Calcium Channel Blockers Flashcards
There are 9 calcium channel blockers available in the US. There three main ones are:
Verapamil
Diltiazem
Nifedipine
all other CCBs are analogues of nifedipine
Calcium channel blockers act on three main tissues
Myocardium
AV node and conducting system
Blood vessels
What are the medical uses of calcium channel blockers
Atrial tachycardias Stable angina Prinzmetals angina Hypertension Threatened miscarriage
Atrial tachycardias and CCBs
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
CCB and stable angina
Diltaizem thought to be the best
Verapamil depresses heart too much
Nifedipine type causes reflex tachycardia
Prinzmetals angina and CCBs
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
HTN and CCBs
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
CCBs and threatened miscarriage
Prematurity is still major cause of infant death
Calcium channels in uterus
Nifedipine effective
What are some other proposed uses of CCBs?
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????
What are the precautions to be aware of with CCBs?
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
What do we know about SHORT ACTING CCBs and angina and MI?
They may worsen angina and cause MI
–so we use amlodipine (T1/2 = 39 hours)
What do we know about edema and CCBs?
Drugs work on arteries but not on the veins
- -dilate arterioles
- -do not dilate veins
- -increased capillary pressure, leading to fluid leaking out
CCBs and anti platelet effect?
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
Molecule mechanism of calcium channel blockers
- 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
How can all drugs block calcium channels, but all act differently?
They all act on different sites inside the channel
Differences in “use dependance” for CCBs
Consequence of this in terms of use
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
What are the various conformation states of calcium channels?
What is the consequence of this?
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
Why are these slow channels?/why is the entry of calcium through these channels so slow?
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
What are the types of calcium channels?
L = voltage gated calcium channel 1 = Cav1
T = voltage gated calcium channel 3 = Cav3
P/Q, N = voltage gated calcium channel 2 = Cav2
L/Cav1
-where are these seen?
Heart and blood vessels
T/Cav3
–what do these do?
regular electrical excitability in many tissues
can enhance amplitude of depolarization in heart, neurons
P/Q, N, Cav2
- where are these found?
- what do they do?
P/Q - purkinje
N - neuronlal
regulate neurotransmitter release in brain
Structure of voltage sensitive calcium channels
Multimeric proteins
Alpha-1 subunit forms the pore and contains drug binding sites
What is the function of the a2gamma subunit?
cause faster opening/closing
What is the function of the B subunit?
Regulates trafficking a1 to membrane
also allows more current after small depolarization
What is the function of the gamma subunit? Where are these found
present skeletal mm channel but rarely elsewhere
we have no idea what the function is
What are other calcium channel blockers?
Mg2+
H+
Older drugs (e.g. barbiturates)
Mg2+ as a calcium channel blocker
weak channel blocker
sometimes used in arrhythmias
H+ as a calcium channel blocker
Strong competitor of calcium
Some drugs don’t work well at low pH
