodil.
DHP – 1st
Verapamil – 2nd
Diltiazem – 3rd
Who causes constipation?
Verapamil
Who causes facial flushing?
DHPs
Who causes tachycardia?
DHPs
What kind of nifedipine is contraindicated in MI
Prompt release nifedipine
