Calcium Channel Blockers

Question 1

How does Ca2+ enable contraction in vascular smooth muscle cells?

Answer 1

inward flux of Ca ions, Ca binds calmoldulin, Ca-calmodulin complex activates myosin kinase which phosphorylates a light chain of myosin, myosin can interact with actin, leading to contraction

Question 2

How does Ca2+ enable contraction in the myocardium

Answer 2

with the rise in intracellular Ca, Ca binds to a subunit of troponin; the presence of ATP allows the force-generating interaction b/t actin and myosin

Question 3

Which L-type calcium channel subunit is the binding site for calcium channel blockers?

Answer 3

alpha1 subunit

Question 4

What are three major groups of L-type calcium channel blockers (and examples of each)?

Answer 4

dihydropyridines (nifedipine, amlodipine), phenylalkylamines (verapamil), benzothiazepines (diltiazem)

Question 5

What are the pharmacological effects of all CCBs?

Answer 5

vasodilation and reduction of blood pressure

Question 6

What are the pharmacological effects of non-DHP CCBs?

Answer 6

decrease myocardial contractility, decrease heart rate (except when reflex stimulation), decrease rate of conductance through the AV node

Question 7

What is the significance of a vascular, cardiac selectivity ratio?

Answer 7

CCBs differ in their relative potency of cardiac and vascular effects

Question 8

Do the cardiac depressant or vasodilatory properties of DHPs dominate?

Answer 8

vasodilatory

Question 9

Do the cardiac depressant or vasodilatory effects of nifedipine and diltiazem dominate?

Answer 9

neither

Question 10

What effect do DHPs have on the SNS?

Answer 10

activate the SNS, increase HR

Question 11

What are the clinical indications for CCBs?

Answer 11

HTN, SVT, subarachnoid hemorrhage, hypertrophic cardiomyopathy (without systolic dysfunction), angina (?)

Question 12

As single agents, are ACEIs or CCBs more effective for low-renin HTN (as in African Americans)?

Answer 12

CCBs

Question 13

What are the major side effects of DHPs?

Answer 13

hypotension, flushing, HA, ankle edema, palpitations

Question 14

What are the additional major side effects of nifedipine and diltiazem?

Answer 14

conduction disturbances, heart failure, bradycardia

Question 15

PK of CCBs

Answer 15

highly protein-bound, high first-pass metabolism, low bioavailability

Question 16

Which CCB has a slow onset of action and prolonged onset of action?

Answer 16

amlodipine

Question 17

Give an example of a racemic drug

Answer 17

verapamil

Question 18

Which stereoisomer of verapamil is more active and is cleared more avidly by the liver?

Answer 18

L-isomer

Question 19

Which drugs will be affected by CCBs, and why?

Answer 19

drugs metabolized by CYP 3A4, CCBs inhibit CYP 3A4

Question 20

Clinically important PK CCB interactions

Answer 20

diltiazem & cyclosporine, diltiazem & amiodarone (and statins), verapimil & digoxin (P-glycoprotein inhibition)

Question 21

Clinically important PD CCB interaction

Answer 21

verapamil or diltiazem & beta-blockers: bradycardia and/or heart block

Question 22

CCB effects on risk of MI

Answer 22

increase risk

Question 23

Should short-acting CCBs be used to lower BP acutely?

Answer 23

no