Antiarrhythmic Drugs (part 1) Flashcards
Arrhythmias frequent problem which occurs in:
25% of patients with heart failure
50% of anesthetized patients
80% of patients with myocardial infarction
anti-arrhythmic drugs also produce arrhythmia
What are the 3 requirements for normal cardiac excitation?
- PACEMAKER (impulse generator; normally the sinoatrial (SA) node)
- CONDUCTION FIBRES (atrioventricular (AV) node; bundle of His; Purkinje Fibers)
- healthy MYOCARDIUM (atria, ventricles)
ie capable of robust excitation-contraction coupling
Describe the pathway of a normal cardiac excitation?
- SA node
- To both Atrium’s (contraction)
- AV node
- Purkinje Fibers (for rapid excitation - so that it is a timely manner)
- Ventricle (contracts) - allows blood to be expelled into rest of body
What are the 2 reasons why AV node is imp.?
- Normally only electrical activity b/t atrium & ventricle
- Opposes a delay in conduction - allows atrium to contract & ventricles to fill
Normal cardiac rhythm =
SINUS RHYTHM
Arrhythmia =
any rhythm that is not a normal sinus rhythm with normal atrioventricular (AV) conduction
What 3 things are apart of the Cardiac Conduction System?
- SA node
- AV node
- Conduction fibres
What is the MAIN PACEMAKER & initiator of heartbeat?
SA node
What spontaneously discharges 60 to 100 beats per minute (bpm)?
SA node
What rate can be changed by nerves innervating the heart?
both the SA node & AV node
What is the only normal ELECTRICAL CONNECTION BETWEEN ATRIA AND VENTRICLES?
AV node
What DELAYS CONDUCTION of action potential by 0.1 sec. Important to allow atria to contract and ventricles to fill before
AV node
What spontaneously discharges at 40 to 60 bpm (normally overridden)?
AV node
What function is to excite the ventricular mass as near simultaneously as possible?
Conduction fibres
What spontaneously discharge at 20 to 40 beats bpm (overridden)?
Purkinje fibres (Conduction fibres)
What has specialization due to unique ELECTRICAL PROPERTIES of myocytes in each area?
Conduction fibres
What is the Internal & External Electrodes of the Cardiac Action Potentials?
Internal Electrodes
- SA node pacemaker impulse
- Conduction to atria
- AV node
- Bundle of His - Purkinje fibres
- Contraction
External Electrodes (ECG)
What falls under the waves?
- P wave
- QRS complex
- T wave
What falls under the intervals?
- PR interval
- QRS interval
- QT interval
P wave:
atrial DEpolarization
QRS complex:
ventricular DEpolarization
T wave:
ventricular REpolarization
PR interval:
conduction time atria to ventricles
QRS interval:
time for all ventricular cells to be activated
QT interval:
duration of ventricular action potential
What does a normal cardiac rhythm = SINUS RHYTHM look like:
note - action potential differences!!
SLOW rise & NO plateau
spontaneous discharge
RAPID DEpolarization with plateau
What are action potential differences due to?
action potential differences due to different ion channels expressed in myocytes
PACEMAKING vs NON-PACEMAKING cells
(the drugs target either pacemaking or non-pacemaking cells)
Most Antiarrhythmic Drugs Act on…
Ion Channels (act directly/indirectly on them)
What are the Class 1 antiarrhythmic drugs? What do they act on?
- Procainamide
- Lidocaine
- Flecanide
primarily block Na+ channels
What are the Class 2 antiarrhythmic drugs? What do they act on?
- Propranolol
- Metoprolol
- Esmolol
primarily block B-adrenergic receptors (INDIRECTLY influence electrical activity of heart)
What are the Class 3 antiarrhythmic drugs? What do they act on?
- Amiodarone
- Sotalol
primarily block K+ channels
What are the Class 4 antiarrhythmic drugs? What do they act on?
- Verapamil
primarily block Ca2+ channels
What are the Class 5 antiarrhythmic drugs? What do they act on?
- Magnesium
- Adenosine
- Digoxin
other mechanisms
What happens when Na+ channels open?
explosive Na+ INFLUX driven by both chemical & electrical forces!!
What happens when K+ channels open WHEN MEMBRANE IS DEPOLARIZED?
explosive K+ EFFLUX driven by both chemicals & electrical forces!!
Describe Non-pacemaker cells
FAST
atria, ventricles, pukinje fibres
phases 0-4
Describe Pacemaker cells
SLOW
SA node; AV node
phases 0, 3, & 4
What are the phases of non-pacemaker cells?
each event is mediated by diff. ion channels
Phase 0 - Na+ INward
Phase 2 - Ca2+ INward
Phase 3 - K+ OUTward
Phase 4 - Pacemaker current
What is hERG?
imp. family of K+ channel in heart
ex: 1st gen of anti-histamines
Non-pacemaker (fast) cells
Phase 4
– diastolic (resting) potential
- NO TIME-DEPENDENT CURRENTS DURING PHASE 4
- as a result, resting potential is substantially more negative (-80 mV) than SA/AV nodes
Non-pacemaker (fast) cells
Phase 0
- depolarization
- lots of voltage gated Na CHANNELS,
– low threshold potential - easily opened - threshold reached - “active” voltage gated Na channels open
– rapid depolarization - Na channels quickly become “INACTIVE” - ends depolarization
Non-pacemaker (fast) cells
Phase 1
- slight repolarization
chloride channels open briefly and chloride enters cell
What is a main difference b/t pacemaker & non-pacemaker cells?
have extended plateau phase (pacemaker cells don’t)
Non-pacemaker (fast) cells
Phase 2
- plateau
- opening of voltage gated L-type Ca CHANNELS
- Ca enters cell
– causes further release of Ca from sarcoplasmic reticulum - Ca dependent CONTRACTION
Non-pacemaker (fast) cells
Phase 3
- repolarization
- K CHANNELS activate (open)
- movement of K out of the cell repolarizes the membrane
– returns to resting membrane potential - Ca is removed from the cytoplasm and tissue relaxes
- REPOLARIZATION ALLOWS Na+ CHANNELS TO RECOVER FROM INACTIVATION
Why is Na+ channel inactivation important:
Physiological: limits Na+ channel availability, which is establishes how quickly tissue can be stimulated
Pharmacology: Class I and III primarily act by reducing Na+ channel availability by increasing their inactivation
When inactivated Na+ channels are closed and thus…
unavailable
repolarization allows Na+ channels to recover from ______ and return to the “resting” state
inactivation
Describe the Absolute & Relative Refractory Period
during phase 3 – Na+ channels recover from “INACTIVE” to “RESTING” state
if the MAJORITY of Na+ channels remain in the “INACTIVE” state
- myocyte can not be depolarize – this is the ABSOLUTE REFRACTORY PERIOD (ARP)
if only a PORTION of the Na+ channels are in the “INACTIVE” state
- myocyte may depolarize, but will do so less rapidly – this is the RELATIVE REFRACTORY PERIOD (RRP)
Reduced Na+ channel availability during the Absolute/Relative Refractory Period…
limits how quickly this tissue can be stimulated
Availability of _____ Na+ channels is key for allowing rapid phase 0 depolarization
resting
a rapid phase 0 depolarization results in a strong and rapid transmission of this impulse to surrounding fibers (propagation) = strong/effective contraction of atria and ventricles
Availability of resting Na+ channels is key for allowing rapid phase 0 depolarization
CONSEQUENTLY…
decreased Na+ channel availability will:
- decreases the rate of depolarization
- decreases the strength and speed of the impulse
Na+ channel availability is decreased by
pathological conditions: e.g. hypokalemia, ischemia will cause slow depolarization of the resting membrane potential
drug treatment: e.g. Class 1 and III antiarrhythmic drugs
favours ectopic foci/re-entry mechanisms
How would altering the Na, Ca and/or K channels in the “fast” cells (atria, purkinje fibers, ventricles) alter the appearance of the action potential?
Class I (block Na+ influx) & Class III (block K+ efflux) drugs
What does the Pacemaker (slow) look like?
0 - Ca2+ influx
3 - K+ efflux
4 - K+ efflux
What are the 3 main differences that Pacemaker (slow) cells have?
- Pace heart (spon. depol) - automaticity
- No phase 1 - therefore no role of Cl- in these cells
- Don’t have plateau phase
Sinoatrial (SA) Node / Atrioventricular (AV) Node
Phase 4
SPONTANEOUS DEPOLARZATION (and thus capable of pacemaker activity/automaticity)
pacemaker current - = increased Na+ influx
increased Ca influx
decreased K efflux
intrinsic firing rate: SA > AV > Bundle of His > Purkinje fibers
note Bundle of His and purkinje fibres are “fast” cells, but with very slow Phase 4 depolarization
Phase 0
threshold reached - voltage gated L-type Ca CHANNELS open
rapid depolarization
then L-type calcium channels close
Phase 1 or Phase 2 is absent in SA/AV node
Phase 3
voltage gated K CHANNELS open and membrane repolarizes
How would altering the Na?, Ca and/or K channels in the “slow” cells (SA node, AV node) alter the appearance of the action potential?
Non-pacemaker (fast)
- Class 1 - Na+ influx
- Class III - K+ efflux
Pacemaker (slow)
- Class II - block Na+ influx (If)
- Class IV - Ca2+ influx
Sum up Pacemaker (slow)
SA node & AV node
RMP (mV): -40 to -65
Phase 0: Calcium
Phase 2: no
Automaticity: yes (property of cells that spon. depolarize)
Non-pacemaker (fast)
Atrial & Ventricular muscle
RMP (mV): -80 to -95
Phase 0: Sodium (inactivation/refractory period)
Phase 2: yes
Automaticity: no
