antiarrhythmics (exam 2) Flashcards
arrhythmia
disturbance of electrical signals in the heart to an irregular rate or rhythm
how do arrhythmias occur
damage or structural abnormality in tissue
electrolyte abnormality
drugs that can alter cardiac functions
symptoms of arrhythmias
palpitations
lightheadedness
syncope
fatigue
cardiac arrest
how are arrhythmias classified?
where they originate
how the affect heart rate
type of impulse abnormality
location of arrhythmias
atrial (supraventricular)
ventricular
effect on HR of arrhytmias
tachycardia
bradycardia
type of abnormality of arrhythmias
disturbance of impulse formation (ectopic, EAD, DAD)
disturbance of impulse conduction (heart block, reentry)
HCN channels have a key role in ___________________ and are important ________________
controlling cardiac pacemaker activity
regulators of neuronal excitability
HCN channels
voltage gated ion channel
dually gated by membrane hyper polarization and cyclic nucleotides
funny current (If)
HCN channel in SA node generates this
responsible for spontaneous depolarization that initiates each heart beat
what sets the heart rate?
funny current
____________ HCN channel expression in enlarged ventricles can contribute to arrhythmias
increased
abnormal HCN channel function can lead to
irregular heart rhythms like sinus bradycardia or a-fib
which HCN channel is most important in arrhythmias?
why?
HCN4
regulates heart rate and rhythm
HCN4 channel
nonselective cation channel
conducts Na and K ions through plasma membrane
HCN4 channels generate a ___________________ causing cellular ________________
net inward current (If)
depolarization
upon activation by cAMP, there is a ____________ shift of the HCN4 activation curve and If ______________ causing ____________________
positive
increases
cellular depolarization
Ivabradine (IVA)
blocks HCN from the intracellular side only
causes cellular hyperpolarization
automaticity is due to
leaky Na channels (HCN channels)
HCN channels allow for _____________. The threshold potential is
influx of Na (funny current)
-40mV
“slow response” actions potentials
nodal APs found in the SA and AV node
pacemaker depolarization phase occurs due to
pacemaker repolarization phase occurs due to
Ca2+ influx
K+ efflux
myocardial action potential phase 4
at rest (-90mV)
myocardial action potential phase 0
depolarization due to Na influx
myocardial action potential phase 1
notch due to K efflux
myocardial action potential phase 2
plateau due to Ca influx and K efflux
myocardial action potential phase 3
depolarization due to K efflux
absolute refractory period of myocardial action potential
phase 0 to part of phase 3
can you generate an action potential during the absolute refractory period?
no, impossible!
relative refractory period
remainder of phase 3
can you generate an action potential during the relative refractory period?
yes, but it is difficult
refractory period is due to the
inactivation of VG Na channels
cardiac conduction pathway
SA node –> AV node –> bundle of His –> purkinje fibers
longer duration in cardiac muscle is crucial for
preventing summation of contractions and maintaining a coordinated heartbeat
electrocardiogram
test that measures the electrical signals that control heart rhythm
measures electrical impulses
P wave
atrial depolarization
QRS complex
record of movement of electrical impulses through the ventricles (ventricular depolarization)
ST segment
when the ventricle is contracting but no electricity is flowing through it
T wave
lower heat chambers are resetting electrically and preparing for the next contraction
(ventricular repolarization)
The ST segment appears as a
straight level line between the QRS complex and T wave
QT prolongation
when the corrected QT interval is greater than 440 mx in men and 460 ms in women
QT prolongation can lead to life threatening ventricular tachyarryhtmia called
torsade de pointes (TdP)
PR interval time
0.12-2 sec
QT interval time
around 0.38 s
where does atrial repolarization occur?
QRS complex
ectopic pacemaker
cardiac cells gain abnormal automaticity and begin spontaneously depolarizing
delayed afterdepolarization
2nd depolarization occurs immediately following a complete action potential
early afterdepolarization
2nd depolarization occurs during action potential phase 2 or 3
heart block
failure in the normal propagation of AP from atrium to ventricle
heart block results in
bradycardia or skipped beats
reentry (accessory pathway)
impulse reenters and excites areas of the heart more than once due to dysfunction of the refractory period
normal action potentials cancel each other out in the
third phase
heart rate and rhythm is set by
whichever tissue is spontaneously generating action potentials most frequently
which node controls heart rate and rhythm
SA node (60-100 APs/min)
exception to tachyarrhythmias
heart block - bradyarrhythmia
arrhythmias that require treatment fall into one of these categories
significantly decrease cardiac output
precipitate more serious arrhythmias
precipitate thromboembolism
non pharmacological approached for arrhythmias
ablation therapy
electrical cardioversion
vagal maneuvers
antiarrhythmic medications can be classified as
rhythm control or rate control drugs
rhythm control drugs
decrease the automaticity of ectopic pacemakers or reentrant loops more than that of the SA node
rhythm control drugs work at the _______________ level while rate control drugs work at the _________________ level
myocardial action potential
nodal action potential
rhythm control drugs are used for
chemical cardioversion or in prevention of arrhythmia
rate control drugs
alter the heart rate but do not usually affect the rhythm
can reduce HR in tachyarrhythmia but the rhythm remains abnormal
Class Ia Na channel blockers
disopyramide (Norpace)
quinidine (Quinidex)
procainamide (Procan)
Class Ib Na channel blockers
Lidocaine (xylocaine)
mexiletine (mexitil)
class Ic Na channel blockers
flecainide
Propafenone (rhythmol)
class III: K channel blockers
amiodarone
dronedarone (Multaq)
Dofetilide
Ibutilide (corvert)
Sotalol (Betaspace)
drugs that are rhythm control medications
Na channel blockers (class I)
K channel blockers (class III)
drugs that are rate control medications
Class II: beta blockers
Class IV: non-DHP CCBs
MSC
MSC rate control medications
digoxin
adenosine (adenocard)
primary way to control rhythm for rhythm control medications
prolonging the inactivation of VG Na channels which delays the next action potential
inactivation of the VG Na channels is ______________ dependent
time and voltage
Class I antiarrhythmics MOA
directly binds to VG Na channels and keeps them inactivated
increases the effective refractory period
Class III antiarrhythmics MOA
prolonging the action potential by blocking VG K channels
increases the action potential duration
Na channel blockers used as rhythm control drugs bind more easily to ____________ channels but bind poorly to _______________ channels. These are called _________________.
open and inactivated
closed
use-dependent or state-dependent
effect of blocking open channels
slowing of phase 0 of AP
effect of blocking inactive channels
keeps them inactive and prolongs refractory period
which Na channel blockers prolong QRS on ECG?
which don’t?
Class Ia and Ic
Class Ib
Class Ia Na channel blockers MOA
intermediate on-off (moderate block)
prolongs the AP duration
Class Ib Na channel blockers MOA
fast on-off (weak block)
slightly shortens the AP duration
Class Ic Na channel blockers MOA
slow on-off (strong block)
does not alter the AP duration
considerations of use for Class Ia drugs
effective against atrial and ventricular arrhythmias
can cause QT prolongation due to K channel block which causes Torsades
Procainamide ADRs
lupus like syndrome (50% patients)
hypotension
Nausea/diarrhea, rash, fever, hepatitis
Procainamide’s metabolite ______________ has stronger ____________________ block and can increase the risk of _______________. It also accumulates in ___________-
NAPA
K channel block
torsades
renal failure
Quinidine ADRs
mild antimuscarinic effects
N/V/D
cinchonism (HA, dizziness, tinnitus at toxic concentrations)
quinidine is an inhibitor of
CYP2D6
quinidine is also used to treat
malaria
disopyramide ADRs
moderate antimuscarinic effects
negative inotropic effect –> HF
Class Ib Na channel blockers are effective against
ventricular arrhythmias, especially after MI
lidocaine ADRs
neurologic - paresthesia, tremor, nausea of central origin, lightheadedness, seizures
lidocaine is only used for arrhythmias bu
IV route due to extensive 1st pass metabolism by oral route
mexiletine ADRs
N/V (can be minimized with food)
neurological - tremor, blurred vision, lethargy
mexiletine is an analogue of ______________ that was modified to reduce ________________
lidocaine
first pass metabolism so it can be taken orally
class Ic Na channel blockers are used for
atrial arrhythmias and a-fib (pill in pocket)
Class Ic Na channel blockers should not be used in patients with a history of
structural abnormalities (MI, HF) because they are more likely to cause an arrhythmia
most common ADR of flecainide
blurred vision
Propafenone is given as a _________ and reduces __________________ so avoid in _______________
racemate
heart rate (beta 1) and increases risk of bronchospasm (beta 2)
asthma/COPD
Class III: K channel blockers target the
rapid delayed rectifier K channels (IKr)
how do K channel blockers restore normal rhythm?
specifically block K channels responsible for phase 3 which prolongs AP
increases refractory period
cardiac tissue which is ____________ remains in the _____________ and is unable to reactivate
overactive
refractory period
considerations for use of K channel blockers
QT prolongation (risk of torsades)
K channel blockers become less effective in which conditions?
ischemic myocardial tissue
hyperkalemia
amiodarone contains _______________ which in a dose of 200mg releases _____ of iodine which is _____________ higher than the normal iodine daily intake
two iodine molecules
6 mg
20x
amiodarone can be considered a
nonselective anti arrhythmic
amiodarones brand spectrum of action may account for its
high efficacy and relatively low incidence of TdP despite causing QT prolongation
amiodarone is a highly _______ drug and is highly ______________
lipophillic
bound to plasma proteins
Due to accumulation in tissue and a long half life, amiodarone can be detected for ____________ following discontinuation
up to 1 year
amiodarone inhibits
3A4, 2C9, a p-gp
amiodarones active metabolite is
desethylamiodarone
what is the most common ADR for amiodarone?
pulmonary fibrosis
ADRs of amiodarone
pulmonary fibrosis
hepatitis
photodermatitis
UV photosensitivity
asymptomatic corneal micro deposits
QT prolongation
nausea
peripheral neuropathy
what issue with the thyroid is more common?
hypothyroidism due to very high iodine levels
what is the most commonly used rhythm control drug?
amiodarone
6 Ps of amiodarone
Prolongs AP duration
photosensitivity
pigmentation of skin
peripheral neuropathy
pulmonary alveolitis and fibrosis
peripheral conversion of T4 to T3 (hypothyroidism)
dronedarone is designed to mimic
amiodarone but with less toxicity and shorter half lofe
how is dronedarone different from amiodarone?
removal of iodine atoms
multiple MOAs
is dronedarone more effective than amiodarone?
no
has other toxic effects (death, stroke, hospitalization for HF)
what is sotalol’s additional mechanism of action?
nonselective beta blocker
inhibits K channels
does sotalol bind to plasma proteins?
no
considerations for use of sotalol
few drug interactions
high risk for torsades
dofetilide and ibutilide are __________ as K channel blockers
very selective
Ibutilide is only available as _____ and is used for ____________________
IV
chemical cardioversion in atrial flutter/fibrillation
beta blockers and CCBs are often used as first line in
atrial fibrillation
Digoxin MOA
increases intracellular Ca by inhibition of Na/K/ATPase, leading to positive inotropic effect
increases cardiac contractility
adenosine is a naturally
occurring purine nucleoside that forms from the breakdown of ATP
adenosine binds to
adenosine receptors (A1, A2, A3)
activation of the A1 receptors in cardiac tissue predominately affects the _______ by _______________________
AV node
inhibition of Ca channels and activation of K channels
activation of the A2 receptors in ____________ causes ____________
arterial smooth muscle
vasodilation which lowers blood pressure
adenosine receptors cause numerous effects such as
bronchospasm
sedation
ADRs of adenosine
flushing, headache, hypotension
dyspnea, burning sensation in the chest
nausea
adenosine is less effective in the presence of
adenosine receptor antagonists (caffeine, theophylline)
what makes adenosine ideal for continuous IV use?
short half life of 10s
torsades de pointes
polymorphic ventricular tachycardia characterized by “twisting of the QRS” which is proceeded by prolongation of the QTc interval
does everyone die from TdP?
no, it is potentially fatal but sometimes it resolves on its own
what type of arrhythmia is torsades?
early afterdepolarization
what is the most common cause of TdP?
drug induced in patients with underlying risk factors
drug induced QT prolongation is defined as
QTc of 500ms or greater
or
increase of 60ms or greater in QT interval
what are characteristics of drugs that are associated with TdP?
drugs that block IKr and prolong the action potential
what are the most common drugs that are associated with TdP?
class Ia and III antiarrhythmics
