Calcium Channel Blockers Flashcards
Calcium blockers have usually what suffix in their names?
-epine in their names except two, Verapamil and Diltiazem
What are the group of drugs that block calcium channels, preventing calcium from entering your membranes?
CALCIUM CHANNEL BLOCKERS
What are the different types of calcium channel blockers?
● First, we have the dihydropyridines.
○ The 1st generation representative is nifedipine, which is the oldest calcium channel blocker
○ The 2nd generation you have isradipine, nicardipine, and felodipine
○ The 3rd generation you have amlodipine
● Second, you have the phenylalkylamines under which is your verapamil
● Next is your benzothiazepines under which is your diltiazem
● The main effect is to decrease contractility primarily for verapamil and diltiazem
● You also have decrease in heart rate and decrease conduction velocity
● Basically, the main action of your calcium channel blockers is it will produce smooth muscle relaxation which will end up in dilation and decrease in blood pressure
What basically happens when you have a calcium channel blocker?
○ It will block the calcium from entering your smooth muscle
● When the calcium enters the calcium channels, you will have an activation in the myosin light chain kinase, which will produce phosphorylation and then you will have actin-myosin cross-bridging which will lead to contractions and vasoconstriction
○ Thus, if you block that then you will have vasodilation mainly your arteriolar smooth muscle or your arterioles
● On the heart, your calcium will stimulate release from the internal stores this will lead to constriction of the heart or contraction
○ If you block it, you will have a decrease in your AV conduction velocity and a decrease in SA node pacemaker rate so you have a decrease in your heart rate and a decrease in myocardial contractility because of the decrease in your calcium entry
Mediate entry of extracellular Ca++ into smooth M and cardiac myocytes, SA and AV nodal cells in response to electrical depolarization
L-type/slow Ca++ channels
○ Relaxation esp in arterial beds
○ Negative inotropic effects in cardiac myocytes
○ All blockers exert these 2 actions
■ Ratio differs according to class, presence of chronotropic and dromotropic effects
AKA Ca++ entry blockers - inhibit Calcium reflux
Phenylalkylamine
Verapamil, Gallopamil
Benzothiazepine
Diltiazem, Clenazem
Dihydropyridines:
○ Amlodipine, Clevidipine, Felodipine
○ Isradipine, Lercanidine, Nicardipine
○ Nifedipine, Nimodipine, Nisoldipine, Aranidipine, Azelnidipine, Cilinidipine, Efonidipine, Manidipine, Nivaldipine
UPDATES ON CLASSIFICATION
● Based on formula and length of action
1st Generation
● Nifedipine, Nicardipine, Verapamil and Diltiazem
2nd Generation
● Longer action, enhanced vascular selectivity
● Slow release
○ Nifedipine SR, Felodipine ER, Diltiazem SR
● Benidipine, Manidipine, Nilvadipine, Nintrendipine
3rd Generation
● Long action
○ Amlodipine - Sustained blood concentration with long t1⁄2
● Lipophilic and highly histotrophic
○ Lercanidipine, Lacidipine
● Azelnidipine - Lipophilic, high affinity to vascular tissue
UPDATES ON CCBS AND THE HEART
● Framingham study
○ HR one of the most important factors of CVD
● Short-acting DHPs
○ Relax tachycardia and rapid BP decrease
● CCBs with sustained action to avoid reflex tachycardia
○ Amlodipine, Lercanidipine, Azelnidipine
○ Nifedipine SR
● CCBs with blocking action on multiple Calcium channels
○ Cilnidipine, Efonidipine
● Some CCBs have anti-atherosclerotic action and possess antioxidant activity → cardioprotection
○ Amlodipine, Benipidine
○ Prevent myocardial remodeling induced by chronic nitric oxide inhibition in rats
● HPN - one of the most important risk factors for the progression of renal disease
○ ACE inhibitors and ARBs - treatment of choice in patients with renal disease → reduce proteinuria
○ AASK study, Amlodipine - retards progression of
renal disease (less than Ramipril)
○ Possible renal protective action of CCBs
■ Dilation of efferent arteriole → reduces glomerular capillary pressure
● ACE Inhibitors and Angiotensin Receptor Blockers (ARB)
○ Treatment of choice in patients with renal disease who also have hypertension
■ Reduces proteinuria
■ Improves renal disease
● AASK study
○ Amlodipine - retards progression of renal disease (less than Ramipril)
● Possible renal protective action of Calcium CHannel Blockers
○ Dilation of efferent arterioles → reducing glomerular capillary pressure
MECHANISM OF ACTION: CCB
● Increased concentration of cytosolic Ca++ → increase contraction in both cardiac and smooth muscle cells
● Cardiac Myocytes
○ Entry of extracellular Ca++ causing a larger Ca++ release from intracellular stores (Ca++ induced Ca++ release) → initiating contraction
● Bind to alpha1 subunit of the L-type voltage-gated Ca++ channels
○ Reduce Ca++ influx through these channels
● Dihydropyridines - does not have or produce any negative inotropy or negative chronotropy
● Verapamil and Diltiazem - Negative inotropy and negative chronotropy causing the decrease in Heart Rate, increased due to SNS activation
SOME CALCIUM CHANNEL BLOCKERS BLOCK OTHER CALCIUM CHANNELS
Efonidipine:
● Long acting CCB
● Blocks both L-type and T-type channels
Benidipine, Nilvadipine, Aranidipine:
● T-type blockers
Cilnidipine, Amlodipine:
● L-type and N-type blockers
● N-type
○ Distributed along nerve and brain
○ Inhibits SNS
PHARMACOLOGICAL ACTIONS
Vascular Tissue
● Depolarization of vascular smooth muscle cells ○ depends on primarily on influx of Ca++
● 3 mechanisms during contraction:
○ Voltage gated Ca++= channels open in response to depolarization of membrane → extracellular Ca++ moves into cell
○ Agonist induced contractions occur with or without depolarization → release of intracellular Ca++
○ Receptor operated Ca++ channels allow entry of extracellular Ca++ in response to receptor occupancy
● All blockers decrease Ca++ entry
● Relax arterial smooth muscles, decreased arterial resistance, BP and cardiac afterload
PHARMACOLOGICAL ACTIONS
Cardiac Cells
● By inhibiting Ca++ influx, Ca++ channel blockers reduce the peak size of the systolic Ca++ transient → negative inotropic effect
● Greater degree of peripheral vasodilation seen with dihydropyridines → accompanied by baroreceptor reflex-mediated increase in sympathetic tone
○ So we all know that when you have vasodilation your sympathetic nervous system will become activated and there will be a decrease in your blood pressure
○ When you have a decrease in your blood pressure the body will try to adapt and adjust so you will have an activation of your sympathetic nervous system which will produce tachycardia, so this is what will happen with your short acting dihydropyridines
PHARMACOLOGICAL ACTIONS
SA and AV nodes
● Depolarization depends on the movement of Ca++ through slow channel
● Ca++ channel blocker effect depends on whether the agent delays the recovery of the slow channel
● Nifedipine - does not affect rate of recovery of slow Ca++ channel
○ Does not directly affect pacemaking or conduction thru AV node
● Verapamil - reduces magnitude of the Ca++ current through slow channel and also decreases rate of recovery of the channel
○ Blockade enhanced as frequency of stimulation increases → frequency/use dependence
○ Also inhibits fast Na+ and K+ repolarizing currents
Hemodynamic profiles of Ca++ channel blockers
● Depend mainly on ratio of vasodilation and negative ino and chrono effects on heart
● Dihydropyridines
○ Dilate BV at several fold lower concentration that those required for decrease myocardial force
■ So that is why you see great vasodilation even without the ino or chronotropic effects on the heart
○ Decrease in arterial BP → reflex sympathetic activation
■ Stimulation of HR, AV conduction velocity, myocardial force = opposite of the direct effect of Ca++ channel blockers
Dihydropyridines
● In clinical use – share most pharmacodynamic props
● Amlodipine, clevidipine, felodipine, isradipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine
● Cause little effect on venous return and preload, more direct (-) ino and chrono effects at doses that produce arteriolar dilatation and afterload reduction
Verapamil
● Consequence of a reflex increase in adrenergic tone are generally offset by direct cardiodepressant effects of drug
○ To note that dihydropyridine can cause a reflex activation of sympathetic nervous system, however in verapamil, even the production of negative inotropic effect immediately when it produces vasodilation, so sympathetic nervous system will not be activated as much because it is offset by direct cardiodepressant effect of the drug
● In pts w/o heart failure - there will be an improved ventricular performance due to reduction in peripheral vascular resistance and BP w/ minimal changes in heart rate
Verapamil
Patients with heart failure:
○ IV Verapamil cause marked decrease in contractility and Left ventricular function
○ Can cause 2nd degree AV block especially when given in combination with beta blockers (contraindicated)
○ Thus do not give Verapamil or Ditilazem together with beta blockers because of its cardiodepressant effects.
Nifedipine
● Immediate-release-quickly absorbed after oral intake
○ Used to be given sublingually
○ Cause abrupt decrease in BP (hypotensive patient) resulting to, reflex activation of SNS and leading to tachycardia
○ Flush, increase risk of angina pectoris by abruptly decreased coronary perfusion pressure with tachycardia
○ Now removed from practice
● Sustained-release preparation
○ Reduce fluctuations of plasma concentration
○ Once or twice a day
