Pharm: Antiarrhythmic drugs Flashcards
Describe the cardiac conduction system
The sinoatrial node is the pacemaker, and is located in the wall of the right atrium. The SA stimulus spreads across the atria to the AV node, which has a 150ms delay. The his-Purkinje system then rapidly depolarizes the ventricles leading to cardiac contraction
How does the action potential from a cardiac pacemaker cell differ from a ventricular cell?
Pacemaker cells do not have rapid depolarization caused by fast sodium channels
Pacemaker cells also have spontaneous phase 4 depolarization unlike the ventricles
What are the major ionic fluxes associated with each phase of the action potential?
Phase 0: Na and Ca in Phase 1: Transient K out Phase 2: Plateau from Ca2+ in Phase 3: K+ out Phase 4: resting membrane (K+ permeable, but K in = K out)
Which direction does the concentration gradient favor for Na+, Ca2+ and K+?
Na+: In
Ca2+: In
K+: Out
Describe the states of the Na+ channels in cardiomyocytes
3 states, differing based on the conformation of the m (activation) and h (inactivation) gates.
Resting: m closed, h open
Activated: m and h open, only occurs for 1-2msec
Inactivated: m open, h closed
The channels are restored from inactivated to resting state with time and/or voltage
How does membrane potential alter the availability of sodium channels?
Fewer channels are available at higher potentials
Channels close between -55 and -75 mV
What is the primary determinant of the refractory period?
Action potential duration
What channels are not present in pacemaker cells that are found in normal myocytes?
Fast sodium channels
What factors increase the risk for arrhythmia?
Digitalis treatment
General anesthesia
Acute MI
What are the symptoms of cardiac arrhythmias?
Wilde range from asymptomatic to severe hemodynamic consequences with reduced cardiac output and death
What do all arrhythmias result from?
1) disturbed impulse formation
2) disturbed impulse conduction
3) a combination of both
What can alter the rate of phase 4 depolarization in cardiac pacemaker cells?
Hypokalemia, beta stimulation, and acidosis increase the rate of depolarization, thus reaching threshold faster
Beta blockade, vagal stimulation decrease the depolarization thus reaching the threshold slower
From where in the AP do EAD’s originate? How are DAD’s different?
EAD’s originate from the plateau phase, more often in slow heart rates
DAD’s originate from the resting potential, more often in high heart rates
How does re-entry occur?
A unidirectional block must be present
A loop is formed from conduction down a normal branch that can loop retrograde through the block slowly and then trigger another impulse down the normal branch
What is the general goal of anti-arrhythmic therapy?
Reduce ectopic pacemaker activity and/or modify conduction characteristics to disable re-entry circuits
What are the main pharmacological mechanisms for anti-arrhythmic drugs?
Na+ channel blockade
Blockade of sympathetic autonomic effects
Prolong the effective refractory period
Ca++ channel blockade
What pharmacological changes are beneficial in order to correct cells with abnormal automaticity?
Reduced phase 4 slope
Increase max Em
Increase threshold potential
Increase action potential durration
Why is it beneficial to prolong Na+ channel recovery time for arrhythmia treatment?
Prolonging recovery time may prevent re-entry, block tachycardia and prevent premature beats from occurring by decreasing the likelihood that a new action potential will fire
Describe use-dependent/state-dependent drug action
A drug binding with high affinity to the active and inactive channel, but dissociating from the resting channels
This in theory targets depolarized cells that are involved with tachyarrhthmias while leaving unaffected cells alone
What is the major danger of anti-arrhythmic drugs?
The do not act specifically, and can end up depressing conduction in normal cells leading to drug-induced arrhythmias
-Dosage, HR, acidosis, electrolytes and ischemia all impact the effect
Should anti-arrhythmic drugs be used in patients with asymptomatic or minimally symptomatic arrhythmias?
No. Increased mortality is associated with anti-arrhythmia treatment
What are the classes of anti-arrhythmic drugs?
I: Na+ channel blockers II: beta blockers III: Prolong action potential duration IV: Ca++ channel blockers Other
Describe the effect of class I anti-arrhythmic drugs
Reduced conduction velocity by blocking fast sodium channels, reduces the rate and magnitude of phase 0 depolarization
What are the 3 subclasses of class I antiarrhythmic drugs and how do they differ?
IA: intermediate kinetics, APD prolonged
IB: fast kinetics, APD decreased
IC: slow kinetics, APD unchanged
