Download Antiarrhythmic drugs

Antiarrhythmic drugs
Cardiac arrhythmia or dysarrhythmia
Is a disturbance in cardiac rhythm.
There are two types of cardiac tissues:
1- Atrial and ventricular muscle: which are responsible for pumping
action of the heart.
2- The conducting tissue: which is able to initiate or generate
electrical impulses (action potential) which lead to muscle cell
contraction.
The ability to generate electrical impulses spontaneously is called
(automaticity) and it is a feature of the conducting tissue i.e. sinoatrial
(SA)node (the highest frequency of spontaneous discharge); AV node and
his-purkinge system.
Mechanism of action potential of the conducting tissue of the heart:
in the resting state the interior of the cell is electrically negative with
respect to the exterior of the cell due to disposition of ions mainly Na +,
K+ and Ca+across its membrane,i.e. it is polarized. The ionic changes of
action potential will lead to rapid redistribution of ions, causing the
anterior of the cell to become positive (depolarization), then there will be
slow flow of ions and restore the resting potential (repolarization).
The ionic movement of action potential can be separated into 4
phases:
Phase 0: a phase of rapid depolarization due to fast inflow of Na+ into the
cells.
Phase 1: a short initial period of rapid repolarization caused mainly by
outflow of K+ from the cell.
Phase 2: a period of delay in repolarization caused by inflow of Ca + into
the cell.
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Phase 3: a second period of rapid repolarization caused mainly by
outflow of K+ from the cell.
Phase 4: it is a fully repolarized state during which Na + and Ca+ move
out of the cell while K+ move back into the cell. During this phase the
interior of the cell become gradually less negative until a threshold
potential is reached causing rapid depolarization (phase 0) to occur and
the cycle is repeated.
Absolute refractory period: it is the period during which cardiac cells
will not respond to any stimulus i.e. will not depolarize, it includes phase
1 and 2.
Relative refractory period: include phase 3 the cell will depolarize only
if the stimulus is unusually strong.
Antiarrhythmic drugs
Has been classified according to their effects on the action potential
Class I: sodium channel blockers.
Includes those drugs with local anesthetic or called membrane stabilizing
effect. Their dominant effect is to reduce the maximal rate of
depolarization and this is achieved by reducing rapid inflow of Na +
during phase 0, can be classified into 3 groups:
A- Drugs that lengthen the action potential duration and lengthen the
refractoriness in both atrial, His bundle and ventricular conducting
system so they are effective in the treatment of both ventricular
and supraventricular (atrial) arrhythmia. These drugs include:
Quinidine, Procainamide, and Disopiramide (all have
anticholinergic atropine like effect).
B- Drugs that shorten the action potential duration and refractoriness,
they are effective only for ventricular but not atrial arrhythmia.
They include: Lignocaine(lidocaine), mexiteline, phenytoin and
tocainide.
C- Drugs with negligible effect on action potential duration and
refractoriness. They are effective for both ventricular and
supraventricula arrhythmia, e.g. Flecainide, Propafenone and
Moricizine.
Class II: Drugs that reduce sympathetic tone to the heart by blocking β1receptors of the heart, reduce automaticity (phase 4) and protect against
ectopic pacemaker e.g. propranolol.
Class III: Potassium channel blockers: these drugs prolong refractoriness
without effect on Na+ inflow in phase 0. They prevent re-entrant
arrhythmia, e.g. Amiodarone and Bretylium.
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Class IV: Ca+- channel blockers: they depress Ca+ inflow in phase 2 and
prolong condiction and refractoriness of SA and AV nodes, they are
effective in treatment of supraventricular tachycardia SVT, e.g.
verapamil.
Class I a:
Quinidine: its effective in prevention and treatment of supraventricular
and ventricular tachycardia and incombination with digoxin to treat atrial
fibrillation or flutter ( Quinidine displace digoxin from tissue binding so
digoxin dose should be reduced). It is well absorbed from the gut,
metabolized in the liver, some of it excreted unchanged in urine, the
active metabolite may accumulate in patients withrenal impairment.
Side effects:
1- Nausea. Vomiting and diarrhea.
2- Cinchonism characterized by blurred vision, tinnitus, headache and
disorientation.
3- Serious ventricular arrhythmia associated with QT prolongation i.e.
torsades depoints.
Drug interaction: Quinidine has narrow therapeutic index; enzyme
inducers like rifampicin, phenytoin and phenobarbitone) increase
Quinidine clearance and decrease its plasma level. Quinidine clearance is
reduced by cimetidine, prpranolol, elderly and patient with liver cirrhosis
so these dose must be reduced.
Procainamide: like quinidine it is effective in the treatment and
prevention of supraventricular and ventricular arrhythmia. it is well
absorbed orally, metabolized in the liver and excreted in urine.
Side effects: lupus erythematosus in 25-30 %, nausea, vomiting, asystol o
ventricular arrhythmia, CNS depression and hallucination.
Disopyramide: it is effective in ventricular arrhythmias especially after
myocardial infarction and in supraventricular arrhythmia and wolff
Parkinson white syndrome WPW*. It is used orally well absorbed, partly
metabolized in the liver and partly excreted unchanged in urine.
Side effects: anticholinergic side effects like dry mouth, blurred vision,
urinary retention, constipation; and cardiac effects like hypotension and
heart failure (negative inotropic effect).
*WPW syndrome: Abnormal communication between atria and
ventricle.
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Class Ib:
Lignocaine: it is used for ventricular arrhythmia especially those with
myocardial infarction. It is not given orally because of extensive 1 st pass
metabolism. It is given I.V and some times I.M. it is eliminated by liver
so the dose should be adjusted in patients with liver dysfunction.
Adverse effects: are uncommon unless infusion is rapid or there is
significant cardiac failure. They include: hypotension, dizziness, blurred
vision, sleepiness, slurred speech, sweating, confusion and convulsions.
Mexiletine: similar ti lignocaine, but is effective orally. It is used for
ventricular arrhythmia especially those complicating myocardial
infarction.
Adverse effects: nausea, vomiting, hiccough, tremor, confusion, cardiac
arrhythmia and hypotension.
Tocainide: similar to the action of lignocaine, but it is effective orally. It
is used for ventricukar tachyarrhythmia. It has pulmonary toxicity which
may lead to pulmonary fibrosis.
Phenytoin: it is used as second line agent in the treatment of ventricular
arrhythmia but it is used commonly in the treatment of digitalis induced
arrhythmia and in patients with prolong QT- syndrome.
Class Ic:
Flecainide: it is absorbed orally, metabolized slightly in the liver and
excreted unchanged in urine. It slows conduction in all cardiac tissue with
a minor effect on the duration of the action potential and refractoriness.
Automaticity is reduced by an increase in the threshold potential. It is
useful in treating refractory ventricular arrhythmia and in suppressing
premature ventricular conduction. It has negative inotropic effect and can
aggravate congestive heart failure.
Adverse effects: nausea, headache, dizziness and blurred vision.
Propafenone: it has additional class II effect (β- blocking effect equal to
low dose of propranolol); it is metabolized in the liver about 7% of
patients are slow metaboliser. It slows the conduction in cardiac tissue
and considered as a broad spectrum antiarrhythmic agent.
Adverse effects: similar to those of flecainide and common in poor
metabolisers, in addition conduction block may occur, cardiac failure
may be worsen and ventricular arrhythmia may be exacerbated.
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Class II: β-adrenergic blockers.
1- They reduce automaticity of SA node.
2- They prolong refractoriness of AV node.
3- Some members have membrane stabilizing effect (class I effect)
e.g. labetolol, oxprenolol, propranolol, acebutolol and alprenolol.
(LOPA).
4- Sotalol has class III effect.
Βblockers are used for supraventricular arrhythmias, particularly those
associated with exercise, emotion or hyperthyroidism and for ventricular
tachycardia.
Class III: K-channel blockers prolong refractoriness.
Bretylium:
It prolong the cardiac refractory period also it prevent the release of
noradrenaline from sympathetic nerve after initial release. It has been
used in the treatment of ventricular arrhythmia refractory to other drugs
especially those complicating myocardial infarction or cardiac surgery.
Adverse effects: are related to the initial release of catecholamine
causing transient hypertension and worsening of arrhythmia, other side
effects are nausea, vomiting and postural hypotension.
Amiodarone:
It prolongs the effective refractory period of myocardial cells, AV node
and accessory pathway; also it has β- blocking effect.
Amiodarone is used in chronic ventricular arrhythmias, atrial fibrillation
and supraventricular tachycardia associated with WPW syndrome. The
drug is well absorbed orally, metabolized in the liver and eliminated by
biliary tract. The onset of action after oral and I.V therapy is delayed for
about 6 weeks.
Loading dose is used: 200 mg x 8 hrs for 1 week, then 200 mg x 12 hrs
for 1 week ten maintenance dose 200 mg per day.
Side effects: photosensitivity, blue skin discoloration caused by iodine
accumulation in the skin, hypo or hyperthyroidism, pulmonary fibrosis,
hepatotoxicity and neuropathy. It potentiates digoxin and warfarin effect.
Class IV: calicium channel blockers.
They block calicium channels causing depression of myocardial
contractility (negative inotropic effect), also they suppress impulse
generation and conduction in SA and AV nodes (negative chronotropic
effect).
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Nifedipine has no significant antiarrhythmic effect because at therapeutic
concentration it acts almost always on non cardiac calicium channels.
Verapamil and deltiazim are more effective against atrial and
ventricular dysrhythmia and treatment of reentrant supraventricular
tachycardia.
Other antiarrhythmic drugs:
1- Digoxin: it shorten the refractory period in atrial and ventricular
myocardial cells, while prolong the effective refractory period and
diminishing conduction velocity in purkinje fibers. Digoxin is used
to control the ventricular response rate in atrial fibrillation and
flutter. At toxic conc. Dogoxin causing ectopic ventricular beats
that may result in ventricular tachycardia and fibrillation. This
arrhythmia is usually treated with lidocaine and phenytoin.
2- Adenosine: at high doses the drug decreases conduction velocity,
prolongs the refractory period and decrease automaticity in the AV
node. I.V adenosine is the drug of choice for supraventricular
tachycardia.
Side effects: flushing, chest pain and hypotension.
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