Transcript Antiarrythmic drugs

Antiarrhythmic Drugs
Arrhythmia
Heart condition where disturbances in
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Pacemaker impulse formation
Contraction impulse conduction
Combination of the two
Results in rate and/or timing of contraction of
heart muscle that is insufficient to maintain
normal cardiac output (CO)
To understand how antiarrhythmic drugs work,
need to understand electrophysiology of
normal contraction of heart
Normal heartbeat and atrial arrhythmia
Normal rhythm
Atrial arrhythmia
AV septum
Ventricular Arrhythmia
Ventricular arrhythmias are
common in most people and are
usually not a problem but…
VA’s are most common cause of
sudden death
Majority of sudden death occurs in
people with neither a previously
known heart disease nor history of
VA’s
Medications which decrease
incidence of VA’s do not decrease
(and may increase) the risk of
sudden death treatment may be
worse then the disease!
Electrophysiology - resting potential
A transmembrane electrical gradient (potential) is
maintained, with the interior of the cell negative with
respect to outside the cell
Caused by unequal distribution of ions inside vs. outside
cell
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Na+ higher outside than inside cell
Ca+ much higher “
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K+ higher inside cell than outside
Maintenance by ion selective channels, active pumps
and exchangers
Cardiac Action Potential
Divided into five phases (0,1,2,3,4)
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Phase 4 - resting phase (resting membrane potential)
Phase cardiac cells remain in until stimulated
Associated with diastole portion of heart cycle
Addition of current into cardiac muscle (stimulation)
causes
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Phase 0 – opening of fast Na channels and rapid depolarization
Drives Na+ into cell (inward current), changing membrane potential
Transient outward current due to movement of Cl- and K+
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Phase 1 – initial rapid repolarization
Closure of the fast Na+ channels and outflow of K
Phase 0 and 1 together correspond to the R and S waves of the
ECG
Cardiac Action Potential
Phase 2 - plateau phase
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sustained by the balance between the inward movement of Ca+ and
outward movement of K +
Has a long duration compared to other nerve and muscle tissue
Normally blocks any premature stimulator signals (other muscle tissue
can accept additional stimulation and increase contractility in a
summation effect)
Corresponds to ST segment of the ECG.
Phase 3 – repolarization
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K+ channels remain open,
Allows K+ to build up outside the cell, causing the cell to repolarize
K + channels finally close when membrane potential reaches certain
level
Corresponds to T wave on the ECG
ECG (EKG) showing wave
segments
Contraction
of atria
Contraction of
ventricles
Repolarization of
ventricles
In normal atrial, Purkinje, and ventricular cells, the action potential upstroke (phase
0) is dependent on sodium current. From a functional point of view, it is convenient
to describe the behavior of the sodium current in terms of three channel states).
The cardiac sodium channel protein has been cloned, and it is now recognized that
these channel states actually represent different protein conformations. In addition,
regions of the protein that confer specific behaviors, such as voltage sensing, pore
formation, and inactivation, are now being identified. The gates described below
and in Figure represent such regions.
Depolarization to the threshold voltage results in opening of
the activation (m) gates of sodium channels If the
inactivation (h) gates of these channels have not already
closed, the channels are now open or activated, and sodium
permeability is markedly increased, greatly exceeding the
permeability for any other ion. Extracellular sodium therefore
diffuses down its electrochemical gradient into the cell, and the
membrane potential very rapidly approaches the sodium
equilibrium potential, ENa (about +70 mV when Nae = 140
mmol/L and Nai = 10 mmol/L). This intense sodium current is
very brief because opening of the m gates upon depolarization
is promptly followed by closure of the h gates and inactivation
of the sodium channels
Most calcium channels become activated and inactivated in what appears to
be the same way as sodium channels, but in the case of the most common
type of cardiac calcium channel (the "L" type), the transitions occur more
slowly and at more positive potentials. The action potential plateau (phases 1
and 2) reflects the turning off of most of the sodium current, the waxing and
waning of calcium current, and the slow development of a repolarizing
potassium current.
Final repolarization (phase 3) of the action potential results from completion
of sodium and calcium channel inactivation and the growth of potassium
permeability, so that the membrane potential once again approaches the
potassium equilibrium potential. The major potassium currents involved in
phase 3 repolarization include a rapidly activating potassium current (IKr)
and a slowly activating potassium current (IKs). These two potassium
currents are sometimes discussed together as "IK.". It is noteworthy that a
different potassium current, distinct from IKr and IKs, may control
repolarization in sinoatrial nodal cells. This explains why some drugs that
block either IKr or IKs may prolong repolarization in Purkinje and ventricular
cells, but have little effect on sinoatrial nodal repolarization
Mechanisms of Arrhythmias
Many factors can precipitate or exacerbate arrhythmias: ischemia, hypoxia,
acidosis or alkalosis, electrolyte abnormalities, excessive catecholamine
exposure, autonomic influences, drug toxicity (eg, digitalis or antiarrhythmic
drugs), overstretching of cardiac fibers, and the presence of scarred or
otherwise diseased tissue. However, all arrhythmias result from (1)
disturbances in impulse formation, (2) disturbances in impulse conduction, or
(3) both.
Disturbances of Impulse Formation
The interval between depolarizations of a pacemaker cell is the sum of the
duration of the action potential and the duration of the diastolic interval.
Shortening of either duration results in an increase in pacemaker rate. The
more important of the two, diastolic interval, is determined primarily by the slope
of phase 4 depolarization (pacemaker potential). Vagal discharge and receptor-blocking drugs slow normal pacemaker rate by reducing the phase 4
slope (acetylcholine also makes the maximum diastolic potential more
negative). Acceleration of pacemaker discharge is often brought about by
increased phase 4 depolarization slope, which can be caused by hypokalemia,.
adrenoceptor stimulation, positive chronotropic drugs, fiber stretch,
acidosis, and partial depolarization by currents of injury .
Latent pacemakers (cells that show slow phase 4 depolarization even
under normal conditions, eg, some Purkinje fibers) are particularly prone
to acceleration by the above mechanisms. However, all cardiac cells,
including normally quiescent atrial and ventricular cells, may show
repetitive pacemaker activity when depolarized under appropriate
conditions, especially if hypokalemia is also present.
Afterdepolarizations (the Figure below) are depolarizations that interrupt
phase 3 (early afterdepolarizations, EADs) or phase 4 (delayed
afterdepolarizations, DADs). EADs are usually exacerbated at slow heart
rates and are thought to contribute to the development of long QT-related
arrhythmias (see Molecular & Genetic Basis of Cardiac Arrhythmias).
DADs on the other hand, often occur when intracellular calcium is
increased. They are exacerbated by fast heart rates and are thought to be
responsible for some arrhythmias related to digitalis excess, to
catecholamine, and to myocardial ischemia
Disturbances of Impulse Conduction
Severely depressed conduction may result in simple block, eg, atrioventricular nodal
block or bundle branch block. Because parasympathetic control of atrioventricular
conduction is significant, partial atrioventricular block is sometimes relieved by
atropine. Another common abnormality of conduction is reentry (also known as "circus
movement"), in which one impulse reenters and excites areas of the heart more than
once
In order for reentry to occur, three conditions must coexist, as indicated in Figure
beiowe: (1) There must be an obstacle (anatomic or physiologic) to homogeneous
conduction, thus establishing a circuit around which the reentrant wavefront can
propagate; (2) there must be unidirectional block at some point in the circuit, ie
conduction must die out in one direction but continue in the opposite direction (as
shown in the Figure, the impulse can gradually decrease as it invades progressively
more depolarized tissue until it finally blocks—a process known as decremental
conduction); and (3) conduction time around the circuit must be long enough so that
the retrograde impulse does not enter refractory tissue as it travels around the
obstacle, ie the conduction time must exceed the effective refractory period.
Importantly, reentry depends on conduction that has been depressed by some critical
amount, usually as a result of injury or ischemia. If conduction velocity is too slow,
bidirectional block rather than unidirectional block occurs
if the reentering impulse is too weak, conduction may fail, or the impulse may arrive
so late that it collides with the next regular impulse. On the other hand, if conduction
is too rapid, ie almost normal, bidirectional conduction rather than unidirectional
block will occur. Even in the presence of unidirectional block, if the impulse travels
around the obstacle too rapidly, it will reach tissue that is still refractory = 10
mmol/L). This intense sodium current is very brief because opening of the m gates
upon depolarization is promptly followed by closure of the h gates and inactivation of
the sodium channels
Slowing of conduction may be due to depression of sodium current, depression of
calcium current (the latter especially in the atrioventricular node), or both. Drugs that
abolish reentry usually work by further slowing depressed conduction (by blocking
the sodium or calcium current) and causing bidirectional block. In theory,
accelerating conduction (by increasing sodium or calcium current) would also be
effective, but only under unusual circumstances does this mechanism explain the
action of any available drug.
Lengthening (or shortening) of the refractory period may also make reentry less likely.
The longer the refractory period in tissue near the site of block, the greater the
chance that the tissue will still be refractory when reentry is attempted. (Alternatively,
the shorter the refractory period in the depressed region, the less likely it is that
unidirectional block will occur.) Thus, increased dispersion of refractoriness is one
contributor to reentry, and drugs may suppress arrhythmias by reducing such
dispersion
Antiarrhythmic drugs
Biggest problem – antiarrhythmics can
cause arrhythmia!
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Example: Treatment of a non-life threatening
tachycardia may cause fatal ventricular
arrhythmia
Must be vigilant in determining dosing, blood
levels, and in follow-up when prescribing
antiarrhythmics
Classification of antiarrhythmics
(based on mechanisms of action)
Class I – blocker’s of fast Na+ channels
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Subclass IA [markedly Na block]
Cause moderate Phase 0 depression
Prolong repolarization
Increased duration of action potential
Includes
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Quinidine – 1st antiarrhythmic used, treat both atrial and
ventricular arrhythmias, increases refractory period
Procainamide - increases refractory period but side
effects
Disopyramide – extended duration of action, used mainly
for treating ventricular arrhythmias
Classification of antiarrhythmics
(based on mechanisms of action)
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Subclass IB [inhibitory effect]
Weak Phase 0 depression
Shortened repolarization
Decreased action potential duration
Includes
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Lidocane (also acts as local anesthetic) – blocks Na+
channels mostly in ventricular cells, also good for
digitalis-associated arrhythmias
Mexiletine - oral lidocaine derivative, similar activity
Phenytoin – anticonvulsant that also works as
antiarrhythmic similar to lidocane
Tocainide
Classification of antiarrhythmics
(based on mechanisms of action)
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Subclass IC [very major block]
Strong Phase 0 depression
No effect of repolarization
No effect on action potential duration
Includes
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Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart,
Also inhibits abnormal automaticity
Propafenone
Also slows conduction
Weak β – blocker
Also some Ca2+ channel blockade
CLASS IA
Quinidine ;the first antiarrhythmic
 Slow conduction and increase refractoriness in the
retrograde fast pathway limb of AV nodal tachycardias
and over the accessory pathway
 Slow ventricular response in WPW syndrom
 Inhibit peripheral and myocardial α-adrenergic receptor
so cause hypotension with IV administration
 Inhibit muscarinic receptor increase sympathetic tone
that may explain part of proarrhythmic effect
Indication
The use of quinidine for atrial flutter and fibrillation has been replaced by other
Drugs
It can be used for ventricular tachyarrhythmia but the proarrhythmic effect
;non cardiac side effect and drug interaction have led to dramatic reduction
in its use
Caution
Idoisyncrasy and is best prevented by a test dose of 0.2 g also by serial
measurements of QRS duration
Side effect
Diarrhea;nausea;headache;dizziness with a high rate of discontinuation and
Hypersensitivity reaction
CI
QT prolongation with VT or prior therapy with drugs predispose torsade de
pointes
Procainamide
Like quinidine but does not prolong the QT interval to the same extent ;
Has less interaction with muscarinic receptors ;direct sympathetic inhibition
(vasodilation)
Indication
Supraventricular including WPW syndrom and ventricular arrhythmias including VT
In sustained VT procainamide is more effective than lidocaine at the cost of QRS and
QT widening
Giving orally ;not for long time due to the short half-life and the long-term danger of
Lupus syndrom
Giving IV if lidocaine failed
Advantage over quinidine
less side effect for GI;QRS prolongation or torsades;hypotension
No interaction with digoxin
Side effect
Early ;rash and fever
later;arthralagia; rash and lupus syndrom
With IV giving there is more hypotension and QRS and QT widening
CI
severe renal or cardiac failure
Disopyramide
Like quinidine also it prolong QRS and QT intervals (risk of torsade)
It improves AV nodal conduction due to its anticholinergic effect
Unlike quinidine its use is more for maintenance of sinus rhythm after conversion
Of AF
Used for VT orally(100-200 mg 6 hourly) less dose if CHF
Iess GI side effect ; prominent vagolytic(urinary retention and dry mouth)
Negative inotropic effect ;hypotension; torsades
Pyridostgmine bromide or bethanecol may be used to reduse anticholinergic side
Effects
No digoxin interaction ;with class III cause torsades
Class IB
These drugs inhibit the fast Na current while shortening the action potential
duration in a non diseased tissues
Shortening of the repolarization period will ensure that QT prolongation
does not occur
These drug act selectively on diseased or ischemic tissue where they are
thought to promote conduction block thereby interrupting reentry circuits
Lidocaine
has become standard IV agent for suppression of serious VT
associated with AMI and with cardiac surgery
The prophylaxis by lidocaine to prevent VT and VF in AMI is now outmoded
Lidocaine is more effective in presence of high external K concentration
therefore the hypokalemia must be corrected
It has no value in treating SVT
Side effect its generally free from hemodynamic side effect even in patient
with CHF. The higher infusion rate of 3-4 mg / min may result in drowsiness
Numbness, speech disturbances, and dizziness. Occasionally there is sinoaterial
Arrest especially during coadminstration of other drugs that depress nodal function
Drug interaction and combination
Cimitidin, propranolol, or halothane will reduce hepatic clearance of lidocaine and
Increase toxicity, while enzyme inducer the dose needed to be increased
Beta blocker with lidocaine may produce bradyarrhythmia because beta blocker
Reduce liver blood flow
Phenytoin has 4 specific uses
1st in digitalis-toxic arrhythmias it maintains AV conduction especially in presence of
Hypokalemia
2nd for VA occurring after congenital heart surgery
3rd for congenital prolonged QT syndrome when beta blocker has failed
4th in patient with epilepsy and arrhythmias
Long half life permit once daily dosage with the risk serious side effect including
Dysarthria, pulmonary infiltrate, and macrocytic anemia
Phenytoin is hepatic enzyme inducer so alter the dose requirement of many drugs
Including the antiarrhythmic (quinidine, lidocaine, and mexiletine)
Mexilitine
Like lidocaine is use for VA , unlikely lidocaine it can be given orally
Advantage for VA
Efficacy comparable to quinidine
Little or no hemodynamic depression
No QT prolongation
No vagolytic effect
But GI & CNS side effect limit the dose & possible therapeutic benefit
Class IC
They are potent ant arrhythmic used in control of paroxysmal SVT and VT
resistant to other drug they have three major electrophysiological effect
1st powerful inhibitor of fast Na channel
2nd may variably prolong the action potential duration by delaying
inactivation of slow Na channel
3rd inhibition of rapid repolarization action which may explain their marked
inhibitory effect on his-purkinje conduction with QRS widening
From 2nd & 3rd faster heart rate, increase sympathetic activity and diseased
or ischemic myocardium we conclude the cause of proarrhythmia so these
drugs must be avoided in patient with structural heart disease
Flecainide
Used for treatment of SVT & VT
Its proarrhythmic effect limit its use especially in presence of structure heart disease
because of poor LV function which predispose proarrhythmia
It have negative inotropic effect
Indication
life threaten sustained VT
Paroxysmal SVT including WPWS, & paroxysmal atrial flutter & fibrillation
It contraindicated in patient with structure heart disease & in patient with right bundle
Branch block & left anterior hemiblock (unless a pacemaker is implanted)
Propafenone
Is relatively safe in suppressing SV arrhythmias(WPW syndrome & recurrent atrial
Fibrillation ) with no structural heart disease
Has a potent membrane stabilizing activity & increase PR & QRS times without effect
on the QT interval. It also has mild beta blocking & Ca antagonist properties
Indication
Life threatening ventricular arrhythmias & also SV arrhythmias
There is strong evidence in use of propafenonoe in acute conversion of atrial
fibrillation & maintenance of sinus rhythm
it has GI side effect & proarrhythmia
Relative C/I
Preexisting sinus, AV or bundle branch or depressed LV function
Patient with asthma
Moricizine
Is a phenothiazine derivative use for management of life threaten VA
it has both class IB & class IC properties but it was ineffective as well as
harmful
Classification of antiarrhythmics
(based on mechanisms of action)
Class II – β–adrenergic blockers
Have complex action including inhibition of spontaneous depolarization (
phase 4) & indirect Ca channel blocker which are less likely to be in the
open state when not phosphorylated by the cyclic AMP
Arguments of beta blocker
The role of tachycardia in precipitating some arrhythmias
The increase sympathetic activity in patient with sustained VT or AMI
Role of 2nd messenger of beta adrenergic activity(CAMP) to cause ischemia
related VF
The associated antihypertensive & ant ischemic effect
Indications
Unwanted sinus tachycardia
Paroxysmal atrial tachycardia due to emotion or exercise
Exercise induced VA
Arrhythmia of pheochromocytoma
Heridatory prolong QT syndrome
Arrhythmia of mitral valve
Post MI arrhythmia
Beta blocker include porpranolol, sotalol & acebutolol
Acebutolol is attractive because of its cardioselectivity & its specific benefit in one
Large post infarct survival trial
Classification of antiarrhythmics
(based on mechanisms of action)
Class III – K+ channel blockers
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Developed because some patients negatively
sensitive to Na channel blockers (they died!)
Cause delay in repolarization and prolonged
refractory period
Includes
Amiodarone – prolongs action potential by delaying K+ efflux
but many other effects characteristic of other classes
Ibutilide – slows inward movement of Na+ in addition to
delaying K + influx.
Bretylium – first developed to treat hypertension but found to
also suppress ventricular fibrillation associated with
myocardial infarction
Dofetilide - prolongs action potential by delaying K+ efflux
with no other effects
Amiodarone
Chiefly class III but with also powerful class I activity, class II & class IV
Its established antiarrhythmic benefit & mortality reduction need to be
balance against:
Slow onset of action of oral therapy that require large loading dose
Serious side effect
Serious drug interaction that predispose to torsade de point
Amiodarone also has;
powerful class I effect
Non competitively block alpha & beta receptor
Weak Ca antagonist which explain bradycardia & AV nodal inhibition & low
incidence of torsade de point
Indications
For recurrent VF of hemodynamically unstable VT
Prophylactic control of life threatening VT especially post MI & CHF
IV amiodarone is used for initiation of treatment & prophylaxis of ventricular
Fibrillation or destabilizing VT but should monitor hypotension
• Preventing reoccurrence of paroxysmal AF
• Cardiac side effect
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Amiodarone inhibit SA or AV node which can be serious in patient with prior
Sinus node dysfunction or heart block
In heart failure torsade de point rarely occur but we should avoid
hypokalemia and digoxin toxicity
• Pulmonary side effect
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Pneumonitis leading to pulmonary fibrosis occurring in 10-17% at dose of
400 mg/day
Thyroid side effect
It contain iodine & similar to thyroxin structure, it inhibit peripheral conversion of
T4 to T3 with main rise in T4 serum level but in most patient thyroid function is not
Altered
6% of patient develop hypothyroidism
0.9% of patient develop hyperthyroidism
Other side effect
CNS side effect, proximal muscle weakness, peripheral neuropathy, neural symptom
Testicular dysfunction, corneal microdeposite, photosensitivity
Drug interaction
Class IA antiarrhythmic, phenothiazine TCA, thiazide and sotalol will increase the
Effect of amiodarone in prolonging QT interval
It increase quinidine & procainamide level
It increase phenytoin level
It prolong prothrombin time & cause bleeding in patient on warfarin
It increase plasma digitoxin concentration
C/I:
Severe sinus node dysfunction
2nd or 3rd degree heart block
Cardiogenic shock
Sever chronic lung disease
Sotalol
Its combine class II & class III properties, its active against:
Sinus tachycardia, paroxysmal SVT, WPW arrhythmia with either antegrade or retroGrade conduction, recurrence of AF, ischemic VA & recurrent sustained VT or fibrillation
Sotalol is used when amiodarone toxicity is feared but it is less active than amiodarone
side effect:
Are those of beta blocker (fatigue & bradycardia) also bronchospasm may be also
Produced
Pure class III agents: Ibutilide & Dofetilide
Ibutilide
is a methane sulfonamide derivative which prolong repolarization by inhibition of
Delayed K current & by selective enhancement of the slow inward Na current
It has no negative inotropic effect
It used IV because of the 1st pass metabolism
Its used in termination of AF & flutter with both single & repeated IV infusion
Its effective as amiodarone in cardioversion of AF . Efficacy was higher in atrial flutter
Than in AF
ADVERSE AFFECT:
QT interval prolongation & is dose dependent ,maximal at the end of infusion & return
To base line within 2-4 hours following infusion
Torsade de point is most significant adverse effect associated with it in about
4.3% occurring shortly after infusion period
Dose 1mg over 10 min
Dofetilide:
Is a methane sulfonamide drug prolong action potential period & QT interval
In a concentration related manner
Its effect is by inhibition of the rapid component of the delayed K current
It has mild negative chronotropic but not inotropic
Its given orally
Indication
Cardioversion of persistent AF or atrial flutter to normal sinus rhythm
Maintenance of sinus rhythm
Dose : must be individualized by the calculated creatinin clearance & the QT prolongation
Drug-interaction:
Hepatic enzyme inhibitor will increase the level of it also drug as diuretic will add
Prolongation of QT interval (due to hypokalemia )
Novel Class III Agents
Azimilide
Block both the slowly activating and rapidly activating components of
the delayed rectifier K current, whereas sotalol,amiodarone,or
dofetilide block only the rapidly activating component
The advantage of blocking slow repolarization K current may be in
condition of tachycardia and sympathetic stimulation when other
blockers like sotalol are less likely to be effective
Dronedarone
amiodarone-like drug thought not to have noncardiac tissue side
effect because it lacks iodine in its structure
Classification of antiarrhythmics
(based on mechanisms of action)
Class IV – Ca2+ channel blockers
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slow rate of AV-conduction and increase refractory period of
nodal tissue in patients with atrial fibrillation (slow the ventricular
response rate in atrial arrhythmias)
Terminate or prevent reentrant arrhythmias in which the circuit
involves the AV node
Now ,For termination of junctional tachycardias adenosine is the
first choice
Includes
Verapamil – blocks Na+ channels in addition to
Ca2+; also slows SA node in tachycardia
Diltiazem
Intravenous Magnesium
Weakly blocks the calcium channel as well as inhibiting
sodium and potassium channels
It can be used to slow the ventricular rate in AF but is
poor at terminating junctional tachycardias
It may be agent of choice in torsade de pointes
It can be used for refractory ventricular fibrillation but
now superseded by IV amiodarone
Adenosine
It has multiple cellular effects including ;
Opening of adenosine-sensitive inward repolarisation K channel to
hyperpolarise with inhibition Of sinus & especially the AV node & indirectly to
inhibit Ca channel opening
Indications
For paroxysmal narrow complex SVT ,usually AV nodal reentry or AV reentry
such as in the WPW syndrome or in patients with a concealed accessory
pathway.
In wide-complex tachycardia of uncertain origin ,it can help the management
by differentiating between VT or SVT . the latter case ,adenosine is likely to
stop the tachycardia,whereas in VT there is unlikely to be any major adverse
hemodynamic effect and the tachycardia continues
Side effect & contraindications
Headache (via vasodilation) ,provocation of chest pain ,flushing & excess sinus or AV
nodal inhibition . the precipitation of bronchoconstriction in asthmatic patients can last
for 30 min .
Transsient new arrhythmias at the time of chemical cardioversion occur in about
65%.
Because of a direct effect on atrial & ventricular myocardial refractoriness it has
proarrhythmic effects including atrial and ventricular ectopy.
contraindication
Asthma ,second or third degree AV block,sick sinus syndrome
Atrial flutter is a relative contraindication
Digoxin
Historically been the drug of choice for rate control in AF
,but its limitation must be recognized.
The effects of digoxin are mediated by enhancement of vagal tone .it is less
effective during state of high sympathetic tone as seen at the onset of an episode
,during exercise ,or in critically ill patient
Digoxin is most effective as oral therapy in stable elderly patient who do not
exercise vigorously or who may have underlying conduction disease or in
combination with Ca channel blocker or B-blocker.
References
.Drug for the heart by
Lionel H. Opie& Bernard J.Gersh
.Basic & clinical pharmacology by
Bertram G Katzung