calcium channel blockers Flashcards
what does calcium do
what happens if you block calcium channels
the influx of calcium ions through voltage-sensitivity, long lasting (L-type) Ca channels provides the activator calcium required for contraction of cardiac and smooth muscle cells.
Ca influx through L-type Ca channels also contributes to the upstroke of the AP in the SA and AV nodes of the heart.
CCB (calcium channel blockers) reduce cardiac automaticity and Av nodal conduction, cause vasodilation
what are the CCB classes and drugs
Phenylalkylamines- Verapamil
Benzothiazipines- Diltiazem
1,4-Dihydropyridines- Nifedipine, Amlodipine
CCB binding sites
Each of the different CCB interacts with a specific domain on different spots of the L-type Ca channel
all three classes influences the gating, so only one class is perscribed at a time
factors that account for the preference of CCB for cardiovascular cells
the voltage-sensitive L type Ca channels, which is the binding site on a variety of tissues, including neurons, cardiac cells, vascular smooth muscle and sk muscle
But CCBs dont affect all these cells (only cardiac and vascular smooth muscle cells)
CCBs only have a low affinity of the N and P type in the nervous system, CCBs dont do anything from intracellular stores (Sarco-ret)
sk muscle and CCB
sk muscle has a large store of Ca but insensitive CCB relatively. the lack of effect of is due to CCBs not messing with intracellular stores of Ca. sk muscle expresses a diifferent isoform compared to cardiac and vascular variants of the channel
neurons and CCs
neurons express L-type Ca channels, but Ca influx through N and P type (neuronal, and purkinje) that mediates NT release, so CCBs have little effect on NT release and few CNS SEs
Cardiac cells and CCs
all cardiac cells densely express L-type Ca channels
The upstroke of AP in the SA and aV node depends on Ca Channels, required for contraction of atrial and ventricular muscle cells
Vascular smooth muscle cells and CC
vascular smooth muscle cells (VSMCs) rely solely on L-type CCs for excitability and contraction. Most VSMCs do not generate action potentials but have a graded membrane potential, as the VSMCs depolarize the CCs open and Ca influx activates the contractile proteins to mediate a graded contraction
selectivity of CCBs for Cardiac versus arterial muscle
each of the three classes of CCBs acts preferentially on either Cardiac muscle or vascular smooth muscle. The pheylalkylamines (verapamil) and benzothiazepines (diltiazem) act preferentiallu on cardiac cells. whereas the 1,4 dihydropyridines (nifedipine) act preferentially on arterial muscle cells.
use-dependence of CCBs
the activity of a CCB in a particular tissue is affected by the location of the binding site on the channel protein and the frequency of the channel opening.
Verapamil and diltazem- located deep in channel, and access is increased when the channel opens with high frequency. so bc cardiac cells are rapidly firing they are more selective than vascular cells
voltage dependence of CCBs
dihydropyridines bind to the outside of the CC. They bind to the depolarized state of the channel with extreme high affinity.
resting membrane potential is highly depolarized compared to cardiac, dihydropyridine bind preferentially to smooth muscle to induce vasodilation (specifically arteries not veins)
dihydropyridines significantly reduce cardiac afterload but not preload
angina which ccb do you use
diltiazem is used
reduced cardiac workload (decreases SA node firing rate) and reduces cardiac afterload by causing peripheral vasodilation.
diltiazem is a potential dilator of coronary arteries permitting increased blood flow to the myocardium to prevent or reduce ischemia
dihydropyridines are also used as coronary vasodilators, reduce myocardial oxygen demand and in arterial pressure
dark chocolate= good heart health
supraventricular arrythmias
atrial flutter/fibrilation, paroxysmal supraventricular tachycardia- diltiazem/verapamil are useful to reduce the firing rate of the SA node and reduce conduction through AV node. Verapamil is helpful in reducing ventricular response rate if the atria is firing too fast
verapamil + diltiazem are indicated for supraventricular tachychardia
hypertension
dihydropyridine (potent vasodilator)
reduced blood pressure can trigger reflex tachycardia. This can increase the workload of the heart, nifedipine should dilate the coronary arteries if healthy to partially offset this challenge.
add a beta blocker (propranolol) in conjuction with dihydropyridines to prevent reflex tachycardia. Nifedipine and other dihydropyridine drugs are contraindicated in tachyarrythmias.
pharmacokinetics of CCBs
Absorption- well absorbed after oral admin diltiazem, nifedipine, and nicardipine do not undergo lots of 1st pass metabolism, but verapamil and isradipine undergo extensive 1st pass (big difference between IV and oral)
Protein binding- binding % are higher for the dihydropyridines than either diltiazem or verapamil
t.5= 3-6 hours, there are slow release dihydropyridines cause less reflex tachycardia.
