Calcium Channel Blockers and Nitrates Flashcards
What are the CCBs you need to know, and which ones are cardioselective and vasoselective
-
Vascular selective Dihydropyrines:
- Amlodipine (Dihydropyridines)
-
Cardioselective:
- Diltiazem (Benzothiapzipines)
- Verapamil (Phenylalkylamines)
What are the nitrates you need to know?
- GTN (Glyceryl trinitrate)
- Isosorbide mononitrate/ dinitrate
Which targeted channels are in the cardiac and vascular smooth muscle?
And which type of channel is found on neurons and pacemaker cells?
L-type channels: These are the long lasting Ca2+ channels found in cardiac and vascular smooth muscle. They have a large sustained conductance, and inactivate slowly, there are widespread in the CV system and are responsible for plateau phase (slow inward current) of action potential. may trigger release of internal Ca2+.
T-type: found on neurons and pacemaker cells
What is the MOA for CCBs?
They inhibit Ca2+ influx through L-type Ca2+ channels, and influence Ca2+ entry into:
- Vascular (arteriolar) smooth muscle: vasodilate by reducing vascular tone in coronary arteries and peripheral arterioles by not veins due to not enough Ca2+ coming in.
- Cardiac muscle, this reduces formce of contraction (-ve inotrope), so less Ca2+ is present for cross bridge formation, so there’s a weaker contraction
- SA nodal tissues: Reduces rate of contracton (-ve chronotrope)
- AV node: to decrease conduction velocity into ventricles (-ve dromotrope)
CCBs do not dilate veins
Pic of how cardioselective CCBs act upon the heart (verapamil and diltiazem)
What actions do each of the vasoselective, and cardioselective drugs have?
Vasoselective drugs (dihydropyridines) act as vasodilators of arteriolar smooth muscle
Cardioselective drugs (verpaminl and diltiazem) act as -ve inotropes and -ve chrono tropes and reduce SA node automaticity. They are also -ve dromodrops, thus reduceing AV node conduction velocity.
What are the main therapeutic uses for the following:
- Dihydropyridines (amlodipine)
- Diltiazem
- Verapamil
And what are the adantages with these drugs (think about advantages comapred to beta blockers)
- Hypertension: Dihydropyridines (amlodipine)
- Arrythmias: Diltiazem (Acts on SA and AV node)
- Angina: Verapamil/ Diltiazem (reduces O2 consumption)
Advantages:
- Do not induce bronchoconstriction
- Do not adversely affect lipid prolfies (don’t increase LDL profiles, whereas Beta blockers do)
What is the MOA of Amlodipine? (Dihydropyridine CCBs)
They bind to and inhibit the L- and T- Type Ca2+ channels.
This has an anti-hypertensive effect by causing vasodialtion. Dihydropyridines primarily act on arterial smooth muscle (only affect cardiac muscle a small amount), due to the channels being in their inactive state for longer in arteriolar SM.
Amlodipine dilates peripheral arterioles reducing total peripheral resistance (afterload) and cardiac O2 consumption.
side note: since it doesn’t really dilate veins, it has little effect on most venous beds, so it doesn’t impact on preload (due to little change in venous return), however it does drop afterload.
Why is Amlodipine vasoselective?
Amlodipine directly binds to and stabilises the inactivated L-type Ca2+ channel state.
Inactivated channels are more likely to exst in arterial SM because depolarisations are longer lasting than in cardiac muscle (this is why it only effects Cardiac muscle a small amount since there are less Ca2+ channels in the inactive state)
What is afterload and preload?
Preload: End diastolic pressure
Afterload: systemic resistance that needs to be overcome to eject blood out into the aorta and arteries (It’s pretty much TPR)
Why do you need to be cautious with dihydropyridine (vasoselctive) CCBs if the patient has angina?
High does of fast aciting dihydropyridines can produce excessive peripheral dilation and marked hypotension. This can cause baroreceptors to increase the heart rate, which may result in tachycardia and increased inotropy - this can dramitcally increase O2 demand, exacerbating angina.
They also shouldn’t be used in patients with tachycardia, as it can prevoke a rebound tachycardia.
Some dihydropyridines are also associated with peripheral oedema (need to make sure it isn’t due heart faliure first)
What are the pharmokinetics of amlodipine? (dihydropyridine)
- Completely abosrbed from GI tract with systemic availability of ~64%
- Has a slow onset of action, with the peak plasma levels occurring 6-12 hours after. Takes ~7days to reach steady state levels.
- Amlodipine is extensively hepatically metabolised and excreted as inactive metabolites (~60%) in urine.
- only 10% exrcreted unchanged in urine
- Only daily dosing achievse clinical BPcontrol
- (renal faliure has little effect on plasma levels of active compound)
- They are affected by CYP3A4 interactions
What is the MOA for verapamil? (Phenylalkylamines)?
Verapamil binds to open L-type channel Ca2+ binding domain, and stop it from reactivating. This makes them relatively cardioselective. It promotes inactivated channel conformation, and slows channel recovery from inactivation. This increases the refractory period of drug-bound channel. Consequently, channel inhibition increases at higher rates.
- Since they are somewhat cardioselective they reduce cardiac contractility and cardiac work, and hence O2 cosumption.
Verapamil is also acts as a vasodilator with selectivity for the arterial portion of the peripheral vasculature. Systemic vascular resistance is reduced usually without reflex tachycardia or hypertension.
What is verapmil therapeutically used for?
Angina:
- Verapamil reduces myocardial O2 demand
- Verapamil reverses coronary vasospasm
- Verapamil prolonges diastole, therefore increasing coronary perfusion (since it increases refractory period of drug bound channel)
Hypertension
- Verapamil produces an antihypertensive effect by a combination of vascular and cardiac effects.
When shouldn’t Verpamil be used?
- Don’t use verapamil in heart faliure.
- With concomitant Beta-blocker use
- This is a -ve chronotrope and inotrope, therfore these also slow heart rate and decrease cardiac contractility
- they will have a synergistic effect with verapamil
- This is a -ve chronotrope and inotrope, therfore these also slow heart rate and decrease cardiac contractility
- You need to be careful giving to a patient with bradycardia and pre-existing conduction defects (e.g. heart block)
What are the pharmokinetics for Verapamil?
- It has a rapid & near complete oral absorption
- Has extensive 1st pass metabolism (very low bioavailability)
- Affected by liver viability e.g. in aged or cirrhotic patients
- L-verapamil is metabolised rapidly by 1st pass; hence an iv. route avoids 1st pass to have a greater effect on cardiac action potentials.
- verapamil is a substrate for CYP3A4
What is the MOA for Diltiazem? (Benzothiazipines)
It inhibits Ca2+ influx during membrane depolarisation of primarily cardiac and vascular smooth muscle.
Diltiazem interferes with the slow cardiac inward (depolarising) current in excitable tissue - this is what makes it good as an anti-arrhythmic
Diltiazem not suitable for heart faliure patients & on combination with B-blockers
What are the clinical uses for Diltiazem? (Benzothiazipine)
And what are it’s pharmokinetics?
- It’s effective as an antiarhythmic in AF, as it reduces influx of Ca2+
- Angina, by reducing O2 demand
- Can revere coronary vasospasm
Diltiazem PKs:
Similar to other CCBs,
- Highly absorbed (90%),
- undergos extensive 1st pass metabolism
In relation to Diltiazem, what happens if CYP3A4 is inhibited?
And what happens if 3A4 is induced?
The levels of Diltiazem can be potentiated, which can result in there being too much diltiazem in the system which may cause hypotension, bradycardia, AV block
If there is induction of 3A4 (where it’s activity is increases, so diltiazem is metabolised faster) you lose the effect of diltiazem (less of it is present in the body), this results in hypertension, chest pain, SV arrhythmias
What are the adverse effects of CCBs?
- Extensions of the drug action (relaxed vascular SM)
- facial flushing, constipation
- Excessive dosing can lead to:
- hypotension
- Bradycardia
- AV block
- Heart faliure
- Don’t use verapamil or diltiazem in conjunction with B-blockers, can cause cardiac depression (since b blockers have a negative inotropic and chronotropic effect)
What does NO do?
And through what molecule do many endogenous vasodilators, like acetylcholine, histamine etc cause vasodilation?
- They relax smooth muscle (vasodilation)
- Inhibit platelet aggregation (antithrombotic)
- Inhibit leukocyte-endothelial interactoons (anti-inflammatory)
Many endogenous vasodilators (e.g. acetylcholine, histamine) act via NO production
- NO is synthesised from L-arginine mainly by eNOS
- NO is released from endothelial and acts upon vascular smooth muscle causing vasodilation.
How is NO synthesised?
Ligands binding to vascular endothelial receptors results in NO synthesis from L-arginine via eNOS enzyme.
On the endothelial cell are receptor operated Ca2+ channels, they are linked to the channel and allow Ca2+ to come in when activated.
Once in the cell, Ca2+ binds to calmodulin, and comes Ca-calmodulin. This activates eNOS enzyme by binding to it. eNOS then converts L-arginine to citruline and NO.
How does NO cause vasodilation?
NO from endothelium and extrinsic sources acts on vascular smooth muscle, and when it does this is increases guanylate cyclase activity, and this allows the formation cGMP.
cGMP then activates cGMP dependant protein kinases to promote smooth muscle relaxation.
cGMP is terminated by phosphodiesterase 5 (PDE 5)
How to nitrodilators work
Nitrodilators release NO in plasma or form NO within cells.
- Sodium nitroprusside, GTN (nitrates)
