Antiarrhythmic Drugs - part 2 Flashcards
What currents can be/are modulated by beta AR activity?
the two key currents of pacemaker APs
- L-type Ca+ for upstroke (0)
- “funny” currents (4) that spontaneously depolarize
these are important for setting HR
Explain the way in which B-adrengeric receptors accomplish their signaling to HCN in pacemaker cells
What does this mean for the cell and the ability to conduct?
bAR stimulation resulints in increased cAMP formation, which directly increases the activity of hyper polarized activated cyclic-nucleotide gated cation channels (HCN)
–> this results in increased depolarizating currents during phase 4 of the AP and helps return the cell to firing threshold sooner
HCM modulated by
- cAMP –> more cAMP, more easily it will conduct
- membrane potential –> more depolarized channel opens better
Explain the relationship between Ca2+ channels and the bAR
bAR stimulation and cAMP formation also increased protein kinase A activity, which increases phosphorylation of L-type voltage gated calcium channels
–>this increases the ant of current these channels can pass and also allows them to open are more negative membrane potentials
Blockade of Beta adrengeric receptor signaling in pacemaker cells results in …
- Decreased Ca activity –> slows 0 upstroke phase
- L-type voltage gated Ca channels now have to depolarize more in order to open –> AP will fire less frequently
- Decreased diastolic pacemaker current due to dec HCN channel activity –> slope of 4 flattens –> longer to return to threshold
- AP slightly wider, so increased ERP
What do cardioselective b-blockers preferentially inhibit?
beta 1 adrenergic receptors in the heart
and not B2 or alpha receptors
Which B-blockers are often used as anti-arrhythmics
Esmolol Acebutolol Propanolol (Sotolol) others can be used too
Esmolol
Cardioselective (B1)
Short half life (due to plasma esterase hydrolysis)
Given IV
Acebutolol
Cardioselective
Weak partial agonist at B1AR (sympathomomimetic)
Weak Na+ channel blockade
Propanolol
Non-selective
Weak Na+ channel blockade
Clinically, when are B-blockers used?
Arrhythmias involving catecholamines
Atrial arrhythmias (protect ventricular rate)
Post MI prevention of ventricular arrhythmias
Prophylaxis in long QT syndrome
Recall, in the pacemaker cells, which current in responsible for the upstroke?
What is the implication of this?
Calcium channels - iCaL - phase 0
Blocking L-type voltage gated Calcium channels should therefore provide some specificity for controlling the upstroke of pacemaker cells but should do little to manipulate the excitability of myocytes
What effects does a calcium channel blockade have?
Slows the pacemaker AP upstroke
Makes the firing threshold a more depolarized voltage
AP amplitude may be diminished
AP width is increased
–> ERP is increased
Which calcium channel blockers are used as anti-arrhythmics?
Verapamil
Diltiazem
MOA of verapamil, diltiazem
Frequency dependent block of Cav1.2 channels
Selective block for channels opening more frequently
Accumulation of blockade in rapidly depolarizing tissue
– i.e. heart in tachycardia
Clinically, when are Ca channel blockers used?
Block re-entrant arrhythmias involving AV node
CHIEFLY used to protect ventricular rate in a flutter and a fib
What effect on the ECG do both B blockers and Ca channel blockers have?
Increase PR interval
- increase AV refractoriness
- slow phase 0 (ca+ current)
- slow phase 4 (HCN current)
See summary slide in notes for more
Class I drugs have different binding affinities for the different states of the ion channel. Differentiate between them.
Ia - O > I
Ib - I»_space; O
Ic - O
Important points about class IA
Mixed blockade: Na+ and K+ Preferentially blocks open state Moderate, incomplete dissociation (seconds) Widens QRS Prolongs QT
Important points about class IB
Na+ channel block Blocks open and inactivated state Rapid, complete dissociation (milliseconds) Slight narrowing of AP No clinically significant effect on ECG
Important points about class IC
Strong Na+ channel block
Blocks open state
Very slow, incomplete dissociation (> 10 seconds)
Widens QRS
Class I drugs are helpful in controlling arrhythmias by doing one or more of the following
- Suppress ectopic pacemaker activity
- Suppress aberrant activity arising from damaged tissue such as ischemic tissue
- Abolish re-entry circuits
How can class I drugs suppress the ectopic focus?
- blocking HCN channels that produce phase 4 pacemaker current
- blocking sodium channels to slow conduction in the ectopic focus –> increases firing threshold
- increasing refractoriness via K+ channel block properties of class IA
How can class I drugs suppress activity of damaged tissue in which there is rapid heart rates?
Frequency dependent blocks
Normally, class I drugs dissociated from channels between beats, but in cells firing rapidly, there is no time to dissociate Therefore each AP results in more and more channels being blocked --> eventually this silences activity from these cells
Note: these drugs spare normal electrical activity while controlling inappropriately high rates of depolarization
How can class I drugs suppress activity of damaged tissue in which there is a depolarized membrane potential?
Voltage dependent block
Depolarized membrane potentials significantly increased the number of channels that are constitutively in the inactivated state –> this increases the number of channels that are blocked by class I drugs, which slows electrical activity selectively in this depolarized tissue
How can class I drugs abolish re-entry arrhythmias?
Class 1 drugs will increase the amount of time it takes for sodium channels to recover from inactivation, which can prolong the ERP of the cell
If conduction is slowed enough, retrograde impulses will encounter refractory tissue
Class IA drugs
Quinidine
Procainamide
Disopyramide
Quinidine
2-8% risk of Torsades de Pointes
Anti-muscarinic activity
Procainamide
Lupus-like syndrome
Ganglionic blocker
Disopyramide
Anti-muscarinic activity
Class IB drugs
Lidocaine
Mexiletine
Lidocaine
IV only; not effective orally
Among top choices for rapid control of ventricular arrhythmias
Only ventricular, not atrial
Mexiletine
Orally available, similar to lidocaine in efficacy
Class IC drugs
Flecainide
Propafenone
Flecainide
Ventricular and supra ventricular
Orally available
Propafenone
Ventricular and supra ventricular
B-AR blocking activity
Orally available
