Ca Channel Blockers Flashcards
How is Ca involved in cardiac muscle cells
- Action Potentials cause Ca channels to open causing Ca to rush in
- Cardiac muscle contraction is dependent on Ca entering the cell
What drug(s) are in the Phenylalkylamines class
Verapamil
What drug(s) are in the Benzothiazepines class
diltiazem
What drug(s) are in the 1,4-Dihydropyridines class?
- Nifedipine
- Amlodipine
Compare the chemical structures of the different drug classes
They are all so different! But they all work on L-type Ca channels
Widespread use of CBCs
Angina pectoris Hypertension treatment of supraventricular arrhythmias *Atrial flutter *atrial fibrillation *Paroxysmal SVT
What do the Calcium Channel Blockers (CCBs) target
L-type Ca channels in vascular smooth muscle and cardiac muscle
Describe the L-type Calcium chanenl
It is a channel made up of four subunits that forms a pore
Describe the binding of the Benzothiazepines and phenylalkylamines
Use dependent binding
-They bind when the Calcium channel is in the open state. the binding pocket is inside the pore so the pore has to be open in order for them to bind
Describe the binding of 1,4-dihydropyrimidines
Voltage dependent binding
- depends on membrane potential. When the membrane is more depolarized (more positive) there is more binding!
- Vascular smooth muscle is more positive so there is more binding of these drugs there, as opposed to in the heart
Describe the three conformation states of the Calcium channel and what that means for drug binding
- When Calcium rushes in the drug is in the open state: All drugs can bind! Especially think about the usage dependent binding of the Benzothiazepines and phenylalkylamines
- Inactivated State: Only the 1,4 dihydropyrimidines can bind because this is when the cell is quire depolarized but closed
- closed state: no binding
Describe the results of the Washington University paper
There are different binding sites for the use dependent vs voltage dependent drugs but there is some aa overlap so some binding overlap
Describe why two classes of Ca Channel Blockers are not given togetehr
They have allosteric interactions, both up-regulating and down-regulating binding of each other. Therefore it makes interactions and effects unpredictable so we don’t give them together.
Mechanism of Action of CCBs
- increase the time that Ca channels are non-conducting
- relaxation of the arterial smooth muscle, but not much effect on the venous smooth muscle (so decrease afterload but not preload)
- significant reduction in afterload but not preload (bc no effect on veins and pre-load is related to the veous return)
Why dont CCBs work on neurons
Neurons have N-type ad P-type Ca channels to mediate neurotransmitter release.
CCBs work on L-type Ca Channels
Why don’t CCBs work on skeletal muscle
Skeletal muscle relies on intracellular Ca for contraction, but this Ca is only to act as a voltage sensor.
SO really you can think that it is voltage dependent and not dependent on Ca entry
Ca entry across the t -tubule membrane is NOT required for skeletal muscle contraction.
Why do CCBs work on cardiac cells
cardiac cells rely on L-type Ca channels for contraction (fast response cells) and for the upstroke of the action potential in slow response cells.
Cardiac cells are dependent on Ca entering for contraction
Why do CCBs work on vascular smooth muscle
Vascular smooth muscle relies on Ca influx through L-type Ca channels for contraction
-Ca entry is required to maintain th epulsating tone of vascular smooth muscle
Why does the different binding sites of CCBs result in differing pharmacological effects
- use-dependent binding works on cardiac cells
- voltage dependent binding works on smooth muscle
Explain why Dihydropyridines are selective vasodilators and the side effect related to this
- they dilate blood vessels through the voltage dependent Ca channels
- This causes Reflex tachycardia: a potential reflex increase in HR, myocardial contractility and oxygen demand due to the decreased resistance casued by dilation
Explain how the Non-dihydropyridines are more potent for cardiac tissues vs vasculature and the effects this causes
- -effects th eheart via the use dependent Ca channels
- helps to slow the heart rate by blocking the channels. The heart can’t contract as much if the Ca channel which allows contraction is blocked!
- On that note it also decreases contractility
- Heart rate moderating, reduced inotropism, peripheral and coroanry vasodialtion
Common uses of CCBs
Angina
Arrhythmias
HTN
Explain the CCB use for angina
- Diltiazem, Verapamil: reduces workload, lowers heart rate, reduces cardiac afterload, increases coronary blood flow
- Nifedipine: reduces myocardial oxygen demand, reduces arterial pressure
Explain the CCBs uses for Arrythmias (atrial fibrillation/flutter; supraventricular tachycardia)
-Diltiazem, Verapamil: reduces firing rate of the SA node, reduce conduction through the AV node (1,4 Dihydropyridines are not classified as anti-arrhythmic drugs)
(bc they block the AV node if someone is suffering from an AV block CCB use is contraindicated)
