Calcium Channel Blockers

Question 1

There are 9 calcium channel blockers available in the US. There three main ones are:

Answer 1

Verapamil
Diltiazem
Nifedipine

all other CCBs are analogues of nifedipine

Question 2

Calcium channel blockers act on three main tissues

Answer 2

Myocardium
AV node and conducting system
Blood vessels

Question 3

What are the medical uses of calcium channel blockers

Answer 3

Atrial tachycardias
Stable angina
Prinzmetals angina
Hypertension
Threatened miscarriage

Question 4

Atrial tachycardias and CCBs

Answer 4

E.g. flutter and fibrillation

Block excess impulses coming through AV node and conduction system

Diltiazem of verapamil used

Nifedipine-type cause vasodilation and relfex tachycardia

Question 5

CCB and stable angina

Answer 5

Diltaizem thought to be the best

Verapamil depresses heart too much

Nifedipine type causes reflex tachycardia

Question 6

Prinzmetals angina and CCBs

Answer 6

Best drugs for variant angina

Alls CCBs relax vasospasm
—blood vessels most affects - brain, heart, skeletal mm

Beta blockers are not effective at all for this b/c they do not affect vasospasms

Question 7

HTN and CCBs

Answer 7

Higher the BP, the greater the effect seen

Good for all patient categories

• -where as beta blockers are not so good in elderly or in African Americas
• -CCBs are better in elderly!

No effect on lipids

Question 8

CCBs and threatened miscarriage

Answer 8

Prematurity is still major cause of infant death

Calcium channels in uterus

Nifedipine effective

Question 9

What are some other proposed uses of CCBs?

Answer 9

Migrane

• -verapamil has some effect
• -blocks initial vasopasm

Prevention of 2nd heart attack

• -beta blockers are good for this
• -found that CCBs don’t work????

Question 10

What are the precautions to be aware of with CCBs?

Answer 10

Vasodilation
–leads to dizziness and facial flossing

Decreased exercise tolerance
–verapamil, diltiazem

Constipation

• -there are calcium channels in gut
• • 7% with verapamil

CNS effects

• -insomnia
• -nervousness
• -increased effect of morphine

Short acting CCBs

Edema

Antiplatelet effect

Question 11

What do we know about SHORT ACTING CCBs and angina and MI?

Answer 11

They may worsen angina and cause MI

–so we use amlodipine (T1/2 = 39 hours)

Question 12

What do we know about edema and CCBs?

Answer 12

Drugs work on arteries but not on the veins

• -dilate arterioles
• -do not dilate veins
• -increased capillary pressure, leading to fluid leaking out

Question 13

CCBs and anti platelet effect?

Answer 13

Have the ability to produce petechiae

CCBs block calcium channels in platelets. In order to work, platelets need to change shape. Calcium mediates this. Without calcium, cannot clot

Bleeding in peptic ulcer

Question 14

Molecule mechanism of calcium channel blockers

Answer 14

• bind inside channel
• binding is a function of voltage for nifedipine
  
  • –strong voltage fluctuations displace the drug
• “use dependence”
  
  • –some require channels being used in order to be more effect because they get in only when the channel is open; this is not true for all

Question 15

How can all drugs block calcium channels, but all act differently?

Answer 15

They all act on different sites inside the channel

Question 16

Differences in “use dependance” for CCBs

Consequence of this in terms of use

Answer 16

Verapamil and diltiazem are use dependent

• -can get in only when the channel is open electrically
• -this explains why these drugs are better when BP is high

Nifedipine blocks right away without the need to depolarize

Question 17

What are the various conformation states of calcium channels?
What is the consequence of this?

Answer 17

Open, resting, and inactive

Drugs can have different preferences for these different states

• -verapamil has preference for open state
• -nifedipine has preference for inactive state

Question 18

Why are these slow channels?/why is the entry of calcium through these channels so slow?

Answer 18

There are glutamate residues in the channels

Calcium binds to these in a step wise process in the channel

Explains

• –slow calcium entry
• –ion selectivity

Question 19

What are the types of calcium channels?

Answer 19

L = voltage gated calcium channel 1 = Cav1

T = voltage gated calcium channel 3 = Cav3

P/Q, N = voltage gated calcium channel 2 = Cav2

Question 20

L/Cav1

-where are these seen?

Answer 20

Heart and blood vessels

Question 21

T/Cav3

–what do these do?

Answer 21

regular electrical excitability in many tissues

can enhance amplitude of depolarization in heart, neurons

Question 22

P/Q, N, Cav2

• where are these found?
• what do they do?

Answer 22

P/Q - purkinje
N - neuronlal

regulate neurotransmitter release in brain

Question 23

Structure of voltage sensitive calcium channels

Answer 23

Multimeric proteins

Alpha-1 subunit forms the pore and contains drug binding sites

Question 24

What is the function of the a2gamma subunit?

Answer 24

cause faster opening/closing

Question 25

What is the function of the B subunit?

Answer 25

Regulates trafficking a1 to membrane

also allows more current after small depolarization

Question 26

What is the function of the gamma subunit? Where are these found

Answer 26

present skeletal mm channel but rarely elsewhere

we have no idea what the function is

Question 27

What are other calcium channel blockers?

Answer 27

Mg2+
H+
Older drugs (e.g. barbiturates)

Question 28

Mg2+ as a calcium channel blocker

Answer 28

weak channel blocker

sometimes used in arrhythmias

Question 29

H+ as a calcium channel blocker

Answer 29

Strong competitor of calcium

Some drugs don’t work well at low pH